*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.

*DTL Required- Physicians must sign toxicity grid

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

CURRENT SITES CREDENTIALED: SJMH (AA, Brighton, Chelsea, Canton), LVHN, GenHur, Sparrow, St. John, Macomb, Livonia, Saginaw, Holy Cross

ELIGIBILITY CRITERIA:

Disease Related Criteria

a. Participants must have a confirmed diagnosis of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) (collectively referred to as CLL throughout) according to the 2018 International Workshop on CLL (see Section 4.0). Participants must have been diagnosed within 12 months prior to registration.

b. Participants must have CLL-International Prognostic Index (CLL-IPI) Score ≥ 4 (See Section 4.3) and/or complex cytogenetics (defined as 3+ chromosomal abnormalities).

c. Cytogenetic and FISH analyses must be completed at the site’s CLIA-approved laboratory within 12 months prior to registration. FISH panel should use probes to detect for abnormalities in chromosomes 13q, 12, 11q, and 17p.

d. TP53 mutation status (if completed) must be obtained within 12 months prior to registration.

e. IgVH mutational status must be obtained prior to registration (at any time prior to registration).

f. Serum beta-2 microglobulin level must be obtained within 28 days prior to registration.

g. Participants must not meet any of the IWCLL specified criteria for active CLL therapy (see Section 4.4). 

Prior/Concurrent Therapy Criteria

a. Treatment with high dose corticosteroids and/or intravenous immunoglobulin for autoimmune complications of CLL must be complete at least 4 weeks prior to enrollment.

b. Palliative steroids must be at a dose of at most 20 mg/day of prednisone or equivalent corticosteroid at the time of registration.

c. Prior therapy with anti CD20 monoclonal antibodies is not allowed.

d. Participants must not have received or be currently receiving any prior CLL\u0002directed therapy, including non-protocol-related therapy, anti-cancer immunotherapy, experimental therapy, or radiotherapy.

e. Participants must not be receiving or planning to receive any other investigational agents before completing protocol therapy.

Clinical/Laboratory Criteria

a. Participants must be ≥ 18 years of age.

b. Participants must have ECOG Performance Status ≤ 2.

c. Participants must have adequate marrow function as evidenced by platelet count ≥ 100,000/mm3 and absolute neutrophil count (ANC) ≥ 1,000/mm3 within 28 days prior to registration. 

d. Participants must have adequate kidney function as evidenced by creatinine clearance ≥ 30mL/min (by Cockroft Gault) within 28 days prior to registration. Creatinine clearance = (140 - age) x wt (kg) x 0.85 (if female) 72 x creatinine (mg/dl)

e. Participants must have adequate liver function as evidenced by AST and ALT 3.0 x Upper Limit of Normal (ULN), and total bilirubin ≤ 2.0 x ULN (or 5.0 x ULN if the Participant has a history of Gilbert’s disease), within 28 days prior to registration.

f. Participants must be able to take oral medications.

g. Human immunodeficiency virus (HIV)-infected participants on effective anti\u0002retroviral therapy with undetectable viral load within 6 months prior to registration are eligible for this trial.

h. Participants with history of malignancy are allowed providing the cancer has not required active treatment within 2 years prior to registration (hormonal therapy is permissible). The following exceptions are permissible: basal cell, squamous cell skin, or non-melanomatous skin cancer, in situ cervical cancer, superficial bladder cancer not treated with intravesical chemotherapy or BCG within 6 months, localized prostate cancer requiring no more than chronic hormonal therapy, or localized breast cancer requiring no more than chronic hormonal therapy.

i. Participants must not have current, clinically significant gastrointestinal malabsorption, in the opinion of treating doctor.

j. Participants must not have cirrhosis. 

k. Obinutuzumab has been associated with hepatitis reactivation. Participants must not have uncontrolled active infection with hepatitis B or C. Participants with latent hepatitis B infection must agree to take prophylaxis during and for 6 months following active protocol therapy with V-O. Active infection with hepatitis B or C:

• Active infection is defined as detectable hepatitis B DNA or hepatitis C RNA by quantitative PCR. Latent infection with hepatitis B:

• Latent infection is defined as meeting all of the following criteria: o Hepatitis B surface antigen positive o Anti-hepatitis B total core antibody positive o Anti-hepatitis IgM core antibody undetectable o Hepatitis B PCR undetectable

• Participants with latent hepatitis B infection must agree to take prophylaxis with anti-hepatitis agents during and for 6 months following active protocol therapy with V-O.

