*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, St. John Detroit, St. John Macomb

Disease Related Criteria

a. Participants must have been assigned to S1800D by the SWOG Statistics and Data Management Center (SDMC). Assignment to S1800D is determined by the LUNGMAP or S1400 protocol.

b. Participants must have measurable or non-measurable disease (see Section 10.1) documented by CT or MRI. Measurable disease must be assessed within 28 days prior to randomization. Non-measurable disease must be assessed within 42 days prior to randomization. The CT from a combined PET/CT may be used only if it is of diagnostic quality as defined in Section 10.1a. All known sites of disease must be assessed and documented on the Baseline Tumor Assessment Form (RECIST 1.1).

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

d. Participants with spinal cord compression or brain metastases must have received local treatment to these metastases and remained clinically controlled and asymptomatic for at least 7 days following stereotactic radiation and/or 14 days following whole brain radiation, and prior to sub-study randomization.

e. Participants with spinal cord compression or brain metastases must not have residual neurological dysfunction, unless no further recovery is expected, and the participant has been stable on weaning doses of corticosteroids (≤ 10 mg daily prednisone or equivalent) prior to sub-study randomization.

f. Participants must not have leptomeningeal disease that requires CNS-specific treatment prior to registration and must not be planning to receive the CNS-specific treatment through the first cycle of the protocol therapy.

g. Participants must not have experienced the following:

• Any Grade 3 or worse immune-related adverse event (irAE). Exception: asymptomatic nonbullous/nonexfoliative rash. • Any unresolved Grade 2 irAE.

• Any toxicity that led to permanent discontinuation of prior anti-PD-1/PD-L1 immunotherapy. Exception to the above: Toxicities of any grade that requires replacement therapy and has stabilized on therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) are allowed. h. Participants must not have any history of organ transplant that requires use of immunosuppressives.

i. Participants must not have history of (non-infectious) pneumonitis that required steroids or current pneumonitis/interstitial lung disease.

j. Participants must not have any known allergy or reaction to any component of the investigational formulations. If there is a known allergy or reaction to standard of care formulations, participants must be able to safely receive at least one of the standard of care options.

k. Participants must not have any Grade III/IV cardiac disease as defined by the New York Heart Association Criteria (i.e., participants with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort), unstable angina pectoris, and myocardial infarction within 6 months prior to sub-study randomization, or serious uncontrolled cardiac arrhythmia (see Appendix 18.1).

l. Participants must not have experienced any arterial thromboembolic events, including but not limited to myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable angina, within 6 months prior to sub-study randomization.

m. Participants must not have an active or uncontrolled infection in the opinion of the treating investigator.

n. Participants must not have a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen.

o. Participants must not have any of following:

• cirrhosis at a level of Child-Pugh B (or worse) (See Appendix 18.4);

• 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.

p. Participants must not have any family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes or risk factors for Torsade de Pointes including heart failure of hypokalemia.

Prior/Concurrent Therapy Criteria

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

b. Participants with a known sensitizing mutation for which an FDA-approved targeted therapy for NSCLC exists (e.g. EGFR, ALK gene fusions, ROS1, BRAF, RET, NTRK, and MET sensitizing mutations), must have previously received at least one of the approved therapy(s).

c. Participants must have received exactly one line of anti-PD-1 or anti-PD-L1 therapy for advanced disease (Stage IV or recurrent, or Stage III in certain circumstances outlined below) given alone or in combination with platinum-based chemotherapy. Participants must have experienced disease progression during or after this regimen.

• Continuing the same agent(s) after progression counts as a single line of therapy. However, a change or addition in agent(s) after progression (e.g. the addition of chemotherapy to anti-PD-1 monotherapy after progression) counts as a subsequent line of therapy and would exclude the participant.

• For participants who received consolidation anti-PD-1 or anti-PD-L1 therapy following concurrent chemoradiation for Stage III disease as their only line of anti-PD-1 or anti-PD-L1 therapy:

1. If they experienced disease progression less than (<) 365 days from the first date of anti-PD-1 or anti-PD-L1 therapy, this counts as the single line of anti-PD-1 or anti-PD-L1 therapy for advanced disease.

2. If they experienced disease progression more than or equal to (≥) 365 days from the first date of anti-PD-1 or anti-PD-L1 therapy, this is not considered a line of anti-PD-1 or anti-PD-L1 therapy for advanced disease.

d. Participants must have recovered (≤ Grade 1) from any side effects of prior therapy, except for alopecia.

e. Participants must not have received anti-CTLA4 therapy (e.g. ipilimumab, tremelimumab), or other immune-modulatory therapy (e.g. anti-TIM-3, anti-LAG-3, anti-GITR, IL-2, IL-15).

f. Participants must not have received any prior systemic therapy (systemic chemotherapy, immunotherapy or investigational drug) within 21 days prior to sub\u0002study randomization.

g. Participants must not have received any radiation therapy within 14 days prior to sub-study randomization. h. Participants must not have received nitrosoureas or mitomycin-c within 42 days prior to sub-study randomization.

i. Participants must not have received systemic treatment with corticosteroids (> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 7 days prior to sub-study randomization. Inhaled or topical steroids, and adrenal replacement doses ≤ 10 mg daily prednisone or equivalent are permitted in the absence of active autoimmune disease.

j. Participants must not have received a live attenuated vaccination within 28 days prior to sub-study randomization (See Appendix 18.6). All COVID-19 vaccines that have received FDA approval or FDA emergency use authorization are acceptable.

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

l. Participants must not have had a major surgery within 14 days prior to sub-study randomization. Participant must have fully recovered from the effects of prior surgery in the opinion of the treating investigator.

Clinical/Laboratory Criteria

a. Participants must be able to safely receive at least one of the investigator’s choice of standard of care regimens specified in protocol Section 7.5, per the current FDA\u0002approved package insert.

