Effective 09/09/22, Pre-Registration (Step 0) is closed to patient accrual.

Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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

- SRS TREATMENT IS REQUIRED TO BE DONE AT SJMH ANN ARBOR ONLY.

*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, Lehigh Valley

Eligibility Criteria:

3.2.1 Documentation of Disease

-Histologic Documentation: Histologically-proven glioblastoma (WHO 2021 criteria)

-Stage: Progressive or recurrent disease per RANO criteria

-No IDH mutation (IDH1 R132H negative by IHC or sequencing)

3.2.2 Prior Treatment

-Patients must be in first recurrence of glioblastoma following radiation therapy and temozolomide.

-No prior therapies except radiation, surgery, temozolomide, TTFields, and/or Gliadel wafers (placed during the first surgery at diagnosis of GBM). Prior radiation therapy, TTFields, or placement of Gliadel wafers must be completed at least 12 weeks prior to registration. Prior temozolomide must be completed at least 3 weeks prior to registration.

-No prior use of nivolumab or other anti-PD1 agents.

-Patients must be neurologically stable off corticosteroids for at least 5 days prior to registration.

3.2.3 Age: ≥ 18 years

3.2.4 Karnofsky Performance Status: ≥ 60% (i.e. patient must be able to care for themselves with occasional help from others)

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

-Patients must have been previously registered to A151216, with the result of lung cancer harboring an EGFR exon 19 deletion or L858R mutation. The testing must have been performed by one of the following two criteria:
--Patient registered to A151216 and the assessment performed centrally by the protocol specified laboratory.
--By a local CLIA certified laboratory. These patients will also have been registered to A151216, but can be enrolled on A081105 regardless of the central lab results.
-Patients with known resistant mutations in the EGFR TK domain (T790M) are NOT eligible.
-Patients that are both EGFR mutant and ALK rearrangements will be registered to A081105.
-Patients must have completely resected stage IB, II or IIIA non-squamous NSCLC with negative margins.
-ECOG Performance Status 0-1.

*DTL Required- Physicians must sign toxicity grid CREDENTIALING REQUIRED. Please check your site's credentialing status. CURRENT SITES CREDENTIALED: SJMH (AA, Brighton, Chelsea, Canton), GenHur, Sparrow, Livonia, Saginaw, St. John, Macomb, LVHN, Holy Cross

Eligibility Criteria:

- Previously registered to A151216

- Central and/or local testing of EGFR with no EGFR exon 19 deletion of EGFR L858 R mutation

- Central and/or local testing of ALK with no ALK rearrangement (failed testing is considered negative)

- Central and/or local testing of PD-L1 IHC using one of the following assays: DAKO 22C3, DAKO 28-8, or SP263

Note: Local testing results of EGFR and ALK by a local CLIA certified laboratory is acceptable. The report must indicate the result as well as the CLIA number of the laboratory that performed the assay. Local result of PD-L1 by DAKO 22C3, Dako 28-8, or SP263 are acceptable for enrollment on A081801. Patients with local results for EGFR, ALK and PD-L1 still need to be registered to A151216 and follow all the submissions requirements but do NOT need to wait for the results to proceed to A081801 registration.

- Completely resected stage IB (= 4 cm), II or IIIA NSCLC with negative margins (complete R0 resection). Patients will be staged according to the 7th edition of the AJCC Cancer Staging Manual, 2010.

Note: Patients with pathologic N2 disease, completely resected, are eligible. However, patients known to have N2 disease prior to surgery are not eligible; guidelines do not recommend up-front surgery for this population.

- Complete recovery from surgery. Registration to A081801 must be 30-77 days following surgery.

- No prior neoadjuvant or adjuvant therapy for current lung cancer diagnosis.

- No prior allogeneic tissue/solid organ transplant

- Patients must NOT have uncontrolled intercurrent illness including, but not limited to, serious ongoing or active infection, symptomatic congestive heart failure, uncontrolled cardiac arrhythmia, unstable angina pectoris, that would limit compliance with study requirements.

- No current pneumonitis or history of (non-infectious) pneumonitis that required steroids.

- HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.

- Age =18 years

- ECOG PS: 0-1

- No active auto-immune disease that has required systemic treatment within the last 2 years (e.g., disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid release therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.

-Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects.

Therefore, for women of childbearing potential only, a negative pregnancy test done = 7 days prior to registration is required.

- No patients with a "currently active" second malignancy that is progressing or has required active treatment within the last 3 years. Participants with non-melanoma skin cancers or carcinoma in situ (e.g., breast carcinoma or cervical cancer in situ) that have undergone potentially curative therapy are eligible.

- No hypersensitivity (= Grade 3) to pembrolizumab and/or any of its excipients

- No live vaccine within 30 days prior to registration. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette·Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.

- No known history of Hepatitis B (defined as HBsAg reactive) or known Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.