• Participants who have received IVIG therapy within 6 months who are hepatitis B core total antibody positive but PCR undetectable are not mandated to take prophylaxis.

l. Participants must not have had major surgery within 30 days prior registration or minor surgery within 7 days prior to registration. Examples of major surgery include neurosurgical procedures, joint replacements, and surgeries that occur inside the thoracic or abdomino-pelvic cavities. Examples of minor surgery include dental surgery, insertion of a venous access device, skin biopsy, or aspiration of a joint. If there is a question about whether a surgery is major or minor, this should be discussed with the Study Chair.

m. Participants must not have known bleeding disorders (e.g., von Willebrand’s disease or hemophilia). n. Participants must not have a history of stroke or intracranial hemorrhage within 6 months prior to enrollment.

o. Participants must not require continued therapy with a strong inhibitor or inducer of CYP3A4/5, as venetoclax is extensively metabolized by CYP3A4/5 (see Section 18.1).

p. Participants must not have uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura. 

q. Participants must not have any currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification

r. Participants must not have a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to enrollment (see Section 18.2).

s. Participants must not be pregnant or nursing, as there are no safety data available for these drug regimens during pregnancy. 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 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 agree to have specimens submitted for translational medicine (MRD) and specimens must be submitted as outlined in Section 15.1.

b. Participants must be offered participation in banking for future research. With participant’s consent, specimens must be submitted as outlined in Section 15.3.

Quality of Life Criteria

a. Participants who are able to complete patient reported outcome (PRO) forms in English, Spanish, French, German, Russian or Mandarin must agree to participate in the quality of life assessments as outlined in Section 15.4. (Those participants who are unable to read and write in English, Spanish, French, German, Russian or Mandarin may be registered to S1925 without contributing to the quality of life portion of the study.)

**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-PD\u00021/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, Sparrow

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 anti\u0002PD-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.

CREDENTIALING REQUIRED. Please check your site's credentialing status.
CURRENT SITES CREDENTIALED: SJMH (Ann Arbor, Brighton, Canton, Chelsea), Livonia, St. John, Macomb, Genesys, Hurley, Oakland, Saginaw, Lehigh

Eligibility Criteria:

Disease Related Criteria

a. Participants must be female and have Stage I, II, or III hormone receptor positive breast cancer based on clinical or pathologic evaluation (See Section 4.0).

b. Participants must have been pre- or peri-menopausal at the time of breast cancer diagnosis by satisfying one of the following:

1. had a menstrual period (by self-report) within the 12 months before breast cancer diagnosis, or

2. had a serum or plasma estradiol and/or FSH concentration consistent with premenopausal status (based on institutional standards) within the 12 months before breast cancer diagnosis or when checked after breast cancer diagnosis.

c. Participants must not have distant metastatic breast cancer.  

Prior/Concurrent Therapy Criteria

a. Participants must have started initial treatment with standard of care oral endocrine therapy (ET) (i.e., tamoxifen, anastrozole, exemestane, or letrozole; see Section 7.1 for details) within 14 days prior to randomization or be planning to start initial treatment with standard of care oral ET (+/- GnRHa injection) within 14 days after randomization.

NOTE: For participants who will be starting GnRHa injection followed by initiation of oral ET after achieving ovarian suppression, participants must be planning to start initial treatment with standard of care GnRHa therapy within 14 days after randomization.

b. Participants who currently have ovarian function (estradiol above the postmenopausal range) must be planning to undergo ovarian suppression or ablation (see Section 7.1) concomitantly with oral ET medication, starting before or at the same time as oral ET initiation. 