Note: Pemetrexed is not FDA-approved for squamous cell NSCLC and must not be used to treat participants with squamous cell NSCLC.

b. Participants must have an ANC ≥ 1.5 x 10^3/uL, platelet count ≥ 100 x 10^3/uL, and hemoglobin ≥ 9 g/dL obtained within 28 days prior to sub-study randomization.

c. Participants must have adequate hepatic function as defined by serum bilirubin ≤ Institutional Upper Limit of Normal (IULN) and ALT and AST ≤ 2 x IULN within 28 days prior to sub-study randomization. For participants with liver metastases, bilirubin and ALT and AST must be ≤ 5 x IULN.

d. Participants must have a serum creatinine ≤ the IULN or calculated creatinine clearance ≥ 50 mL/min using the following Cockcroft-Gault Formula. This specimen must have been drawn and processed within 28 days prior to sub-study randomization.

e. Participants’ most recent Zubrod performance status must be 0-1 (Section 10.4) and be documented within 28 days prior to sub-study randomization.

f. Participants must have history and physical exam must be obtained within 28 days prior to sub-study randomization.

g. Participants with known human immunodeficiency virus (HIV) infection must be receiving anti-retroviral therapy and have an undetectable viral load at their most recent viral load test within 6 months prior to sub-study randomization.

h. Participants must have an ECG performed, with a QTcF ≤ 470 msec, within 28 days prior to sub-study randomization.

i. Participants must not have an active autoimmune disease that has required systemic treatment within two years prior to sub-study randomization (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.

j. Participants must not have any history of primary immunodeficiency.

k. Participants must not be pregnant or nursing. Women/men of reproductive potential must have agreed to use an effective contraceptive method during the study and 4 months after completion of study treatment. 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 during the study and 4 months after study completion.

Specimen Submission Criteria

a. Participants must also be offered participation in banking and in the correlative studies for collection and future use of specimens as described in Section 15.0.

*DTL Required- Physicians must sign toxicity grid

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

CURRENT SITES CREDENTIALED: Trinity Health SJMH IHA (Ann Abror, Brighton, Canton, Chelsea), Livonia, Genesys, Oakland

Eligibility Criteria:

 5.1 Disease Related Criteria

a. Participants must have been assigned to S1800E by the SWOG Statistics and Data Management Center (SDMC). Assignment to S1800E is determined by the LUNGMAP protocol.

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

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

5.2 Prior/Concurrent Therapy Criteria

a. Participants must have received exactly one anti-PD-1 or anti-PD-L1 therapy for advanced disease (Stage IV or recurrent disease, or Stage I-III disease in certain circumstances outlined below). Anti-PD-1 or anti-PD-L1 therapy may have been given alone or in combination with other therapy. For participants who received neoadjuvant, adjuvant, and/or consolidation anti-PD-1 or anti-PD-L1 therapy for Stage I-III disease:

• If they experienced disease progression within (≤) 365 days from initiation (Cycle 1 Day 1) or anti-PD-1 or anti-PD-L1 therapy, this counts as the single allowed anti-PD-1 or anti-PD-L1 therapy for advanced disease.

• If they experienced disease progression more than (>) 365 days from initiation (Cycle 1 Day 1) or anti-PD-1 or anti-PD-L1 therapy, this is not considered anti-PD-1 or anti-PD-L1 therapy for advance disease. These participants must have received anti-PD-1 or anti-PD-L1 therapy for Stage IV or recurrent disease.  

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

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

d. Participants must have received platinum-based chemotherapy and experienced disease progression (in the opinion of the treating investigator) during or after this regimen.

e. Participants with a known sensitizing molecular alteration for which a 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.

f. Participants must have recovered (≤ Grade 1) from any side effects from the most recent anti-cancer treatment prior to randomization.

g. Participants must not have received prior therapy with docetaxel for this disease.

h. Participants must not have received any palliative radiation therapy within 14 days (or palliative bone radiation therapy within 7 days) prior to randomization.

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

j. Participants must not have undergone major surgery within 28 days prior to randomization, or subcutaneous venous access device placement within 7 days prior to randomization. Participants must not have postoperative bleeding complications or wound complications from a surgical procedure performed within 2 months prior to randomization. The participant must not have elective or planned major surgery to be performed during the course of this study 

5.3 Clinical/Laboratory Criteria

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

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

- hemoglobin ≥ 9.0 g/dL - platelets ≥100 x 10^3/uL

- total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) unless history of Gilbert’s disease. Participants with history of Gilbert’s disease must have total bilirubin ≤ 5 x institutional ULN. 

- AST and ALT ≤ 3 × institutional ULN. Participants with history of liver metastasis must have AST and ALT ≤ 5 x ULN

b. Participants must have a creatinine ≤ the IULN or calculated creatinine clearance ≥ 50 mL/min using the following Cockcroft-Gault Formula. This specimen must have been drawn and processed within 28 days prior to randomization 

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

-Patients must have resectable melanoma in order to be eligible for this study. Patients must have clinically detectable Stage III (clinically detectable N1b, N1c, N2b, N2c, N3b and N3c) or Stage IV resectable melanoma. Patients with melanoma of mucosal or acral origin are eligible. Patients with melanoma of uveal origin are not eligible. Patients with a history of brain metastases are not eligible.
-Patients are eligible for this trial either at initial presentation of their melanoma or at the time of the first detected nodal, satellite/in-transit, distant metastases, or recurrent disease in prior lymphadenectomy basin or distant site. Nodal, satellite/in-transit metastasis, distant metastases or disease in a prior complete lymphadenectomy basin must have been confirmed histologically by H & E stained slides.
-Patients with multiple regional nodal basin involvement are eligible. Gross or microscopic extracapsular nodal extension is permitted.
-Patients must not have received previous neoadjuvant treatment for their melanoma. Patients may have received prior non-immunotherapy adjuvant therapy. Patients must not have had prior immunotherapy including, but not limited to ipilimumab, interferon alfa-2b, high dose IL-2, PEG-IFN, anti-PD-1, anti-PD-L1 intra-tumoral, or vaccine therapies. Patients must not be planning to receive any of the prohibited therapies listed in Section 7.2

during treatment phases on the study.
-Patients must not be planning to receive concomitant other biologic therapy, hormonal therapy, other chemotherapy, surgery, while on protocol therapy.
-Patients may have received prior radiation therapy, including after prior surgical resection. All adverse events associated with prior surgery and radiation therapy must have resolved to = Grade 1 prior to randomization.
-All patients must have disease status documented by a complete physical examination and imaging studies within 42 days prior to randomization. Imaging studies must include a total body PET-CT scan that is of diagnostic quality with iodine contrast-enhanced images (with or without brain) or a CT of the chest, abdomen and pelvis with intravenous contrast. For patients with melanoma arising from the head and neck, dedicated neck imaging (CT with intravenous contrast or iodine contrast-enhanced PET-CT through the region) is required. If the patient has unknown primary with disease in the axilla, neck imaging is required to assure region is clear of cancer. CT imaging should be done with intravenous contrast if there are no contraindications for it. Any other clinically-indicated imaging studies if performed (e.g. bone scan) must show no evidence of disease.
-All patients must have a CT or MRI of the brain within 42 days prior to randomization. The brain CT or MRI should be performed with intravenous contrast (unless contraindicated).
-Patients must have Zubrod Performance Status = 2

