Clinical Trials

Criteria

Inclusion Criteria:

• HER2-positive status will be based on pretreatment biopsy material and defined as an immunohistochemistry (IHC) score of 3+ and/or positive by in situ hybridization (ISH) according to current American Society of Clinical Oncology (ASCO) College of American Pathologists (CAP) guidelines. Central testing is not required

  * Known hormone receptor (HR) status as defined by ASCO/CAP guidelines. Hormone receptor positive status can be determined by either known positive estrogen receptor (ER) or known positive progesterone receptor (PR) status; hormone receptor negative status must be determined by both known negative ER and known negative PR

• Patients with residual HR-negative, HER2 positive (+) disease in the breast and/or lymph nodes per the surgical pathology report are eligible; however, patients with HR+ HER2+ cancers must have node-positive residual disease per the surgical pathology report in order to qualify for the study. The presence of residual invasive disease in the breast is not mandatory for these patients. Note: The presence of micrometastases in lymph nodes after preoperative therapy counts as residual disease, whereas the presence of isolated tumor cells does not
• Patients with synchronous bilateral invasive disease are eligible provided both lesions were confirmed to be HER2-positive, and at least one of the lesions meets the criteria outlined above. Multifocal disease is allowed, as long as the largest biopsied breast tumor was HER2-positive
• Patients with clinical stage T1-4, N0-3 disease at presentation and residual invasive disease postoperatively as defined above are eligible. (Note: Patients with T1a/bN0 tumors are not eligible)
• Patients must have received neoadjuvant chemotherapy with one of the following regimens: docetaxel/trastuzumab/pertuzumab (THP), paclitaxel/methotrexate/cisplatin (TMP), doxorubicin/cyclophosphamide/paclitaxel/trastuzumab/pertuzumab (AC-TH(P)); docetaxel/carboplatin/trastuzumab/pertuzumab (TCH(P)); fluorouracil/doxorubicin/cyclophosphamide-docetaxel/trastuzumab/pertuzumab (FAC-TH(P)), or fluorouracil/epirubicin/cyclophosphamide-docetaxel/trastuzumab/pertuzumab (FEC-TH(P)). Note: apart from TCHP, where T is docetaxel, treatment with docetaxel or paclitaxel is acceptable

• Patients may have received =< 2 cycles of T-DM1 in the adjuvant setting. Note: These patients will be randomized to receive a further 14 cycles of T-DM1 and tucatinib/placebo as tolerated. The most recent cycle of T-DM1 should have been administered =< 5 weeks prior to registration

  * N.B: Both of the following two criteria need to be met for the patient to be eligible for this study

  • An interval of no more than 12 weeks between the completion date of the last definitive treatment (e.g. postoperative chemotherapy or radiation, or if neither given, breast surgical date) and the date of registration
  • Patients must be registered on study within =< 180 days of the date of the most recent definitive breast cancer surgery (not including reconstructive surgery)
• All systemic chemotherapy should have been completed preoperatively unless participating in EA1181 (CompassHER2 pathologic complete response [pCR])
• Toxicities related to prior systemic treatment should have resolved or be at baseline, apart from alopecia and peripheral neuropathy =< grade 1

• Adequate excision: surgical removal of all clinically evident disease in the breast and lymph nodes as follows:

  • Breast surgery: total mastectomy with no gross residual disease at the margin of resection, or breast-conserving surgery with histologically negative margins of excision
  • For patients who undergo breast-conserving surgery, the margins of the resected specimen must be histologically free of invasive tumor and ductal carcinoma in situ (DCIS) as determined by the local pathologist. If pathologic examination demonstrates tumor at the line of resection, additional operative procedures may be performed to obtain clear margins. If tumor is still present at the resected margin after re-excision(s), the patient must undergo total mastectomy to be eligible. Patients with margins positive for classic lobular carcinoma in situ (LCIS) are eligible without additional resection
  • Lymph node surgery ** The axilla needs to be evaluated with either sentinel node biopsy or axillary lymph node dissection. If patients have a sentinel lymph node biopsy and sentinel nodes are negative, no further axillary treatment is necessary. If patients have isolated tumor cells (ITCs) in the setting of residual breast disease, at least one of the following is required: axillary lymph node dissection (ALND) or planned nodal irradiation. If patients have micro- or macro-metastatic nodal disease, an ALND is required
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Absolute neutrophil count (ANC) >= 1,000/mm^3
• Hemoglobin >= 8 g/dL (Note: packed red blood cells [PRBC] transfusion is not permitted to achieve eligibility)
• Platelet count >= 100,000/mm^3
• Creatinine =< 1.5 x upper limit of normal (ULN)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) or direct bilirubin within the institutional normal range for patients with Gilbert's syndrome
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN)
• Screening left ventricular ejection fraction (LVEF) >= 50% on echocardiogram (ECHO) or multiple-gated acquisition (MUGA) after receiving neoadjuvant chemotherapy and no decrease in LVEF by more than 15% absolute points from the pre-chemotherapy LVEF. Or, if pre-chemotherapy LVEF was not assessed, the screening LVEF must be >= 55% after completion of neoadjuvant chemotherapy. Note: LVEF assessment may be repeated once up to 3 weeks following the initial screening assessment to assess eligibility

Exclusion Criteria:

• Prior receipt of T-DM1 in the neoadjuvant setting is not allowed

  • Systemic therapy must have consisted of at least 9 weeks of preoperative taxane and trastuzumab (or Food and Drug Administration [FDA]-approved biosimilar) with or without pertuzumab. Patients who have received at least 9 weeks of preoperative taxane, pertuzumab and margetuximab are also eligible. Note: Patients who complete at least nine of a planned twelve doses of weekly paclitaxel, or three of a planned four doses of docetaxel, but discontinue prematurely due to toxicity (i.e. peripheral neuropathy =< grade 1) are eligible. Patients receiving dose-dense chemotherapy regimens are also eligible. Prior use of nab-paclitaxel (Abraxane) instead of paclitaxel or docetaxel is permitted. Prior use of subcutaneous trastuzumab (Hylecta) is also allowed
  • Patients who received neoadjuvant systemic therapy which included experimental HER2-targeted therapy/therapies are potentially eligible, as long as the investigational agent was not a HER2-targeted antibody-drug conjugate (e.g. T-DM1, DS-8201a [trastuzumab deruxtecan]) or a HER2 targeted tyrosine kinase inhibitor (TKI) (e.g. tucatinib, lapatinib, neratinib)
• No adjuvant treatment with any anti-cancer investigational drug within 28 days prior to registration
• Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing potential only, a negative serum pregnancy test done =< 7 days prior to registration is required
• Patients with known active and/or untreated hepatitis B or hepatitis C or chronic liver disease are ineligible. Patients with a diagnosis of hepatitis B or C that has been treated and cleared and normal liver function are eligible to participate in the study if the other eligibility parameters are met
• Stage IV (metastatic) breast cancer
• History of any prior (ipsi- or contralateral) invasive breast cancer within 3 years of registration
• Patients with ER+ HER2+ residual invasive disease that is lymph node-negative per the surgical pathology report
• Evidence of recurrent disease following preoperative therapy and surgery
• Patients for whom radiotherapy would be recommended for breast cancer treatment but for whom it is contraindicated because of medical reasons (e.g., connective tissue disorder or prior ipsilateral breast radiation)
• History of exposure to the following cumulative doses of anthracyclines: doxorubicin > 240 mg/m^2; epirubicin or liposomal doxorubicin-hydrochloride (Myocet) > 480 mg/m^2. For other anthracyclines, exposure equivalent to doxorubicin > 240 mg/m^2

• Cardiopulmonary dysfunction as defined by any of the following:

  • History of National Cancer Institute (NCI) CTCAE version (v) 5.0 grade >= 3 symptomatic congestive heart failure (CHF) or New York Heart Association (NYHA) criteria class >= II
  • Angina pectoris requiring anti-anginal medication, serious cardiac arrhythmia not controlled by adequate medication, severe conduction abnormality, or clinically significant valvular disease
  • High-risk uncontrolled arrhythmias: i.e., atrial tachycardia with a heart rate > 100/min at rest, significant ventricular arrhythmia (ventricular tachycardia) or higher-grade atrioventricular block (AV)-block (second degree AV-block type 2 [Mobitz 2] or third degree AV-block)
  • Significant symptoms (grade >= 2) relating to left ventricular dysfunction, cardiac arrhythmia, or cardiac ischemia while or since receiving preoperative therapy
  • History of a decrease in left ventricular ejection fraction (LVEF) to < 40% with prior trastuzumab treatment (e.g., during preoperative therapy)
  • Uncontrolled hypertension (systolic blood pressure > 180 mmHg and/or diastolic blood pressure > 100 mmHg)
• Current severe, uncontrolled systemic disease
• Major surgical procedure unrelated to breast cancer or significant traumatic injury within 28 days prior to registration or anticipation of the need for major surgery during the course of study treatment
• History of intolerance, including grade 3 to 4 infusion reaction or hypersensitivity to trastuzumab or murine proteins or any components of the product
• Peripheral neuropathy of any etiology that exceeds grade 1
• Assessment by the investigator as being unable or unwilling to comply with the requirements of the protocol
• Use of a strong CYP3A4 or CYP2C8 inhibitor within 2 weeks, or use of a strong CYP3A4 or CYP2C8 inducer within 5 days prior to registration is prohibited. Please note that use of sensitive CYP3A substrates should be avoided two weeks before registration and during study treatment. Additionally, CYP3A4 or CYP2C8 inducers are prohibited as concomitant medications within 5 days following discontinuation of tucatinib treatment

Criteria

Inclusion Criteria:

• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2

• Triple Negative Breast Cancer:

  • Patients with a history of stage T1cN1-2 or T2-4N0-2 breast cancer according to the primary tumor-regional lymph node anatomic staging criteria of the American Joint Committee on Cancer (AJCC), 8th edition as determined by the investigator in radiologic assessment, clinical assessment or both
  • Patients must have no residual invasive disease in the breast or lymph nodes after the completion of neoadjuvant therapy. Residual ductal carcinoma in situ (DCIS) is allowed. Isolated tumor cells are considered node-negative
  • Estrogen (ER) and progesterone (PR) =< 10%; HER2-negative by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines (immunohistochemistry [IHC] and fluorescence in situ hybridization [FISH])
  • If invasive disease was present in both breasts, participation in the study is permitted as long as the eligibility criteria are met for both tumors/breasts
• Patients must have received neoadjuvant chemotherapy in combination with pembrolizumab for a minimum of 6 cycles. All systemic chemotherapy and ICI therapy should have been completed preoperatively

• An interval of no more than 12 weeks between the completion date of the final surgery and the date of randomization

  * Note: Adjuvant radiation can be given on study. If given, it is encouraged to be given concurrently with pembrolizumab, per investigator discretion. Treatment with adjuvant pembrolizumab is strongly discouraged prior to participation in this trial, but if administered (e.g., if patients are awaiting pathology results), pembrolizumab may be administered for up to 6 weeks post-surgery and must be completed prior to registration

• Use of investigational anti-cancer agents must be discontinued at time of registration

• Adequate excision: Surgical removal of all clinically evident disease in the breast and lymph nodes as follows:

  • Breast surgery: Total mastectomy or breast-conserving surgery with histologically negative margins, including no ink on tumor for DCIS, at the time of excision

    ** For patients who undergo breast-conserving surgery, the margins of the resected specimen must be histologically free of ductal carcinoma in-situ (DCIS) as determined by the local pathologist. If pathologic examination demonstrates DCIS at the line of resection, additional operative procedures may be performed to obtain clear margins. If DCIS is still present at the resected margin after re-excision(s), the patient must undergo total mastectomy to be eligible. Patients with margins positive for classic lobular carcinoma in situ (LCIS) are eligible without additional resection

  • Lymph node surgery:

    • For a patient with clinically N0 disease, a sentinel lymph node biopsy should have been performed at time of surgical evaluation, and if pathologically node positive, the patient is no longer eligible. Isolated tumor cells are considered node-negative

    • For a patient with clinically N1 disease at diagnosis (with positive results from a fine-needle aspiration, core biopsy, or sentinel node biopsy performed prior to preoperative therapy) additional surgical evaluation of the axilla following preoperative therapy is required

      *** If they become cN0 (no palpable adenopathy), then a sentinel lymph node biopsy could have been performed at time of surgery (axillary dissection would also be permitted); if the sentinel lymph node biopsy is positive, the patient is no longer eligible

    • If sentinel node biopsy performed before preoperative therapy was negative, no additional surgical evaluation of the axilla is required after preoperative therapy. If sentinel node biopsy performed before preoperative therapy was positive, an ALND is required after preoperative therapy
    • If the only sentinel node identified by isotope scan is in the internal mammary chain, surgical evaluation of the axilla is still required
    • If sentinel node evaluation after preoperative therapy is negative, no further additional surgical evaluation of the axilla is required
    • Axillary dissection without sentinel node evaluation is permitted as the initial or sole axillary evaluation after preoperative therapy
• If breast-conserving surgery was performed but patient will not be receiving breast radiation, the patient is not eligible
• Not pregnant and not nursing, because this study involves an agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown. Therefore, for women of childbearing potential only, a negative serum or urine pregnancy test done =< 7 days prior to randomization is required
• Absolute neutrophil count (ANC) >= 1,000/mm^3
• Platelet Count >= 100,000/mm^3
• Estimated glomerular filtration rate (eGFR) >= 15 mL/min/1.73m^2

• Total Bilirubin =<1.5 x upper limit of normal (ULN)

  * Patients with Gilbert's disease with a total bilirubin =< 2.5 x ULN and direct bilirubin within normal limits are permitted

• Aspartate aminotransferase (AST) serum aspartate aminotransferase [SGOT] / alanine aminotransferase (ALT) serum glutamic pyruvic transaminase [SGPT] =< 3 x institutional ULN
• Patients must be willing to provide tumor tissue from the diagnostic core biopsy. If inadequate tumor tissue is available, patients are still eligible to participate in the trial
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months prior to registration are eligible for this trial

Exclusion Criteria:

• No stage IV (metastatic) breast cancer
• No history of any prior (ipsi- or contralateral) invasive breast cancer. Prior DCIS is allowed
• No evidence of recurrent disease following preoperative therapy and surgery
• No known active liver disease, e.g. due to hepatitis B virus (HBV), hepatitis C virus (HCV), autoimmune hepatic disorders, or sclerosing cholangitis

• No history of intolerance, including Grade 3 or 4 infusion reaction or hypersensitivity to pembrolizumab or murine proteins or any components of the product

  * Note: Prior immune-related adverse events (irAEs) are allowed if they resolved and the patient tolerated subsequent therapy without requiring chronic steroids for the irAE

• No medical conditions that require chronic systemic steroids (>10 mg prednisone daily or equivalent) or any other form of immunosuppressive medications and has required such therapy in the last two years. Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic therapy
• Patients who are unable or unwilling to comply with the requirements of the protocol per investigator assessment are not eligible

Criteria

Inclusion Criteria:

• ? The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the U.S., authorization permitting release of personal health information.

