Cohort 2 is re-activated for patient accrual Effective 11/15/2024**

**ePRO training required prior to first patient enrollment.**

Eligibility Criteria

5.1 Disease Related Criteria

a. Participants must be planning to receive ICI-based therapy for a solid tumor malignancy. This therapy must be given according to NCCN guidelines at Category 1 or 2A and not in the context of a clinical trial. See Section 18.1 for ICI-based therapies.

5.2 Prior/Concurrent Therapy Criteria

a. Participants who have received prior ICI-based therapy must have completed ICI based therapy at least 180 days prior to registration.

b. Participants must not have discontinued any prior ICI-based therapy (if applicable) because of irAE. c. Participants must not have received chemotherapy, biologic, or targeted-therapy within 14 days prior to registration. Hormonal therapy is allowed.

d. Participants must have recovered from side effects of prior therapy to the following standards per treating physician’s discretion:

• = Grade 1 for any non-hematologic side effects (excluding neuropathy and alopecia); lab-related parameters of liver and renal function will be considered at the discretion of the treating physician)

• = Grade 2 for neuropathy and/or alopecia

• Grade 3 or less for any hematologic side effects

e. Participants must be planning to begin standard of care ICI-based therapy within 7 calendar days after registration.

f. Participants must not be planning to receive ICI-based therapy in combination with chemotherapy or any other non-ICI therapy for treatment of their cancer. Palliative radiation is allowed.

5.3 Clinical/Laboratory Criteria a. Participants must be at least 18 years of age.

b. Participants must complete their history and physical examination within 28 days prior to registration.

c. Participants who can complete the S2013 Feasibility Questionnaire in English or Spanish must participate at the scheduled assessments.

d. Participants must be able to complete Patient-Reported Outcome (PRO) instruments in English, Spanish, or French and must be planning to complete PROs at all scheduled assessments.

e. Participants must complete the pre-registration (baseline) PRO forms within 14 days prior to registration.

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

*DTL Required- Physicians must sign toxicity grid

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

Eligibility Criteria:

Step 1 – Specimen Submission

a. Disease Related Criteria

1. Participants must have histologically confirmed melanoma that is Stage III or IV, unresectable, recurrent, or metastatic non-uveal melanoma according to criteria in Section 4.1.

OR Participants must have histologically confirmed squamous cell carcinoma of the head and neck (HNSCC) that is either locally recurrent and non\u0002amendable to curative therapy (e.g., radiation, surgery) or metastatic. The primary tumor location must be the oropharynx, oral cavity, hypopharynx, or larynx. Primary tumor site of nasopharynx (any histology) or unknown primary tumor are not eligible.

Note: For participants with primary oropharyngeal cancer, HPV or p16 status must be known prior to Step 1 registration.

2. Participants must have disease presentation consistent with measurable disease. Note: Current disease measurements will not be required until Step 2 registration.

3. Participants must have had documented progression within 12 weeks after the last dose of PD-1 checkpoint inhibition-based therapy. Participants must have been receiving checkpoint inhibition for a minimum of 6 weeks prior to progression. Participants who recur during adjuvant anti-PD1 treatment or within 12 weeks of completion of adjuvant anti-PD1 treatment are eligible if they have measurable disease and considered unresectable. 4. Participants with known human immunodeficiency virus (HIV)-infection must be receiving anti-retroviral therapy and have an undetectable viral load test within 6 months prior to Step 1 registration.

5. Participants with evidence of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load within 28 days prior to Step 1 registration.

6. Participants with a history of hepatitis C virus (HCV) infection must have no detectable viral load within 28 days prior to Step 1 registration.

7. Participants must not have an active infection requiring systemic therapy (except HBV, HCV or HIV as mentioned above)

Prior/Concurrent Therapy Criteria

1. Participants must have recovered to baseline or ≤ Grade 1 CTCAE v5 toxicities related to any prior treatments, unless adverse events are deemed clinically nonsignificant by the treating investigator or stable on supportive therapy.

2. Participants must not have received surgery, chemotherapy, radiation therapy, biologic agents, or steroids within 14 days prior to Step 1 registration.

3. Participants must not have received more than one prior primary radiotherapy regimen, curative or adjuvant, to the head and neck, with the additional following criteria.