*** Please see the current version of protocol for full eligibility list**

*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, Genesys, Hurley, St. John, Macomb, Holy Cross

Eligibility Criteria:

Disease Related Criteria

a. Participants must have histologically-confirmed (local site pathological confirmation sufficient) extrapulmonary poorly differentiated, small cell neuroendocrine carcinoma (NEC) as defined in Section 4.0 that is metastatic.

b. Participants must have radiologically evaluable disease, measurable or non\u0002measurable, per RECIST 1.1 criteria. All measurable and non-measurable lesions must be assessed by CT scan within 28 days prior to registration. For patients who received one cycle of platinum + etoposide prior to registration, at least 21 days must have elapsed between Day 1 of platinum + etoposide and the pre\u0002registration CT scan. All known sites of disease must be assessed and documented on the Baseline Tumor Assessment Form.

c. Participants must have brain MRI (or CT head with contrast if there is contraindication to MRI brain) within 28 days prior to registration. Participants with asymptomatic central nervous system (CNS) metastases are eligible if one or more of the following apply:

• Participants who have received treatment for brain metastases must have:

o No evidence of radiological progression (by MRI brain or CT head with contrast if there is contraindication to MRI brain) within 28 days prior to registration

o Discontinued all corticosteroids at least 14 days prior to registration

• Participants with treatment-naïve brain lesions must have:

o No lesion measuring >2.0 cm in size in any axis

o MRI brain or CT head with contrast (if there is contraindication to MRI brain) demonstrating no evidence for mass effect, edema, or other impending neurological compromise within 28 days prior to registration.

o No evidence of radiological progression (by MRI brain or CT head with contrast if there is contraindication to MRI brain) within 28 days prior to registration

o No need for >2 mg of dexamethasone (or equivalent of >10 mg prednisone) per day at time of registration.

d. Participants must not have symptomatic central nervous system (CNS) metastases.

e. Participants must not have known or suspected leptomeningeal disease.

f. Participants must not have small cell NEC mixed with urothelial carcinomas.

Prior/ Concurrent Therapy Criteria

a. Participants with prior history of non-metastatic (localized/locally advanced disease) extrapulmonary poorly differentiated small cell NEC may have had prior platinum-based therapy ± radiation ± surgery provided that all therapy was completed ≥ 6 months prior to registration.

b. Participants must discontinue denosumab prior to study registration and plan to replace with a bisphosphonate while on the study.

c. Participants must not have had prior treatment for metastatic disease EXCEPT one cycle of platinum (carboplatin/cisplatin) + etoposide is allowed prior to registration. Other chemotherapy regimens are not allowed.

d. Participants must not have had prior treatment with an anti-PD-1, anti-PD-L1, anti\u0002PD-L2, CD137 agonists, anti-CTLA-4 agent, or any other immune checkpoint inhibitors for any neuroendocrine neoplasm. Immune checkpoint inhibitors given for other cancer indications are allowed provided last therapy was given at least 12 months prior to study registration.

e. Participants must not have received treatment with systemic immunostimulatory agents including, but not limited to, interferon and interleukin2 [IL-2] within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to registration.

f. Participants must not have had history of known severe allergy, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies, including to Chinese hamster ovary cell products or to any component of the atezolizumab formulation, cisplatin, carboplatin, or etoposide.

g. Participants must not be on active systemic therapy for another cancer with the exception of hormonal therapy including androgen deprivation therapy (e.g., gonadotropin-releasing hormone (GnRH) agonists or antagonists), which can be continued while participants are receiving protocol therapy. Use of enzalutamide or apalutamide is permitted after completion of chemotherapy; however, glucocorticoid-containing regimens, including abiraterone, are not permitted.

Clinical/ Laboratory Criteria

a. Participants must be ≥ 18 years of age.

b. Participants must have a Zubrod Performance Status of ≤ 2 (see Section 10.4) within 28 days prior to registration.