  • The patient must have an ECOG performance status of 0 or 1.
  • The patient must have undergone a lumpectomy and the margins of the resected specimen or re-excision must be histologically free of invasive tumor and DCIS with no ink on tumor as determined by the local pathologist. If pathologic examination demonstrates tumor at the line of resection, additional excisions may be performed to obtain clear margins. (Patients with margins positive for LCIS are eligible without additional resection.)
  • The tumor must be unilateral invasive adenocarcinoma of the breast on histologic examination.
  • Patient must have undergone axillary staging (sentinel node biopsy and/or axillary node dissection).
  • The following staging criteria must be met postoperatively according to AJCC 8th edition criteria: By pathologic evaluation, primary tumor must be pT1 (less than or equal to 2 cm).

By pathologic evaluation, ipsilateral nodes must be pN0. (Patients with pathologic staging of pN0(i+) or pN0(mol+) are NOT eligible.)

• Oncotype DX Recurrence Score of less than or equal to 18 on diagnostic core biopsy or resected specimen.

  ** For patients with a T1a tumor (less than or equal to 0.5 cm in size) who do not already have an Oncotype DX Recurrence Score at study entry, a specimen (unstained blocks or slides) must be sent to the Genomic Health centralized laboratory.

• The tumor must have been determined to be ER and/or PgR positive assessed by current ASCO/CAP Guideline Recommendations for hormone receptor testing. Patients with greater than or equal to 1% ER or PgR staining by IHC are considered positive.
• The tumor must have been determined to be HER2-negative by current ASCO/CAP guidelines.
• Patients may be premenopausal or postmenopausal at the time of study entry. For study purposes, postmenopausal is defined as: Age 56 or older with no spontaneous menses for at least 12 months prior to study entry; or a documented hysterectomy; or Age 55 or younger with no spontaneous menses for at least 12 months prior to study entry (e.g., spontaneous or secondary to hysterectomy) and with a documented estradiol level in the postmenopausal range according to local institutional/laboratory standard; or Documented bilateral oophorectomy.
• The interval between the last surgery for breast cancer (including re-excision of margins) and study entry must be no more than 70 days.
• The patient must have recovered from surgery with the incision completely healed and no signs of infection.
• Bilateral mammogram or MRI within 6 months prior to study entry. HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. Patients must be intending to take endocrine therapy for a minimum 5 years duration (tamoxifen or aromatase inhibitor). The specific regimen of endocrine therapy is at the treating physician's discretion.

Exclusion Criteria:

• ? Definitive clinical or radiologic evidence of metastatic disease.

  • pT2 - pT4 tumors including inflammatory breast cancer.
  • Pathologic staging of pN0(i+) or pN0(mol+), pN1, pN2, or pN3 disease.
  • Patient had a mastectomy.
  • Palpable or radiographically suspicious ipsilateral or contralateral axillary, supraclavicular, infraclavicular, or internal mammary nodes, unless there is histologic confirmation that these nodes are negative for tumor.
  • Suspicious microcalcifications, densities, or palpable abnormalities (in the ipsilateral or contralateral breast) unless biopsied and found to be benign.
  • Non-epithelial breast malignancies such as sarcoma or lymphoma.
  • Proven multicentric carcinoma (invasive cancer or DCIS) in more than one quadrant or separated by 4 or more centimeters. (Patients with multifocal carcinoma are eligible.)
  • Paget's disease of the nipple.
  • Any history, not including the index cancer, of ipsilateral invasive breast cancer or ipsilateral DCIS treated or not treated. (Patients with synchronous or previous ipsilateral LCIS are eligible.)
  • Synchronous or previous contralateral invasive breast cancer or DCIS. (Patients with synchronous and/or previous contralateral LCIS are eligible.)
  • Surgical margins that cannot be microscopically assessed or are positive at pathologic evaluation. (If surgical margins are rendered free of disease by re- excision, the patient is eligible.)
  • Treatment plan that includes regional nodal irradiation.
  • Any treatment with radiation therapy, chemotherapy, biotherapy, and/or endocrine therapy administered for the currently diagnosed breast cancer prior to study entry.

(Short course endocrine therapy of less than 6 weeks duration is acceptable post core biopsy pre surgery if the Oncotype DX Recurrence Score is assessed on the biopsy core and is less than or equal to 18.)

• History of non-breast malignancies (except for in situ cancers treated only by local excision and basal cell and squamous cell carcinomas of the skin) within 5 years prior to study entry.
• Current therapy with any endocrine therapy such as raloxifene (Evista®), tamoxifen, or other selective estrogen receptor modulators (SERMs), either for osteoporosis or breast cancer prevention. (Short course endocrine therapy of < 6 weeks duration is acceptable post core biopsy pre surgery if the Oncotype DX Recurrence Score is assessed on the biopsy core and is less than or equal to 18.)
• Patients intending to continue on oral, transdermal, or subdermal estrogen replacement (including all estrogen only and estrogen-progesterone formulas) are not eligible. Patients that discontinue oral, transdermal, or subdermal estrogen replacement prior to registration are eligible.
• Prior breast or thoracic RT for any condition.
• Active collagen vascular disease, specifically dermatomyositis with a CPK level above normal or with an active skin rash, systemic lupus erythematosis, or scleroderma.
• Pregnancy or lactation at the time of study entry or intention to become pregnant during treatment. (Note: Pregnancy testing according to institutional standards for women of childbearing potential must be performed within 2 weeks prior to study entry.)
• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of study therapy or that may affect the interpretation of the results or render the patient at high risk from treatment complications.
• Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements or interfere with interpretation of study results.
• Use of any investigational product within 30 days prior to study entry.

Inclusion Criteria:

• A patient cannot be considered eligible for this study unless ALL of the following conditions are met.

  • The patient or a legally authorized representative must provide study-specific informed consent prior to pre-entry and, for patients treated in the U.S., authorization permitting release of personal health information.
  • Female patients must be greater than or equal to 18 years of age.
  • Patients must be premenopausal (evidence of functioning ovaries) at the time of pre-entry. For study purposes, premenopausal is defined as:
  • Age 50 years or under with spontaneous menses within 12 months; or
  • Age greater than 50-60 years with spontaneous menses within 12 months plus follicle-stimulating hormone (FSH) and estradiol levels in the premenopausal range; or
  • Patients with amenorrhea due to IUD or prior uterine ablation must have FSH and estradiol levels in the premenopausal range; or
  • Patients with prior hysterectomy must have FSH and estradiol levels in the premenopausal range.
  • The patient must have an ECOG performance status of less than or equal to 2 (or Karnofsky greater than or equal to 60%).
  • Patients may have ipsilateral or contralateral synchronous breast cancer if the highest stage tumor meets entry criteria, and the other sites of disease would not require chemotherapy or HER2-directed therapy.
  • Patients may have multicentric or multifocal breast cancer if the highest stage tumor meets entry criteria, and the other sites of disease would not require chemotherapy or HER2-directed therapy.
  • Patient may have undergone a total mastectomy, skin-sparing mastectomy, nipple-sparing mastectomy, or a lumpectomy.
  • For patients who undergo a lumpectomy, the margins of the resected specimen or re-excision must be histologically free of invasive tumor and DCIS (ductal carcinoma in situ) with no ink on tumor as determined by the local pathologist. If pathologic examination demonstrates tumor at the line of resection, additional excisions may be performed to obtain clear margins. Positive posterior margin is allowed if surgeon deems no further resection possible. (Patients with margins positive for LCIS (lobular carcinoma in situ) are eligible without additional resection.)
  • For patients who undergo mastectomy, the margins must be free of residual gross tumor. (Patients with microscopic positive margins are eligible if post-mastectomy RT (radiation therapy) of the chest wall will be administered.)
  • Patient must have undergone axillary staging with sentinel node biopsy (SNB), targeted axillary dissection (TAD), or axillary lymph node dissection (ALND).
  • The following staging criteria must be met postoperatively according to AJCC 8th edition criteria:
  • By pathologic evaluation, primary tumor must be pT1-3. (If N0, must be T1c or higher.)
  • By pathologic evaluation, ipsilateral nodes must be pN0 or pN1 (pN1mi, pN1a, pN1b, pN1c).
  • Patients with positive isolated tumor cells (ITCs) in axillary nodes will be considered N0 for eligibility purposes.
  • Patients with micrometastatic nodal involvement (0.2-2 mm) will be considered N1.
  • Oncotype DX RS (recurrence score) requirements*:
  • If node-negative:
  • Oncotype DX RS must be RS 21-25, or
  • Oncotype DX RS must be 16-20 and disease must be high clinical risk, defined as: low histologic grade with primary tumor size greater than 3 cm, intermediate histologic grade with primary tumor size greater than 2 cm, or high histologic grade with primary tumor size greater than 1 cm.
  • If 1-3 nodes involved:

  • Oncotype DX RS must be less than 26.

    * Patients with a "Low Risk" or "MP1" MammaPrint (a genomic test that analyzes the activity of certain genes in early-stage breast cancer) result must have eligibility assessed with an Oncotype DX RS at pre-entry (see Section 3.1). Blocks or unstained slides must be sent to the Genomic Health centralized laboratory for testing at no cost to these patients. If MammaPrint High Risk or MP2, these patients are not eligible.

  • The tumor must be ER and/or PgR-positive (progesterone receptor) by current ASCO/CAP guidelines based on local testing results. Patients with greater than or equal to 1% ER and/or PgR staining by IHC will be classified as positive.
  • The tumor must be HER2-negative by current ASCO/CAP (American Society of Clinical Oncology/College of American Pathologists) guidelines based on local testing results.
  • The interval between the last surgery for breast cancer (including re-excision of margins) and pre-entry must be no more than 16 weeks.
  • Short course of endocrine therapy of less than 6 weeks duration before pre-entry is acceptable either as neoadjuvant or adjuvant therapy. An Oncotype DX RS must be performed on core biopsy specimen obtained prior to initiation of neoadjuvant endocrine therapy if received.
  • Patients with a prior or concurrent non-breast malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. This would include prior cancers treated with curative intent.
  • HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
  • Radiation therapy should be used according to standard guidelines; the intended radiation therapy should be declared prior to pre-entry.

Exclusion Criteria:

• ? Definitive clinical or radiologic evidence of metastatic disease.

  • pT4 (pathological state) tumors, including inflammatory breast cancer.
  • History of ipsilateral or contralateral invasive breast cancer. (Patients with synchronous and/or previous DCIS or LCIS are eligible.)
  • If prior ipsilateral DCIS was treated with lumpectomy and XRT (ionizing radiation therapy), a mastectomy must have been performed for the current cancer.
  • Life expectancy of less than 10 years due to co-morbid conditions in the opinion of the investigator.

