Arm 1 (tafasitamab + lenalidomide + tazemetostat) Temporary Closed to Accrual Effective 06//13/2024

*DTL Required- Physicians must sign toxicity grid

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

Eligibility Criteria:

5.1. Disease Related Criteria

a. Participants must have:

• Histologically confirmed relapsed/refractory LBCL as outlined by the World Health Organization (WHO) guidelines, classified as one of the following:

o Large B-cell lymphoma, GBC and non-GCB types

o Follicular lymphoma, grade 3B

o Transformed lymphoma

o High grade B-cell lymphoma with or without MYC, BCL2 and/or BCL6 rearrangements

b. Participants must have staging imaging performed within 28 days prior to registration, as follows. Positron emission tomography (PET)-computed tomography (CT) baseline scans are strongly preferred; diagnostic quality magnetic resonance imaging (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. All measurable lesions (longest diameter >= 1.5 cm) must be assessed within 28 days prior to registration. Tests to assess non-measurable disease must be performed within 28 days prior to registration. All disease must be documented on the Baseline Tumor Assessment Form.

c. Participants must not have active lymphomatous involvement of the CNS because the treatments used in this study are not effective to sufficiently penetrate the blood brain barrier. d. Participants must not have known abnormalities associated with MDS (e.g., del 5q, chr 7 abn) and myeloproliferative neoplasms (MPN) (e.g., JAK2 V617F) observed in cytogenetic testing and DNA sequencing. Testing is not required for eligibility determination.

e. Participants must not have a known prior history of T-LBL/T-ALL. Testing is not required for eligibility determination.

f. Participants must have cell of origin (COO) determination of germinal center (GC)(GCB or non-GC GCB) of LBCL based on Hans immunohistochemistry algorithm (CD10, BCL6, MUM1) as noted on pathology report).

5.2. Prior/Concurrent Therapy Criteria

a. Participants must not be a candidate based on investigator assessment to receive autologous stem cell transplant (ASCT) or must have declined ASCT. Participants who had disease progression after stem cell transplant or cellular therapy (such as chimeric antigen receptor (CAR) T-cell) are eligible.

b. Participants must not have received prior treatment with tafasitamab and/or lenalidomide.

c. Participants must not have had prior BTK inhibitor or tazemetostat.

d. Participants must have had 1-5 prior systemic treatment regimens including one systemic multiagent regimen for aggressive lymphoma.

e. Participants who have received prior systemic therapy must have completed their last treatment prior to registration. Participants must have recovered from previous therapy.

f. Steroid use for the control of non-Hodgkin lymphoma symptoms is allowable, but must be discontinued prior to Cycle 1, Day 1.

g. Participants must not have any known allergy or reaction to any component of tafasitamab, lenalidomide, tazemetostat or zanubrutinib.

h. Participants must not be receiving direct vitamin K inhibitors or strong or moderate CYP3A inhibitors or inducers at the date of registration. NOTE: Because the list of these agents is constantly changing, it is important to regularly consult a frequently updated medical reference.

5.3. Clinical/Laboratory Criteria

a. Participant must be ≥ 18 years old.

b. Participant must have Zubrod Performance Status of 0-3 (see Section 10).

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

d. Participants must have adequate organ and marrow function as defined below within 28 days prior to registration:

- Absolute neutrophil count ≥1.0 x 10^3/uL

- Platelets ≥75 x 10^3/uL

If there is documented lymphomatous involvement of the bone marrow as assessed by bone marrow biopsy within 90 days prior to registration, participants must have:

- ANC ≥ 0.75 x 103/µL and;

- Platelets ≥ 50 x 103/µL

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

Eligibility Criteria:

5.1 Disease Related Criteria

a. Participants must have documented multiple myeloma satisfying standard International Myeloma Working Group (IMWG) see section 4.1. diagnostic criteria within 28 days prior to registration.

b. Participants must have measurable disease within 28 days prior to registration as defined by any of the following:

1. immunoglobulin (Ig) G myeloma (serum monoclonal paraprotein [M\u0002protein] level ≥0.5 gram/deciliter [g/dL] or urine M-protein level ≥200 milligram[mg]/24 hours[hrs]; OR

2. IgA, IgM, IgD, or IgE multiple myeloma (serum M-protein level ≥0.2 g/dL or urine M-protein level ≥200 mg/24 hrs); OR

3. light chain multiple myeloma (serum immunoglobulin free light chain ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio).

