Combination immunotherapy for advanced renal cell cancer

Phase 2 Advanced Renal Cell Cancer Combination ImmunoThErapy Clinical Trial

This study is testing a new combination of immunotherapy drugs to see if they work better than the standard treatment for patients with advanced kidney cancer who haven't been treated before.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 120 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Hoosier Cancer Research Network (Academic / other)
• Drugs / interventions: radiation, prednisone, botensilimab, balstilimab, ipilimumab, nivolumab
• Locations: 13 sites (La Jolla, California and 12 other locations)
• Trial ID: NCT05928806 on ClinicalTrials.gov

What this trial studies

This Phase II clinical trial evaluates the efficacy and safety of two novel immunotherapy agents, botensilimab and balstilimab, compared to the standard treatment of ipilimumab and nivolumab in treatment-naïve patients with metastatic clear cell renal cell carcinoma (ccRCC). The study will enroll 120 patients, who will be randomized in a 2:1 ratio to receive either the experimental combination or the standard treatment. Patients will be monitored for treatment response and safety over a maximum period of 96 weeks. The trial aims to include patients across all IMDC risk groups, utilizing a Simon's two-stage design for analysis.

Who should consider this trial

Good fit: Ideal candidates include adults aged 18 and older with histologically confirmed advanced or metastatic clear cell renal carcinoma and an ECOG performance status of 2 or less.

Not a fit: Patients with renal carcinoma that is amenable to curative surgery or radiation therapy may not benefit from this study.

Why it matters

Potential benefit: If successful, this trial could provide a more effective treatment option for patients with advanced renal cell carcinoma.

How similar studies have performed: Previous studies have shown promise with similar immunotherapy combinations, but this specific approach is novel.

Eligibility criteria

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 at least 10 (preferably 20) 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.

Where this trial is running

La Jolla, California and 12 other locations

• University of California San Diego — La Jolla, California, United States (Recruiting)
• Yale University, Yale Cancer Center — New Haven, Connecticut, United States (Recruiting)
• Georgetown University — Washington, District of Columbia, United States (Recruiting)
• Winship Cancer Institute of Emory University — Atlanta, Georgia, United States (Recruiting)
• Indiana University Melvin and Bren Simon Comprehensive Cancer Center — Indianapolis, Indiana, United States (Recruiting)
• Beth Israel Deaconess Medical Center — Boston, Massachusetts, United States (Recruiting)
• Dana-Farber - Partners Cancer Care, Inc — Boston, Massachusetts, United States (Recruiting)
• John Theurer Cancer Center — Hackensack, New Jersey, United States (Recruiting)
• Cornell University — Ithaca, New York, United States (Recruiting)
• Columbia University Irving Medical Center — New York, New York, United States (Recruiting)
• Ohio State University Comprehensive Cancer Center — Columbus, Ohio, United States (Recruiting)
• Penn Medicine Abramson Cancer Center — Philadelphia, Pennsylvania, United States (Recruiting)
• University of Texas Southwestern Medical Center — Dallas, Texas, United States (Recruiting)

Study contacts

• Principal investigator: Michael B Atkins, MD — Georgetown University
• Study coordinator: Michael B Atkins, MD

Conditions Advanced Renal Cell Carcinoma