Known results from most recent lab studies obtained as part of routine care prior to study entry showing ANY of the following values:

• ANC (absolute neutrophil count) less than 1200/mm3;
• Platelet count less than 100,000/mm3;
• Hemoglobin less than 10 g/dL;
• Total bilirubin greater than ULN (upper limit of normal) for the lab or greater than 1.5 x ULN for patients who have a bilirubin elevation due to Gilbert's disease or similar syndrome involving slow conjugation of bilirubin;
• AST(aspartate aminotransferase)(SGOT)/ALT (alanine transminase)(SGPT): greater than 3 × institutional ULN;
• Renal function of GFR (glomular filtration rate) less than 30 mL/min/1.73m2.
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better.
• Non-epithelial breast malignancies such as sarcoma or lymphoma.
• Any treatment with radiation therapy, chemotherapy, or biotherapy administered for the currently diagnosed breast cancer prior to pre-entry. (Patients with prior ET of more than 6 weeks duration for treatment of this cancer are not eligible.) Prior tamoxifen given for breast cancer prevention is allowed. Prior AI or GnRH for fertility preservation is allowed.
• Hormonally based contraceptive measures must be discontinued prior to pre-entry (including progestin/progesterone IUDs).
• Patients with evidence of chronic hepatitis B virus (HBV) infection are ineligible unless the HBV viral load is undetectable on suppressive therapy. Patients with a history of hepatitis C virus (HCV) infection are ineligible unless they have been treated and cured or have an undetectable HCV viral load if still on active therapy.
• Pregnancy or lactation at the time of pre-entry. (Note: Pregnancy testing according to institutional standards for women of childbearing potential must be performed within 2 weeks prior to pre-entry.)
• Other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements or interfere with interpretation of study results.

Inclusion Criteria

1. Have histologically documented TNBC (defined as ER expression ≤10% by IHC, PR expression≤10% by IHC and HER2 0 or 1+ by IHC or FISH ratio <2 or HER2 gene copy number of <6).

2. Early-stage breast cancer (stage I-III) and scheduled to undergo NAC treatment with curative intent.

3. Be informed of the investigational nature of the study and all pertinent aspects of the trial.

4. Have the ability to understand and the willingness to sign a written informed consent document in accordance with institutional and federal guidelines.

5. Be ≥ 18years of age.

6. Patient who are scheduled to start NAC.

7. Be willing to provide blood samples before and during treatment.

8. Have available biopsy tissue.

Exclusion Criteria

1. Receiving concurrent anti-neoplastic therapy for another malignancy.

2. Stage IV disease.

3. Current or history of another primary cancer within 5 years of study entry, with the exception of basal or squamous cell skin cancer, or non-invasive malignancy.

4. History of allogeneic bone marrow or organ transplant.

5. Blood transfusion within two weeks before collection of blood for central ctDNA testing.

6. Started systemic therapy for their breast cancer.

7. Pregnancy

Criteria

Inclusion Criteria:

• STEP 1 REGISTRATION

• Patients must have a diagnosis of hormone receptor positive (estrogen receptor positive [ER+] and/or progesterone receptor positive [PR+]), HER-2 negative, metastatic (M1) breast cancer and must be receiving or plan to receive first-line systemic treatment for metastatic disease. (Systemic treatment is any treatment meant to treat the whole body such as endocrine therapy +/- targeted therapy +/- chemotherapy).

  • NOTE: Participants are eligible if they have either de-novo metastatic breast cancer and/or recurrent breast cancer from an earlier stage that is now metastatic
• Patients must be registered to step 1 between 14 days prior to and 60 days after start of first-line systemic treatment for metastatic disease

• Patients must have been tested for the following breast cancer specific STMs after diagnosis of metastatic disease and within +/-14 days of initiation of first-line systemic treatment for metastatic disease:

  • CEA (must be tested)
  • CA 15-3 or CA 27.29 (at least one of these must be tested)
  • At least one of the tested STMs must have been >= 2 x the institutional upper limit of normal at this time.

Testing all three STMs is encouraged but only two are required. Patients must plan to have the same two STMs tested for the duration that the patient is on protocol-specified disease monitoring.

• Patients must have systemic radiographic imaging prior to initiation of systemic therapy or within 30 days of initiation of treatment for metastatic breast cancer and prior to step 1 registration. Modality of imaging is at the discretion of the treating physician.

  • Note: the treating physician can order additional imaging tests at any point prior to randomization at their discretion
• Patients must be willing to obtain disease monitoring (imaging and/or serum tumor markers) from a consistent facility in which the registering site has access to the results for the duration of the study intervention (312 weeks after step 2 randomization). Imaging and STMs do not need to be completed at the same facility.
• Patients with known cirrhosis, untreated B12 deficiency, thalassemia, or sickle cell anemia are not eligible as these could cause falsely elevated STM levels
• Patients with known brain leptomeningeal metastases are not eligible as they may require regular radiographic monitoring to assess treatment response
• Patients must not be currently enrolled or plan to participate in a first-line treatment trial for metastatic breast cancer with a defined monitoring schedule
• Patients who are able to complete questionnaires in English or Spanish must participate in patient-reported outcome (PRO) assessments
• Patients must not be pregnant due to the potential harm to the fetus from radiation exposure from radiographic imaging
• Except for breast cancer (and previous history of breast cancer), no other prior malignancy is allowed except for adequately treated basal (or squamous cell) skin cancer, in situ cervical cancer or other cancer for which the patient has been disease free for five years
• Patients must not have received prior systemic therapy for metastatic breast cancer, except for their current line of therapy.
• Patients must have decision making capacity and be able to provide informed consent
• Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines; use of legally-authorized representative is not permissible for this study
• As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system
• STEP 2 RANDOMIZATION

• Patients must be tested for the breast cancer specific STMs that were tested prior to STEP 1 Registration between 56 and 140 days after initiation of first-line systemic therapy for metastatic disease:

  • CEA (must be tested)
  • CA 15-3 or CA 27.29 (whichever was tested prior to Step 1)

Testing all three STMs is encouraged but only two are required. Patients must plan to have the same two STMs tested for the duration that the patient is on protocol-specified disease monitoring.

• At least one of the STMs that was previously elevated must have decreased from the assessment at step 1 by >= 10% at this time.
• Patients must not have known progression since registration to step 1
• Patients must be registered to step 2 randomization between 56 days and 140 days after the initiation of first-line systemic therapy for metastatic disease; This window is inclusive; patients may be registered to Step 2 on day 56 or Day 140. Patients must have been eligible for Step 1 in order to be eligible for Step 2 Randomization
• Baseline questionnaires must be completed within 28 days prior to step 2 randomization; (Note: Those patients who cannot complete the PRO questionnaires in English or Spanish can be registered to step 2 without contributing to PRO research)

Criteria

Stage: Clinical stage II or III rectal adenocarcinoma defined as T4N0 or any T with node positive disease (any T, N+); also T3N0 requiring abdominal perineal resection (APR) or coloanal anastomosis

Tumor site: Rectum; =< 12cm from the anal verge

No prior systemic chemotherapy, targeted therapy, or immunotherapy; or radiation therapy administered as treatment for colorectal cancer within the past 5 years is allowed

Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects * Therefore, for women of childbearing potential only, a negative pregnancy test (urine or serum according to institutional guidelines) done =< 14 days prior to registration is required. Female subjects agree to use highly effective contraception combined with an additional barrier method (e.g, diaphragm, with a spermicide) while on study and for >= 9 months after last dose of study drug, and the same criteria are applicable to male subjects if they have a partner of childbirth potential. Male subject agrees to use a condom and not donate sperm while in this study and for >= 6 months after the last treatment

Age >= 18 years

Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (or Karnofsky >= 60%)

Absolute neutrophil count (ANC) >= 1,500/mm^3

Platelet count >= 100,000/mm^3

Creatinine =< 1.5 x upper limit of normal (ULN) OR calculated (calc.) creatinine clearance >= 50 mL/min

Total bilirubin =< 1.5 x upper limit of normal (ULN)

Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x upper limit of normal (ULN)

No upper rectal tumors (distal margin of tumor > 12 cm from the anal verge)

No recurrent rectal cancer; prior transanal excision, prior distal sigmoid cancer with a low anastomosis

No known mismatch repair deficient rectal adenocarcinoma

Human immunodeficiency virus HIV-infected patients on effective anti-retro viral therapy with undetectable viral load within 6 months are eligible for this trial

Patients with known history or current symptoms of cardiac disease, or history of treatment with cardio toxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification1. To be eligible for this trial, patients should be class 2B or better

Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on this study. Patients on strong CYP3A4 inhibitors must discontinue the drug for 14 days prior to registration on the study

* Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients must discontinue the drug 14 days prior to the start of study treatment

Criteria

Key Inclusion Criteria:

• Recurrent or persistent endometrial carcinoma which has progressed or recurred after at least 1, but no more than 2, prior lines of therapy. Prior hormonal therapies (e.g., tamoxifen, aromatase inhibitors) will not count toward the prior regimen limit. Chemotherapy given in conjunction with radiotherapy as a radiosensitizer will be counted as a systemic therapeutic regimen
• Formalin-fixed, paraffin-embedded tumor tissue, a specimen as proximal to the current recurrence as possible, must be submitted to the Central Lab for molecular testing (FoundationOne® assay).
• Life expectancy > 12 weeks
• Recovery from effects of recent radiotherapy, surgery, or chemotherapy

Key Exclusion Criteria:

• Endometrial tumors with the following histologies: squamous carcinomas, sarcomas
• Other invasive malignancies within the last 5 years, except for:
• non-melanoma skin cancer with no evidence of disease within the past 5 years
• localized breast cancer with previous adjuvant chemotherapy treatment for breast cancer completed > 5 years ago
• Have synchronous primary invasive ovarian or cervical cancer
• Have an active or history of autoimmune disease or immune deficiency
• Have a history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis based on a screening chest computed tomography (CT) scan
• Have active tuberculosis
• Have severe infections within 4 weeks
• Have received therapeutic oral or IV antibiotic medication within 2 weeks, except prophylactic antibiotic medication
• Have significant cardiovascular disease
• Are administered treatment with a live attenuated vaccine within 4 weeks, or anticipation of need for such a vaccine during the course of the study
• Have prior allogeneic bone marrow transplantation or solid organ transplant
• Prior treatment with T-cell costimulating or immune checkpoint blockade therapies including, but not limited to, CD137 agonists, anti-PD-1, anti-PD-L1, and anti-CTLA-4 therapeutic antibodies
• Have treatment with systemic immunostimulatory agents (including but not limited to interferons, interleukin-2) within 4 weeks or 5 half-lives of the drug, whichever is longer, prior to initiation of study treatment
• Have treatment with systemic immunosuppressive medications within 2 weeks except acute, low-dose, systemic immunosuppressant medications, corticosteroids for chronic obstructive pulmonary disease and asthma, or mineralocorticoids and low-dose corticosteroids for patients with orthostatic hypotension or adrenocortical insufficiency
• Have a history or clinical evidence of any untreated CNS disease, seizures not controlled with standard medical therapy, or history of cerebrovascular accident (stroke), transient ischemic attack or subarachnoid

Criteria

Inclusion Criteria:

• At least 18 years of age at the time of signing informed consent.
• Histologically confirmed EC including: endometrioid, serous, undifferentiated, and carcinosarcoma.
• TP53 wt assessed by next generation sequencing (NGS), evaluated by a central vendor.
• Completed a single line, at least 12 weeks of platinum-based therapy (not including adjuvant or neoadjuvant therapy for Stage I-III disease) and achieved confirmed partial or complete response (PR or CR) by imaging, according to RECIST version 1.1. The participants should have received treatment for:

Primary Stage IV disease, defined as:

• had a primary or later debulking surgery during first-line platinum-based therapy with R0 resection (R0 resection indicates a macroscopic complete resection of all visible tumor) and achieved CR after at least 12 weeks platinum-based therapy, OR
• had a primary or later debulking surgery during first-line platinum-based therapy with R1 resection (R1 resection indicates incomplete removal of all macroscopic disease) and achieved PR or CR after at least 12 weeks platinum-based chemotherapy, OR
• had no surgery and achieved PR or CR after at least 12 weeks platinum-based chemotherapy

OR

At first relapse (i.e., relapse after primary therapy including surgery and/or chemotherapy and/or immunotherapy for Stage I-IV disease), defined as:

• had Stage I - III disease at diagnosis and received, at initial diagnosis, adjuvant chemotherapy and relapsed later. Participants should have PR or CR after at least 12 weeks of platinum-based chemotherapy compared with the start of this chemotherapy at the time of relapse,
• had Stage I-III disease at diagnosis and did not receive adjuvant chemotherapy at initial diagnosis and relapsed later. Participants should have PR or CR after at least 12 weeks of platinum-based chemotherapy compared with the start of this chemotherapy at the time of relapse, OR

• had Stage IV disease at diagnosis and received initially chemotherapy with or without surgery and relapsed later. At the time of relapse, participants should have PR or CR after at least 12 weeks of platinum-based chemotherapy compared with the start of this chemotherapy at the time of relapse.

  • Previous treatment with anti-programmed cell death protein 1(PD-1) or anti-programmed death-ligand 1(PD-L1) monoclonal antibody and concomitant biologic agents (e.g., bevacizumab, trastuzumab) is allowed.
  • Must be able to initiate study drug 3 to 8 weeks after completion of their final dose of chemotherapy.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
  • Participants must have adequate bone marrow function and organ function within 2 weeks before starting study drug as defined by the following laboratory criteria:
• Hepatic function: total bilirubin up to less than (<) 3*upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to (<=) 2.5*ULN in participants without liver metastasis. For participants with known liver involvement of their tumor: AST and ALT (<=) 5*ULN
• Hematopoietic function within 1 week: Absolute neutrophil count (ANC) greater than or equal to (>=) 1.5*10^9/liter (L); platelet count >= 100*10^9/L; hemoglobin >= 9.0 gram per deciliter (g/dL) per local laboratory results

• Renal function: estimated creatinine clearance (CrCl) of >= 20 milliliter per minute (mL/min), calculated using the standard local formula, as applicable

  - In the opinion of the Investigator, the participant must:

• Have a life expectancy of at least 12 weeks, and

• Be fit to receive investigational therapy

  • Premenopausal females of childbearing potential must have a negative pregnancy test (serum ?-human chorionic gonadotropin test) prior to the first dose of study drug. Female participants of childbearing potential must agree to use highly effective methods of contraception throughout the study and for 90 days following the last dose of study drug.
  • Written informed consent signed in accordance with federal, local, and institutional guidelines prior to the first screening procedure.