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

 ***CREDENTIALING is required

 Sites Credentialed- SJMH, Saginaw, Sparrow, SJMO, Lehigh Valley (Cedar Crest, Muhlenberg)

-All patients must have a histologically or cytologically proven diagnosis of adenocarcinoma of the prostate. Patients with pure small cell carcinoma* (SCC), sarcomatoid, or squamous cell carcinoma are not eligible. (*morphology must be consistent with SCC; synaptophysin or chromogranin positive by immunohistochemical staining is insufficient to diagnose SCC).
-Patients must have an intact prostate. No prior local therapy for prostate adenocarcinoma is allowed (e.g., brachytherapy, HIFU, cryotherapy, laser ablative therapies). Any prior therapy for benign conditions, such as obstruction, are acceptable (e.g., transurethral resection of the prostate, greenlight laser ablation, microwave ablation).
-Patients must have evidence of metastatic disease on technetium bone scan and CT or MRI within 42 days prior to starting standard systemic therapy. Metastatic disease that is detected by PET scan only (NaF, PSMA, FACBC, C11) but not conventional imaging (Tc99 bone scan, CT or MRI) or solitary metastases by conventional imaging, must be confirmed histologically or cytologically.
-Patients with known brain metastases are not eligible. Brain imaging studies are not required for eligibility if the patient has no neurologic signs or symptoms suggestive of brain metastasis. If brain imaging studies are performed, they must be negative for disease.
-Patients must have received no more than 28 weeks of SST. SST is defined as current NCCN guidelines for metastatic prostate cancer.
-Patients must not have progressed while on SST
-Patients with oligometastatic prostate cancer may receive metastasis directed therapy to up to four sites of disease prior to randomization. Acceptable approaches are included in Section 7.0
-

Patients must have a PSA documented prior to initiation of SST and within 28 days prior to registration. Any additional PSAs measured while receiving SST should be recorded.

-Patients must have a testosterone lab documented within 28 days prior to randomization. Any additional testosterone labs measured while receiving SST should be recorded as well as pretreatment initiation if available.
-No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, adequately treated Stage 0, I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years.

-Patients must have a testosterone < 50 ng/dL within 28 days prior to randomization.

-Patients must have a Zubrod performance status of 0 – 1 within 28 days prior to randomization (see Section 10.5).

**Effective 10/29/21, the TruCulture TM collection has been permanently halted.**

**Effective 03/01/2024 Step 1 Registration is Closed To Accrual**

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

Current sites credentialed: SJMH (Ann Arbor, Brighton, Canton, Chelsea), Livonia, Sparrow, SJMO, St. John, Macomb

- Patients must have histologically proven, T2-T4a N0M0 urothelial carcinoma of the bladder within 70 days prior to randomization. Patients with mixed urothelial carcinoma will be eligible for the trial, but the presence of small cell carcinoma will make a patient ineligible. Patients with lymph nodes = 1.0 cm in shortest cross-sectional diameter on imaging (CT / MRI) must have a biopsy of the enlarged lymph node showing no tumor involvement within 70 days prior to randomization. These patients may be suitable for neoadjuvant chemotherapy and radical cystectomy and are eligible for this trial if they seek out a bladder sparing treatment strategy, however patients who have received prior systemic chemotherapy for bladder cancer are not eligible for the trial.
-Patients must undergo a TURBT within 70 days prior to randomization. In a situation where a patient is referred from outside to the enrolling institution, patient must have a repeat cystoscopy by the urologist who will be following the patient on the clinical trial to assess the adequacy of the prior TURBT. Patient may then undergo repeat TURBT if deemed necessary as standard of care by the treating urologist. Patients may have either completely or partially resected tumors as long as the treating urologist attempted maximal resection. Patient must not have T4b disease.
-Patients must undergo radiological staging within 70 days prior to randomization. Imaging of chest, abdomen, and pelvis must be performed using CT or MRI. Patients must not have evidence of T4bN1-3 disease. Eligibility is based on the local radiology report.
-Patients with hydronephrosis are eligible if they have unilateral hydronephrosis and kidney function meets criteria specified in Section 5.3e.
-Patients must not have had urothelial carcinoma or histological variant at any site outside of the urinary bladder within the previous 24 months except Ta/T1/Carcinoma in situ (CIS) of the upper urinary tract including renal pelvis and ureter if the patient had undergone complete nephroureterctomy.
-Patients must not have diffuse CIS based on cystoscopy and biopsy.

- Patient must be planning to receive one of the protocol specified chemotherapy regimens.
-All adverse events associated with any prior surgery and intravesical therapy must have resolved to CTCAE Grade = 2 prior to randomization.
-Patient must not have received any systemic chemotherapy for their bladder cancer.
-Patient must not have had prior pelvic radiation.
-Patients must not have received prior treatment for muscle invasive bladder cancer including neoadjuvant chemotherapy for the current tumor.

-Patients must not have received any systemic therapy (including, but not limited to, interferon alfa-2b, high dose IL-2, PEG-IFN, anti-PD-1, anti-PD-L1), for non-muscle invasive bladder cancer. Prior intravesical BCG, interferon, and intravesical chemotherapy are allowed.

- Patients must not have received any of the following prohibited therapies within 28 days prior to randomization or be planning to receive any of the following prohibited therapies during protocol treatment:

• Anti-cancer systemic chemotherapy or biological therapy not specified in the protocol.