-Required Initial Laboratory Values

   -Absolute Neutrophil Count (ANC) = 1,500/mm3

   -Platelet Count = 100,000/mm3

   -Hemoglobin =8 gm/dl

   -Calc. Creatinine Clearance = 45 mL/min

   -Total Bilirubin = 1.5 x upper limit of normal (ULN)

   -AST / ALT = 2.5 x upper limit of normal (ULN)

*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, SJMO, Sparrow

Eligibility Criteria:

Documentation of Disease

- Histologic or cytologic diagnosis of Stage IV NSCLC using version AJCC 8th edition (includes M1a, M1b, and M1c stage disease). Patients with Stage IIIB and IIIC disease are eligible if they are not a candidate for combined chemotherapy and radiation.

- PD-L1 IHC: PD-L1 expression Tumor Proportion Score (TPS) <1% in tumor cells. If PD-L1 expression TPS is unevaluable or the testing could not be completed patients are not eligible. The assay must have been performed locally by a CLIA (or equivalent) certified laboratory. The type of assay will be recorded.

- For non-squamous patients only (adenocarcinoma or adenosquamous): EGFR, ALK and ROS1 testing must be done locally. No patients with known actionable EGFR mutations (except exon 20 insertion), ALK or ROS1 mutations that can be treated with oral tyrosine inhibitors.

- Measurable disease based on RECIST 1.1, including at least two cancerous deposits. At least one deposit must be RECIST measurable (and not to be irradiated) while at least one OTHER deposit (measurable or non-measurable) must meet criteria for SBRT (See Section 7.3)

___ 3.2.3 Age ≥ 18 years

___ 3.2.4 ECOG Performance Status 0-2

Prior Treatment

- No prior systemic chemotherapy or immunotherapy for advanced NSCLC.

- No prior treatment with checkpoint inhibitors for metastatic lung cancer.

- Chemotherapy for non-metastatic disease (e.g., adjuvant therapy) or immunotherapy for locally advanced Stage III disease is allowed if terminated at least 6 months prior to registration.

-No systemic immunostimulatory or immunosuppressive drugs, including >10mg prednisone equivalent per day, within 2 weeks or 5 half-live of the drug, whichever is shorter.

≥ 1 week since palliative (including CNS) radiotherapy to any tumor site.

- No prior allogeneic tissue/solid organ transplant.

- Comorbid Conditions

- No uncontrolled intercurrent illness including, but not limited to, serious ongoing or active infection, symptomatic congestive heart failure, uncontrolled cardiac arrhythmia, unstable angina pectoris, that would limit compliance with study requirements.

- No current pneumonitis or history of non-infectious pneumonitis that required steroids.

- HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration.

- No active auto-immune disease that requires systemic therapy within 2 years prior to registration. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid release therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.

- No known history of Hepatitis B (defined as HBsAg reactive) or known Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.

-No patients with symptomatic central nervous system metastases and/or carcinomatous meningitis. Patients with small asymptomatic brain metastases are eligible as are patients with treated brain metastases that require no steroids.

-Not pregnant and not nursing, because this study involves radiation as well as potentially chemotherapy which have known genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing potential only, a negative urine or serum pregnancy test done ≤ 7 days prior to registration is required. -- No patients with a “currently active” second malignancy that is progressing or has required active treatment within the last 2 years. Participants with non\u0002melanoma skin cancers or carcinoma in-situ (e.g., breast carcinoma, urothelial carcinoma or cervical cancer in situ) or localized prostate cancer (T1-3, N0, M0) that have undergone potentially curative therapy are eligible.

- No hypersensitivity (≥ Grade 3) to immunotherapy and/or any of its excipients.

- No live vaccine within 30 days prior to registration. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g.,FluMist®) are live attenuated vaccines and are not allowed. COVID-19 vaccine is allowed.

- Required Initial Laboratory Values: Absolute Neutrophil Count (ANC) ≥ 1,500/mm3 Platelet Count ≥ 100,000/mm3 Calc. Creatinine Clearance ≥ 45 mL/min Total Bilirubin ≤ 1.5 x upper limit of normal (ULN) AST / ALT ≤ 2.5 x upper limit of normal (ULN)

-Patients must have histologically confirmed LPS (only dedifferentiated and pleomorphic. Well differentiated not eligible), UPS/MFH, or GIST.
-Must have measurable disease
-Must have locally advanced/ unresectable or metastatic disease
-Must have at least one prior systemic therapy for sarcoma, including adjuvant systemic therapy
-No prior therapy with ipilimumab or nivolumab, or any agent targeting PD-1, PD-L1 or

CTLA-4.
-Patients should have resolution of any toxic effects of prior therapy (except alopecia) to grade 1 or less.
-Must not have symptomatic, untreated, or uncontrolled brain metastases present.
-ECOG Performance Status 0 or 1.

*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), Livonia, Genesys Hurley, Lehigh, Sparrow

Eligibility Criteria:

3.2.1 Documentation of Disease:

-Histologic Documentation: Histologically confirmed diagnosis head and neck squamous cell carcinomas (HNSCC). 