Exclusion Criteria:

• Participants meeting any of the following exclusion criteria are not eligible to enroll in this study:
• Has any uterine sarcomas (carcinosarcomas - not excluded), clear cell or small cell carcinoma with neuroendocrine differentiation
• Received a blood or platelet transfusion during the 2 weeks prior to Cycle 1 Day 1 (C1D1). Participants' hemoglobin must be assessed within 2 weeks of screening and at least 1 week post transfusion
• Concurrent systemic steroid therapy higher than physiologic dose (> 10 milligram per day [mg/day] of prednisone or equivalent). Systemic steroid therapy as pre-medication for taxane is allowed

• Insufficient time since or not recovered from procedures or anti-cancer therapy, defined as:

  • Not recovered from major surgery <= 28 days prior to Day 1 dosing. Minor procedures, such as biopsies, dental work, or placement of a port or intravenous (IV) line for infusion are permitted
• Having ongoing clinically significant anti-cancer therapy-related toxicities CTCAE Grade > 1, with the exception of alopecia. In specific cases, participants whose toxicity has stabilized or with Grade 2 non-hematologic toxicities can be allowed following documented approval by the Sponsor's Medical Monitor
• Palliative radiotherapy within 14 days of the intended C1D1. Palliative radiotherapy may be permitted for symptomatic control of pain from bone metastases, provided that the radiotherapy does not involve target lesions, and the reason for the radiotherapy does not reflect evidence of disease progression.
• Any gastrointestinal dysfunctions that could interfere with the absorption of selinexor (e.g., bowel obstruction, inability to swallow tablets, malabsorption syndrome, unresolved nausea, vomiting, diarrhea CTCAE v 5.0 > grade 1).
• Participants unable to tolerate two forms of antiemetics for at least 2 cycles will not be eligible for the trial.
• Active, ongoing or uncontrolled active infection requiring parenteral antibiotics, antivirals, or antifungals within 1 week of screening.
• Serious psychiatric or medical condition that could interfere with participation in the study or in the opinion of the Investigator would make study involvement unreasonably hazardous.
• Previous treatment with an XPO1 inhibitor.
• Stable disease or PD on the post-chemotherapy scan or clinical evidence of progression prior to randomization.
• Participants who received any systemic anticancer therapy including investigational agents <= 3 weeks (or <= 5 half-lives of the drug [whichever is shorter]) prior to C1D1.
• Major injuries or surgery within 14 days prior to C1D1 and/or planned major surgery during the on-treatment study period.
• Other malignant disease with disease-free <= 3 years except: curatively treated carcinoma in situ of the cervix, basal cell carcinoma of the skin, or ductal carcinoma in situ (DCIS) of the breast.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to selinexor, or other agents used in the study.
• Active brain metastases (e.g., stable for < 8 weeks, no adequate previous treatment with radiotherapy and/or surgery, symptomatic, requiring treatment with anti-convulsant therapy. Corticoid therapy is allowed if administered as stable dose for at least 1 month before randomization).
• Females who are pregnant or lactating.
• Any other life-threatening illness, active medical condition, organ system dysfunction, or serious active psychiatric issue which, in the Investigator's opinion, could compromise the participant's safety or the participant's ability to remain compliant with study procedures.

Criteria

Inclusion Criteria:

• Histologic documentation: HER2 negative adenocarcinoma as defined by American Society of Clinical Oncology (ASCO) College of American Pathologists (CAP) guidelines (Bartley et al., Journal of Clinical Oncology [JCO] 2017) with known PD-L1 CPS (Any CPS is allowed, but should be known prior to registration)
• Stage: unresectable or metastatic
• Tumor site: esophagus, gastroesophageal junction, or stomach
• Measurable disease or non-measurable but evaluable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• No prior systemic treatment for unresectable or metastatic disease
• Prior neoadjuvant or adjuvant cytotoxic chemotherapy or adjuvant immunotherapy is allowed as long as it was completed at least 1 year prior to registration
• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1
• Absolute neutrophil count (ANC) >= 1,500/mm^3
• Platelet count >= 100,000/mm^3
• Creatinine =< 1.5 x upper limit of normal (ULN) OR calculated (calc.) creatinine clearance >= 30 mL/min
• Total bilirubin =< 1.5 x ULN
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN (in patients with liver metastasis: =< 5 x ULN if clearly attributable to liver metastases)
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial

• Patients positive for human immunodeficiency virus (HIV) are eligible only if they meet all of the following:

  • On effective anti-retroviral therapy
  • Undetectable HIV viral load by standard clinical assay =< 6 months of registration
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better

• Patients who will receive nivolumab in addition to chemotherapy must not have any contraindications to immune checkpoint inhibitors

  • Patients must not have active autoimmune disease that has required systemic treatment within 6 months prior to registration. Patients are permitted to receive immunotherapy if they have vitiligo, type I diabetes, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (precipitating event)
  • Patients must not have a condition requiring systemic treatment with either corticosteroids (>10mg/day prednisone equivalents) or other immunosuppressive medications within 14 days prior to registration. Inhaled or topical steroids and adrenal replacement doses (=< 10mg/day prednisone equivalent) are permitted
  • Patients must not have a history of noninfectious pneumonitis requiring steroids
  • Patients with prior immune mediated adverse events related to immunotherapy that resulted in permanent treatment discontinuation with these agents are ineligible
• This study includes the use of the mandatory patient completed measure, PRO-CTCAE. For this study the PRO-CTCAE is available in English, Spanish, Korean, Chinese (Simplified), and Russian, hence patients must be able to speak, understand and read in these languages. Ad-hoc translation of patient-reported measures is not permitted

Exclusion Criteria:

• Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects

  * Therefore, for women of childbearing potential only, a negative serum or urine pregnancy test done =< 7 days prior to registration is required

• No known Gilbert's syndrome or known homozygosity for UGAT1A1*28 polymorphism
• No baseline grade >= 2 peripheral neuropathy, neurosensory toxicity, or neuromotor toxicity per CTCAE version (v) 5.0 regardless of causality
• No medical condition such as uncontrolled infection or uncontrolled diabetes mellitus which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient
• No untreated, symptomatic brain metastasis. Patients with treated brain metastases are eligible if the following criteria are met: 1) follow-up brain imaging done at least in 4 weeks after central nervous system (CNS)-directed therapy shows no evidence of progression and 2) the patient no longer requires steroids, or is on a stable steroid dose for more than four weeks
• No allogeneic tissue/organ transplant

Inclusion Criteria:

• Metastatic pancreatic adenocarcinoma. Adenosquamous carcinoma, squamous carcinoma, acinar cell carcinoma, and carcinoma not otherwise specified are also acceptable
• BRCA1/2 or PALB2 mutation (somatic or germline) identified on any Clinical Laboratory Improvement Amendments (CLIA)-certified gene panel. Mutations must be considered pathogenic or likely pathogenic by a reference database such as ClinVar or OncoKb.org. (Submission of mutation report will be required)
• Measurable disease
• Potential trial participants should have recovered from clinically significant adverse events of their most recent therapy/intervention prior to enrollment

• Clinical or radiographic progression on first-line FOLFIRINOX (or nanoliposomal irinotecan, fluorouracil, leucovorin, and oxaliplatin [NALIRIFOX]) for metastatic disease

  • Patients whose front-line chemotherapy was required to be simplified due to toxicity associated with any of the constituent components of FOLFIRINOX/NALIRIFOX (e.g. simplified to leucovorin calcium, fluorouracil, and oxaliplatin [FOLFOX], leucovorin calcium, fluorouracil, and irinotecan [FOLFIRI], fluorouracil [5-FU] [including capecitabine]) will be eligible
  • Patients with progressive disease while on maintenance PARP inhibitor treatment after FOLFIRINOX (or NALIRIFOX), irrespective of how long ago they received FOLFIRINOX/NALIRIFOX, will also be eligible
  • Patients who develop metastatic disease during or within 6 months after completing FOLFIRINOX/NALIRIFOX in either the locally advanced or adjuvant/neoadjuvant settings will be eligible

• Patients may not have received prior cisplatin for their pancreatic cancer in any setting

  * Note: Patients may have previously received gemcitabine +/- nab-paclitaxel for resectable (neoadjuvant/adjuvant) or locally advanced disease if (1) treatment was completed > 1 year ago and (2) in the opinion of the treating provider, re-treatment with gemcitabine/nab-paclitaxel is appropriate

• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (Karnofsky performance status >= 60)
• Absolute neutrophil count >= 1,500/mm^3
• Platelet count >= 100,000/mm^3
• Hemoglobin >= 8.0 g/dL
• Creatinine =< 1.8 x institutional upper limit of normal (ULN) or calculated creatinine clearance (Calc. CrCl) > 40 mL/min

• Total bilirubin =< 2.0 x institutional ULN

  * Any elevated bilirubin should be asymptomatic at enrollment (except for participants with documented Gilbert's syndrome who may only be included if the total bilirubin =< 3 x ULN or direct bilirubin =< 1.5 x ULN)

• Aspartate transaminase (AST)/alanine transaminase (ALT) =< 3 x institutional ULN

  * AST/ALT of =< 5 x ULN if liver metastases are present

• Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects

  * Therefore, for women of childbearing potential only, a negative pregnancy test done =< 14 days prior to registration is required

• Patients with > grade 2 peripheral sensory neuropathy are not eligible
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial

• Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression for at least 8-weeks.

  * Patients with known, new or progressive brain metastases (active brain metastases) or leptomeningeal disease are ineligible

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load anytime within 6 months prior to registration are eligible for this trial

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.

  * Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load

• Concomitant chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on this study. Patients on strong CYP3A4 inhibitors must discontinue the drug for 14 days prior to registration on the study
• Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients must discontinue the drug 14 days prior to the start of study treatment

Exclusion Criteria:

• N/A

Criteria

Inclusion Criteria:

1. 18 years of age and older
2. Life expectancy of ? 3 months
3. Histological/cytological diagnosis of de novo adenocarcinoma of the pancreas

4. Unresectable, locally advanced stage disease according to the following criteria:

   • Head/uncinate process:

     1. Solid tumor contact with SMA>180°
     2. Solid tumor contact with the CA>180°
     3. Solid tumor contact with the first jejunal SMA branch
     4. Unreconstructible SMV/PV due to tumor involvement or occlusion (can be d/t tumor or bland thrombus)
     5. Contact with most proximal draining jejunal branch into SMV

   • Body and tail

     1. Solid tumor contact of >180° with the SMA or CA
     2. Solid tumor contact with the CA and aortic involvement
     3. Unreconstructible SMV/PV due to tumor involvement or occlusion (can be d/t tumor or bland thrombus)
   • No distant metastasis, including non-regional lymph node metastasis
   • No borderline resectable (per Al-Hawary MM, et al., Radiology 201414)
5. ECOG score 0-2
6. Amenable and assigned by the investigator to receive therapy with gemcitabine and nab-paclitaxel
7. Able to operate the NovoTTF-100L(P) System independently or with the help of a caregiver
8. Signed informed consent form for the study protocol

Exclusion Criteria:

1. Prior palliative treatment (e.g. surgery, radiation) to the tumor
2. Cancer requiring anti-tumor treatment within the 5 years before inclusion, excluding treated stage I prostate cancer, in situ cervical or uterus cancer, in situ breast cancer and non-melanomatous skin cancer.

3. Serious co-morbidities:

   1. Clinically significant (as determined by the investigator) hematological, hepatic and renal dysfunction, defined as: Neutrophil count < 1.5 x 10^9/L and platelet count < 100 x 10^9/L; bilirubin > 1.5 x Upper Limit of Normal (ULN); AST and/or ALT > 2.5 x ULN; and serum creatinine > 1.5 x ULN.
   2. History of significant cardiovascular disease unless the disease is well controlled. Significant cardiac disease includes second/third degree heart block; significant ischemic heart disease; poorly controlled hypertension; congestive heart failure of the New York Heart Association (NYHA) Class II or worse (slight limitation of physical activity; comfortable at rest, but ordinary activity results in fatigue, palpitation or dyspnea).
   3. History of arrhythmia that is symptomatic or requires treatment. Patients with atrial fibrillation or flutter controlled by medication are not excluded from participation in the trial.
   4. History of cerebrovascular accident (CVA) within 6 months prior to randomization or that is not stable.
   5. Active infection or serious underlying medical condition that would impair the ability of the patient to receive protocol therapy.
   6. History of any psychiatric condition that might impair patient's ability to understand or comply with the requirements of the study or to provide consent.
4. Concurrent anti-tumor therapy beyond gemcitabine and nab-paclitaxel
5. Implantable electronic medical devices in the torso, such as pacemakers
6. Known severe hypersensitivities to medical adhesives or hydrogel, or to one of the chemotherapies used in this trial.
7. Pregnancy or breast-feeding (female patients with reproductive potential and their partners must accept to use effective contraception throughout the entire study period and for 3 months after the end of treatment). All patients who are capable of becoming pregnant must take a pregnancy test which is negative within 72 hours before beginning treatment. The definition of effective contraception is left up to the decision of the investigator.
8. Unable to follow the protocol for medical, psychological, familial, geographic or other reasons.
9. Admitted to an institution by administrative or court order.