All disease must be assessed and documented on the Baseline/Pre-Registration Tumor Assessment Form 

5.2 Prior/Concurrent Therapy Criteria

a. Participants must not have received any prior systemic therapy for multiple myeloma with the exception of any one or more of the following:

1. An emergency use of a short course of corticosteroids (equivalent of dexamethasone 160 mg) any time before registration, or

2. Up to one complete cycle of a non-daratumumab and hyaluronidase-fihj containing anti- myeloma regimen (1 cycle = 21 or 28 days depending on the regimen being used), or

3. Localized palliative radiation therapy for multiple myeloma, as long as the radiation therapy is completed at least 3 days prior to starting the systemic treatment as per the study protocol. 

5.3 Clinical/Laboratory Criteria

a. Participants must have a calculated myeloma frailty index (Myeloma Frailty Score Calculator; http://www.myelomafrailtyscorecalculator.net/) categorized as frail or intermediate fit (regardless of age) within 28 days prior to registration.

1. For Participants Meeting “Frail” Status:

i. Participants with any degree of kidney dysfunction are allowed; however, participants on dialysis are not eligible.

ii. Participants must have adequate bone marrow function as evidenced by:

a. Hemoglobin ≥7 g/dL AND

b. Platelets ≥50x109/L AND

c. ANC ≥0.75 x109/L. 

2. For Participants Meeting “Intermediate Fit” Status, one or more of the following criteria must be present:

i. Kidney dysfunction showing calculated CrCl <30 ml/min (participants on dialysis are not eligible) 

ii. Participants must have bone marrow function assessed and meet the below criteria ranges:

a. Hemoglobin between 7-8 g/dL, OR

b. Platelets between 50-75 x109/L, OR

c. ANC between 0.75-1 x109/L.  

iii. R-ISS stage III disease.

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

c. Participants must have whole body imaging within 60 days prior to registration. The recommended method of imaging is a PET/CT; a low-dose whole body CT scan or whole-body MRI or skeletal survey should be done only if a PET/CT scan cannot be done or is non-feasible. This must be documented in the comments section of the Onstudy form.  

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

Eligibility Criteria:

5.1 Disease Related Criteria

a. Participant must have histologic diagnosis of prostate adenocarcinoma.

b. Participant must have high or very high-risk disease defined by at least one of the following:

• cT3a – cT4x

• Grade Group 4 or 5 (Gleason sum 8-10)  

• PSA > 20 ng/mL prior to registration

c. Participant must have documented evidence of germline mutation (pathogenic/likely pathogenic variant) in BRCA2 or BRCA1 through testing in a CLIA-certified lab. NOTE: Local lab report is sufficient for eligibility.

d. Participant must not have evidence of distant metastatic disease by conventional imaging within 90 days prior to registration. NOTE: cN1 detected only by PSMA-PET is permitted if urologist deems sites of disease to be potentially completely resectable. 

5.2 Prior/Concurrent Therapy Criteria

a. Participant may have initiated gnRH agonist, gnRH antagonist, oral anti-androgen (e.g. bicalutamide, nilutamide, flutamide), or other agent intended to treat prostate cancer prior to registration. The effectiveness of the current depot of such treatment must not extend beyond 1 month after study registration. Agents listed above cannot be started after participant registration.

b. Participant must not have received prior RT to the pelvic region. 

5.3 Clinical/Laboratory Criteria

a. Participant must be ≥ 18 years old.

b. Participant must have Zubrod Performance Status of 0-2 (see Section 10.5).

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

d. Participant must have adequate organ and marrow function as defined below within 28 days prior to registration:

- absolute neutrophil count ≥1.5 x 10^3/uL

- platelets ≥100 x 10^3/uL

- AST/ALT ≤ 3 × institutional ULN  

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

CURRENT SITES CREDENTIALED: SJMH (Ann Arbor, Brighton, Chelsea, Canton, Livonia) Genesys, Hurley, Holy Cross, Lehigh Valley, Sparrow, St. John, Oakland, and Saint Mary's Saginaw.

Eligibility Criteria:

5.1 Disease Related Criteria

a. Participants must have histologically confirmed ER-negative, PR-negative, and HER2-negative breast cancer (TNBC) defined as ER<5%, PR<5%, and HER2 negative (per 2020 ASCO CAP guidelines). NOTE: Participants with weakly ER or PR positive disease, defined as ER and/or PR between 1-4% by immunohistochemistry, are eligible if adjuvant endocrine therapy is not recommended/planned by the treating physician.

b. Participants must have AJCC 8 anatomic tumor clinical stage either

- T2-T4, N0, M0 or

- T1-T3, N1-2, M0.