Clinical/Laboratory Criteria

1. Participants must be ≥ 18 years of age.

2. Participants must have a Zubrod Performance Status 0 or 1. See Section 10.4.

***Please see the most recent version of the protocol for complete eligibility list**

*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, Genesys, Hurley, Sparrow, LVHN

Eligibility Criteria

Disease Related Criteria

a. Participants must have a histologically or cytologically confirmed diagnosis of adenocarcinoma of the colon or rectum. The date of diagnosis will be determined according to the pathologic date of diagnosis.

b. Participants must have measurable disease according to RECIST1.1 criteria. CT scans or MRIs used to assess measurable disease (as defined in Section 10.1) must have been completed within 28 days prior to registration. CT scans or MRIs used to assess non-measurable disease must have been completed within 42 days prior to registration. All disease must be assessed and documented on the Baseline Tumor Assessment Form. c. Participants must have documented unresectable and/or metastatic disease on CT or MRI imaging. All disease must be assessed and documented on the Baseline Tumor Assessment Form.

d. Participants must have BRAFV600E mutated colorectal cancer as tested in a CLIA\u0002certified laboratory.

e. Participants must have proficient mismatch repair (pMMR) or Microsatellite Stable (MSS) status as tested in a CLIA-certified laboratory and documented by the treating clinician. Proficient mismatch repair status can be determined by intact expression by immunohistochemistry of all 4 mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2). Microsatellite instability can be determined by polymerase chain reaction (PCR).

f. Participants with brain metastases must have completed surgery or radiation therapy ≥ 28 days prior to registration. These participants must have a CT or MRI of the brain showing no new or enlarging lesions within 42 days prior to registration. These participants must also be neurologically asymptomatic and without corticosteroid treatment for at least 7 days prior to registration. Metastatic brain parenchymal disease must have been treated and participant must be off steroids for 7 days prior to registration. The presence of leptomeningeal disease (LMD) is not considered stable disease, and participants with LMD are not eligible for this study.

g. Participants must not have a known positive serology for human immunodeficiency virus (HIV). Encorafenib is contraindicated with concomitant use of non\u0002nucleoside analog reverse transcriptase inhibitors like efavirenz and etravirine. In addition, it is recommended in the Investigator Brochure of encorafenib to avoid using encorafenib with protease inhibitors. Therefore, because all participants on this study would receive encorafenib for either randomized arm of treatment, participants with HIV who receive these components of highly active antiretroviral therapy (HAART) would be at high risk for complications of drug-drug interaction.

h. Participants with known evidence of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load on suppressive therapy within 28 days prior to registration.

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

Clinical/Laboratory Criteria

a. Participants must be of age ≥ 18 years at the time of informed consent.

b. Participants must have a Zubrod performance status of 0 or 1

**See Protocol for full eligibility criteria list***

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

**Canton will not be participating**

***Registering MD is also the Treating Investigator***

Eligibility Criteria:

Recruitment Center Definition and Eligibility Criteria Recruitment Centers must have completed the S2108CD Recruitment Center Application and be approved for participation in the study. Eighteen Recruitment Centers will be selected to participate in the study based on the eligibility criteria listed below.

a. A Recruitment Center is defined as an outpatient clinic, or group of clinics, belonging to the same NCORP or MU-NCORP, that will be contributing physicians and patient participants to the study.

b. Participating Recruitment Centers must meet the following requirements:

1. Recruitment Centers must be part of an NCORP or MU-NCORP site with CCDR funding. Each clinic included in the Recruitment Center must be associated with CTEP site ID.

2. Recruitment Centers must order large panel next generation sequencing genomic tests on at least 10 unique patients per month.

3. Recruitment Centers must have at least 4 practicing oncologists (including medical, gynecologic, or neuro-oncologists) at the site willing to participate in the study and register within three months of study activation.

4. Recruitment Centers must be willing to register a total of 66 patients (over 2 years) to the study.

5. Recruitment Centers must be able to send at least one member of the clinical team to attend the Recruitment Center’s cases presented to the S2108CD Genomic Tumor Board, should the Recruitment Center be randomized to the intervention arm.

6. Recruitment Centers must be willing and able to document the number of unique patients for whom GTT were ordered at the Recruitment Center and submit this monthly via Rave®.

7. Recruitment Centers must not have an existing Genomic Tumor Board. For the purposes of this study, a Genomic Tumor Board is defined as an interdisciplinary team of clinicians and scientists that reviews genomic testing results and provides guidance on treatment options based primarily on genomic data to the treating physician. The existence of a general multidisciplinary tumor board that addresses all aspects of patient care and treatment is not considered an exclusion criterion. A general multidisciplinary tumor board is defined as an interdisciplinary team of clinicians that primarily discusses all aspects of cancer care, including diagnostic aspects (pathology and radiology), therapeutic options (surgical, radiation and medical) as well as palliative and psychosocial support options.