• Immunotherapy not specified in this protocol.

• Systemic or intravesical use of any non-study anti-cancer agent (investigational or non-investigational).

• Investigational agents other than atezolizumab.

• Live vaccines: 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. Prior administration of intravesical BCG is allowed.

• Glucocorticoids for any purpose other than to modulate symptoms from an event of suspected immunologic etiology. The use of physiologic doses of corticosteroids (defined as 10 mg prednisone) are acceptable, however site investigators should consult with the Study Chair for any dose higher than 10 mg prednisone. Dexamethasone 4 mg iv with chemotherapy to prevent nausea is allowed.

•RANKL infusion: Concurrent denusumab (which binds the cytokine RANKL) for any known indication is prohibited due to interaction with study medication.
-Patients must not have a major surgical procedure within 28 days prior to randomization. If patient had any surgical procedure then they should have recovered to full presurgical performance status and surgical adverse events should have resolved to grade < 2. TURBT is not considered a major surgical procedure.
-Patients must not have received treatment with systemic immunosuppressive medications (including, but not limited to, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 14 days prior to randomization. Exceptions:

• Patients may have received acute, low dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea).

• The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed. Physiological doses equivalent of 10 mg prednisone daily are allowed. Short term steroids given as antiemetic therapy, e.g. 4 mg dexamethasone or equivalent once a week, is allowed.
-Patients must not have received a live, attenuated vaccine within 4 weeks prior to randomization or anticipate that such a live, attenuated vaccine will be required while on protocol treatment and up to 5 months after the last dose of protocol treatment.

- Inactivated influenza vaccination should be given during influenza season only (approximately October to March). Patients must not receive live, attenuated influenza vaccine within 4 weeks prior to randomization or while on protocol treatment and up to 5 months after the last dose of protocol treatment.
-Patients must not have undergone prior allogeneic bone marrow transplantation or prior solid organ transplantation.
-Patient may or may not be radical cystectomy candidates.

*DTL Required- Physicians must sign toxicity grid

CREDENTIALING REQUIRED. Please check your site's credentialing status.
CURRENT SITES CREDENTIALED: SJMH, Livonia, LVHN (PA055)

Eligibility Criteria:

Disease Related Criteria

a. All patients must have histologically confirmed newly diagnosed, previously untreated Stage III or IV classical Hodgkin lymphoma (nodular sclerosing, mixed cellularity, lymphocyte-rich, or lymphocyte-depleted, or not otherwise specified (NOS)). Nodular lymphocyte predominant Hodgkin Lymphoma is not eligible.

b. Patients must have bidimensionally measurable disease (at least one lesion with longest diameter ≥ 1.5 cm) documented on the Lymphoma Baseline Tumor Assessment Form in Rave.

c. Patients must have a whole body or limited whole body PET-CT scan performed within 42 days prior to registration. (A contrast-enhanced (diagnostic) CT, MRI or MR-PET is acceptable in event that PET-CT is contra-indicated, however if it is later possible to administer a PET-CT, then PET-CT is strongly preferred for the interim scan (after Cycle 2) (if performed) and the EOT assessment. Otherwise, if PET-CT is not subsequently possible, then the same modality as baseline must be used throughout the trial.) NOTE: All images from PET-CT, CT, MRI or MR-PET scans performed as standard of care to assess disease (within 42 days prior to registration) must be submitted as indicated in Section 15.4 and associated radiology reports must be submitted as indicated in Section 14.4a.

-Age criteria: Patients must be ≥ 12 years of age.

Prior/Concurrent Therapy Criteria

a. Patients must not have received any prior chemotherapy, radiation, or antibody\u0002based treatment for classical Hodgkin lymphoma. Steroid pre-treatment is permitted as outlined in Section 5.4k

b. Patients must not have had prior solid organ transplant.

c. Patients must not have had prior allogeneic stem cell transplantation.

d. Patients must not have received a live vaccine within 30 days prior to planned Day 1 of protocol therapy (e.g. measles, mumps, rubella, varicella, yellow fever, rabies, BCG, oral polio vaccine, and oral typhoid).

e. At registration, investigator must declare intent-to-treat with Residual PET Radiation Therapy (Residual PET RT- RPRT) to be administered after patient completes 6 cycles of therapy if, after end of treatment, the patient meets criteria specified in Section 7.5 for receiving RT). Patients will be stratified by investigator’s intent-to-treat with Residual PET RT. • All pediatric patients (< 18 years of age) will be considered intent-to-treat with Residual PET RT at time of registration.

- Clinical/Laboratory Criteria

Please note that eligibility criteria and the timing of documentation prior to registration differ by age. a. Patients must have a performance status corresponding to Zubrod scores of 0, 1 or 2. Use Lansky for patients ≤ 17 years of age. *The conversion of the Lansky to ECOG scales is intended for NCI reporting purposes only. See Sections 10.3 and 18.4. b. Patients must have adequate renal function as indicated below:

Adults (age 18 or older):

• Creatinine clearance ≥ 30 mL/min, as estimated by the Cockcroft and Gault formula. The creatinine value used in the calculation must have been obtained within 28 days prior to to registration. Estimated creatinine clearance is based on actual body weight

c. Patients must have adequate hepatic function, evidenced by the following*: • Total bilirubin ≤ 2 x IULN, and • AST and ALT ≤ 3 x IULN * unless due to Gilbert’s disease, lymphomatous involvement of liver or vanishing bile duct syndrome For adults (age 18 or older), above hepatic function must be documented within 28 days prior to registration. For pediatric Patients (age 12-17), above hepatic function must be documented within 14 days prior to registration.

d. Patients must have adequate cardiac function defined as follows: Patients must have an echocardiogram (ECHO), MUGA, or functional cardiac imaging scan with a left ventricular ejection (LVEF) fraction ≥ 50% or a shortening fraction of ≥ 27%. For all patients, the ECHO, MUGA, or functional cardiac imaging scan must be performed within 42 days prior to registration.

e. Patients with known human immunodeficiency virus (HIV) infection must be receiving anti-retroviral therapy and have an undetectable or unquantifiable viral load at their most recent viral load test within 6 months prior to registration.

