Molecular Residual Disease-Guided Treatment of Renal Cell Carcinoma, MRD GATE RCC Trial

Inclusion Criteria

• Must have histologically confirmed diagnosis of RCC with clear cell component with or without sarcomatoid features
• Patients must have at least ONE available assessment of molecular residual disease by the Signatera® (Natera Incorporated [Inc.]) assay performed within the last 90 days prior to enrollment in study
• Be ≥ 18 years of age on the day of signing informed consent
• Female participants of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to enrollment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
• Female participants of childbearing potential must be willing to use an adequate method of contraception should they be allocated to treatment arm, for the course of the study through 120 days after the last dose of study drug * Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the participant
• Male participants of childbearing potential must agree to use an adequate method of contraception, starting with the first dose of trial therapy through 120 days after the last dose of study therapy * Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the participant
• The participant provides written informed consent for the trial. The participant may also provide consent for Future Biomedical Research; however, the participant may participate in the main trial without participating in Future Biomedical Research
• Have intermediate-high risk, high risk RCC as defined by the following pathological tumor-node-metastasis and Fuhrman grading status (Oza, 2022 #4431) * Intermediate-high risk RCC ** pT2, grade (Gr.) 4 or sarcomatoid, N0, M0 ** pT3, any Gr., N0, M0 * High risk RCC ** pT4, any Gr. N0, M0 ** pT any stage, any Gr., N+, M0
• Have received no prior systemic therapy for advanced RCC unless having recently initiated immunotherapy with pembrolizumab for no more than 6 weeks or 1 dose prior to enrollment
• Have undergone a partial nephroprotective or radical complete nephrectomy
• Must have undergone a nephrectomy ≥ 28 days prior to signing informed consent and ≤ 12 weeks prior to enrollment
• Must be tumor free as assessed by the investigator and validated by either CT or MRI scan of the brain and chest abdomen pelvis (CAP) ≤ 28 days from enrollment
• Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2
• Absolute neutrophil count (ANC) ≥ 500/µL * Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements should be adapted according to local regulations and guidelines for treatments
• Platelets ≥ 90,000/µL * Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements should be adapted according to local regulations and guidelines for treatments
• Hemoglobin ≥ 8.0 g/dL * Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements should be adapted according to local regulations and guidelines for treatments
• Creatinine OR measured or calculated creatinine clearance ≤ 2.5 (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) OR GFR > 30 by Cockroft-Gault * Creatinine clearance (CrCl) should be calculated per institutional standard * Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements should be adapted according to local regulations and guidelines for treatments
• Total bilirubin ≤ 1.5 × upper limit of normal (ULN) OR direct bilirubin ≤ ULN for participants with total bilirubin levels > 1.5 × ULN * Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements should be adapted according to local regulations and guidelines for treatments
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 2.5 × ULN * Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements should be adapted according to local regulations and guidelines for treatments
• International normalized ratio (INR) OR prothrombin time (PT) ≤ 1.5 × ULN unless participant is receiving anticoagulant therapy as long as INR or PT is within therapeutic range of intended use of anticoagulants * Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements should be adapted according to local regulations and guidelines for treatments

Exclusion Criteria

• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study treatment
• Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed
• Has a known additional malignancy that is progressing or required active treatment ≤ 3 years ago. Exceptions include early-stage cancers (carcinoma in situ or stage 1) treated with curative intent, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in situ cervical cancer, in situ prostate cancer, or in situ breast cancer that has undergone potentially curative therapy
• Has an active infection requiring systemic therapy
• Has a history of, or is currently on, dialysis
• Has a known history of human immunodeficiency virus infection with detectable viral load within 120 days of study enrollment. No human immunodeficiency virus testing is required unless mandated by local health authority
• Has a known active hepatitis B (hepatitis B surface antigen reactive) or hepatitis C virus (HCV) (eg, HCV RNA [qualitative] is detected)
• Has a known history of active tuberculosis (Bacillus tuberculosis)
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the participant’s participation for the full duration of the trial, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
• Has a known psychiatric or substance abuse disorder that would interfere with the cooperation with the requirements of the trial in the opinion of the investigator
• Has had a prior solid organ transplant
• Has severe hypersensitivity (≥ grade 3) to pembrolizumab and/or any of its excipients
• A woman of childbearing potential (WOCBP) who has a positive urine pregnancy test within 72 hours before enrollment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Participants must be excluded/discontinued from the trial in the event of a positive or borderline positive test result
• Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of study treatment
• Has received prior anticancer therapy and not recovered from adverse events (AEs) due to previously administered agents. Note: denosumab may be allowed for bone protective purposes if dosing has been stable for ≥ 2 weeks before screening
• Has received a live vaccine within 30 days prior to the first dose of study treatment. 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, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed
• Is currently participating in or has participated in a trial of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment