*DTL Required- Physicians must sign toxicity grid

CREDENTIALING REQUIRED. Please check your site's credentialing status.
CURRENT SITES CREDENTIALED: SJMH TH (Brighton, Canton, Chelsea, Ann Arbor), Livonia, Genesys, Hurley, Sparrow

Eligibility Criteria:

5.1 Disease Related Criteria

a. Participants must have been assigned to S1900K by the SWOG Statistics and Data Management Center (SDMC). Assignment to S1900K is determined by the LUNGMAP protocol.

b. Participants must have documentation of NSCLC with a MET exon 14 skipping mutation determined by tissue-based or blood-based (circulating tumor DNA [ctDNA]) NGS assay done within a laboratory with CLIA, ISO/IEC, CAP, or similar certification. Documentation must either be 1) NGS test results from tissue submitted for LUNGMAP screening, or 2) submitted documentation in the LUNGMAP Rave Electronic Data Capture System of a MET exon 14 skipping mutation from a previously completed tissue or blood-based NGS test (see Section 5.1c and 18.8 of LUNGMAP).

NOTE: Participants previously tested for and determined to have a MET exon 14 skipping mutation, outside of LUNGMAP, must also submit tissue for central FMI testing on the LUNGMAP screening protocol, if available. See LUNGMAP Section 18.8. 

c. Participants must have measurable disease (Section 10.1) documented by CT or MRI. The CT from a combined PET/CT may be used to document measurable disease ONLY if it is of diagnostic quality as defined in Section 10.1c: otherwise, it may be used to document non-measurable disease only. Measurable disease must be assessed within 28 days prior to sub-study randomization. Pleural effusions, ascites and laboratory parameters are not acceptable as the only evidence of disease. Non-measurable disease must be assessed within 42 days prior to sub-study randomization. All known sites of disease must be assessed and documented on the Baseline Tumor Assessment Form. Participants whose only measurable disease is within a previous radiation therapy port must demonstrate clearly progressive disease (in the opinion of the treating investigator) prior to substudy randomization to be considered measurable.

d. Participants must have a CT or MRI scan of the brain to evaluate for CNS disease within 42 days prior to sub-study randomization.

e. Participants must not have leptomeningeal disease, spinal cord compression or brain metastases unless: (1) metastases have been locally treated and have remained clinically controlled and asymptomatic for at least 3 days following the stereotactic radiation and/or 14 days following whole brain radiation, and prior to sub-study randomization, AND (2) participant has no residual neurological dysfunction and has been off corticosteroids for at least 24 hours prior to sub-study randomization

f. Participants must not have other known actionable oncogenic alterations, such as (but not limited to) EGFR sensitizing mutations, EGFR T790M mutation, ALK gene fusion, ROS1 gene rearrangement, RET gene rearrangement, NTRK rearrangement, HER2 mutation, KRAS activating mutations, and BRAF V600E mutation.

5.2 Prior/Concurrent Therapy Criteria

a. Participants must have progressed (in the opinion of the treating physician) following the most recent line of therapy.

b. Participants must have received at least one line of systemic treatment for Stage IV or recurrent NSCLC.

c. Participants must have recovered (≤ Grade 1) from any side effects of prior therapy except alopecia and vitiligo.

d. Participants must not have received any prior systemic therapy (systemic chemotherapy, immunotherapy or investigational drug) within 21 days prior to sub-study randomization.

**PLEASE SEE THE CURRENT VERSION OF PROTOCOL FOR FULL ELIGIBILITY LIST** 

*Credentialing required. Please check your site's credentialing status.

CURRENT SITES CREDENTIALED: SJMH (AA, Brighton, Canton, Chelsea), Genesys, Livonia

Eligibility Criteria:

Disease Related Criteria- Patient

a. Patients must have a diagnosis of a metastatic solid tumor or a hematologic malignancy and must receive anti-cancer treatment per the timing described in Section 5.2a (i.e. chemotherapy, hormonal therapy, targeted therapy, biologic therapy, immune therapy, bone marrow transplant). Registration must occur within 120 days after diagnosis. Patients with indolent hematologic diseases undergoing observation alone are not eligible.

b. Patients with recurrent solid tumors will be allowed as long as 1) this is the first presentation of metastatic disease and 2) the diagnosis of the metastasis is at least 180 days (6 months) after the diagnosis date of the previous earlier stage cancer.

c. Patients with a history of secondary malignancy are allowed as long as they were not diagnosed within the previous 24 months, are not on active therapy, and are disease-free. Patients with adequately treated basal cell or squamous cell skin cancer, and in situ cervical cancer at any point prior to enrollment are eligible.

 Prior/Concurrent Therapy Criteria – Patient

a. Patients who have started anti-cancer treatment for the current diagnosis must have started within 60 days prior to registration.

b. Patients who are planning to start anti-cancer treatment for the current diagnosis must start within (≤) 30 days after registration.

c. Patients are allowed to be co-enrolled on other clinical trials (including nontreatment studies and studies that may or may not include investigational drugs).

d. Patients may not be enrolled in hospice care at the time of registration.

Clinical/Laboratory Criteria - Patient

a. Patients must be at least 18 years of age.

b. Patients must have a Zubrod performance status of 0-2.

c. Patients must complete the baseline PRO questionnaires prior to registration and must be able to complete questionnaires in English or Spanish.

d. Patients must provide their full name, primary address in the U.S., birth date and social security number at registration for the purposes of accessing credit report data. (This may be obtained directly from the patient, study questionnaires, or the medical record.)

e. Patients must provide email and telephone number for the purposes of being contacted by financial navigators.