f. Patients must not have known active Hepatitis B (HBV) or Hepatitis C Virus (HCV) at date of registration. Patients with previously treated HBV or HCV that have an undetectable viral load within 6 months prior to registration and no residual hepatic impairment are eligible.

g. Patients must not have any known central nervous system lymphoma.

h. Patients must not have a history of or active interstitial pneumonitis or interstitial lung disease. i. Patients must not have had a diagnosis of inherited or acquired immunodeficiency (unless allowed under Section 5.4e).

j. Patients must not have any known uncontrolled intercurrent illness including, but not limited to symptomatic congestive heart failure, unstable angina pectoris, hemodynamically unstable cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. k. Patients must not have a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to registration. Inhaled or topical steroids, and adrenal replacement doses >10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Steroid use for the control of Hodgkin lymphoma symptoms is allowable, but must be discontinued prior to Cycle1, Day1.

l. Patients with peripheral neuropathy must have < Grade 2 at date of registration.

m. Patients must not have active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, immunosuppressive drugs, or corticosteroids with doses higher than prednisone 10 mg or equivalent). Autoimmune diseases include but are not limited to autoimmune hepatitis, inflammatory bowel disease (including ulcerative colitis and Crohn’s disease), as well as symptomatic disease (e.g.: rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g., Wegener’s Granulomatosis]); CNS or motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre Syndrome and Myasthenia Gravis, multiple sclerosis or glomerulonephritis). Vitiligo, alopecia, hypothyroidism on stable doses of thyroid replacement therapy, psoriasis not requiring systemic therapy within the past 2 years are permitted.

n. No second prior malignancy is allowed except for adequately treated basal (or squamous cell) skin cancer, any in situ cancer or other cancer for which the patient has been disease free for two years.

o. Females of childbearing potential must not be pregnant or nursing, and have a negative pregnancy test within 28 days prior to registration. Women/men of reproductive potential must have agreed to use an effective contraceptive method while receiving study drug and for women until 6 months after receiving the last dose of study drug or, for men, until 7 months after receiving the last dose of study drug. 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.

Specimen Submission Criteria

a. Patients must have one formalin-fixed paraffin embedded (FFPE) diagnostic tumor block or at least 1 diagnostic, 4-5 micron, H&E slide collected prior to registration and available for submission, as outlined in Sections 12.1 and 15.1a.

b. Patients must be offered participation in banking for planned translational medicine and future research, as outlined in Section 15.2. With patient consent, any residuals from the mandatory tissue submission will also be banked for future research. Note: Streck tubes must be ordered in advance, as indicated in Section 15.2c. Allow 5-7 days for shipment of the collection kits.

- Patient-reported outcomes and PRO-CTCAE criteria

a. Patients who can complete Patient-Reported Outcome instruments in English, Spanish, or French must complete the PROMIS Fatigue, the FACT/GOG-Ntx, and the PROMIS Global prior to registration.

b. Patients who can complete Patient-Reported Outcome instruments in English, Spanish, or French must also agree to complete the PROMIS Fatigue, the FACT/GOG-Ntx, the PROMIS Global, and the PRO-CTCAE (or Ped PRO-CTCAE) at the scheduled on-study assessment timepoints.

CREDENTIALING REQUIRED. *Please check your site's credentialing status.
CURRENT SITES CREDENTIALED: SJMH (Ann Arbor, Chelsea, Canton, Brighton), Saginaw, St. John, St. John Macomb, SJMO, Lehigh Valley POCONO 

Eligibility Criteria:

Disease Related Criteria

a. Patient must have a histologically confirmed diagnosis of small-cell lung cancer (SCLC).

b. Patient must have an MRI of the brain performed within 28 days prior to registration documenting no evidence of brain metastases or leptomeningeal disease. Patient also must not have a history of brain metastases or leptomeningeal disease.

Prior/Concurrent Therapy Criteria

a. Immunotherapy concurrent with and/or adjuvant to first-line therapy is allowed at the discretion of the treating physician. Patients with LS-SCLC must have completed platinum-based chemotherapy and either definitive thoracic radiotherapy (including SBRT for early-stage T1-2 N0 M0 disease who do not undergo surgery) or definitive surgical resection; thoracic radiation in addition to definitive surgical resection is allowed at the discretion of the treating physician, but is not required. Patients with ES-SCLC must have completed platinum-based chemotherapy either with or without thoracic radiotherapy at the discretion of the treating physician.

b. All adverse events from prior treatment must have resolved to = Grade 2 (CTCAE Version 5.0) prior to randomization.

c. Patient must have had a response to first-line therapy and no evidence of progression in opinion of the treating investigator. Systemic imaging (CT or PET/CT including the chest and abdomen) must be performed within 28 days prior to randomization.

d. No more than 8 weeks may have elapsed between Day 1 of the last cycle of chemotherapy and randomization.

e. Patient must not have received prior radiotherapy to the brain or whole brain radiotherapy. Patients who have undergone prior stereotactic radiosurgery for benign tumors or conditions (e.g., acoustic neuroma, grade I meningioma, trigeminal neuralgia) may be considered on a case-by-case basis.

Clinical/Laboratory Criteria

a. Patient must be = 18 years of age.

b. Patient must have Zubrod Performance Status of 0-2 (see Section 10.9).

c. Patient must not have a contraindication to MR imaging, such as implanted metal devices or foreign bodies.

d. Patient must not have a contraindication to gadolinium contrast administration during MR imaging, such as allergy or insufficient renal function

e. Patient must not have other metastatic malignancies requiring current active treatment.

f. Patient must not have any severe active comorbidities, defined as follows:

• Unstable angina and/or congestive heart failure requiring hospitalization within 6 months prior to randomization

• Transmural myocardial infarction within 6 months prior to randomization

• Acute bacterial or fungal infection requiring intravenous antibiotics at the time of randomization

• Chronic obstructive pulmonary disease exacerbation or other acute respiratory illness precluding study therapy at the time of randomization

• Severe hepatic disease defined as a diagnosis of Child-Pugh class B or C hepatic disease

• HIV positive with CD4 count < 200 cells/microliter. Note that patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count = 200 cells/microliter within 16 weeks prior to randomization. Note also that HIV testing is not required for eligibility for this protocol. 

g. Patient must not be pregnant because of fetal risks from radiation exposure. Men must have agreed to use an effective contraceptive method during PCI and for six months after completing PCI. Women of reproductive potential must have agreed to use an effective contraceptive method during PCI. 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.

