*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: FEV180% 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.

*DTL Required- Physicians must sign toxicity grid

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

Eligibility Criteria:

Disease Related Criteria

a. Participants must have been assigned to S1900G by the SWOG Statistics and Data Management Center (SDMC). Assignment to S1900G is determined by the LUNGMAP protocol.

b. Participants must have documentation of NSCLC with a sensitizing EGFR mutation and have radiologically or clinically progressed (in the opinion of the treating physician) on osimertinib, alone or in combination with other agent(s), as their most recent line of therapy. Any number of prior lines of therapy is allowed.

c. Participants must have a MET amplification determined by tissue-based or blood\u0002based (circulating tumor DNA [ctDNA]) NGS assay.  

d. Participants must have either measurable disease or non-measurable disease (Section 10.1) documented by CT or MRI.

Prior/Concurrent Therapy Criteria

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

b. Participants must not have received an anti-VEGF or VEGFR inhibitor or MET inhibitor.

c. Participants must not have received any anti-cancer drug (investigational or standard of care drug, except osimertinib) within 21 days prior to sub-study randomization.

Note: osimertinib may continue up to the day prior to study treatment initiation.

d. Participants must not have received any radiation therapy within 14 days prior to sub-study randomization.  

***Please see the current version of the protocol for complete eligibility criteria list.**** 

*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, Canton, Chelsea) and Livonia, Sparrow, Genesys, Hurley

Eligibility Criteria:

5.1 Disease Related Criteria

a. Participants must have been assigned to S1900J by the SWOG Statistics and Data Management Center (SDMC). Assignment to S1900J is determined by the LUNGMAP protocol.

b. Participants must have documentation of NSCLC with MET amplification determined by FMI tissue-based NGS assay.

c. Participants must have measurable disease (Section 10.1) documented by CT or MRI. The CT from a combined PET/CT may be used to document measurable disease ONLY if it is of diagnostic quality as defined in Section 10.1c.3: otherwise, it may be used to document non-measurable disease only. 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 known sites of disease must be assessed and documented on the Baseline Tumor Assessment Form. Participants whose only measurable disease is within a previous radiation therapy port must demonstrate clearly progressive disease (in the opinion of the treating investigator) prior to sub-study registration to be considered measurable.

d. Participants must have a CT or MRI scan of the brain to evaluate for CNS disease within 42 days prior to sub-study registration. e. Participants with asymptomatic CNS metastasis (brain metastases or leptomeningeal disease) must be clinically stable and asymptomatic for at least 14 days prior to sub-study registration.

NOTE: Participants can be on a low-dose corticosteroid treatment (≤10 mg prednisone or equivalent) for at least 14 days prior to study treatment.

f. Participants must not have other known actionable oncogenic alterations, such as (but not limited to) EGFR sensitizing mutations, EGFR T790M mutation, MET Exon-14 skipping mutant NSCLC, ALK gene fusion, ROS1 gene rearrangement, RET gene rearrangement, NTRK rearrangement, HER2 mutation, KRAS activating mutations, and BRAF V600E mutation. 

5.2 Prior/Concurrent Therapy Criteria

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

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

c. Participants must have recovered (≤ Grade 1) from any side effects of prior therapy. 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 been previously treated for any cancer with MET TKIs such as tepotinib, capmatinib, and crizotinib.

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

f. Participants must not have a prior treatment with anti-PD-1 or anti-PD-L1 antibody within 6 weeks of sub-study 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: SJMH TH (Brighton, Canton, Chelsea, Ann Arbor), Livonia, Genesys, Hurley, Sparrow

Eligibility Criteria:

5.1 Disease Related Criteria

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

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

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

c. Participants must have measurable disease (Section 10.1) documented by CT or MRI. The CT from a combined PET/CT may be used to document measurable disease ONLY if it is of diagnostic quality as defined in Section 10.1c: otherwise, it may be used to document non-measurable disease only. Measurable disease must be assessed within 28 days prior to sub-study randomization. Pleural effusions, ascites and laboratory parameters are not acceptable as the only evidence of disease. Non-measurable disease must be assessed within 42 days prior to sub-study randomization. All known sites of disease must be assessed and documented on the Baseline Tumor Assessment Form. Participants whose only measurable disease is within a previous radiation therapy port must demonstrate clearly progressive disease (in the opinion of the treating investigator) prior to sub\u0002study randomization to be considered measurable.

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

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

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

5.2 Prior/Concurrent Therapy Criteria

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

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

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

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

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

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

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

Eligibility Criteria:

Disease Related Criteria- Patient

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

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

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

Prior/Concurrent Therapy Criteria – Patient

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

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

c. Patients are allowed to be co-enrolled on other clinical trials (including non\u0002treatment studies and studies that may or may not include investigational drugs).

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

Clinical/Laboratory Criteria - Patient

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

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

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

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

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

Spouse Caregiver Criteria

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

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

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

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

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

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

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

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

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

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

Eligibility Criteria:

5.1 Disease Related Criteria

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

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

• Tumor diameter = 2 cm as assessed by diagnostic CT

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

• Moderately differentiated, poorly differentiated, or undifferentiated histology

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

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

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

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

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

5.2 Prior/Concurrent Therapy Criteria

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

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

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

5.3 Clinical/Laboratory Criteria

a. Patient must be = 18 years old.

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

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

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

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

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

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

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

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

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

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

l. Patient must not have an active autoimmune disease that has required systemic treatment in past two years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.

m. Patient must be tested for hepatitis B within 28 days prior to randomization. Patient must not have active (chronic or acute) hepatitis B virus (HBV) infection. Patients may have past or resolved HBV infection.

Active HBV is defined as having a positive hepatitis B surface antigen (HBsAg) test.

Past or resolved HBV is defined as having a negative HBsAG test and a positive total hepatitis B core antibody (HBcAb) test.

n. Patient must be tested for hepatitis C within 28 days prior to randomization. Patient must not have active hepatitis C virus (HCV) infection.

Active HCV is defined as having a positive HCV antibody test followed by a positive HCV RNA test.

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

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

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

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

s. Patients must not be pregnant due to the potential teratogenic side effects of the protocol treatment. Women of reproductive potential and men must have agreed to use an effective contraception method for the duration of protocol treatment, and for 5 months (150 days) after the last dose of atezolizumab. A woman is considered to be of "reproductive potential" if she has had a menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation. However, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures.

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

5.4 Specimen Submission Criteria

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