Physician Participant Criteria

a. Physician participant must be a registering investigator of the Recruitment Center that is participating in the study. If the physician is a registering investigator at more than one Recruitment Center, he/she must choose one Recruitment Center to identify with and enroll patients from.

b. Physician participants must be board-eligible or board-certified in Medical Oncology, Gynecologic Oncology, or Neurology with certification or eligible for certification in Neuro-oncology.

c. Physician participants must be willing to offer participation in the study to all eligible patients under their care for the duration of the study. A single physician may enroll multiple patients on the study.

d. Physician participants must be willing to complete all study questionnaires and, as part of the implementation objective, participate in interviews if invited.

e. Physician participants must complete all baseline questionnaires prior to registration.

f. Physician participants at a Recruitment Center randomized to the intervention arm must be willing to participate in the educationally enhanced GTB (EGTB).

Patient Participant Criteria

a. Disease Related

1. Patient participants must have a solid tumor malignancy that is either recurrent, relapsed, refractory, metastatic, or newly diagnosed Stage III or Stage IV.

2. Patient participants must be under the care of a physician enrolled on the study.

3. Patient participants must not be going on hospice care at the time of registration.

b. Prior/Concurrent Therapy Criteria

1. Patient participants may have started anti-cancer treatment for the current diagnosis.

2. The treating physician anticipates that the patient will start a new anti\u0002cancer treatment (either first or subsequent lines) within 6 months after registration

3. Patient participants are allowed to be co-enrolled on other clinical trials including non-treatment studies and studies that include investigational drugs. Patients may be enrolled on genome-informed therapeutic trials, such as LungMAP, MATCH, or TAPUR.

c. Clinical/Laboratory Criteria

1. Patient participant must have a genomic tumor test (GTT) ordered prior to registration with results pending. The genomic testing may be a commercially available panel (such as FoundationOne, Caris, or Tempus) or a non-commercial tumor panel performed at an academic medical center.

NOTE: Qualifying GTTs are defined as a genomic test conducted on the tumor tissue, tumor cells, or cellfree DNA (cfDNA). They must be CLIA\u0002certified NGS tissue or liquid biopsy panels, including hotspot, whole gene, or DNA and RNA (including expression data) panels. Fluorescence-in-situ hybridization (FISH) and immunohistochemistry test results assessing cancer-relevant proteins (e.g. Her2/neu, ALK, MET) and immune parameters (e.g. PD-L1 tests) are also permissible if performed in the context of a larger panel that includes NGS or expression profiling. These tests can come from any commercial or academic laboratory within the US and they should be ordered with the intent to influence genome-informed treatment decision. Oncotype DX and other panels used for making treatment decisions based on a prognostic read-out (e.g. liquid biopsy minimal residual disease (MRD)) are not permitted.

2. Patient participants must be at least 18 years of age.

3. Patient participants must have a Zubrod performance status of 0-2.

4. Patient participants with tests assessing cancer-risk defining germline variants only (“germline test”) are not eligible.

*DTL Required- Physicians must sign toxicity grid

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

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

Eligibility Criteria:

Disease Related Criteria

a. Participants must have a histologically confirmed diagnosis of metastatic papillary renal cell carcinoma (PRCC), either type 1 or type 2. (NOTE: A designation of type 1 or type 2 should be made by the local pathologist if possible but is not required). Mixed histologies which contain type 1 or type 2 along with any other RCC histology/histologies will be allowed provided that they contain a papillary component.

b. Participants must have measurable disease per RECIST 1.1 criteria (see Section 10.1). All measurable lesions must be assessed by CT or MRI within 28 days prior to registration. All non-measurable lesions must be assessed by CT or MRI, or nuclear medicine bone scan within 42 days prior to registration. 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 S2200 Section 10.1.c. If there is clinical suspicion for bone metastases at the time of enrollment (at the discretion of the investigator), bone scan must be performed at baseline (within 42 days prior to registration).

c. Participants with new or progressive brain metastases (active brain metastases) must not require immediate CNS specific treatment at the time of study registration or anticipated during the first cycle of therapy. Patients with leptomeningeal disease are excluded from enrolling.

d. Participants with measurable disease, per RECIST v1.1, must be present outside the CNS.

e. Participants must have no history of intracranial hemorrhage or spinal cord hemorrhage.

f. Participants must not have undergone stereotactic radiotherapy within 7 days prior to initiation of study treatment, whole-brain radiotherapy within 14 days prior to initiation of study treatment, or neurosurgical resection within 28 days prior to initiation of study treatment.

g. Participants must not have ongoing requirements for corticosteroids as therapy for CNS disease.

h. Participants, if needed, must receive a stable dose of anti-convulsant therapy.

i. Participants must not have cavitating pulmonary lesions.