Spouse Caregiver Criteria

a. Spouse caregiver must be willing to participate in the trial.

b. Spouse caregiver must be legally married, or file their tax returns as married filing jointly.*

c. Spouse caregiver must be living in the same household with the eligible patient enrolling in this trial. d. Spouse caregivers must be at least 18 years of age.

e. Spouse caregivers must provide their full name, primary address in the U.S., birth date and social security number at registration for the purposes of accessing credit report data.

f. Spouse caregivers must provide email and telephone number for the purposes of being contacted by the financial navigators.

g. Spouse caregivers must be able to complete questionnaires in English or Spanish and must complete the baseline questionnaires prior to patient registration.

*The study team acknowledges that other types of caregivers may also face financial hardship following a patient’s cancer diagnosis and may similarly benefit from financial education and navigation. The decision to focus solely on spouse caregivers was scientific, to facilitate analysis of primary endpoint (household financial hardship).

**DTL is required for this study- Physicians must sign the toxicity grids

CREDENTIALING REQUIRED. Please check your site's credentialing status. 

Current sites credentialed: SJMH (Ann Arbor, Brighton, Canton, Chelsea), St. Mary's Livonia, St. John Hospital, St. John Macomb, Genesys, SJMO (21st Century Oncology Only), Saginaw, Sparrow, Lehigh Valley

Eligibility Criteria:

5.1 Disease Related Criteria

a. Patient must have histologically or cytologically proven Stage I-IIA or limited T3N0M0 non-small cell lung cancer (NSCLC) as defined in Section 4.0, without radiographic evidence of nodal or distant involvement (N0M0). Patient may have T3 disease with the exclusion of multifocal tumors and pericardial involvement.

b. Disease must have one or more of the following high-risk features:

• Tumor diameter = 2 cm as assessed by diagnostic CT

• Tumor SUV max = 6.2 as assessed by FDG PET/CT

• Moderately differentiated, poorly differentiated, or undifferentiated histology

c. Patient must have undergone diagnostic chest CT with contrast (unless medically contraindicated) within 42 days prior to randomization. PET-CT may be used if the CT portion is of identical diagnostic quality to a stand-alone CT. All disease must be assessed within 42 days prior to randomization.

d. Patient must have undergone FDG PET/CT of chest within 90 days prior to randomization.

e. Patient must not have evidence of hilar or mediastinal nodal involvement. Any patient with radiographically suspicious hilar or mediastinal nodes (including features such as non-calcified nodes with a short axis diameter > 1 cm, abnormal morphology, and/or elevated FDG avidity) must undergo cytologic sampling of suspicious nodes to rule out involvement prior to randomization. Mediastinal nodal sampling for other patients is optional.

f. Patient must have undergone history and physical examination within 28 days prior to randomization.

g. Patient must be medically or surgically inoperable as documented by a board certified thoracic surgeon or multi-disciplinary tumor board consensus OR patient’s unwillingness to undergo surgical resection must be clearly documented.

5.2 Prior/Concurrent Therapy Criteria

a. Patient must not have received any prior treatment for NSCLC.

b. Patient must not have undergone prior radiation to overlapping regions of the chest (such that protocol lung constraints cannot be met with a cumulative plan).

c. Patient must not have received treatment with systemic immunostimulatory or immunosuppressive agents, including corticosteroids, within 14 days prior to randomization.

5.3 Clinical/Laboratory Criteria

a. Patient must be = 18 years old.

b. Patient must have Zubrod Performance Status of 0-2 (see Section 10.3).

c. Patient must have adequate liver function defined as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) = 3 x IULN within 28 days prior to randomization.

d. Patient must have adequate renal function defined as calculated creatinine clearance = 30 mL/min using the following formula. The serum creatinine value used in the calculation must have been collected within 28 days prior to randomization.

e. Patient must have ANC, platelets, and hemoglobin measured within 28 days prior to randomization. The purpose of these tests is to collect baseline values to compare with on-treatment values.

f. Patient must have TSH measured within 28 days prior to randomization. The purpose of this test is to collect baseline values to compare with on-treatment values.

g. Patient must not have significant cardiovascular disease (NYHA Class II or greater; see Appendix 18.2).

h. Patient must not have myocardial infarction within 90 days prior to randomization.

i. Patient must not have unstable arrhythmias or unstable angina.

j. Patient must not have known left ventricular ejection fraction <40% within 28 days prior to randomization.

k. Patient must not have had an infection = Grade 3 (CTCAE Version 5.0) within 28 days prior to randomization.

l. Patient must not have an active autoimmune disease that has required systemic treatment in past two 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) is not considered a form of systemic treatment and is allowed.

m. 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.

n. 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 RNA test.

o. Patient must have an FEV1 = 700 cc and a DLCO = 5.5 m/min/mmHg from pulmonary function testing documented within 90 days prior to randomization.

p. Patient must not have known human immunodeficiency virus (HIV) unless he/she is on effective anti-retroviral therapy, has had at least one viral load test within 6 months prior to randomization, and had undetectable viral load at all viral load tests within 6 months prior to randomization.

q. Patient must not have a history of clinically significant interstitial lung disease or evidence of active pneumonitis on the screening chest CT.

r. No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, localized prostate 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 five years.

s. Patients must not be pregnant due to the potential teratogenic side effects of the protocol treatment. Women of reproductive potential and men must have agreed to use an effective contraception method for the duration of protocol treatment, and for 5 months (150 days) after the last dose of atezolizumab. A woman is considered to be of "reproductive potential" if she has had a 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.

Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with atezolizumab, breastfeeding must be discontinued prior to randomization.

5.4 Specimen Submission Criteria

a. Patient must agree to have specimens submitted for translational medicine and banking as outlined in Section 15.2.

*DTL Required- Physicians must sign toxicity grid

CREDENTIALING REQUIRED. Please check your site's credentialing status.
CURRENT SITES CREDENTIALED: SJMH (AA, Brighton, Canton, Chelsea), St. Mary's Livonia 

**All research staff who intend to administer the FIL tool must complete the protocol training.(see section 15.5)**

Eligibility Criteria:

 Disease Related Criteria

a. Participants must have histologically or cytologically confirmed DLBCL, Ann Arbor Stage IIX (bulky), III or IV. Participants with DLBCL transformed from FL or marginal zone lymphoma (MZL, including MALT lymphomas), lymphoplasmacytic lymphoma (LPL), or nodular lymphocyte-predominant Hodgkin Lymphoma (NLPHL) are eligible. Participants with Grade IIIB follicular lymphoma (FL) and high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements are also eligible. See Section 4.0 for staging. Participants with DLBCL that arose from prior CLL (Richter's transformation) are not eligible.

b. As defined by the WHO, eligible lymphoma subtypes include the following: • DLBCL, not otherwise specified (NOS) • DLBCL, germinal-center B-cell type (GCB) • DLBCL, activated B-cell type (ABC) • T-cell histiocyte-rich B-cell lymphomas (THRBCL) • Primary cutaneous DLBCL, leg type • Intravascular large B cell lymphoma • EBV+ DLBCL, NOS • DLBCL associated with chronic inflammation • HHV8+ DLBCL, NOS • High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements • High grade B-cell lymphoma, NOS • Follicular lymphoma grade 3b

c. Staging imaging must have occurred within 28 days prior to registration. PET-CT baseline scans are strongly preferred; Diagnostic quality MRI, contrast-enhanced CT, or contrast-enhanced MRI scans are also acceptable if PET-CT is not feasible at baseline. Note: PET-CT will be required at end of treatment (EOT) and progression for response assessment (See Sections 7.5c, and 7.5d). All measurable lesions must be assessed within 28 days prior to registration. Tests to assess non-measurable disease must be performed within 42 days prior to registration.

d. Participants 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 (must be within 26 weeks prior to registration). Participants with known HIV must have a CD4 count checked within 28 days before starting therapy, but may proceed with therapy regardless of CD4 count.

e. All participants must be screened for chronic hepatitis B virus (HBV) within 28 days prior to registration. Participants with known HBV infection (positive serology) must also have a HBV viral load performed within 28 days prior to registration, and participants must have an undetectable HBV viral load on suppressive therapy within 28 days prior to registration. Participants found to be HBV carriers during screening are eligible and must receive standard of care prophylaxis. Participants with active Hepatitis B (HBV viral load > 500 IU/mL) within 28 days prior to registration are not eligible.

f. Participants with a known history of hepatitis C virus (HCV) infection must have an undetectable HCV viral load within in 28 days prior to registration.

g. Participants must not have known lymphomatous involvement of the CNS 

h. Participants must not have active inflammatory bowel disease (such as, Crohn’s disease, ulcerative colitis), celiac disease (i.e., sprue), prior gastrectomy or upper bowel removal, or any other gastrointestinal disorder or defect that would interfere with the absorption, distribution, metabolism, or excretion of the study drug and/or predispose the subject to an increased risk of gastrointestinal toxicity.

Prior/Concurrent Therapy Criteria

a. Participants must not have received any prior cytotoxic chemotherapy or rituximab for treatment of the newly diagnosed DLBCL. Participants who received a short course of glucocorticoids (≤ 7 days) per the pre-phase are eligible. (See Section 7.1). Inhaled, nasal, and topical steroid use is allowed. Prior cytotoxic chemotherapy and/or antibody therapy for an indolent lymphoma prior to transformation is allowed. \

b. Participants must not have received more than a cumulative of 250 mg/m2 of prior anthracycline therapy (at any time prior to registration).

c. Participants must not currently be receiving any other investigational agents. d. Participant must not have a history of allergic reactions attributed to azacitidine, mannitol, or other hypomethylating agents.  Clinical/Laboratory Criteria

a. Participants must be age ≥ 75.

b. Participants must have a Zubrod performance status of 0-2. See Section 10.3.

c. Participants must have adequate renal function, as demonstrated by a creatinine clearance, calculated by the Cockcroft and Gault formula, of ≥ 30 ml/min that was obtained within 28 days prior to registration. Calculated Creatinine Clearance = (140 - age) X (weight in kg) † 72 x serum creatinine * Multiply this number by 0.85 if the participant is a female. † The kilogram weight is the participant weight with an upper limit of 140% of the IBW. * Actual lab serum creatinine value with a minimum of 0.8 mg/dL.

d. Participants must have adequate liver function within 28 days prior to registration, as evidenced by: AST≤ 2.5 x IULN, ALT ≤ 2.5 x IULN and Total Bilirubin ≤ 2 x IULN, unless due to Gilbert’s disease, hemolysis, or lymphomatous involvement of liver.

Note: If Total bilirubin is elevated, and Direct bilirubin is subsequently performed (within 28 days prior to registration) and resulted to be ≤ 2 x IULN, the participant will be considered eligible. 

e. Participants must have adequate bone marrow function within 28 days prior to registration, as evidenced by:

• ANC ≥ 1000/mcL and

• Platelets ≥ 75,000/ mcL. If there is a documented lymphomatous involvement of the bone marrow, bone marrow function within 28 days prior to registration, as evidenced by:

• ANC ≥ 500/mcL and

• Platelets ≥ 50,000/ mcL.

f. Participants must have a left ventricular ejection (LVEF) fraction ≥ 45% as measured by echocardiogram or radionuclide (MUGA) ventriculography within 56 days prior to registration. 

g. For the duration of the study treatment period and for at least 4 months following the last dose of study drug, male participants must agree to use effective contraceptive methods during sexual contact with a female of childbearing potential (FCBP) and must agree to refrain from semen or sperm donation during the same timeframe. Effective contraceptive methods include a history of vasectomy, use of hormonal contraception or an intrauterine device (IUD) by the female partner, or use of condoms. • A FCBP is a sexually mature woman who:

1) has not undergone a hysterectomy or bilateral oophorectomy;

or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).

h. Participants must not have active infection (systemic fungal, bacterial, or viral infection) that is not controlled (defined as ongoing signs/symptoms related the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment).

i. Participants must not have active cardiac disease within 26 weeks prior to registration, including: symptomatic congestive heart failure (NYHA Class 4), unstable angina pectoris, hemodynamically unstable cardiac arrhythmia, or myocardial infarction. See Section 18.5: New York Heart Association Criteria

j. Participants must not have ≥ Grade 2 neuropathy, by CTCAE v. 5.0, within 28 days prior to registration.

k. Participants must not have any other known uncontrolled intercurrent illness including, but not limited to ongoing psychiatric illness/social situations that would limit compliance with study requirements.  

Eligibility Criteria:

Disease Related Criteria:

a. Patients must have histologically or cytologically confirmed small bowel adenocarcinoma. Ampullary adenocarcinomas are not eligible. Patients must have metastatic disease or locally advanced unresectable disease.

b. Brain metastases are allowed if they have been adequately treated with radiotherapy or surgery and stable for at least 30 days prior to registration. Patients must be neurologically asymptomatic and without corticosteroid treatment for at least 7 days prior to registration.

c. Patients must have measurable or non-measurable disease. All scans needed for assessment of measurable disease must be performed within 28 days prior to registration. Non-measurable disease must be assessed within 42 days prior to registration. All disease must be assessed and documented on the Baseline Tumor Assessment Form.

Prior/Concurrent Therapy Criteria:

a. Patients must have progressed on prior therapy with a fluoropyrimidine and/or oxaliplatin, given either for metastatic / locally advanced disease or as adjuvant therapy completed within the previous 12 months.

b. Patients must not have received prior treatment with irinotecan, taxane, or ramucirumab for small bowel adenocarcinoma.

c. Patients must have completed prior chemotherapy, immunotherapy, or radiation therapy at least 14 days prior to registration and all toxicity must be resolved to Grade 1 (with the exception of Grade 2 neuropathy) prior to registration. In CTCAE version 5.0 Grade 2 sensory neuropathy is defined as "moderate symptoms; limiting instrumental activities of daily living (ADLs)"

d. Patients must not have had major surgery within 28 days prior to registration, or minor surgery within 7 days prior to registration, and must not be planned for elective major surgery to be performed during protocol treatment.

e. Patients must not be currently enrolled in or have discontinued within the last 28 days a clinical trial involving an investigational product or non-approved use of a drug, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study. Patients participating in surveys or observational studies are eligible to participate in this study.

f. Patients must not be receiving chronic antiplatelet therapy, including dipyridamole or clopidogrel, or similar agents.

Clinical/Laboratory Criteria

a. Patients must have a complete medical history and physical exam within 28 days prior to registration.

b. Patients must be = 18 years of age.

c. Patients must have a Zubrod Performance Status of 0 or 1

d. Patients must have adequate bone marrow function as evidenced by all of the following: ANC = 1,500/mcL and platelets = 100,000/mcL. These results must be obtained within 28 days prior to registration.

e. Patient must have adequate hepatic function as evidenced by a total bilirubin =1.5 x institutional limit normal (IULN), and SGOT (AST) and SGPT (ALT) = 3.0 x IULN (or 5.0 x IULN if liver metastases are present). These results must be obtained within 28 days prior to registration.

f. Patient must not have a known bleeding diathesis

g. Patients must have adequate renal function as evidenced by ONE of the following: serum creatinine = 1.5 x IULN OR calculated creatinine clearance = 40 mL/min. This serum creatinine result must have been obtained within 28 days prior to registration.

* The kilogram weight is the patient’s actual body weight with an upper limit of 140% of the IBW.

** Actual lab serum creatinine value with a minimum of 0.8 mg/dL

h. Patient must have urinary protein = 1+ on dipstick or routine urinalysis (UA) within 28 days prior to registration. If dipstick or routine analysis is = 2+, a 24 - hour urine collections for protein must demonstrate <1000 mg of protein in 24 hours.

i. Patient must not have uncontrolled or poorly-controlled hypertension (> 160 mmHg systolic or > 100 mm HG diastolic for > 4 weeks) despite standard medical management.

j. 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.

k. Patient tumors must not have known deficient mismatch repair (dMMR) or microsatellite instability high (MSI-H).

l. Patients must not be pregnant or nursing and must have had a negative pregnancy test within 4 weeks of starting treatment. Women/men of reproductive potential must have agreed to use an effective contraceptive method. 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.

m. Patients must not have an active infection requiring systemic therapy.

n. Patient must not have liver dysfunctions manifested by either (1) Child-Pugh B (or worse) (see Appendix 18.2) or (2) cirrhosis (any degree) and a history of hepatic encephalopathy or clinically meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is defined as ascites from cirrhosis requiring diuretics or paracentesis.

o. Patients must not have known dihydropyrimidine dehydrogenase deficiency.

p. Patients must not have a history of deep vein thrombosis (DVT), pulmonary embolism (PE), or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered "significant") during the 90 days prior to registration.

q. Patients must not have experienced any arterial thrombotic event (including but not limited to myocardial infarction, unstable angina, stable angina markedly limiting ordinary physical activity, cerebrovascular accident, or transient ischemic attack) within 120 days prior to registration.

r. Patients must not have a prior history of GI perforation/fistula or other risk factors for perforation within 120 days prior to registration.

s. Patients must not have experienced any Grade 3-4 GI bleeding within 90 days prior to registration.

t. Patient must not have experienced any serious or non-healing wound, ulcer, or bone fracture within 28 days prior to registration.

Specimen Submission Criteria

a. Patients must be offered the opportunity to participate in specimen banking as outlined in Section 15.1.

**Effective 08/15/22, Step 1 (Screening) is closed to accrual ** 

Effective 12/15/22, Step 2 randomization is closed to patient accrual.

Eligibility Criteria:

STEP 1: SCREENING REGISTRATION

Disease Related Criteria

1. Participants must have histologically or pathologically confirmed diagnosis of extensive stage small cell lung cancer (ES-SCLC) at the time of protocol entry as defined in Section 4.0. Participants with mixed histology are excluded.

Prior/Concurrent Therapy Criteria

1. Participants must have completed at least one cycle of frontline induction treatment with platinum plus etoposide plus atezolizumab prior to Step 1 Screening Registration. Cycle 1 of frontline induction treatment may or may not contain atezolizumab.

NOTE: Participants may be screened while receiving consolidation thoracic radiation or during prophylactic cranial irradiation (PCI) at the time of Step 1 Screening Registration. Participants may or may not receive consolidation thoracic radiation and/or PCI per the discretion of their treating investigator.

2. Participants must not have received any immunotherapy for SCLC prior to starting the frontline induction treatment for ES-SCLC.

3. Participants must not have received any investigational agent for the treatment of ES-SCLC.

 Clinical/Laboratory Criteria

1. Participants must be ≥ 18 years of age at the time of Step 1 Screening Registration.

d. Specimen Submission Criteria

1. Participants must have adequate tumor tissue available from a core biopsy defined as: • at least two (3-5 microns) unstained slides, or; • one (3-5 microns) unstained slide plus one H&E stained slide

- Participants must agree to have this tissue submitted to M.D. Anderson Cancer Center (MDACC) for SLFN11 immunohistochemistry (IHC) testing (See Section 15.2). Note: A histologic review will be performed at MDACC to confirm adequate cellularity for the testing. If inadequate cellularity, additional unstained slides from the same participant may be submitted if it doesn’t exceed the window of starting maintenance therapy.

STEP 2: RANDOMIZATION

- After a participant has been registered to Step 1 the tissue must be submitted to M.D. Anderson Cancer Center per Section 15.2. Sites will receive a notification from the SWOG Statistical and Data Management Center within 2 weeks after tissue submission.

Disease Related Criteria

1. Site must have received notification from the SWOG Statistics and Data Management Center (SDMC) that the participant’s tumor sample is SLFN11 positive.  

2. Participants must have their disease assessed either by CT of chest/abdomen/pelvis (with contrast, unless contraindicated) (see Section 10.1) within 28 days prior to Step 2 Registration or by PET/CT of chest/abdomen/pelvis (with contrast, unless contraindicated) within 42 days prior to Step 2 Registration. Participants may have a complete response to induction therapy. All known sites of disease must be assessed and documented on the Baseline Tumor Assessment Form (RECIST 1.1).

3. Patients must have a CT or MRI scan of the brain to evaluate for CNS disease within 42 days prior to Step 2 randomization. Patient must not have leptomeningeal disease, spinal cord compression or brain metastases unless: (1) metastases have been locally treated and have remained clinically controlled and asymptomatic for at least 14 days following treatment, and prior to Step 2 randomization, AND (2) patient has no residual neurological dysfunction and has been off corticosteroids for at least 24 hours prior to Step 2 randomization.

4. Participants must not have had disease progression based on post induction imaging in the opinion of treating investigator.

Prior/Concurrent Therapy Criteria

1. Participants must be registered to Step 2 Randomization prior to the start of maintenance atezolizumab.

2. Participants must have received no fewer than 2 cycles and no more than 4 cycles of induction treatment with platinum/etoposide/atezolizumab.

3. Participant must not have received radiation treatment (RT) or prophylactic cranial irradiation (PCI) within 14 days prior to Step 2 Randomization.

4. Participants must not be taking strong P-gp inhibitors (e.g., dronedarone, quinidine, ranolazine), P-gp inducers (e.g., rifampin), or breast cancer resistance protein (BCRP) inhibitors (e.g., elacridar) within 7 days prior to randomization. Participants must not plan to receive the therapies listed above while on protocol treatment (See Section 3.2c3 for the full list of agent names). 

5. Participants must not have experienced the following during induction treatment:

• Any Grade 3 or worse immune-related adverse event (irAE) in the opinion of the treating investigator. Exception: asymptomatic nonbullous/nonexfoliative rash.

• Any unresolved Grade 2 irAE.

• Any toxicity that led to permanent discontinuation of prior anti-PD1/PD-L1 immunotherapy. Exception to the above: Toxicities of any grade that require replacement therapy and have stabilized on therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) are allowed.

Clinical/Laboratory Criteria

1. History and physical exam must be obtained within 28 days prior to Step 2 randomization. 

2. Participants must have adequate cardiac function. Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, must have a clinical risk assessment of cardiac function and be considered class 2B or better on the New York Heart Association Functional Classification (see Section 18.2).

3. Participants must have Zubrod performance status 0-2 (see Section 10.5) documented within 28 days prior to Step 2 Randomization.

4. Participants must have normal organ and marrow function within 28 days prior to Step 2 Randomization as defined below: • Leukocytes≥ 3,000/mcL • Absolute neutrophil count ≥ 1,500/mcL • Platelets ≥ 100,000/mcL • Total bilirubin ≤ institutional upper limit of normal (ULN) • AST/ALT ≤3 × institutional ULN • Creatinine ≤ institutional ULN OR estimated creatinine clearance > 30 mL/min Calculated Creatinine Clearance = (140 - age) X (weight in kg) † 72 x serum creatinine * Multiply this number by 0.85 if the participant is a female. † The kilogram weight is the participant weight with an upper limit of 140% of the IBW. * Actual lab serum creatinine value with a minimum of 0.8 mg/dL.

