Overview

This study is a randomized, open label, multicenter Phase II trial to evaluate the efficacy and safety of botensilimab (a novel Fc enhanced Tree depleting anti-CTLA4) and balstilimab (a novel anti-PD1) relative to ipilimumab and nivolumab in treatment naïve patients with metastatic ccRCC. The study will plan to enroll 120 eligible patients randomized in a 2:1 fashion to Arm A and Arm B. Patients in all IMDC Risk Groups are included. This study utilizes a Simon's two stage design which is described in the protocol. Patients randomized to Arm A will receive botensilimab in combination with balstilimab. Patients randomized to Arm B will receive ipilimumab in combination with nivolumab. Study treatment on both arms will continue until toxicity, disease progression or a maximum of 96 total weeks (12 weeks induction, 84 weeks maintenance).

Eligibility

Inclusion Criteria:

1. Patient must have ECOG PS of ≤ 2 within 28 days of C1D1.
2. Age ≥ 18 years old at the time of informed consent.
3. Patient must have histological confirmation of renal carcinoma with clear cell component including advanced RCC (not amenable to curative surgery or radiation therapy) or metastatic RCC.
4. Patient must have measurable disease by CT or MRI per RECIST 1.1 criteria. Radiated lesions cannot be used as measurable lesions unless there is clear evidence of progression.
5. Patient must have defined IMDC risk categorization of either favorable, intermediate or poor based on clinical variables of increased risk (below).
   • No risk factors (0) = favorable risk
   • 1-2 risk factors = intermediate risk
   • ≥ 3 risk factors = poor risk