Additional Criteria

a. Patients who speak and understand English or French must agree to participate in cognitive function testing.

b. Patient must be offered the opportunity to have specimens submitted for banking

**Effective 11/16/2020, Cohort #1 (patients with squamous cell lung cancer) is closed to patient accrual.

**Effective 04/06/2020, Cohort #2 (patients with non-squamous cell lung cancer (adenocarcinoma, large cell, NSCLC NOS, mixed histology with any non-squamous component)) is Temporarily Closed**

*DTL Required- Physicians must sign toxicity grid

-Patients must be assigned to S1900A. S1900A

biomarker eligibility defined as LOH high and/or deleterious BRCA1/2 mutation is as follows using the FMI tissue- assay:
-

Biomarker-positive group	Alteration type	Eligible alteration
LOH	Loss of Heterozygosity (LOH)	Genomic LOH ? 21%
BRCA	Homologous Recombination Deficiency (HRD)	Deleterious mutations in BRCA1 or BRCA2

Patients must not have had prior treatment with any PARP inhibitor, including rucaparib, talazoparib, veliparib, olaparib, or niraparib.
-Patients must not have a ? Grade 3 hypercholesterolaemia (defined by NCI CTCAE v5) within 28 days prior to sub-study registration.

-Patients must not have EGFR sensitizing mutations, EGFR T790M mutation, ALK gene fusion, ROS 1 gene rearrangement, and BRAF V600E mutation unless they have progressed following all standard of care targeted therapy.

-Must have CD4 count ? 400/mcL.

-Patients must not have received any prior systemic therapy (systemic chemotherapy, immunotherapy or investigational drug) within 21 days prior to sub-study registration. Patients must have recovered (? Grade 1) from any side effects of prior therapy. Patients must not have received any radiation therapy within 14 days prior to sub-study registration.

-Patients must have measurable disease (see S1900A Section 10.1) documented by CT or MRI.

-Patient must not have had a major surgery within 14 days prior to sub-study registration.

-Patients must have an ANC ? 1,500/mcl, platelet count ? 100,000 mcl, and hemoglobin ? 9 g/dL obtained within 28 days prior to sub-study registration.

-Patients must have Zubrod performance status 0-1 (see S1900A Section 10.4) documented within 28 days prior to sub-study registration.

**Please note that the scan timing should be counted from the registration date NOT from the treatment start date.**

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

DTL Required- Physicians must sign the toxicity grid.

CURRENT SITES CREDENTIALED: SJMH (Ann Arbor, Brighton, Canton, Chelsea),Genesys, Sparrow, St. Mary's Livonia, St. John, St. John Macomb, St. Mary's Saginaw

CT scan schedule - schedule first scan 6 weeks (+/- 7 days) from date of sub-study registration.

Eligibility Criteria:

Disease Related Criteria

a. Patients must be assigned to S1900C. Assignment to S1900C is determined by the LUNGMAP protocol genomic profiling using the FoundationOne assay. Biomarker eligibility for S1900C is based on the identification of a pathogenic somatic mutation in STK11 or STK11 bi-allelic loss on tumor.

b. Patients must have histologically or cytologically confirmed Stage IV or recurrent non-squamous, mixed squamous/non-squamous (e.g., adeno-squamous carcinoma), or non-small cell lung cancer not otherwise specified (NSCLC NOS). Patients with pure squamous cell carcinoma are not eligible.

c. Patients with evidence of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load on suppressive therapy within 28 days prior to sub-study registration.

d. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. Patients with HCV infection who are currently on treatment must have an undetectable HCV viral load within 28 days prior to sub-study registration.

e. Patients with known human immunodeficiency virus (HIV) infection are eligible, provided 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 sub-study registration.

Prior/Concurrent Therapy Criteria

a. Patients must have received at least one line of anti-PD-1 or anti-PD-L1 therapy for Stage III, IV or recurrent disease.

Any number of additional, non-platinum-based chemotherapy or targeted therapy regimens for recurrent or metastatic disease are allowed.

1. Patients may not have received more than one line of anti-PD-1 or anti-PD-L1 therapy in the Stage IV or recurrent setting. Anti-PD-1 or anti-PD-L1 therapy may have been given alone or in combination with platinum-based chemotherapy, an anti-CTLA4 therapy, or other immune-modulatory therapy. Patients must have experienced disease progression>42 days following initiation (Cycle 1 Day 1) of the anti-PD-1 or anti-PD-L1 containing regimen.

2. Patients who did not receive anti-PD-1 or anti-PD-L1 therapy in combination with platinum-based chemotherapy, must have also received prior platinum-based chemotherapy and experienced disease progression >42 days following initiation (Cycle 1 Day 1) of platinum based chemotherapy.

3. Patients who received anti-PD-1 or anti-PD-L1 therapy following concurrent chemoradiation for Stage III disease as their only line of anti-PD-1 or anti-PD-L1 therapy, are eligible if they experienced disease progression less than (<) 365 days from the date of initiation of anti-PD-1 or anti-PD-L1 therapy.

b. Patients who received prior adjuvant platinum-based therapy post-surgical resection for Stage I-III disease (i.e. the patient has not received platinum-based chemotherapy for Stage IV or recurrent disease) must have had disease progression during or after platinum-based chemotherapy that occurred less than (<) 365 days from the last date that the patient received that therapy.

c. Patients must be able to swallow capsules whole.

d. Patients must not have had prior exposure to any agent with a PARP inhibitor (e.g., veliparib, olaparib, rucaparib, niraparib, talazoparib) as its primary pharmacology.

e. Patients must not be taking, nor plan to take while on protocol treatment strong P-gp inhibitors (e.g. droneradone, quinidine, ranolazine, itraconazole, ketononazole), P-gp inducers (rifampin, ritonavir, tipranavir), or strong breast cancer resistance protein (BCRP) inhibitors (e.g. elacridar).

f. Patients must have progressed following their most recent line of therapy.

g. Patients must not have received prior systemic immunotherapy within 28 days prior to sub-study registration and must not have received any prior systemic therapy (including systemic chemotherapy or investigational drug) within 21 days prior to sub-study registration. Patients must have recovered (= Grade 1) from any side effects of prior therapy. Patients must not have received any radiation therapy within 14 days prior to sub-study registration. (See 5.2c.2 for criteria regarding therapy for CNS metastases).

h. Patients must not be planning to receive any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment while receiving treatment on this study. Concurrent use of hormones for non-cancer-related conditions (e.g., insulin for diabetes and hormone replacement therapy) is acceptable.