Note: All participants with clinically suspicious nodes must undergo core needle biopsy or fine needle biopsy per standard clinical practice to pathologically confirm nodal status.

c. Participants must have breast and axillary imaging with mammogram and/or ultrasound and/or MRI within 49 days prior to randomization.

Note: Participants with bilateral invasive breast cancer are eligible if both breast cancers are ER-negative, PR-negative, and HER2-negative provided they meet the other eligibility criteria.

d. Participants must not have T4/N+, any N3, or inflammatory breast cancer.

e. Participants must not have metastatic disease (M1).

5.2 Prior/Concurrent Therapy Criteria

a. Participants must not have received prior systemic therapy or radiation therapy with curative intent for the current breast cancer

b. Participants must not have had previous definitive ipsilateral breast surgery for the current breast cancer

c. Participants must not have current or anticipated use of other investigational agents while participating in this study

d. Participants must not have history of allergic reactions attributed to compounds of similar chemical or biologic composition as study agents

e. Participants must not have severe hypersensitivity (≥ grade 3) to pembrolizumab or any of its excipients.

f. Participants must not have received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g. CTLA-4, OX-40, CD137).

g. Participants must not be currently participating in or have participated in a study of an investigational agent or used an investigational device within 28 days prior to

5.3 Clinical/Laboratory Criteria

a. Participants must be ≥ 18 years old.

b. Participants must have Zubrod Performance Status of 0-2 (see Section 10.10).

c. Participants with evidence of peripheral neuropathy must have it at ≤ Grade 1, by CTCAE v. 5.0, within 28 days prior to randomization.

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

e. Participants must have adequate organ and marrow function as defined below within 28 days prior to randomization:

- Hemoglobin ≥9.0 g/dL or ≥ 5.6 mol/L

- leukocytes ≥3 x 10^3/uL

- absolute neutrophil count ≥1.5 x 10^3/uL

- platelets ≥100 x 10^3/uL

- total bilirubin ≤ 1.5x institutional upper limit of normal (IULN), OR direct bilirubin ≤ IULN for participants with total bilirubin >1.5x IULN (unless history of Gilbert’s disease. Participants with history of Gilbert’s disease must have total bilirubin ≤ 5 x institutional IULN)

- AST and ALT ≤ 3 × institutional ULN

f. Participants must have a serum creatinine ≤ the IULN OR calculated creatinine clearance ≥ 50 mL/min/1.73m2 using the following Cockcroft-Gault Formula. This specimen must have been drawn and processed within 28 days prior to registration

g. Participants must have adequate cardiac function. Participants must have left ventricular ejection fraction ≥50% as assessed by either ECHO or MUGA assessed within 28 days prior to registration. 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 using the New York Heart Association Functional Classification (see Section 18.1) and must be class 2B or better.

h. Participants with known human immunodeficiency virus (HIV)-infection must be on effective anti-retroviral therapy at randomization and have undetectable viral load test on the most recent test results obtained within 6 months prior to randomization.

i. Participants with evidence of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load while on suppressive therapy on the most recent test results obtained within 6 months prior to randomization, if indicated.

**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: Sparrow, St. John, Macomb, GenHur, Hurley, LVHN, SJMH (Ann Arbor, Brighton, Canton, Chelsea), Livonia, SJMO

Eligibility Criteria:

Disease Related Criteria

a. Participants must have histologically or cytologically confirmed non-small cell lung cancer (NSCLC) which is Stage IV or recurrent.

Prior/Concurrent Therapy Criteria

a. Participants must have received at least one line of anti-PD-1 or anti-PD-L1 therapy for any stage of NSCLC. Anti-PD-1 or anti-PD-L1 may have been given alone or in combination with other therapy.

b. Participants must not have received more than one line of anti-PD-1 or anti-PD-L1 for Stage IV or recurrent disease.

c. Participants must have experienced disease progression (in the opinion of the treating physician) more than (>) 84 days following initiation (Cycle 1 Day 1) of their most recent anti-PD-1 or PD-L1 therapy.

d. Participants who received anti-PD-1 or anti-PD-L1 therapy for Stage IV or recurrent disease, must have had a best response on anti-PD-1 or anti-PD-L1 therapy of stable, partial response or complete response (in the opinion of the treating physician).

e. Participants who received neoadjuvant, adjuvant, and/or consolidation anti-PD-1 or anti-PD-L1 therapy as their only line of anti-PD-1 or anti-PD-L1 therapy must have experienced disease progression within (<=) 365 days from initiation (Cycle 1 Day 1) of anti-PD-1 or PD-L1 therapy.

f. Participants must have received platinum-based chemotherapy and experienced disease progression (in the opinion of the treating physician) during or after this regimen. g. Participants with a known sensitizing mutation for which an FDA-approved targeted therapy for NSCLC exists (e.g., EGFR, ALK, ROS1, BRAF, RET, NTRK, KRAS, HER2 and MET sensitizing mutations), must have previously received at least one of the approved therapy(s). Prior targeted therapy for participants with targetable alterations is allowed if all other eligibility criteria are also met.

h. Participants must not be receiving or planning to receive another investigational therapy during study participation.

Clinical/Laboratory Criteria

a. Participants must be ≥ 18 years old.

b. Participants must be able to safely receive the investigational drug combination and the investigator’s choice of standard of care regimens described in Section 7.2, per the current FDA-approved package insert(s), treating investigator’s discretion, and institutional guidelines.

c. Participants must have Zubrod Performance Status of 0-2 (see Section 10.3).  

*DTL Required- Physicians must sign toxicity grid

CREDENTIALING REQUIRED. Please check your site's credentialing status.
CURRENT SITES CREDENTIALED: Trinity Health IHA (Ann Arbor, Brighton, Chelsea, Canton) and Livonia, Genesys, Hurley, sparrow

Eligibility Criteria:

5.1. Disease Related Criteria

a. Participants must have advanced or locally unresectable gastric, gastroesophageal junction or esophageal adenocarcinoma.

b. Participants must have PD-L1 CPS (Combined Positive Score) ≥ 1. This test would have been performed as part of SOC pathology testing, using tissue obtained within two years prior to registration and collected prior to or after a frontline regimen.

c. Participants must have a histologically confirmed diagnosis of MSS and HER2 negative gastric, gastroesophageal junction, or esophageal adenocarcinoma.

d. Participants must have documented unresectable and/or metastatic disease on CT or MRI imaging completed prior to registration. Imaging must have been completed within 28 days prior to registration for participants with measurable disease. CT scans or MRIs used to assess non-measurable disease must have been completed within 42 days prior to registration. All disease must be assessed and documented on the Baseline Tumor Assessment Form.

e. Participants with treated brain metastases must have no evidence of progression on the follow-up brain imaging after CNS-directed therapy. All treatment for brain metastases must have been completed at least 28 days prior to registration.  

5.2. Prior/Concurrent Therapy Criteria

a. Participants must have disease progression or intolerance to frontline standard of care (SOC) chemotherapy plus either nivolumab, pembrolizumab or any other PD-1 or PD\u0002L1 inhibitor. Peri-operative chemotherapy plus nivolumab, pembrolizumab or any other PD-1 or PD-L1 inhibitor will count as one line if disease progression occurs while on the therapy or within 6 months of completing the chemotherapy plus nivolumab or pembrolizumab or other PD-1/PD-L1 inhibitor cycle.

b. Participants must not have received more than one prior line of systemic therapy.

c. Participants must not have a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of registration. Inhaled or topical steroids and adrenal replacement doses <10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Participants are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic corticosteroids are permitted, even if <10 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted, as long as there has been a washout period for corticosteroids of ≥7 days prior to registration.  

d. Participants must not have prior significant immunotherapy related adverse events requiring permanent discontinuation of the immunotherapy agent including events like pneumonitis, myocarditis, renal failure, Guillain barre syndrome, or myasthenia gravis. Participants with endocrinopathy events leading or not to replacement steroids, thyroid hormone, insulin, or cortisol are eligible.

e. Participants must not have received a live attenuated vaccination within 28 days prior to registration (See Appendix 18.5).

f. Participants must not have had a major surgery within 28 days or subcutaneous venous access device placement within 7 days prior registration.

g. Participants must have fully recovered from the effects of prior surgery in the opinion of the treating investigator. Any participants with postoperative bleeding complications or wound complications from a surgical procedure performed in the last eight weeks should be excluded.

h. Participants must not have plans to undergo elective or planned major surgery during the clinical trial.

i. Participants must not have active bleeding or prior history of GI perforation, fistula or significant GI bleeding (requiring transfusion, endoscopic or surgical intervention) within 84 days prior to registration.

j. Participants must not be planning to receive any concurrent chemotherapy, immunotherapy, investigational agents, biologic or hormonal therapy for cancer treatment while receiving treatment on this study.

k. Participants must not have a history of a Grade 3 or 4 allergic reaction attributed to humanized or human monoclonal antibody therapy.

l. Participants must not have a history of grade 3 or 4 immunotherapy related toxicities with the exception of hormonal abnormalities like thyroiditis or thyroid derangements. 

5.3. Clinical/Laboratory Criteria

a. Participants must be ≥ 18 years old.

b. Participants must have Zubrod Performance Status of 0-2 (see Section 10.5).

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

**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: Trinity Health SJMH IHA (Brighton, Ann Arbor, Chelsea, Canton), Livonia, Genesys, Sparrow

Eligibility Criteria:

5.1. Disease Related Criteria

a. Participants must have a histologically confirmed diagnosis of Classic Follicular Lymphoma (cFL). cFL was previously categorized as Grade 1-3A per WHO-HAEM4R, but grading of classic FL is no longer mandatory. Please refer to Section 4.1 regarding classification. NOTE: Participants with Follicular Lymphoma with uncommon features (uFL) are eligible, including FL with diffuse growth pattern (dFL). Diagnosis is as per local pathology. Lymphoma FISH is not required. Molecular testing is not required.

b. Participants must not have Follicular Lymphoma with “blastoid” or “large centrocyte” cytological features, or Follicular large B-cell lymphoma (FLBL) (Previously categorized as follicular lymphoma grade 3B).

c. Participants must have low-tumor burden follicular lymphoma defined as:

1. Nodal or extra-nodal tumor mass with diameter less than 7 cm in its greater diameter

2. Involvement of no more than 3 nodal or extra nodal sites with diameter greater than 3 cm.

3. Absence of B symptoms

4. No symptomatic splenomegaly

5. No compression syndrome (ureteral, orbital, gastrointestinal)

6. No pleural or peritoneal serous effusion related to follicular lymphoma Participants must have Ann Arbor stage II, III, or IV follicular lymphoma. Participants with Stage I disease may be included if they do not wish to undergo radiation or are not candidates for radiation. Please refer to Section 4.2 regarding staging classification.

d. Participants must either be experiencing distress due to their disease or would prefer active management of their disease rather than a watch and wait approach.

e. Participants must have staging imaging performed within 49 days prior to registration, as follows. PET-CT baseline scans are preferred. If a baseline PET-CT scan cannot be obtained, CT scans of the chest, abdomen, and pelvis, along with a bone marrow biopsy, are acceptable. If CT scans are used for staging at baseline, a CT scan of the neck is recommended. All measurable dominant lesions must be assessed within 49 days prior to registration (see Section 10.1a.). Tests to assess non-measurable disease must be performed within 49 days prior to registration. All disease must be assessed and documented on the Baseline Tumor Assessment Form. NOTE: if the initial evaluation is insufficient to detect measurable disease, treating investigators may obtain a CT scan with contrast.

f. Participants must have bi-dimensionally measurable disease (at least one lesion with longest diameter >1.5 cm).

5.2. Prior/Concurrent Therapy Criteria

a. Participants must not have had prior systemic therapy for follicular lymphoma. Radiation therapy for a previous diagnosis of early-stage follicular lymphoma is allowed.

5.3. Clinical/Laboratory Criteria

a. Participant must be ≥ 18 years of age at the time of registration.

b. Participant must have Zubrod Performance Status of 0-2 (see Section 10.4).

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

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

Eligibility Criteria:

a. Disease Related Criteria

1. Participants must have a histologically confirmed diagnosis of prostate cancer at the time of Step 1 Registration.

2. Participants must have castrate-resistant prostate cancer and metastatic disease by bone scan and/or CT/MRI (i.e., soft tissue, visceral, lymph node).

b. Prior/Concurrent Therapy Criteria

1. Participants may have received any prior therapy, but one must be docetaxel or contain docetaxel in either the castrate-sensitive and/or castrate resistant disease state.

c. 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 solid tumor biopsy material (formalin-fixed paraffin\u0002embedded (FFPE) tissue blocks and/or 10 cut slides on four-micron thick unstained positive charged slides of FFPE tissue) available for submission for alterations in TP53, RB1 and PTEN by IHC using CLIA certified assays in the MD Anderson Clinical Pathology Laboratory. This specimen is required for central assessment of the AVPC-MSIHC regardless of whether the site has already locally evaluated the AVPC-MS status.

2. Tumor samples submitted for analysis must have been collected within 12 months prior to Step 1 Screening Registration. Samples from metastatic lesions collected in the castrate-resistant disease state are preferable but not mandatory. Samples obtained during the hormone-naïve disease state are acceptable if collected within 12 months of Step 1 Screening Registration. If more than one tumor sample exists, the sample obtained closest to the date of registration should be submitted to MDACC for analysis.

NOTE: Sites will receive an email from SWOG Statistics and Data Management Center containing participant results of Aggressive Variant Prostate Cancer Molecular Signature (AVPC-MS) assessment within 5-12 business days after tissue submission to MD Anderson Clinical Pathology Laboratory. The participant's AVPC-MS signature result (Positive or Negative) is required BEFORE randomization on to Step 2. If sites receive a non-evaluable AVPC-MS signature result, SWOG Statistics and Data Management Center will provide instructions for resubmission.  

a. Disease Related Criteria

1. Participants must have castrate levels of testosterone with a baseline level < 50ng/dL within 28 days prior to Step 2 Randomization.

2. Participants must have evidence for metastatic prostate cancer by bone scan and/or CT/MRI (i.e., soft tissue, visceral, lymph node). Visceral and/or soft-tissue metastases must be ≥1.0 cm in diameter and lymph nodes must be >1.5 cm diameter in the short axis. Scans must be obtained within 28 days prior to randomization. 

NOTE: All disease must be assessed and documented on the Baseline/Pre-Registration Tumor Assessment Form.

**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:

Eligibility Criteria: Trinity Health SJMH IHA (Brighton, Ann Arbor, Chelsea, Canton), Livonia, Genesys 

5.1. Disease Related Criteria

a. Participants must have histologically or cytological confirmed diagnosis of clinical Stage II-IIIB (excluding clinical N3 disease) (as defined in Section 4.0) non-small cell lung cancer (NSCLC).

b. Participants must have had a complete (R0) resection of NSCLC (with appropriate lymph node sampling as defined by the NCCN Guidelines) within 84 days (12 weeks) prior to randomization. Acceptable types of surgical resection are: lobectomy, sleeve resection, bi-lobectomy, or pneumonectomy. Wedge resection is not allowed. Note the NCCN Guidelines: N1 and N2 node resection and mapping is a routine component of lung cancer resections. It is recommended at a minimum one N1 and three N2 stations is sampled or complete lymph node dissection. Formal ipsilateral mediastinal lymph node dissection is indicated for participants undergoing resection for N2 disease.

c. Participants must have a pathologic complete response (pCR) (no viable tumor in the resected specimen or lymph nodes), as determined by local pathology review.

d. Participants must have a PD-L1 status result (e.g. (<1% versus >= 1% or unknown).

e. Participants must not have known EGFR mutations, or ALK gene fusion.  

5.2. Prior/Concurrent Therapy Criteria

a. Participants must have received at least two cycles of neoadjuvant platinum-based chemotherapy and anti-PD-1 or anti-PD-L1 therapy. The neoadjuvant treatment must be FDA approved and standard of care as listed in NCCN guidelines.

b. Participants must not be planning to receive any concurrent non-protocol directed chemotherapy, immunotherapy, biologic or hormonal therapy for NSCLC treatment while receiving treatment on this study.

c. Participants must not have received any prior systemic therapy (systemic chemotherapy, immunotherapy or investigational drug) within 28 days prior to randomization.

d. Participants must not have medical contraindications or severe adverse events to receiving anti-PD-1 or anti-PD-L1 therapy. 

e. Participants must not have received post-operative radiation therapy (PORT) for NSCLC.

f. Participants must not have any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, and vitiligo. Note, participants with Grade ≥2 neuropathy may be included at the discretion of the treating investigator. Note, participants with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included at the discretion of the treating investigator.

5.3. Clinical/Laboratory Criteria

a. Participant must be ≥ 18 years old at time of study entry.

b. Participants must have body weight > 30 kg.

c. Participants must have Zubrod Performance Status of 0-2 (see Section 10.2).

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

**PLEASE SEE CURRENT VERSION OF PROTOCOL FOR FULL ELGIBILITY LIST**