Criteria

Inclusion Criteria:

• Patient must have a histologic or cytologic diagnosis of pancreatic adenocarcinoma. Patients with neuroendocrine tumors, acinar cell and adenosquamous carcinomas are excluded. All disease must be assessed and documented on the Baseline Tumor Assessment Form
• Patients must have one of the following mutations: germline mutation in BRCA 1 or 2 that was tested in a Clinical Laboratory Improvement Act (CLIA) certified lab defined as positive and/or deleterious (that is, pathogenic or likely pathogenic variant). (NOTE: Patients with tumor somatic mutations are not eligible)
• Patient must have metastatic disease and received first line platinum-based chemotherapy (i.e. fluorouracil, irinotecan, leucovorin and oxaliplatin [FOLFIRINOX], leucovorin calcium, 5-fluorouracil, and oxaliplatin [FOLFOX], or gemcitabine + cisplatin)
• Patients must have had a computed tomography (CT) or magnetic resonance imaging (MRI) showing stable or responding disease on first line platinum-based chemotherapy within 30 days prior to registration
• Patients with known human immunodeficiency virus (HIV)-infection are eligible providing they are on effective anti-retroviral therapy and have undetectable viral load at their most recent viral load test and within 6 months prior to registration
• Patients with history of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load within 30 days prior to registration
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment must have an undetectable HCV viral load within 30 days prior to registration
• Patients must have received at least 16 weeks but no more than 24 weeks of first line platinum-based therapy for metastatic disease
• Patients' last chemotherapy treatment must be within 30 days prior to registration
• Patients must have resolved or stable =< grade 1 toxicity from prior administration of another investigational drug and/or prior anti-cancer treatment, excluding neuropathy and alopecia
• Zubrod performance status of 0-1
• Patients must have a complete medical history and physical exam within 28 days prior to registration
• Absolute neutrophil count >= 1,500/mcL (within 14 days of registration)
• Platelets >= 100,000/mcL (within 14 days of registration)
• Total bilirubin =< 1.5 institutional upper limit of normal (ULN) (within 14 days of registration)
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x institutional ULN (within 14 days of registration)
• Creatinine =< 1.5 mg/dl (within 14 days of registration)
• Albumin >= 3.0 (within 14 days of registration)
• Hemoglobin >= 9.0 g/dL
• Patients must have CA19-9 obtained within 42 days prior to registration
• Patients must be able to swallow and retain oral medications and have no known gastrointestinal disorders likely to interfere with absorption of the study medication
• Participants with a prior or concurrent malignancy whose natural history or treatment (in the opinion of the treating physician) does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial provided it does not require concurrent therapy
• Patients must be offered the opportunity to participate in specimen banking of formalin-fixed paraffin-embedded (FFPE) tissue and whole blood. If a patient is unable to submit archival tissue, should the patient need to undergo a standard of care biopsy per National Comprehensive Cancer Network (NCCN) guidelines, patients must then be offered the opportunity to submit the fresh tumor tissue from that biopsy. With participant consent, specimens must be collected and submitted via the Southwest Oncology Group (SWOG) Specimen Tracking System
• Patients must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines. For participants with impaired decision making capabilities, legally authorized representatives may sign and give informed consent on behalf of study participants in accordance with applicable federal, local, and Canada Industrial Relations Board (CIRB) regulations
• As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system

Exclusion Criteria:

• Patients must not have a known hypersensitivity to olaparib or any of the excipients of the product
• Patients must not be planning to receive strong or moderate CYP3A inhibitors or inducers while on olaparib treatment. Patients receiving strong or moderate CYP3A inhibitors must discontinue use at least 2 weeks prior to receiving olaparib. Patients receiving strong or moderate CYP3A inducers must discontinue use at least 5 weeks prior to receiving olaparib. Medications should be checked using a frequently updated medical reference for a list of drugs to avoid
• Patients must not have received live vaccines within 42 days prior to randomization and must not be planning to receive live virus or live bacterial vaccines while receiving study treatment and during the 30 day follow up period. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, shingles, yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed
• Patients must not have had prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or any other immune checkpoint inhibitors
• Patients must not have had prior therapy with PARP inhibitors
• Patients must not have had a prior diagnosis of immunodeficiency or receiving systemic steroid therapy (defined as >= 10 mg prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
• Participants must not be pregnant or nursing due to the possibility of harm to the fetus or nursing infant from this treatment regimen. Women/men of reproductive potential must have agreed to use an effective contraceptive method for the course of the study through 6 months after the last dose of study medication. A woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation. However, if at any point a previously celibate participant chooses to become heterosexually active during the time period for use of contraceptive measures, he/she is responsible for beginning contraceptive measures. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
• Patients must not have a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
• Patients must not have an active infection requiring systemic therapy
• Patients must not have active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment

Criteria

Inclusion Criteria:

• Willing and able to provide written informed consent (ICF) and HIPAA authorization for the release of personal health information. A signed informed consent must be obtained before screening procedures are performed.

NOTE: HIPAA authorization may be either included in the informed consent or obtained separately.

• Males 18 years of age and above
• Histological or cytological proof of prostate cancer

• Documented progressive mCRPC based on at least one of the following criteria:

  1. PSA progression defined as 25% increase over baseline value with an increase in the absolute value of at least 1.0 ng/mL that is confirmed by another PSA level with a minimum of a 1 week interval and a minimum PSA of 1.0 ng/mL.
  2. Soft-tissue progression defined as an increase >= 20% in the sum of the LD of all target lesions based on the smallest sum LD since treatment started or the appearance of one or more new lesions.
  3. Progression of bone disease (evaluable disease) or two or more new bone lesions by bone scan.
• Two or more bone lesions
• ECOG 0- 1

• Normal organ function with acceptable initial laboratory values within 14 days of randomization:

  • Albumin > 30 g/L
  • ANC >= 1.5 x 10^9/L
  • Hemoglobin >= 10 g/dL
  • Platelet count >= 100 x 10^9/L
  • Creatinine <= 1.5 x the institutional upper limit of normal (ULN)
  • Bilirubin <= ULN (unless documented Gilbert's disease)
  • SGOT (AST) <= 1.5 x ULN
  • SGPT (ALT) <= 1.5 x ULN
  • WBC count >= 3 x 10^9/L
• Subjects must agree to use a medically acceptable method of birth control (e.g., spermicide in conjunction with a barrier such as a condom) or sexual abstinence for the duration of the study, including 30 days after the last dose of study drug. Sperm donation is prohibited during the study and for 30 days after the last dose of study drug. Female partners must use hormonal or barrier contraception unless postmenopausal or abstinent.
• Serum testosterone < 50 ng/dL. Subjects must continue primary androgen deprivation with an LHRH analogue (agonist or antagonist) if they have not undergone orchiectomy.
• All acute toxic effects of any prior treatment have resolved to NCI-CTCAE v4.0 Grade 1 or less.
• Willing and able to comply with the protocol, including follow-up visits and examinations

Exclusion Criteria:

• Received any other investigational therapeutic agents or other anticancer therapies within 4 weeks prior to randomization.
• Received external beam radiotherapy within the 4 weeks prior to randomization.
• Has an immediate need for external beam radiotherapy.
• Has received any systemic bone-seeking radiopharmaceutical in the past.
• Has received any prostate cancer directed chemotherapy in the castration resistant setting. Subjects who have received up to 6 prior doses of docetaxel in the castration sensitive setting are permitted if they have not experienced disease progression within 36 weeks of last treatment with docetaxel.

• Has received four or more systemic anticancer regimens for mCRPC.

  • Treatment with docetaxel or abiraterone for non-castrate metastatic disease is permissible and does not count towards the lines of therapy for mCRPC
  • A 'line' is a regimen. Combinations of hormones and other types of therapies count as single lines.
• Has known Grade ?3 docetaxel-related toxicities or docetaxel toxicity related dose interruption or discontinuation.
• Has received blood transfusions or growth factors within the last 4 weeks prior to randomization.
• Symptomatic nodal disease (i.e., scrotal, penile, or leg edema).
• Has visceral metastases with >= 3 lung and/or liver metastases or individual lesion >= 2 cm, as assessed by CT scan or MRI of the chest/abdomen/pelvis within the last 8 weeks prior to randomization.
• Symptomatic loco-regional disease that causes ongoing Grade 3 or Grade 4 urinary or rectal symptoms.
• Subjects with a "currently active" second malignancy other than non-melanoma skin cancers or non-invasive bladder cancers or other in-situ or non-invasive malignancies. Subjects are not considered to have a "currently active" malignancy if they have completed therapy and are free of disease for >= 3 years.
• Has imminent or established cord compression based on clinical findings and/or MRI.
• Known bone marrow dysplasia
• Has received any of the following in the 4 weeks prior to randomization: 5-alpha-reductase inhibitors, herbal medications, natural hormonally active foods (e.g., phytoestrogens) or other food supplements known to alter PSA in humans

• Any other serious illness or medical condition that would, in the opinion of the investigator, make this protocol unreasonably hazardous, including but not limited to:

  • Uncontrolled infection
  • NYHA III or IV heart failure
  • Crohn's disease or those with ulcerative colitis who have not undergone a colectomy
  • Known active infection with HIV, Hepatitis B or Hepatitis C

Criteria

Inclusion Criteria:

• INCLUSION CRITERIA FOR PREREGISTRATION (STEP 0: SCREENING)
• Patient must have biopsy-proven (consisting of >= 12 tissue cores) adenocarcinoma of the prostate with cancer present in at least one biopsy core in the most recent biopsy using initial transrectal ultrasound (TRUS) biopsy or TRUS biopsy followed by multiparametric magnetic resonance imaging (mpMRI) of the prostate and a confirmatory targeted biopsy
• Patient must be on active surveillance (very low, low and favorable intermediate risk as defined by the National Comprehensive Cancer Network [NCCN])
• Patient must be scheduled for a follow up prostate biopsy 6 months after the initiation of treatment on this study
• Patient must have a serum PSA < 10 ng/mL or prostate specific antigen density (PSAD) < 0.15 ng/mL/ g obtained within 30 days of registration
• Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Patient must be willing to abstain from consumption of any supplements containing green tea catechins
• Patient must be willing to restrict tea consumption to less than three (3) servings of hot tea or three (3) servings of iced tea per week (serving size of 8 oz)
• Patient must be willing to discontinue current vitamin/mineral supplement use and use one provided by study
• Patient must be willing to take study agent or placebo at the dose specified with meals
• Patient must have the ability to understand and the willingness to sign a written informed consent document
• Absolute neutrophil count >= 1,200/mm^3 (>= 1.2 k/uL) (obtained within 30 days prior to registration)
• Platelets >= 75,000/mm^3 (>= 75 k/uL) (obtained within 30 days prior to registration)
• Total bilirubin =< 1.2 mg/dL (or =< 3.0 mg/dL for patients with Gilbert's syndrome) (obtained within 30 days prior to registration)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 1.5 x upper limit of normal (ULN) (obtained within 30 days prior to registration)
• Serum creatinine =< 1.5 x ULN (obtained within 30 days prior to registration)
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• Sexually active males must use an accepted and effective method of double barrier contraception (vasectomy must be combined with a physical barrier method) or abstain from sexual intercourse for the duration of their participation in the study

• Patients must have archived formalin-fixed paraffin-embedded (FFPE) tumor tissue specimen available for Gleason score confirmation and % Ki-67 expression (5% or more) in tumor tissue for eligibility and stratification. Tumor tissue can be submitted any time during screening

  • Tumor tissue specimen has been collected and is ready to ship to H. Lee Moffitt Cancer Center & Research Institute

    • H. Lee Moffitt Cancer Center & Research Institute will perform Gleason score confirmation and % Ki-67 expression (5% or more) in tumor tissue and notify the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) Operations Office and submitting institution within 3-4 business days of receipt of the tumor tissue specimen
• INCLUSION CRITERIA FOR RANDOMIZATION (STEP 1)
• Patient must meet all Step 0 eligibility criteria at the time of their registration to Step 1
• Patient must have Gleason score (3+3) or predominant Gleason pattern 3 (3+4), =< 33% of biopsy cores, and =< 50% involvement of any biopsy core
• Patient must have % Ki-67 expression of 5% or more in tumor tissue

Exclusion Criteria:

• EXCLUSION CRITERIA FOR PREREGISTRATION (STEP 0: SCREENING)
• Patient must not have had prior treatment for prostate cancer, including focal therapy, with surgery, irradiation, local ablative (i.e., cryosurgery or high-intensity focused ultrasound), or androgen deprivation therapy
• Patient must not have a history of renal or hepatic disease, including history of hepatitis B and C
• Patient must not have prostate cancer with distant metastases
• Patient must not have undergone treatment of hormone therapy, immunotherapy, chemotherapy and/or radiation for any malignancies within the past 2 years. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Patient must not receive any other investigational agents while on this study
• Patient must not have a history of allergic reactions attributed to tea or other compounds of similar chemical or biologic composition to green tea extracts

Criteria

Inclusion Criteria:

• Be diagnosed with Stage I-IV prostate cancer without metastases to bone (lymph node involvement and prior diagnosis of a primary cancer is allowed)
• Be age 60 years or older
• Be starting ADT or have received their first ADT treatment in the past 3 months, with at least 6 planned months of treatment remaining (both luteinizing hormone-releasing hormone (LHRH) antagonists and LHRH agonists are permitted)
• Have a total serum vitamin D between 10 and 27 ng/ml
• Have an total serum calcium of less than or equal to 10.5 mg/dl
• Have a normal GFR (glomerular filtration rate)
• Agree not to take calcium and/or vitamin D supplements for the duration of the intervention other than those provided by the study
• Be able to provide written informed consent
• Be able to swallow pills and capsules
• Be able to speak and read English

Exclusion Criteria:

• Have long term (greater than 3 months) use of any pharmacologic bone-modifying agent including but not limited to oral or IV bisphosphonates, denosumab, or teriparatide prior to enrollment
• Have a diagnosis of stage IV chronic kidney disease
• Have a diagnosis of grade II or greater hypercalcemia (serum calcium greater than 10.5 mg/dl)
• Have a history of hypercalcemia or vitamin D toxicity/sensitivity

Criteria

Inclusion Criteria:

1. Patients >= 18 years of age
2. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
3. Patients must have a confirmed diagnosis of high-grade serous epithelial ovarian, primary peritoneal, or fallopian tube cancer.
4. Patients must be willing to provide an archival tumor tissue block or slides, or must undergo a procedure to obtain a new biopsy using a low-risk, medically routine procedure for IHC confirmation of high FRalpha positivity as defined by the Ventana FOLR1 Assay. Patients must be confirmed FRalpha-high as defined by FRalpha positivity of >= 75% of tumor membrane staining at >= 2+ intensity (PS2+) for entry into the study.

5. Prior BRCA testing on the tumor or prior germline testing is required for eligibility. If not done prior, tumor or germline testing will need to be done at study entry (Pre-screening). Somatic and germline BRCA-positive patients must have received prior treatment with a PARPi in maintenance following first-line treatment.

   Note: Local tumor or germline BRCA testing will be acceptable for stratification. If the patient has not been tested, recommend archival tumor samples to be assessed for tissue BRCA. Patients with homologous recombination deficient-positive tumors who have received prior PARPi plus bevacizumab treatment are eligible.

6. Patients must have relapsed after 1 line (first line) of platinum-based chemotherapy and have platinum-sensitive disease defined as progression greater than 6 months from last dose of primary platinum therapy.
7. Patients must be appropriate for, currently be on, or have completed platinum-based triplet therapy in second line (recurrent platinum-sensitive, high-grade serous epithelial ovarian, primary peritoneal, or fallopian tube cancer)
8. After completion of triplet therapy and before randomization, patients must have received no less than 4 and no more than 8 cycles of platinum-based triplet therapy in second line, to include no less than 3 cycles of bevacizumab in combination with platinum-based chemotherapy. If the number of cycles received is less than 6 due to toxicity, this must be documented and toxicity assessed as unlikely related to bevacizumab.
9. After completion of triplet therapy and before randomization: In the case of interval secondary cytoreductive surgery, patients are permitted to receive only 2 cycles of bevacizumab in combination with the last 3 cycles of platinum-based triplet therapy in the second line. In the case of primary cytoreductive surgery before second-line platinum-based triplet therapy, patients must have no less than 3 cycles of bevacizumab in combination with platinum-based chemotherapy after their surgery and before randomization.
10. Patients will either receive (per investigator's choice), must be receiving, or have received paclitaxel, gemcitabine, or PLD as the partner drug to platinum-based triplet therapy in the second line.
11. After completion of triplet therapy and before randomization, patients must have achieved a  CR, PR, or SD, per the investigator, after completion of triplet therapy in second line to be eligible for randomization into the study population. All patients in both populations will have computed tomography (CT)/magnetic resonance imaging (MRI) scans and CA-125 measurements at least 3 weeks but no more than 8 weeks after their last planned dose of triplet therapy and before randomization.
12. Patients must be randomized no later than 8 weeks from the last dose of triplet therapy in second line.

13. After completion of triplet therapy and before randomization, patients must meet one of the following criteria:

    1. Have at least 1 lesion that meets the definition of measurable disease by RECIST v1.1 (radiologically measured by the investigator), and determined by the investigator to either have SD or a PR to their treatment; or
    2. Have persistently elevated CA-125 without measurable disease and determined by the investigator to either have SD or a PR to their treatment; or
    3. Have clinically no evidence of disease by both radiographic interpretation by the investigator and normalization of their CA-125, determined to be a CR.
14. Patients must have stabilized or recovered (to Grade 1 or baseline) from all prior therapy-related toxicities (except alopecia).
15. Patients must have completed any major surgery at least 4 weeks before the first dose of maintenance treatment and have recovered or stabilized from the side effects of prior surgery before the first dose of maintenance treatment on study.

16. Patients must have adequate hematologic, liver, and kidney functions defined as follows:

    1. Absolute neutrophil count (ANC) >= 1.5 × 109/L (1500/?L) without granulocyte colony-stimulating factor in the prior 10 days or long-acting white blood cell (WBC) growth factors in the prior 10 days of C1D1 of maintenance treatment.
    2. Platelet count >= 100 × 109/L (100,000/?L) without platelet transfusion in the prior 10 days of C1D1 of maintenance treatment
    3. Hemoglobin >= 9.0 g/dL without packed red blood cell (PRBC) transfusion in the prior 10 days of C1D1 of maintenance treatment
    4. Serum creatinine <= 1.5 × upper limit of normal (ULN)
    5. Aspartate aminotransferase and alanine aminotransferase <= 3.0 × ULN
    6. Serum bilirubin <= 1.5 × ULN (patients with documented diagnosis of Gilbert syndrome are eligible if total bilirubin < 3.0 × ULN)
    7. Serum albumin >= 2 g/dL Note: For Run-In patients, these criteria must be met before initiation of triplet therapy and before start of maintenance therapy.
17. Patients must be willing and able to sign the informed consent form (ICF) and to adhere to the protocol requirements.
18. Females of childbearing potential (FCBP) must agree to use highly effective contraceptive method(s) (as defined in Section 5.10.7) while on study medication and for at least 3 months after the last dose.
19. FCBP must have a negative pregnancy test within 4 days before the first dose of maintenance therapy.

Exclusion Criteria:

1. Patients with endometrioid, clear cell, mucinous, or sarcomatous histology; mixed tumors containing any of the above histologies; or low-grade/borderline ovarian tumor

2. More than one line of prior chemotherapy. Lines of prior anticancer therapy are counted with the following considerations:

   1. Neoadjuvant ± adjuvant therapies are considered 1 line of therapy if the neoadjuvant and adjuvant correspond to 1 fully predefined regimen; otherwise, they are counted as 2 prior regimens.
   2. Maintenance therapy (eg, bevacizumab, PARPi) will be considered part of the preceding line of therapy (ie, not counted independently).
3. Patients with PD while on or following platinum-based triplet therapy
4. Patients who receive an intervening dose of bevacizumab after the last dose of triplet therapy before randomization
5. Patients with prior wide-field radiotherapy affecting at least 20% of the bone marrow
6. Patients with > Grade 1 peripheral neuropathy per Common Terminology Criteria for Adverse Events (CTCAE)
7. Patients with active or chronic corneal disorders, history of corneal transplantation, or active ocular conditions requiring ongoing treatment/monitoring, such as uncontrolled glaucoma, wet age-related macular degeneration requiring intravitreal injections, active diabetic retinopathy with macular edema, macular degeneration, presence of papilledema, and/or monocular vision

8. Patients with serious concurrent illness or clinically relevant active infection, including but not limited to the following:

   1. Active hepatitis B or C infection (whether or not on active antiviral therapy)
   2. HIV infection
   3. Active cytomegalovirus infection
   4. Any other concurrent infectious disease requiring IV antibiotics within 2 weeks before the first dose of maintenance therapy Note: Testing at screening is not required for the above infections unless clinically indicated.
9. Patients with a history of multiple sclerosis or other demyelinating diseases and/or Lambert-Eaton syndrome (paraneoplastic syndrome)

10. Patients with clinically significant cardiac disease including, but not limited to, any of the following:

    1. Myocardial infarction <= 6 months prior to C1D1 of maintenance treatment
    2. Unstable angina pectoris
    3. Uncontrolled congestive heart failure (New York Heart Association > class II)
    4. Uncontrolled >= Grade 3 hypertension (per CTCAE)
    5. Uncontrolled cardiac arrhythmias
11. Patients with a history of hemorrhagic or ischemic stroke within 6 months before enrollment
12. Patients with a history of cirrhotic liver disease (Child-Pugh Class B or C)
13. Patients with a previous clinical diagnosis of noninfectious interstitial lung disease, including noninfectious pneumonitis (exception: Grade 1 noninfectious pneumonitis diagnosed on or within 6 weeks after treatment with an immunotherapeutic agent used in the treatment of their malignancy that has resolved per investigator or resolution of the radiologic findings)
14. History of bowel obstruction (including sub-occlusive disease) related to underlying disease within 6 months before the start of maintenance study treatment (triplet therapy for Run-In patients).
15. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess, or evidence of rectosigmoid involvement by pelvic examination, bowel involvement on CT scan, or clinical symptoms of bowel obstruction
16. Clinically significant proteinuria: urine-protein (UPC) ratio >= 1.0 or urine dipstick result >= 2+; patients with UPC ratio >= 1.0 or >= 2+ proteinuria should undergo 24-hour urine collection and must show result <= 1 g of protein in 24-hour period.
17. History of Grade 4 thromboembolic events
18. Patients requiring use of folate-containing supplements (eg, folate deficiency)
19. Patients with prior hypersensitivity to monoclonal antibodies (mAbs)
20. Women who are pregnant or breastfeeding
21. Patients who received prior treatment with MIRV or other FR?-targeting agents
22. Patients with untreated or symptomatic central nervous system metastases
23. Patients with a history of other malignancy within 3 years before enrollment Note: Patients with tumors with a negligible risk for metastasis or death (eg, controlled basal cell carcinoma or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix or breast) are eligible.
24. Prior known hypersensitivity reactions to study drugs or any of their excipients

Criteria

Inclusion Criteria:

1. Provision of signed informed consent (obtained according to institutional guidelines) prior to initiation of any study-related procedures.
2. Age ?18 years at the time of informed consent.
3. Locally advanced or metastatic malignancy with one or more relevant biomarkers related to deoxyribonucleic acid (DNA) damage pathways
4. Subjects must have received prior standard therapy appropriate for their tumor type and stage of disease, or in the opinion of the Investigator, would be unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy, or no standard therapy exists for their tumor type/stage. Prior treatment with immune checkpoint inhibitors is allowed.
5. Subjects must have at least one measurable lesion as defined by RECIST Guideline Version 1.1.
6. Performance Status: Eastern Cooperative Oncology Group (ECOG) score of ?2.
7. Adequate hematologic and organ function
8. Willingness and ability to release archival tissue
9. Females of childbearing potential and male subjects must agree to use an effective method of contraception prior to the first dose and for 90 days after the last dose of ZN-c3.
10. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

Exclusion Criteria:

1. 1. Any of the following treatment interventions within the specified time frame prior to C1D1:

   1. Major surgery within 28 days (any surgical incision should be fully healed prior to study drug administration);
   2. Any chemotherapy within 14 days or 5 half-lives (whichever is shorter);
   3. Radiation therapy within 21 days; however, if the radiation portal covered ?5% of the bone marrow, the subject is eligible irrespective of the end date of radiotherapy.
   4. Autologous or allogeneic stem cell transplant within 3 months.
   5. Current use of any other investigational drug therapy <28 days or 5 half-lives (whichever is shorter).
   6. Inability to discontinue treatment prescription or non-prescription drugs, or to discontinue consumption of food and herbal supplements, that are strong/moderate CYP3A4 inhibitors, P-gp inhibitors, or strong CYP3A4 inducers at least 14 days prior to start of study drug treatment
2. Prior therapy with ZN-c3 or any other WEE1 inhibitor.
3. A serious illness or medical condition(s)
4. Unresolved toxicity of Grade >1 attributed to any prior therapies (excluding Grade ?2 neuropathy, alopecia or skin pigmentation).
5. Pregnant or lactating females (including the cessation of lactation) or females of childbearing potential who have a positive serum pregnancy test within 14 days prior to C1D1.
6. Subjects with active (uncontrolled, metastatic) second malignancies or requiring therapy.
7. Individuals who are judged by the Investigator to be unsuitable as study subjects.
8. 12-lead ECG demonstrating a corrected QT interval using Fridericia's formula (QTcF) of >480 ms, except for subjects with atrioventricular pacemakers or other conditions (e.g., right bundle branch block) that render the QT measurement invalid.
9. History or current evidence of congenital or family history of long QT syndrome or Torsade de Pointes (TdP).
10. Taking medications with a known risk of TdP.
11. Concomitant medication that leads to significant QT prolongation.
12. Administration of strong or moderate CYP3A4 inhibitors or inducers and P-gp inhibitors