Clinical/Laboratory Criteria

a. Patients must have measurable disease (Section 10.1) documented by CT or MRI. The CT from a combined PET/CT may be used to document only non-measurable disease unless it is of diagnostic quality as defined in Section 10.1c. Measurable disease must be assessed within 28 days prior to sub-study registration. Pleural effusions, ascites and laboratory parameters are not acceptable as the only evidence of disease. Non-measurable disease must be assessed within 42 days prior to sub-study registration. All disease must be assessed and documented on the Baseline Tumor Assessment Form. Patients whose only measurable disease is within a previous radiation therapy port must demonstrate clearly progressive disease (in the opinion of the treating investigator) prior to sub-study registration. See Sections 15.5 and Appendix 18.2 for guidelines and submission instructions for required central radiology review. CT and MRI scans must be submitted for central review via TRIAD.

b. Patients must have a CT or MRI scan of the brain to evaluate for CNS disease within 42 days prior to sub-study registration. 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 sub-study registration, AND (2) patient has no residual neurological dysfunction and has been off corticosteroids for at least 24 hours prior to sub-study registration.

c. Patient must not have had a major surgery within 14 days prior to sub-study registration. Patient must have fully recovered from the effects of prior surgery in the opinion of the treating investigator.

d. Patients must have adequate hepatic function as defined by serum bilirubin = Institutional Upper Limit of Normal (IULN) and either ALT or AST = 2 x IULN within 28 days prior to sub-study registration (if both ALT and AST are done, both must be = 2 IULN). For patients with liver metastases, bilirubin and either ALT or AST must be = 5 x IULN (if both ALT and AST are done, both must be = 5 x IULN).

e. Patients must have a serum creatinine = the IULN or calculated creatinine clearance = 60 mL/min using the following Cockroft-Gault Formula. This specimen must have been drawn and processed within 28 days prior to sub-study registration

f. Patients must have Zubrod performance status 0-1 (Section 10.4) documented within 28 days prior to sub-study registration.

g. Patients must not have any Grade III/IV cardiac disease as defined by the New York Heart Association Criteria (i.e., patients with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort), unstable angina pectoris, and myocardial infarction within 6 months, or serious uncontrolled cardiac arrhythmia (Appendix 18.1).

h. Pre-study history and physical exam must be obtained within 28 days prior to sub-study registration.

i. No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years.

j. Patients must not be pregnant or nursing.

k. Patients must not have a history of prior organ transplantation, including allogeneic stem-cell transplantation.

l. Patients must not have received systemic treatment with corticosteroids (> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days prior to sub-study registration. Inhaled or topical steroids, and adrenal replacement doses = 10 mg daily prednisone or equivalent are permitted in the absence of active autoimmune disease.

m. Patients must not have active autoimmune disease that requires systemic steroids (equivalent of >10 mg of prednisone) or immunosuppressive agents within 14 days prior to sub-study registration (for example disease-modifying anti-rheumatic drugs). Exceptions include: patients with controlled type 1 diabetes mellitus, controlled hypo- or hyperthyroidism, vitiligo, resolved childhood asthma/atopy, or psoriasis not requiring immunosuppressive therapy.

n. Patients must not have any impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of talazoparib (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or active peptic ulcer disease). Patients must not have active small or large intestine inflammation such as Crohn's disease or ulcerative colitis within 12 months prior to sub-study registration.

o. Patients must not have known prior or suspected hypersensitivity to monoclonal antibodies (Grade =3).

p. Patients must not have any history of anaphylaxis or uncontrolled asthma.

Uncontrolled asthma is defined as a patient having any one of the following criteria:

1. Poor symptom control: ACQ consistently >1.5 or ACT <20 (or "not well controlled" by NAEPP or GINA guidelines over the 3 months or evaluation).

2. Frequent severe exacerbations: 2 or more bursts of systemic CSs (>3 days each) in the previous year.

3. Serious exacerbations: at least one hospitalization, Intensive Care Unit stay or mechanical ventilation in the previous year.

4. Airflow limitation: FEV1<80% predicted (in the presence of reduced FEV1/FVC defined as less than the normal lower limit) following a withhold of both short- and long-acting bronchodilators.

q. Patients must not have experienced any immune related adverse event, including pneumonitis that led to permanent discontinuation of prior immunotherapy and/or required prolonged high dose of steroids.

r. Patients must not have evidence of active infection requiring systemic therapy.

s. Patients must not have received any live attenuated vaccinations within 28 days prior to sub-study registration.

t. Patients must have an ANC = 1,500/mcl, platelet count = 100,000 mcl, and hemoglobin = 9 g/dL obtained within 28 days prior to sub-study registration. Patients must be transfusion independent (i.e., no blood product transfusions for a period of at least 14 days prior to sub-study registration).

Specimen Submission Criteria

a. Patients must agree to have blood specimens submitted for circulating tumor DNA (ctDNA) as outlined in Section 15.3.

b. Patients must also be offered participation in banking and in the correlative studies for collection and future use of specimens as described in Section 15.4.

**Cohort 1 closed to Accrual Effective 12/13/2023**

***Cohort 2 Closed to Accrual (Effect. 08/15/2024)**

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

DTL Required- Physicians must sign the toxicity grid.