-Stage: Previously untreated for recurrent and/or metastatic disease incurable by local therapies 

-Tumor Site: Primary tumor location of oral cavity, oropharynx, larynx, or hypopharynx.

Note: other primary tumor sites of HNSCC, including nasopharynx primary tumor are not eligible. Unknown primary tumors may be eligible and can be enrolled at the discretion of the treatment team with approval by the study chair.  

3.2.2 Measurable Disease as Defined in Section 11.0.

3.2.3 Must have platinum-refractory disease defined as disease progression during or ≤ 6 months after completion of definitive therapy (chemoradiation therapy) or adjuvant (post-operative) therapy. ___ 3.2.4 Patient must have a combined positive score PD-L1 positive (CPS >/= 1) tumor. 

3.2.5 Prior Treatment: 

Any radiation therapy must be completed > 10 days prior to registration.

-Patients should not have received any prior treatment in the recurrent or metastatic setting. 

-Prior therapy with anti PD-1/PD-L1 monoclonal antibody or cetuximab in the curative setting is allowed if last treatment dose was > 6 months prior to registration without evidence of disease progression during that treatment period.

-Patient has not received a live vaccine within 30 days prior to registration.

-Patient does not have a history of any contraindication or has a severe hypersensitivity to any component of pembrolizumab or cetuximab (≥ Grade 3). 

-Patient has not received chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior to registration.

-Patient with oropharyngeal cancer only must have negative results from testing of HPV status defined as p16 IHC and/or HPV ISH. Note: a CLIA certified ctHPVDNA assay can be used if tissue sample is not available. 

3.2.7 Age ≥ 18 years  

3.2.8 ECOG Performance Status ≤ 2

3.2.9 Required Initial Laboratory Values:

-Absolute Neutrophil Count (ANC) ≥ 1,500/mm3

-Platelet Count ≥ 100,000/mm3

-Hemoglobin (Hgb) ≥ 9 g/dL (if 9 g/dL, then transfusions are acceptable to increase hemoglobin above 9 g/dL)

-Creatinine ≤ 1.5 x upper limit of normal (ULN) OR Calc. Creatinine Clearance ≥ 30 mL/min using the Cockcroft-Gault formula for participant with creatinine levels > 1.5 X institutional ULN

-Total Bilirubin ≤ 1.5 x ULN OR Direct Bilirubin ULN for participant with total bilirubin > 1.5 X institutional ULN

-AST (SGOT)/ALT (SGT) ≤ 3.0 X ULN unless liver metastases are present in which case 5.0 X ULN 

3.2.10 Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic, and teratogenic effects. Therefore, for women of childbearing potential only, a negative pregnancy test done ≤ 7 days prior to registration is required.

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

Effective 08/26/19- The squamous histology cohort is temporarily closed to accrual.

*Credentialing required. Please check your site's credentialing status. See ANVIL (EA5142) for requirements.*
CURRENT SITES CREDENTIALED:
Genesys, SJMH, Livonia, Saginaw, Sparrow, St. Alphonsus, St. John, St. John Macomb, Lehigh, Oakland, Holy Cross

For pre-surgical patients:
-Patients must have a suspected diagnosis of resectable squamous or non-squamous NSCLC
-Suspected clinical stage of large IB, II, or IIIA

For post-surgical patients:
-Patients must have completely resected squamous or non-squamous NSCLC
-Pathologic stage IB, II, or IIIA

All Patients:
-ECOG PS must be 0-1
-No patients who have received neoadjuvant therapy (chemo- or radio-therapy)
-No prior treatment with agents targeting EGFR mutation or ALK rearrangement

To allow time for central genotyping and eligibility for the treatment trial, patients must register within specific windows:
-if no adjuvant therapy, register within 75d of surgery
-if adjuvant chemotherapy only, register within 165d of surgery
-if adjuvant chemotherapy and radiation, register within 225d of surgery

Eligibility Criteria:

3.2.1 Received one or more immuno-oncology therapeutics

Must have received one or more IO therapeutics. These therapeutics include the agents listed in Appendix I.

Agents of interest include:

CTLA-4 inhibitors

Ipilimumab

Tremelimumab

PD-1 inhibitors

Cemiplimab

Nivolumab

Pembrolizumab

PD-L1 inhibitors

Atezolizumab

Avelumab

Durvalumab

3.2.2 Experienced one or more serious AEs

Must have experienced one or more of the following:

• One or more serious (Grade 3–5) AEs that are likely immune-related. AEs included in CTCAE v. 4.03 and/or v. 5.0 that may be immune-related are listed by irAE in Appendix II.

• Diagnosis of a rare infection, e.g., fungal or mycobacterial, after starting IO treatment.

• Hyperprogression, as defined in Appendix III.

Image submission for patients experiencing hyperprogression is required.