5. Participants with evidence of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load on suppressive therapy within in 6 months prior to Step 2 Randomization.

6. Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. For participants with HCV infection who are currently on treatment must have an undetectable HCV viral load within in 6 months prior to Step 2 Randomization.

7. 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 Step 2 Randomization.

8. Participants with known diabetes must not have uncontrolled diabetes. (Uncontrolled diabetes is defined as HgA1C > 7%).

 9. Participants must be able to swallow capsule whole.

10. Participants must not have any known clinically significant liver disease, including cirrhosis, fatty liver, or inherited liver disease.

11. Participants must not have end stage renal or other serious medical illness that may limit survival or the ability to participate in this study.

12. Participants must not have a history of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest computed tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

13. Participants must not have known active tuberculosis (TB).

14. Participants must not have undergone prior allogeneic bone marrow transplantation or prior solid organ transplantation.

15. Participants must not have history of allergic reaction attributed to compounds of similar chemical or biological composition to atezolizumab and/or talazoparib.

16. Participants must not have a prior or concurrent malignancy whose natural history or treatment (in the opinion of the treating physician) has the potential to interfere with the safety or efficacy assessment of the investigational regimen.

17. Participants must not be on corticosteroids at doses greater than prednisone 10 mg daily or equivalent within 7 days prior to Step 2 Randomization.

18. Participants must not receive any live attenuated vaccines within 28 days prior to Step 2 Randomization or at any time during the study and until 5 months after the last dose of protocol treatment.

19. Participants must not have severe infections in the form of severe sepsis or septic shock including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia within 14 days prior to Step 2 Randomization.

20. Participants must not be pregnant due to the potential teratogenic side effects of the protocol treatment. Women of reproductive potential and men must have agreed to use an effective contraception method for the duration of protocol treatment, and for 7 months after the last dose of protocol treatment. A woman is considered to be of “reproductive potential” if she has had a 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 outlined in the protocol, he/she is responsible for beginning contraceptive measures.

Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with atezolizumab, breastfeeding must be discontinued prior to Step 2 Randomization.

Specimen Submission Criteria

1. Participants must be offered the opportunity to participate in specimen banking as outlined in Section 15.3. With participant consent, specimens must be collected and submitted via the SWOG Specimen Tracking System as outlined in Section 15.1.  

Eligibility Criteria: 

5.1 STEP 1 REGISTRATION

a. Disease Related Criteria  

1. Participants must have a histologically proven diagnosis of clear cell or non-clear cell renal cell carcinoma. Participants with collecting duct carcinoma histology are not eligible. Participants with multifocal or bilateral tumors are eligible.

2. Participants must have primary tumor in place.

3. Participants must have the following scans performed, showing clinical evidence of measurable or non-measurable metastatic disease:

• CT scan of the chest (can be performed without contrast if CT contrast cannot be given)

• CT of abdomen and pelvis with contrast OR MRI of the abdomen and pelvis with or without contrast Scans must be performed within the following timeframes:

• Immunotherapy naïve participants must have scans documenting metastatic disease completed within 90 days prior to study registration.

• Pre-randomization completed participants must have scans documenting metastatic disease completed within 90 days prior to first dose of systemic immunotherapy treatment.

4. Participants with treated brain metastases must have no evidence of progression on follow-up brain imaging after CNS-directed therapy. Brain imaging studies are not required, unless clinically indicated. b. Prior/Concurrent Therapy Criteria

1. Participants must not have received the following prior treatment of metastatic renal cell carcinoma:

• Immunotherapy naïve participants must not have received any prior lines of systemic immunotherapy for metastatic renal cell carcinoma.

• Pre-randomization completed participants must not have received any systemic immunotherapy therapy for metastatic renal cell carcinoma beyond the one regimen received off protocol as specified in Step 1 pre-randomization treatment (see Section 7.1) 

2. Participants must not have received more than the following amounts of protocol-directed pre-randomization treatment:

• Immunotherapy naïve participants must not have received any pre-randomization treatment.

• Pre-randomization completed participants must not be planning to receive any additional treatment prior to Step 2 randomization, and must not have received more than the following amounts of pre-randomization treatment:

o 5 total: infusions of nivolumab at 3 mg/kg plus 1 dose (240 mg or 480 mg)

o 7 infusions of nivolumab at 240mg dose

o 4 infusions of nivolumab at 480mg dose

o 4 infusions of ipilimumab

o 5 infusions of pembrolizumab at 200mg dose

o 3 infusions of pembrolizumab at 400mg dose

o 7 infusions of avelumab  

3. Participants must not have received immunotherapy for any cancer within the following timeframes:

• Immunotherapy naïve participants must not have received any immunotherapy within 6 months prior to registration.

• Pre-randomization completed participants must not have received any other immunotherapy within 6 months of the start of protocol specified pre- randomization treatment (see Section 7.1).

4. Participants with symptomatic metastases may have received palliative radiotherapy or receive palliative radiotherapy after registration.

5. Participants must have no clear contraindications to nephrectomy.

c. Clinical Laboratory Criteria

1. Participants must be ≥ 18 years old.

2. Participants must not have a solitary kidney and not have a transplanted kidney.

3. No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, any in situ or T1 cancer, adequately treated Stage I or II cancer from which the participant is currently in complete remission, or any other cancer from which the participant has been disease free for at least two years.