CURRENT SITES CREDENTIALED: SJMH (Ann Arbor, Brighton, Canton, Chelsea), St. Mary's Livonia, Genesys, Sparrow, St John, Macomb

Eligibility Criteria:

Disease Related Criteria

a. Participants must be assigned to S1900E. Assignment to S1900E is determined by the LUNGMAP protocol genomic profiling using the FoundationOne assay. Biomarker eligibility for S1900E is based on the identification of a KRASG12C mutation.

b. Participants must have confirmed Stage IV or recurrent non-squamous non-small cell lung cancer (NSCLC). Mixed histology NSCLC with less than 50% squamous component is allowed.

c. Participants must have measurable disease (Section 10.1) documented by CT or MRI. The CT from a combined PET/CT may be used to document only non\u0002measurable disease unless it is of diagnostic quality as defined in Section 10.1c. Measurable disease must be assessed within 28 days prior to sub-study registration. Pleural effusions, ascites and laboratory parameters are not acceptable as the only evidence of disease. Non-measurable disease must be assessed within 42 days prior to sub-study registration. Participants whose only measurable disease is within a previous radiation therapy port must demonstrate clearly progressive disease (in the opinion of the treating investigator) prior to registration. See Sections 15.0 and Section 18.2 for guidelines and submission instructions for required central radiology review. CT and MRI scans must be submitted for central review via TRIAD.

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

e. Participants with known human immunodeficiency virus (HIV) infection must be receiving anti-retroviral therapy and have an undetectable viral load at their most recent viral load test within 6 months prior to sub-study registration.

f. Participants with EGFR sensitizing mutations, EGFR T790M mutation, ALK gene fusion, ROS1 gene rearrangement, or BRAF V600E mutation must have progressed following all standard of care targeted therapy.

g. Participants with spinal cord compression or brain metastases must have received local treatment to these metastases and remained clinically controlled and asymptomatic for at least 7 days following stereotactic radiation and/or 14 days following whole brain radiation, and prior to sub-study registration.

h. Participants with spinal cord compression or brain metastases must not have residual neurological dysfunction, unless no further recovery is expected, and the participant has been stable on weaning doses of corticosteroids prior to sub-study registration.

i. Participants must not have leptomeningeal disease unless: (1) asymptomatic and (2) only detected on radiographic imaging (i.e., not present in cytology from cerebral spinal fluid [CSF] if CSF sampled).

Prior/Concurrent Therapy Criteria

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

b. Participants must have progressed (in the opinion of the treating physician) following the most recent line of systemic therapy for NSCLC.

c. Participants must have recovered (≤ Grade 1) from side effects of prior therapy. The exception is if a side effect from a prior treatment is known to be permanent without expected further recovery or resolution (i.e., endocrinopathy from immunotherapy or cisplatin neurotoxicity).

d. Participants must not have received any prior systemic therapy (systemic chemotherapy, immunotherapy or investigational drug) within 21 days prior to sub\u0002study registration.

e. Participants must not have received any radiation therapy within 14 days prior to sub-study registration, with the exception of stereotactic radiation to CNS metastases which must have been completed at least 7 days prior to sub-study registration. (See Section 5.1g for criteria regarding therapy for CNS metastases).

f. Participants must not have received prior AMG 510 or other KRASG12C specific inhibitor.

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

h. Participants must not have had a major surgery within 14 days prior to sub-study registration. Participant must have fully recovered from the effects of prior surgery in the opinion of the treating investigator.

Clinical/Laboratory Criteria

a. Participants must be able to swallow tablets whole.

b. Pre-study history and physical exam must be obtained within 28 days prior to sub\u0002study registration. c. Participants must have an ANC ≥ 1,500/uL, platelet count ≥ 75,000/uL, and hemoglobin ≥ 9 g/dL obtained within 28 days prior to sub-study registration.

d. Participants must have adequate hepatic function as defined by serum bilirubin ≤ Institutional Upper Limit of Normal (IULN) and ALT and AST ≤ 2 x IULN within 28 days prior to sub-study registration. For participants with liver metastases, and ALT and AST must be ≤ 5 x IULN.

e. Participants must have a serum creatinine ≤ 1.5 x IULN or calculated creatinine clearance ≥ 50 mL/min using the following Cockcroft-Gault Formula. This specimen must have been drawn and processed within 28 days prior to sub-study 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.

f. Participants must have Zubrod performance status 0-1 (Section 10.4) documented within 28 days prior to sub-study registration. g. Participants must not have any Grade III/IV cardiac disease as defined by the New York Heart Association Criteria (i.e., participants with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort), unstable angina pectoris, and myocardial infarction within 6 months, or serious uncontrolled cardiac arrhythmia (see Appendix 18.1).

h. Participants must not have a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen.

i. Participants must not have gastrointestinal disorders that may impact drug absorption.

j. Participants must not have received strong inducers of CYP3A4 (including herbal supplements such as St. John’s Wort) within 14 days prior to sub-study registration and must not be planning to use strong inducers of CYP3A4 throughout protocol treatment. (See Appendix 18.6 for examples).

k. Participants must not have received CYP3A4 sensitive substrates (with a narrow therapeutic window) within 14 days prior to sub-study registration and must not be planning to use CYP3A4 sensitive substrates (with a narrow therapeutic window) throughout protocol treatment. (See Appendix 18.6 for examples).

l. Participants must not be pregnant or nursing. Participants with uteri must have agreed to use an effective contraceptive method for at least one month after the last dose of AMG 510. Participants with sperm must have agreed to use an effective contraceptive method for at least 3 months after the last dose of AMG 510. Participants are considered to be of "reproductive potential" if they have had menses at any time in the preceding 12 consecutive months and no prior oophorectomy and/or hysterectomy. In addition to routine contraceptive methods, "effective contraception" for participants with uteri 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. Acceptable methods of birth control for participants with sperm include sexual abstinence (refraining from heterosexual intercourse); vasectomy with testing showing there is no sperm in the semen; bilateral tubal ligation or occlusion in the partner; or a condom (the female partner should also consider a form of birth control). 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.

m. Participants of reproductive potential must have a negative serum pregnancy test within 28 days prior to sub-study registration.

Specimen Submission Criteria

a. Participants must agree to have blood specimens submitted for circulating tumor DNA (ctDNA) as outlined in Section 15.0.

b. Participants must be offered the opportunity to participate in specimen banking and in correlative studies for collection and future use of specimens as outlined in Section 15.4 With participant consent, specimens must be collected and submitted via the SWOG Specimen Tracking System as outlined in Section 15.2.