             NOTE: Patients with all IMDC risk factors are eligible, but will be stratified
             according to IMDC risk, and initial analysis will be based on the IMDC intermediate
             and poor risk patients. IMDC Risks:
               -  KPS less than 80%
               -  Less than 1 year from diagnosis including original localized disease to
                  randomization(if applicable)
               -  Hemoglobin less than the lower limit of normal
               -  Corrected calcium concentration greater than 10 mg/dL
               -  ANC greater than the ULN
               -  Platelet count greater than the ULN
          6. Patient must have either a formalin-fixed, paraffin-embedded (FFPE) tissue block or
             unstained tumor tissue sections, obtained from a metastatic lesion, preferably within
             3 months or no more than 12 months with an associated pathology report. This tissue
             must be identified prior to registration. Confirmation of sufficient archival tissue
             must be obtained after informed consent and the tissue must be shipped to the
             appropriate lab by end of Cycle 2. Biopsies should be excisional, incisional, or core
             needle. Fine needle aspiration is unacceptable for submission. Biopsies of bone
             lesions that do not have a soft tissue component are also unacceptable for submission.
             This sample is required to be eligible for the trial. If a patient is having a
             standard of care biopsy, part of that sample may be utilized for eligibility.
          7. Demonstrate adequate organ function as defined below; all screening labs to be
             obtained within 28 days prior to registration.
               -  Hematological
               -  White blood cell (WBC) ≥ 2,000/uL
               -  Absolute Neutrophil Count (ANC) ≥ 1,000/uL; without growth factor support
               -  Hemoglobin (Hgb) ≥ 8.0 g/dL; ≥ 7 days without PRBC transfusion.
               -  Platelets ≥ 75,000/uL; without platelet transfusion
               -  Renal
               -  Calculated creatinine clearance (CrCl)1 ≥ 40 mL/min
               -  Hepatic
               -  Total Bilirubin ≤ 1.5 × upper limit of normal (ULN) *EXCEPT participants with
                  Gilbert Syndrome who must have a Total Bilirubin level of < 3.0 x ULN
               -  Aspartate aminotransferase (AST) ≤ 3.0 × ULN
               -  Alanine aminotransferase (ALT) ≤ 3.0 × ULN
          8. HIV positive patients may be eligible if either:
               -  Patients with CD4 > 200 cells/mm3 OR
               -  Patients with HIV viral load undetectable.
          9. Active HBV or active HCV patients may be eligible if:
               -  Patients with HBV infection are eligible if hepatitis B surface antigen and HBV
                  DNA are negative.
               -  Patients with HCV infection are eligible if HCV RNA is negative.
         10. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L
             or equivalent units of human chorionic gonadotropin [HCG]) within 1 week prior to
             Cycle 1 Day 1.
         11. WOCBP must agree to follow instructions for method(s) of contraception.
         12. Males who are sexually active with WOCBP must agree to follow instructions for
             method(s) of contraception.
        Exclusion Criteria:
          1. Prior adjuvant or systemic therapy for RCC.
          2. Prior treatment with an anti-PD1 or anti-PDL1 agent, anti-CTLA4 antibody or a VEGFR
             TKI or anti-VEGF antibody including in the adjuvant setting.
          3. Radiotherapy within 2 weeks prior to Cycle 1 Day 1.
          4. Expected to require any other form of systemic or localized antineoplastic therapy
             while on trial (including maintenance therapy with another agent, radiation therapy,
             and/or surgical resection).
          5. Currently known active and definitive CNS metastases. Patients who have treated brain
             metastases (with either surgical resection or stereotactic radiosurgery (SRS)) may be
             eligible. Patients must not have taken any steroids ≤ 2 weeks prior to randomization
             for the purpose of managing their brain metastases. Repeat imaging after SRS or
             surgical resection is not required so long as baseline MRI is within 4 weeks of
             registration. Patients with multiple brain metastases treated with SRS (with or
             without WBRT), are not excluded. Patients with definitive CNS metastases treated with
             only WBRT are ineligible. Patients with potential CNS metastases that are too small
             for treatment with either SRS or surgery (e.g. 1-2 mm) and/or are of uncertain
             etiology are potentially eligible, but need to be discussed with and approved by the
             sponsor-investigator.
          6. Persistent toxicity of National Cancer Institute (NCI) Common Terminology Criteria for
             Adverse Events (CTCAE) version 5.0 Grade > 1 severity that is related to prior
             therapy. NOTE: Sensory neuropathy or alopecia of Grade ≤ 2 are acceptable.
          7. Known severe (Grade ≥ 3) hypersensitivity reactions to fully human monoclonal
             antibodies, antibody, or severe reaction to immuno-oncology agents, such as colitis or
             pneumonitis requiring treatment with steroids; or has a history of interstitial lung
             disease, any history of anaphylaxis, or uncontrolled asthma.
          8. Known condition requiring systemic treatment with either corticosteroids (>10 mg daily
             prednisone or equivalent) or other immunosuppressive medications within 14 days of
             randomization. Inhaled or topical steroids, and adrenal replacement steroid doses <10
             mg daily prednisone equivalent are permitted in the absence of active autoimmune
             disease. NOTE: Corticosteroid use as a premedication for IV contrast
             allergies/reactions is allowed.
          9. Active known or suspected autoimmune disease that required systemic treatment within 2
             years of the start of study drug (i.e., with use of disease-modifying agents,
             corticosteroids, or immunosuppressive drugs). Subjects with type I diabetes mellitus,
             hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo,
             psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected
             to recur in the absence of an external trigger (e.g., celiac disease) are permitted to
             enroll.
         10. Uncontrolled adrenal insufficiency based on investigator discretion.
         11. Active infection requiring systemic therapy within 14 days of Cycle 1 Day 1.
         12. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular
             accident/stroke or myocardial infarction within 6 months of enrollment, unstable
             angina, congestive heart failure (New York Heart Association class ≥ II), or serious
             uncontrolled cardiac arrhythmia requiring medication.
         13. Legally incapacitated or has limited legal capacity.
         14. Pregnant or breastfeeding.
         15. Prior allogeneic tissue/solid organ transplant, except for corneal transplants.
         16. Major surgery (e.g., nephrectomy) less than 28 days prior to Cycle 1 Day 1.
         17. Prior malignancy active within the previous 2 years from screening except for locally
             curable cancers that have been apparently cured, such as basal or squamous cell skin
             cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or
             breast.
         18. Any condition including medical, emotional, psychiatric, or logistical that, in the
             opinion of the Investigator, would preclude the participant from adhering to the
             protocol or would increase the risk associated with study participation or study
             treatment administration or interfere with the interpretation of safety results.
         19. Receipt of a live/attenuated vaccine within 30 days of first study treatment. The use
             of inactivated seasonal influenza vaccines (eg, Fluzone®) will be permitted on study
             without restriction.