4. Participants must not have been previously diagnosed with a medical condition that makes them ineligible for immune based combination therapy or nephrectomy 

**PLEASE SEE THE CURRENT VERISON OF PROTOCOL FOR FULL ELIGIBILITY LIST** 

Arm 2 is Closed to Accrual as of 02/15/2024

**DTL is required for this study- Physicians must sign the toxicity grids

Current sites credentialed: SJMH (Ann Arbor, Brighton, Canton, Chelsea), St. Mary's Livonia, Genesys, St. John, Macomb, Saginaw, Sparrow

Eligibility Criteria:

Disease Related Criteria

a. Participant must have predominant histologically and cytologically proven urothelial carcinoma in a metastatic site.

b. Participant must have evidence of metastatic urothelial carcinoma based on CT or MRI within 28 days prior to registration.

c. Participant must have had progression of disease following prior therapy at the discretion of the treating investigator.

d. Participants must not require immediate CNS-specific treatment, in the opinion of the treating investigator if they have active brain metastases (defined as new or progressive brain metastases) or leptomeningeal disease. 

Prior/Concurrent Therapy Criteria

a. Participant must have received previous treatment for metastatic urothelial carcinoma with either a platinum-based chemotherapy regimen, systemic PD1/PDL1 immunotherapy, antibody conjugate, or enfortumab. There is no limit to the number of prior regimens patient may have received for urothelial carcinoma.

• If participant is a candidate for a platinum-based chemotherapy, then participant must have previously received a platinum-based chemotherapy.

• If participant is a candidate for immunotherapy, then participant must have previously received immunotherapy. If participant is not a candidate for immunotherapy, then participant either: (a) must have had prior anti PD1/PDL1 antibody therapy; OR (b) must have not been a candidate for anti PD1/PDL1 antibody therapy in the opinion of the treating physician.

• Participant is eligible if platinum based chemotherapy and/or anti PDL/PDL1 antibody therapy was provided in perioperative setting before or after radical cystectomy and if there is evidence of progression to metastatic disease within 12 months of the last dose of therapy. For instance, a patient treated with ddMVAC in neoadjuvant setting, then radical cystectomy followed by adjuvant pembrolizumab on AMBASSADOR trial will meet the requirement for prior/concurrent therapy if progression of disease occurs within 12 months of discontinuation of pembrolizumab.

b. Participant must have received any planned surgery prior to registration.

c. Participant must not have progressed within 3 months following last dose of gemcitabine. 

d. Participant must not have unresolved toxicities from prior surgeries or radiation therapy > Grade 1 at the time of registration to registration.

Clinical/Laboratory Criteria

a. Participant must be ≥ 18 years of age.

b. Participant must have Zubrod Performance Status 0-2 (see Section 10.0).

c. Participant must have history and physical examination within 28 days prior to registration.

d. Participant must have complete blood count (CBC), complete metabolic panel including liver function tests, and LDH obtained within 28 days prior to registration.

e. Participant must have adequate kidney function as evidenced by measured or calculated creatinine clearance ≥ 50 mL/min within 28 days prior to registration. Calculated creatinine clearance = (140 - age) x wt (kg) x 0.85 (if female) 72 x creatinine (mg/dl)

f. Participant must have adequate hepatic function documented by either AST or ALT ≤ 3 x IULN within 28 days prior to registration. If both AST and ALT are performed, both must be ≤ 3 x IULN. For participants with liver metastases, AST or ALT must be ≤ 5 x IULN.

g. Participant must be on effective anti-retroviral therapy and have undetectable viral load at their most recent viral load test and within 6 months prior to registration if they are known to have human immunodeficiency virus (HIV)-infection.

h. Participants must have undetectable HBV viral load within 28 days prior to registration if participant has known chronic hepatitis B virus (HBV) infection.

i. Participants with a known history of hepatitis C virus (HCV) infection must have an undetectable HCV viral load within 28 days prior to registration.

j. Participants may have a prior or concurrent malignancy provided the natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen per the opinion of the treating investigator. 

k. Participants must not be planning to take strong or moderate CYP3A or CYP2C8 inhibitors or inducers if randomized to Arm 1 and SOC regimen chosen is Paclitaxel or Docetaxel. Participants receiving strong or moderate CYP3A or CYP2C8 inducers must discontinue use at least 2 weeks prior to randomization.

l. Participant must not have a known history of QTc prolongation.

m. Participants must not be pregnant or nursing due to the risk of harm to a fetus or nursing infant. Women and men of reproductive potential must have agreed to use an effective contraceptive method for the course of the study and 6 months (females) or 3.5 months (males) after the last dose.. 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 outlined in the protocol, he/she is responsible for beginning contraceptive measures.

Specimen Submission Criteria

a. Participants must be offered the opportunity to participate in specimen banking as outlined in Section 15.1. 

**DTL is required for this study- Physicians must sign the toxicity grids

Current sites credentialed: SJMH (Ann Arbor, Brighton, Canton, Chelsea), St. Mary's Livonia, Genesys, St. John, Macomb, SJMO, LVHN, Saginaw

Eligibility Criteria: 

Disease Related Criteria

a. 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.

b. Patients must have one of the following mutations: germline mutation in BRCA 1 or 2 that was tested in a 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). The Germline Testing Report must be submitted per Section 14.4a.

c. Patient must have metastatic disease and received first line platinum-based chemotherapy (i.e. FOLFIRINOX, FOLFOX, or gemcitabine + cisplatin)

d. Patients must have had a CT or MRI showing stable or responding disease on first line platinum-based chemotherapy within 30 days prior to registration.

e. 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.

f. Patients with history of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load within 30 days prior to registration.

g. 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.  

Prior/Concurrent Therapy Criteria

a. Patients must have received at least 16 weeks but no more than 24 weeks of first line platinum-based therapy for metastatic disease.

b. Patients’ last chemotherapy treatment must be within 30 days prior to registration.

c. 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

d. Patients must not have a known hypersensitivity to olaparib or any of the excipients of the product.

e. Patients must not be planning to receive strong or moderate CYP3A inhibitors or inducers (See Section 3.2c.3) 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.

f. 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, 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.

g. Patients must not have had prior therapy with an anti-PD-1, anti-PD-L1, or antiPD-L2 agent, or any other immune checkpoint inhibitors.

h. Patients must not have had prior therapy with PARP inhibitors.

i. 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. 

Clinical/Laboratory Criteria

a. Zubrod performance status of 0-1.

b. Patients must be ≥ 18 years old.

c. Patients must have a complete medical history and physical exam within 28 days prior to registration. d. Patients must have adequate organ and marrow function within 14 days of registration, as defined below:

- absolute neutrophil count ≥1,500/mcL

- platelets ≥100,000/mcL

- total bilirubin ≤ 1.5 institutional upper limit of normal (ULN)

- AST/ALT ≤3 × institutional ULN

- creatinine ≤ 1.5 mg/dl

- Albumin ≥3.0 - Hemoglobin ≥9.0 g/dL

e. Patients must have CA19-9 obtained within 42 days prior to registration.

f. 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.

g. 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.

h. 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 outlined in the protocol, 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.

i. Patients must not have a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.

j. Patients must not have an active infection requiring systemic therapy.

k. 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. 

Specimen Submission Criteria

a. Patients must be offered the opportunity to participate in specimen banking of FFPE tissue and whole blood as outlined in Section 15.1. If a patient is unable to submit archival tissue, should the patient need to undergo a standard of care biopsy per 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 SWOG Specimen Tracking System as outlined in Section 15.1. 

*DTL Required- Physicians must sign toxicity grid

CREDENTIALING REQUIRED. Please check your site's credentialing status.
CURRENT SITES CREDENTIALED: SJMH (AA, Brighton, Canton, Chelsea), Livonia, Saginaw

Eligibility Criteria:

Registration Step 1: Initial Registration/Randomization Disease Related Criteria

a. Participants must have had a confirmed diagnosis of Waldenström’s macroglobulinemia (WM)/Lymphoplasmacytic Lymphoma (LPL). Participants must have measurable disease as determined by IgM protein quantification (see Section 10.1a). Testing to establish baseline disease status must be performed within 28 days prior to registration.

b. Participants must have at least one of the criteria to require therapy for WM including anemia, thrombocytopenia, neuropathy related to WM, symptomatic hyperviscosity or serum viscosity levels greater than 4.0 centipoises, WM associated glomerulonephritis or renal disease, bulky disease, or constitutional symptoms. Constitutional symptoms can be described as unintentional weight loss ≥10% within the previous 6 months prior to Screening; Fevers higher than 100.5°F or 38.0°C for 2 or more weeks prior to Screening without evidence of infection; Night sweats for more than 1 month prior to Screening without evidence of infection; Clinically relevant fatigue which is not relieved by rest due to WM.

Prior/Concurrent Therapy Criteria

c. Participants who require ongoing use or received a moderate or strong CYP3A inducer, moderate or strong CYP3A inhibitor, P-gp inihibitor within 7 days prior to the first dose of study drug will be excluded from the study. If such participants can be safely switched to an alternative agent, then the participants will be eligible to enroll.

d. Participants must not have had prior systemic therapy. Prior therapy with rituximab will be allowed as long as the last rituximab dose was at least 12 months prior to registration.

Clinical/Laboratory Criteria

e. Participants must be ≥ 18 years of age.

f. Participants must have history and physical exam within 28 days prior to registration.

g. Participants must have Zubrod Performance Status ≤ 2 (see Section 10.7).  

h. Participants must not be intolerant to rituximab.

i. Participants must have evidence of adequate renal function, as defined by creatinine clearance (CrCl) ≥ 30 mL/min. Values must be obtained within 14 days prior to registration. 

j. Participants must have adequate hepatic function defined by the following within 14 days prior to registration:

1. Total bilirubin ≤1.5 x IULN (institutional upper limit of the norm).

AND

2. AST, ALT and alkaline phosphatase ≤ 3 x IULN

k. Participants must have adequate bone marrow function defined by the following without transfusion or growth factor support within 14 days prior to registration:

1. Platelet count ≥ 50,000 cells/mm3 and

AND

2. Hemoglobin ≥ 7.0 g/dL AND

3. Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3

l. Participants must not have known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics) 4 weeks prior to registration.

m. Participants 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.

n. Participants must not be seropositive for hepatitis C (except in the setting of sustained virologic response, defined as undetectable viral load at least 12 weeks after completion of antiviral therapy). HCV testing is only required if clinically indicated or if the participant has a history of HCV.  

o. Participants must be able to take and swallow oral medication (capsules) whole. Participants may not have any known impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of the study drug (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection.)

p. Participants must not consume grapefruit, Seville oranges or starfruit within 3 days prior to the first dose of venetoclax.

q. Participants must not be pregnant or nursing because venetoclax has not been studied in pregnant or nursing women and the mechanism of action is expected to cause fetal harm. 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" e.g., implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], complete abstinence, or sterilized partner) and a barrier method (e.g., condom, cervical ring, sponge, etc.). This 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 outlined in the protocol, he/she is responsible for beginning contraceptive measures throughout the study and for at least 30 days after competition of therapy.

r. 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 participant is currently in complete remission, or any other cancer from which the participant has been disease free for two years or watchful waiting is appropriate in the opinion of the treating physician. Also, malignancy that in the opinion of the Investigator, is considered cured with minimal risk of recurrence within 5 years, is permissible consideration of eligibility for this trial. Specimen Submission Criteria

s. Participants must be offered the opportunity to participate in specimen banking as outlined in Section 15.1.