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

d. Participants must have adequate marrow function as defined below. These results must be obtained within 14 days prior to registration. For participants who received a cycle of chemotherapy prior to registration, at least 21 days must have elapsed between Day 1 of platinum + etoposide and performance of these tests.

• Absolute neutrophil count (ANC) ≥ 1.5 x 109 /L

• Hemoglobin ≥ 9.0 g/dl

• Platelet count ≥ 100 x 109/L e. Participants must have adequate organ function as defined below. These results must be obtained within 14 days prior to registration. For participants who received a cycle of chemotherapy prior to registration, at least 21 days must have elapsed between Day 1 of platinum + etoposide and performance of these tests.

• Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x institutional upper limit of normal (ULN)

• Serum total bilirubin ≤ 1.5 x ULN

• Measured creatinine clearance (CL) >50 mL/min or Calculated creatinine CL>50 mL/min by the Cockcroft-Gault formula as below (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance.

f. Participants must not have uncontrolled or symptomatic hypercalcemia (>1.5 mmol/L ionized calcium or calcium >12 mg/dL or corrected serum calcium >ULN) within 14 days prior to registration. Participants who have asymptomatic hypercalcemia are eligible provided that medical therapy to treat the hypercalcemia is planned.

g. Participants must not have a diagnosis of immunodeficiency nor be receiving systemic steroid therapy (equivalent of > 20 mg of hydrocortisone per day) or any other form of immunosuppressive therapy within 14 days prior to registration.

h. Participants must not have active or history of autoimmune disease or immune deficiency, including, but not limited to myasthesia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener grandulomatosis, Sjögren syndrome, Guillian-Barré syndrome, or multiple sclerosis with the following exceptions:

• Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study

. • Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.

• Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:

o Rash must cover 10% of body surface area

o Disease is well controlled at baseline and requires only low\u0002potency topical corticosteroids

o No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high\u0002potency or oral corticosteroids within the previous 12 months

i. Participants must not have history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan. NOTE: History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

j. Participants must not have significant cardiovascular disease, such as New York Heart Association Class II or greater cardiac disease (refer to Section 18.2), myocardial infarction within 3 months prior to registration, unstable arrythmias, or unstable angina.

k. Participants must not have had a major surgical procedure other than for diagnosis within 28 days prior to registration. Participant must not plan to receive a major surgical procedure during the course of protocol treatment. NOTE: Patient port placement is not considered a major surgery.

l. Participants must not have severe infections (i.e., CTCAE Grade ≥2) at time of registration, including but not limited to hospitalization for complications for infection, bacteremia, or severe pneumonia.

m. Participants must not have active tuberculosis

n. Participants with evidence of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load, with testing performed as clinically indicated.

o. Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. Participants with active HCV infection who are currently on treatment must have an undetectable HCV viral load, with testing performed as clinically indicated.

p. Participants with known HIV-infection must be on effective anti-retroviral therapy at time of registration and have undetectable HIV viral load within 6 months of registration.

q. Participants must not have prior allogeneic bone marrow transplantation or solid organ transplant.

r. Participants must not have received administration of a live, attenuated vaccine (e.g., FluMist®) within 28 days prior to initiation of study treatment, during treatment with atezolizumab, and not plan to receive for 5 months after the last dose of atezolizumab.

s. Participants must not be pregnant due to the possibility of harm to the fetus. Individuals who are of reproductive potential must have agreed to use an effective contraceptive method (with details provided as a part of the consent process) during the treatment period and for 5 months after the final dose of atezolizumab. A person who has had menses at any time in the preceding 12 consecutive months or who has semen likely to contain sperm is considered to be of "reproductive potential." In addition to routine contraceptive methods, "effective contraception" also includes refraining from sexual activity that might result in pregnancy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) including hysterectomy, bilateral oophorectomy, bilateral tubal ligation/occlusion, and vasectomy with testing showing no sperm in the semen.

Specimen Submission Criteria

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