Inclusion Criteria:

• Participants with a cancer diagnosis: Documentation of disease:

  • Histologic documentation: Histologically confirmed diagnosis of invasive cancer

  • Stage: Stage I-IV per American Joint Committee on Cancer (AJCC) 7th edition, with the exception of patients with leukemia, lymphoma, and multiple myeloma

    • For leukemia: Type (chronic lymphocytic leukemia [CLL], chronic myeloid leukemia [CML], acute lymphoblastic lymphoma [ALL], acute myeloid leukemia [AML])
    • For lymphoma: Stage I-IV based on Ann Arbor staging
    • For multiple myeloma: Stage I, II, III based on Revised International Staging System (RISS)

  • One of the following tumor types:

    • Colorectal
    • Bladder
    • Head and neck
    • Hepatobiliary
    • Lung
    • Lymphoma
    • Leukemia
    • Ovary *** For these specific cancer types only, patients may be enrolled prior to histologic confirmation of malignancy. Sites are required to contact the study chairs to review appropriateness for enrollment
    • Pancreas *** For these specific cancer types only, patients may be enrolled prior to histologic confirmation of malignancy. Sites are required to contact the study chairs to review appropriateness for enrollment
    • Multiple myeloma
    • Gastric, esophageal or gastroesophageal
    • Breast
    • Thyroid

    • Kidney

      • For these specific cancer types only, patients may be enrolled prior to histologic confirmation of malignancy. Sites are required to contact the study chairs to review appropriateness for enrollment
    • Endometrium
    • Prostate

    • Melanoma

      *** For these specific cancer types only, patients may be enrolled prior to histologic confirmation of malignancy. Sites are required to contact the study chairs to review appropriateness for enrollment

    • Sarcoma
• Participants with a cancer diagnosis: No prior definitive systemic or local anti-cancer intervention
• Participants with a cancer diagnosis: Age >= 40 and =< 75
• Participants with a cancer diagnosis: No known current pregnancy by self-report
• Participants with a cancer diagnosis: No known or prior history of in situ or invasive malignancy (excluding in situ non-melanoma skin cancers) other than the current cancer diagnosis
• Participants with a cancer diagnosis: Willingness to provide blood samples for research use
• Participants with a cancer diagnosis: Absence of medical contraindications to a research blood draw volume of 60 mL
• Participants with a cancer diagnosis: No history of organ transplantation

• Participants with a cancer diagnosis: Ability to read and comprehend English or Spanish

  * Eligibility is restricted to individuals who can comprehend and read English or Spanish given that participation in the study will require the ability to read and complete questionnaires that are available only in those two languages

• Participants without a cancer diagnosis and without suspicion of cancer: Age >= 40 and =< 75
• Participants without a cancer diagnosis and without suspicion of cancer: No known current pregnancy by self-report
• Participants without a cancer diagnosis and without suspicion of cancer: No known or prior history of in situ or invasive malignancy (excluding in situ non-melanoma skin cancers)
• Participants without a cancer diagnosis and without suspicion of cancer: Willingness to provide blood samples for research use
• Participants without a cancer diagnosis and without suspicion of cancer: Absence of medical contraindications to a research blood draw volume of 60 mL
• Participants without a cancer diagnosis and without suspicion of cancer: No history of organ transplantation

• Participants without a cancer diagnosis and without suspicion of cancer: Ability to read and comprehend English or Spanish

  * Eligibility is restricted to individuals who can comprehend and read English or Spanish given that participation in the study will require the ability to read and complete questionnaires that are available only in those two languages

• Participants with a high suspicion of cancer: High suspicion of ovarian cancer, pancreatic cancer, kidney cancer, or melanoma by clinical and/or radiological assessment, with plans for histologic or cytologic confirmation within 28 days after study blood draw

  * Examples of highly suspicious cases include: elevated CA125 and abnormal transvaginal ultrasound, suspicious renal or pancreatic mass on imaging, suspicious cutaneous lesion concerning for melanoma

• Participants with a high suspicion of cancer: Central review of radiology reports and/or clinical documentation conducted by study chairs
• Participants with a high suspicion of cancer: Age >= 40 and =< 75
• Participants with a high suspicion of cancer: No known current pregnancy by self-report
• Participants with a high suspicion of cancer: No known or prior history of in situ or invasive malignancy (excluding in situ non-melanoma skin cancers) other than the current cancer diagnosis
• Participants with a high suspicion of cancer: Willingness to provide blood samples for research use
• Participants with a high suspicion of cancer: Absence of medical contraindications to a research blood draw volume of 60 mL
• Participants with a high suspicion of cancer: No history or organ transplantation
• Participants with a high suspicion of cancer: Ability to read and comprehend English or Spanish * Eligibility is restricted to individuals who can comprehend and read English and Spanish given that participation in the study will require the ability to read and complete questionnaires that are available only in those two languages

Criteria

Inclusion Criteria:

• Pathologically (histologically or cytologically) proven diagnosis of renal cell carcinoma prior to registration

• Node-positive unresectable (TxN1Mx) or metastatic (TxNxM1) based on the following diagnostic workup:

  • History/physical examination within 45 days prior to registration
  • CT/magnetic resonance imaging (MRI) of the chest/abdomen/pelvis within 45 days prior to registration
• Patients must have IMDC intermediate (1-2 factors) or poor risk disease (>= 3 factors)
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Patients with measurable disease (node positive or metastatic) as defined by RECIST version 1.1 excluding the primary renal tumor
• Patient not recommended for or refused immediate cytoreductive nephrectomy
• Candidate for standard of care therapy with either immuno-oncology (IO)-IO or IO-VEGF combination regimen
• Primary renal tumor measuring 8 cm or less in anterior to posterior dimension only on axial imaging
• Age >= 18
• Karnofsky performance status >= 60 within 45 days prior to registration
• Hemoglobin >= 8 g/dL (transfusions are allowed) (within 45 days prior to registration)
• Platelet count >= 50,000/mm^3 (within 45 days prior to registration)
• Absolute neutrophil count (ANC) >= 1500/mm^3 (within 45 days prior to registration)

• Calculated (Calc.) creatinine clearance >= 30 mL/min (within 45 days prior to registration)

  • For African American patients specifically whose renal function is not considered adequate by the formula above, an alternative formula that takes race into account (Chronic Kidney Disease Epidemiology Collaboration CKD-EPI formula) should be used for calculating the related estimated glomerular filtration rate (GFR) with a correction factor for African American race creatinine clearance for trial eligibility, where GFR >= 30 mL/min/1.73m^2 will be considered adequate
• Total bilirubin =< 1.5 x upper limit of normal (ULN) (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL) (within 45 days prior to registration)
• Aspartate aminotransferase and alanine aminotransferase (AST and ALT) =< 3 x upper limit of normal (ULN) or < 5 x ULN if hepatic metastases present (within 45 days prior to registration)
• Patients with known human immunodeficiency virus (HIV) on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. Testing is not required for entry into protocol
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. Patients with HCV infection who are currently on treatment are eligible if they have an undetectable HCV viral load
• The patient must agree to use a highly effective contraception, including men with vasectomies if they are having sex with a woman of childbearing potential or with a woman who is pregnant, while on study drug and for 6 months following the last dose of study drug. Childbearing potential is defined as any person who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information

Exclusion Criteria:

• Patients with planned treatment of all metastatic disease with definitive therapy including either surgery, ablative (non-palliative) doses of radiation, or intervention of some type (definitive interventional radiology techniques) to ALL metastatic sites rendering the patient without extra-renal measurable disease. Patients NOT planned for definitive treatment of all metastatic sites are eligible. Lesions radiated palliatively are not eligible for response assessment

• Patients with untreated or unstable brain metastases or cranial epidural disease

  • Note: Patients who have been adequately treated with radiotherapy, radiosurgery, or surgery and stable for at least 4 weeks prior to registration as documented by MRI or CT imaging or deemed stable by clinical investigator are eligible. Treated brain metastases are defined as having no ongoing requirement for steroids and no evidence of progression or hemorrhage after treatment for at least 4 weeks prior to registration as documented by MRI or CT imaging or deemed stable by clinical investigator
• Prior radiotherapy to the kidney that would result in overlap of radiation therapy fields treatment of the primary tumor
• Any prior systemic therapy for metastatic renal cell carcinoma (RCC) note that prior chemotherapy for a different cancer is allowed (completed > 3 years prior to registration)

• Severe, active comorbidity defined as follows:

  • Active autoimmune disease requiring ongoing therapy including systemic treatment with corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications daily. Inhaled steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
  • History of severe allergic, anaphylactic or other hypersensitivity reactions to chimeric or humanized antibodies
  • Active tuberculosis (purified protein derivative [PPD] response without active tuberculosis [TB] is allowed)
  • Uncontrolled hypertension (systolic blood pressure [BP] > 190 mmHg or diastolic BP > 110 mmHg)
  • Major surgery < 45 days prior to registration.
  • Any serious (requiring hospital stay or long term rehab) non-healing wound, ulcer, or bone fracture within 45 days prior to registration
  • Any arterial thrombotic (ST elevation myocardial infarction [STEMI], non-ST elevation myocardial infarction [NSTEMI], cerebrovascular accident [CVA], etc) events within 180 days prior to registration
  • Active New York (NY) Heart Association class 3-4 heart failure symptoms
  • Moderate or severe hepatic impairment (Child-Pugh B or C)
  • Any history of untreated pulmonary embolism or deep venous thrombosis (DVT) within 180 days prior to registration. (Any asymptomatic or treated pulmonary embolism or asymptomatic treated deep venous thrombosis > 30 days prior to registration is allowed)
  • Unstable cardiac arrhythmia within 180 days prior to registration
  • History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess, bowel obstruction, or gastric outlet obstruction within 180 days prior to registration
  • History of or active inflammatory bowel disease
  • Malabsorption syndrome within 45 days prior to registration
• Pregnancy and individuals unwilling to discontinue nursing. For women of child bearing potential must have a negative pregnancy test =< 45 days prior to registration

Criteria

Inclusion Criteria:

• Previously registered to A151216
• Central and/or local testing of EGFR with no EGFR exon 19 deletion or EGFR L858 R mutation
• Central and/or local testing of ALK with no ALK rearrangement (failed testing is considered negative)

• Central and/or local testing of PD-L1 immunohistochemistry (IHC) using one of the following assays: DAKO 22C3, DAKO 28-8, or SP263

  • Note: Local testing results of EGFR and ALK by a local Clinical Laboratory Improvement Act (CLIA) certified laboratory is acceptable. The report must indicate the result as well as the CLIA number of the laboratory that performed the assay. Local result of PD-L1 by DAKO 22C3, Dako 28-8, or SP263 are acceptable for enrollment on A081801. Patients with local results for EGFR, ALK and PD-L1 still need to be registered to A151216 and follow all the submissions requirements but do NOT need to wait for the results to proceed to A081801 registration

• Completely resected stage IB (>= 4 cm), II or IIIA non-small cell lung cancer (NSCLC) with negative margins (complete R0 resection). Patients will be staged according to the 7th edition of the American Joint Committee on Cancer (AJCC) Staging Manual, 2010

  • Note: Patients with pathologic N2 disease, completely resected, are eligible. However, patients known to have N2 disease prior to surgery are not eligible; guidelines do not recommend up-front surgery for this population
• Complete recovery from surgery. Registration to A081801 must be 30-77 days following surgery
• No prior neoadjuvant or adjuvant therapy for current lung cancer diagnosis
• No prior allogeneic tissue/solid organ transplant
• Patients must NOT have uncontrolled intercurrent illness including, but not limited to, serious ongoing or active infection, symptomatic congestive heart failure, uncontrolled cardiac arrhythmia, unstable angina pectoris, that would limit compliance with study requirements
• No current pneumonitis or history of (non-infectious) pneumonitis that required steroids
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• Eastern Cooperative Oncology Group (ECOG) performance status (PS): 0-1
• No active auto-immune disease that has required systemic treatment within the last 2 years (e.g., disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid release therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment
• Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing potential only, a negative pregnancy test done =< 7 days prior to registration is required
• No patients with a "currently active" second malignancy that is progressing or has required active treatment within the last 3 years. Participants with non-melanoma skin cancers or carcinoma in situ (e.g., breast carcinoma or cervical cancer in situ) that have undergone potentially curative therapy are eligible
• No hypersensitivity (>= grade 3) to pembrolizumab and/or any of its excipients
• No live vaccine within 30 days prior to registration. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed
• No known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known hepatitis C virus (defined as HCV ribonucleic acid [RNA] [qualitative] is detected) infection
• Absolute neutrophil count (ANC) >= 1,500/mm^3
• Platelet count >= 100,000/mm^3
• Hemoglobin >= 8 gm/dl
• Calculated (Calc.) creatinine clearance >= 45 mL/min
• Total bilirubin =< 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN)