Prior/Concurrent Therapy Criteria

a. Participants must not have had major surgery within 28 days prior to registration, and participants must have recovered from any adverse effects of surgery.

b. Participants must not have had prior treatment with cabozantinib for any reason.

c. Participants must not have had prior treatment or adjuvant therapy with PD-1/PD\u0002L1 checkpoint inhibitors for any reason within the past 6 months.

d. Participants must not have received more than one prior systemic therapy for advanced or metastatic renal cell carcinoma with the exception of another VEGF inhibitor FDA-approved for advanced RCC

e. (i.e., pazopanib, bevacizumab, sorafenib or axitinib).

Participants must not take within 14 days prior to registration, nor plan to take while on protocol treatment, any strong CYP3A4 inhibitors

g. Participants must complete all prior radiation therapy at least 14 days prior to registration.

Clinical/Laboratory Criteria

a. Participants must be ≥ 18 years of age.

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

c. Participants must have a Zubrod performance status of 0-2 (see Section 10.6).

d. Participants must have adequate hematologic function within 28 days prior to registration.

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

Arm 1 reactivated 08/01/2025

*DTL Required- Physicians must sign toxicity grid

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

Eligibility Criteria:

5.1. Disease Related Criteria

a. Participants must have:

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

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

o Follicular lymphoma, grade 3B

o Transformed lymphoma

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

b. Participants must have staging imaging performed within 28 days prior to registration, as follows. Positron emission tomography (PET)-computed tomography (CT) baseline scans are strongly preferred; diagnostic quality magnetic resonance imaging (MRI), contrast-enhanced CT, or contrast-enhanced MRI scans are also acceptable if PET-CT is not feasible at baseline. NOTE: PET-CT will be required at end of treatment (EOT) and progression for response assessment. All measurable lesions (longest diameter >= 1.5 cm) must be assessed within 28 days prior to registration. Tests to assess non-measurable disease must be performed within 28 days prior to registration. All disease must be documented on the Baseline Tumor Assessment Form.

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

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

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

5.2. Prior/Concurrent Therapy Criteria

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

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

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

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

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

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

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

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

5.3. Clinical/Laboratory Criteria

a. Participant must be ≥ 18 years old.

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

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

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

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

- Platelets ≥75 x 10^3/uL

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

- ANC ≥ 0.75 x 103/µL and;

- Platelets ≥ 50 x 103/µL

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

Eligibility Criteria:

5.1 Disease Related Criteria

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

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

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

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

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

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

5.2 Prior/Concurrent Therapy Criteria

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

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

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

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

5.3 Clinical/Laboratory Criteria

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

1. For Participants Meeting “Frail” Status:

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

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

a. Hemoglobin ≥7 g/dL AND

b. Platelets ≥50x109/L AND

c. ANC ≥0.75 x109/L. 

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

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

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

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

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

c. ANC between 0.75-1 x109/L.  

iii. R-ISS stage III disease.

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

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

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

Eligibility Criteria:

5.1 Disease Related Criteria

a. Participant must have histologic diagnosis of prostate adenocarcinoma.

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

• cT3a – cT4x

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

• PSA > 20 ng/mL prior to registration

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

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

5.2 Prior/Concurrent Therapy Criteria

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

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

5.3 Clinical/Laboratory Criteria

a. Participant must be ≥ 18 years old.

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

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

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

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

- platelets ≥100 x 10^3/uL

- AST/ALT ≤ 3 × institutional ULN  

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

CURRENT SITES CREDENTIALED: SJMH (Ann Arbor, Brighton, Chelsea, Canton, Livonia) Genesys, Hurley, Holy Cross, Lehigh Valley, Sparrow, St. John, Oakland, MyMichigan, Saint Alphonsus. 

Eligibility Criteria:

5.1 Disease Related Criteria

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

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

- T2-T4, N0, M0 or

- T1-T3, N1-2, M0. 

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

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

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

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

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

5.2 Prior/Concurrent Therapy Criteria

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

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

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

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

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

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

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

5.3 Clinical/Laboratory Criteria

a. Participants must be ≥ 18 years old.

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

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

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

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

 - Hemoglobin ≥9.0 g/dL or ≥ 5.6 mol/L

- leukocytes ≥3 x 10^3/uL

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

- platelets ≥100 x 10^3/uL 

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

- AST and ALT ≤ 3 × institutional ULN

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

g. Participants must have adequate cardiac function. Participants must have left ventricular ejection fraction ≥50% as assessed by either ECHO or MUGA assessed within 28 days prior to registration. Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, must have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification (see Section 18.1) and must be class 2B or better.

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

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

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