Criteria

Inclusion Criteria:

• REGISTRATION STEP 1: Participants must have pathologic (cytological or histological) proof of non-small cell lung cancer (NSCLC)
• REGISTRATION STEP 1: Participants must have stage III NSCLC with Zubrod performance status of 2 or stage II NSCLC with Zubrod performance status of 0-2
• REGISTRATION STEP 1: Participants must not be candidates for surgical resection in the opinion of the treating investigator. Participants whose disease was previously resected must have experienced local or regional recurrence at least 12 months after resection
• REGISTRATION STEP 1: Participants must not be candidates for concurrent chemoradiation in the opinion of the treating investigator
• REGISTRATION STEP 1: Participants must have measurable or non-measurable disease documented by computed tomography (CT) or magnetic resonance imaging (MRI). Measurable disease must be assessed within 28 days prior to Registration Step 1. Non-measurable disease must be assessed within 42 days prior to Step 1 registration. The CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic quality. All known sites of disease must be assessed and documented on the Baseline Tumor Assessment Form (RECIST 1.1)
• REGISTRATION STEP 1: Participants must have an MRI or CT scan of the brain with contrast within 28 days prior to Registration Step 1
• REGISTRATION STEP 1: Participants' disease must fit within the radiation constraints in the opinion of a local radiation oncologist
• REGISTRATION STEP 1: Participants may have received prior treatment for their lung cancer, including surgery, chemotherapy, targeted agents, and/or radiation treatment. At least 12 months must have elapsed since last treatment
• REGISTRATION STEP 1: Participants may have had prior radiation therapy as long as the irradiated area does not overlap with the radiation field targeted for this study
• REGISTRATION STEP 1: Participants must have recovered from any adverse effects of prior major surgery to the satisfaction of the treating physician. Biopsies and central IV access placement are not considered major surgery
• REGISTRATION STEP 1: Absolute neutrophil count (ANC) >= 1500/mcl (obtained within 28 days prior to Registration Step 1)
• REGISTRATION STEP 1: Platelet count >= 100,000/mcl (obtained within 28 days prior to Registration Step 1)
• REGISTRATION STEP 1: Hemoglobin >= 9 grams/dL (obtained within 28 days prior to Registration Step 1)
• REGISTRATION STEP 1: Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (obtained within 28 days prior to Registration Step 1)
• REGISTRATION STEP 1: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x IULN (obtained within 28 days prior to Registration Step 1)
• REGISTRATION STEP 1: Serum creatinine =< 1.5 x IULN OR measured or calculated creatinine clearance >= 40 mL/min (obtained within 28 days prior to Registration Step 1)
• REGISTRATION STEP 1: Participants must have percent predicted diffusing capacity of the lungs for carbon monoxide (DLCO) of at least 50% documented within 90 days prior to Registration Step 1
• REGISTRATION STEP 1: Patient must not have had a prior history of interstitial lung disease or > grade 2 (Common Terminology Criteria for Adverse Events [CTCAE] version 5) pneumonitis
• REGISTRATION STEP 1: Participants must not have active autoimmune disease requiring therapy within the past 6 months
• REGISTRATION STEP 1: Participants must not have an active infection requiring therapy
• REGISTRATION STEP 1: Participants must not be pregnant or nursing because atezolizumab has not been studied in pregnant or nursing women and the mechanism of action is expected to cause fetal harm. Women/men of reproductive potential must have agreed to use an effective contraceptive method while on protocol treatment and for five months after last dose of atezolizumab. A woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation. However, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures
• REGISTRATION STEP 1: Participants with known human immunodeficiency virus (HIV) infection must be on effective anti-retroviral therapy and must have undetectable viral load at their most recent viral load test and within 6 months prior to Registration Step 1
• REGISTRATION STEP 1: Patient must be tested for hepatitis B within 28 days prior to randomization. Patient must not have active (chronic or acute) hepatitis B virus (HBV) infection. Patients may have past or resolved HBV infection. Active HBV is defined as having a positive hepatitis B surface antigen (HBsAg) test. Past or resolved HBV is defined as having a negative HBsAG test and a positive total hepatitis B core antibody (HBcAb) test
• REGISTRATION STEP 1: Patient must be tested for hepatitis C within 28 days prior to randomization. Patient must not have active hepatitis C virus (HCV) infection. Active HCV is defined as having a positive HCV antibody test followed by a positive HCV ribonucleic acid (RNA) test
• REGISTRATION STEP 1: No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years. Participants with localized prostate cancer who are being followed by an active surveillance program are also eligible
• REGISTRATION STEP 1: Participants must be offered optional participation in banking of specimens for future research
• REGISTRATION STEP 1: Participants must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines
• REGISTRATION STEP 1: As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system
• REGISTRATION STEP 2: Participants must be registered to Step 2 within 42 days after completion of radiation treatment. Participants must have received at least 44 Gy of radiation treatment
• REGISTRATION STEP 2: Participants must have no evidence of progression per RECIST 1.1 on CT scan of the chest, abdomen, and pelvis performed between 2 and 5 weeks after completion of radiation therapy
• REGISTRATION STEP 2: Any toxicities from radiation therapy must have resolved to < grade 2
• REGISTRATION STEP 2: Absolute neutrophil count (ANC) >= 1500/mcl (obtained within 28 days prior to Registration Step 2)
• REGISTRATION STEP 2: Platelet count >= 100,000/mcl (obtained within 28 days prior to Registration Step 2)
• REGISTRATION STEP 2: Hemoglobin >= 9 grams/dL (obtained within 28 days prior to Registration Step 2)
• REGISTRATION STEP 2: Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (obtained within 28 days prior to Registration Step 2)
• REGISTRATION STEP 2: AST and ALT =< 2.5 x IULN (obtained within 28 days prior to Registration Step 2)
• REGISTRATION STEP 2: Serum creatinine =< 1.5 x IULN OR measured or calculated creatinine clearance >= 40 mL/min (obtained within 28 days prior to Registration Step 2)
• REGISTRATION STEP 2: Participants must not have received steroids in doses of more than prednisone 10 mg daily or equivalent within 14 days prior to Registration Step 2
• REGISTRATION STEP 2: Participants must not have received a live vaccine within 28 days prior to Registration Step 2

Inclusion Criteria:

• Participant must have histologically or cytologically confirmed, locally advanced or metastatic, non-small cell lung cancer (NSCLC) that is not amenable to curative therapy including surgical resection or chemoradiation. Additional Cohort specific disease requirements include: Cohorts 1, 3, 5 and 6: epidermal growth factor receptor (EGFR) exon 19 deletion (Exon19del) or Exon 21 L858R mutation; Cohort 2: EGFR Exon 20ins mutation EGFR Exon19del or Exon 21 L858R mutation (Cohort 1, 3, 5 and 6) or EGFR Exon 20 insertion mutation (Cohort 2) must have been identified as determined by Food and Drug Administration (FDA) approved or other validated test of either circulating tumor deoxyribonucleic acid (ctDNA) or tumor tissue in a clinical laboratory improvement amendments (CLIA) certified laboratory (sites in the United states [US]) or an accredited local laboratory (sites outside of the US). A copy of the initial test report documenting the EGFR mutation must be included in the participant records and a deidentified copy must also be submitted to the sponsor
• Have at least 1 measurable lesion, according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. If the only target lesion has been previously irradiated, it must show signs of disease progression since radiation was completed
• May have a prior or concurrent second malignancy (other than the disease under study) which natural history or treatment is unlikely to interfere with any study endpoints of safety or the efficacy of the study treatment(s)
• Have adequate organ (renal, hepatic, hematological, coagulation and cardiac) functions
• Participant must have eastern cooperative oncology group (ECOG) status of 0 or 1
• Cohort 6: Must be eligible for, and agree to comply with, the use of prophylactic anticoagulation with a direct oral anticoagulant or a low molecular weight heparin during the first 4 months of study treatment
• A female participant must agree not to donate eggs (ova, oocytes) or freeze for future use for the purposes of assisted reproduction during the study and for a period of 6 months after receiving the last dose of study treatment. Female participants should consider preservation of eggs prior to study treatment as anti-cancer treatments may impair fertility

Exclusion Criteria:

• Participant has a medical history of interstitial lung disease (ILD), including drug induced ILD or radiation pneumonitis
• Participant has a history of hypersensitivity to any excipients of the investigational products to be used in their enrollment cohort
• Participant has received a live or live attenuated vaccine within 3 months before Cycle 1 Day 1. The seasonal influenza vaccine and non-live vaccines against Coronavirus disease 19 (COVID-19) are not exclusionary
• For all cohorts (regimens potentially including lazertinib) except cohort 2: Participant is currently receiving medications or herbal supplements known to be potent Cytochrome (CYP3A4/5) inducers and is unable to stop use for an appropriate washout period prior to Cycle 1 Day 1
• Other clinically active liver disease of infectious origin
• Participant has a history of clinically significant cardiovascular disease including, but not limited to: a) All cohorts: diagnosis of deep vein thrombosis or pulmonary embolism within 1 month prior to the first dose of study treatment(s), or any of the following within 6 months prior to the first dose of study treatment(s): myocardial infarction, unstable angina, stroke, transient ischemic attack, coronary/peripheral artery bypass graft, or any acute coronary syndrome. Clinically non-significant thrombosis, such as non-obstructive catheter-associated clots, are not exclusionary; b) All cohorts (regimens potentially including lazertinib) except Cohort 2: Participant has a significant genetic predisposition to venous thromboembolic events (VTE; such as Factor V Leiden); c) All cohorts (regimens potentially including lazertinib) except Cohort 2: Participant has a prior history of VTE and is not on appropriate therapeutic anticoagulation as per NCCN or local guidelines; d) prolonged corrected QT interval by Fridericia (QTcF) interval greater than (>) 480 milliseconds (msec) or clinically significant cardiac arrhythmia or electrophysiologic disease (example, placement of implantable cardioverter defibrillator or atrial fibrillation with uncontrolled rate); e) uncontrolled (persistent) hypertension: systolic blood pressure >160 millimeter(s) of mercury (mmHg); diastolic blood pressure >100 mmHg; f) Congestive heart failure defined as NYHA class III-IV or hospitalization for congestive heart failure (CHF) (any New York Heart Association [NYHA] class) within 6 months of treatment initiation at Cycle 1/day 1 (C1D1); g) pericarditis/clinically significant pericardial effusion; h) myocarditis; i) baseline left ventricular ejection fraction (LVEF) below the institution's lower limit of normal at screening, as assessed by echocardiogram or multigated acquisition (MUGA) scan
• Participant has symptomatic brain metastases. A participant with asymptomatic or previously treated and stable brain metastases may participate in this study. Participants who have received definitive radiation or surgical treatment for symptomatic or unstable brain metastases and have been clinically stable and asymptomatic for at least 2 weeks before Screening are eligible, provided they have been either off corticosteroid treatment or are receiving low-dose corticosteroid treatment (less than or equal to [<=] 10 milligrams per day [mg/day] prednisone or equivalent) for at least 2 weeks prior to treatment allocation

• Study Population
  Patients planning to receive ICI-based therapy for a solid tumor malignancy.
  Criteria

  Inclusion Criteria:

  • Participants must be planning to receive ICI-based therapy for a solid tumor malignancy. This therapy must be given according to Food and Drug Administration (FDA) label or National Comprehensive Cancer Network (NCCN) guidelines at Category 1 or 2A and not in the context of a clinical trial
  • Participants who have received prior ICI-based therapy must have completed ICI based therapy at least 180 days prior to registration
  • Participants must not have discontinued any prior ICI-based therapy (if applicable) because of irAE
  • Participants must not have received chemotherapy, biologic, or targeted-therapy within 21 days prior to registration

  • Participants must have recovered from side effects of prior therapy to the following standards per treating physician's discretion:

    • =< Grade 1 for any non-hematologic side effects (excluding neuropathy and alopecia); lab-related parameters of liver and renal function will be considered at the discretion of the treating physician)
    • =< Grade 2 for neuropathy and/or alopecia
    • Grade 3 or less for any hematologic side effects
  • Participants must be planning to begin standard of care ICI-based therapy within 3 calendar days after registration
  • Participants must not be planning to receive ICI-based therapy in combination with chemotherapy or any other non-ICI therapy for treatment of their cancer
  • Participants must be at least 18 years of age
  • Participants must complete their history and physical examination within 28 days prior to registration
  • Participants who can complete the S2013 Feasibility Questionnaire in English or Spanish must participate at the scheduled assessments
  • Participants must be able to complete Patient-Reported Outcome (PRO) instruments in English, Spanish, or French and must be planning to complete PROs at all scheduled assessments
  • Participants must complete the pre-registration (baseline) PRO forms within 14 days prior to registration

  • Participants must be willing to participate in PRO data collection

    • Note: Prior to registration, participants must decide on their method (paper or electronic) of completing their follow-up questionnaires. Participants who elect electronic (ePRO) completion must have an iPhone, Android phone, or tablet with cellular or WiFi connectivity in order to download the Patient Cloud mobile applications onto the device (personal device or a site provisioned device for multi-users)
  • Participants must be offered the opportunity to participate in the optional specimen banking

  • Note: As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system.

    • Participants must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines