Testing the Safety and Feasibility of Immunotherapy Drugs, Botensilimab and Balstilimab, Before Surgery for Clear Cell Renal Cell Carcinoma, NEO RoBOT Trial

Pilot Phase II Trial Evaluating Safety and Feasibility of Neoadjuvant Botensilimab and Balstilimab in Clear Cell Renal Cell Carcinoma (NEO RoBOT)

This phase II trial tests the effect of botensilimab and balstilimab before surgery (neoadjuvant) in treating patients with high-risk clear cell renal cell cancer that has not spread from where it first started to other areas of the body (non-metastatic). The current standard treatment for patients with non-metastatic clear cell renal cell cancer may include surgery to completely remove the tumor. This typically involves removing the kidney or part of the kidney (nephrectomy). Immunotherapy with monoclonal antibodies, such as botensilimab and balstilimab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Giving neoadjuvant botensilimab and balstilimab may be safe, tolerable, and/or effective in treating patients with high-risk non-metastatic clear cell renal cell cancer before undergoing a nephrectomy.

PRIMARY OBJECTIVE:

I. To investigate the safety and feasibility of neoadjuvant botensilimab and balstilimab in high-risk (T2a-T4Nany M0 or Tany N1M0) non-metastatic clear cell renal cell carcinoma via assessment of ability to undergo timely nephrectomy.

SECONDARY OBJECTIVES:

I. To investigate the safety of neoadjuvant botensilimab and balstilimab in high-risk (T2a-T4Nany M0 or Tany N1M0) non-metastatic clear cell renal cell carcinoma via assessment of National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

II. To investigate the surgical morbidity of neoadjuvant botensilimab and balstilimab in high-risk (T2a-T4Nany M0 or Tany N1M0) non-metastatic clear cell renal cell carcinoma via assessment of Clavien-Dindo classification of surgical morbidity, respectively.

III. To evaluate the objective response rate (ORR) of the primary tumor following neoadjuvant botensilimab and balstilimab per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria, defined as complete response (CR) or partial response (PR), any time after starting treatment.

IV. To evaluate the proportion of patients achieving a major pathologic response (defined as < 10% of viable tumor in the tumor bed) and a partial pathologic response (defined as less than 50% of the viable tumor in tumor bed), through centralized pathology review.

V. To evaluate disease-free survival (DFS), rates of distant metastasis and local recurrence following neoadjuvant botensilimab and balstilimab in high-risk clear cell renal cell carcinoma.

EXPLORATORY OBJECTIVES:

I. To investigate the relationship between tumor cell programmed death ligand 1 (PD-L1) expression, CD8+ T-cell infiltration in the tumor microenvironment, and clinical outcomes.

II. To examine the association of specific genetic alterations (Braun et al., 2020) identified through whole-exome sequencing (WES) and transcriptional clusters (Motzer et al., 2020) identified via ribonucleic acid (RNA) sequencing, in relation to clinical outcomes.

III. To characterize the phenotypes of circulating T cells, cytokines, chemokines, and angiokines at baseline and after neoadjuvant therapy to evaluate their association with therapeutic efficacy and clinical response.

IV. To assess circulating tumor deoxyribonucleic acid (DNA) (ctDNA) to detect minimal residual disease (MRD) as a marker of therapeutic response and post-nephrectomy clinical outcomes.

V. To investigate the correlation between circulating levels of soluble KIM-1 and clinical outcomes, including therapeutic response and post-nephrectomy clinical outcomes.

OUTLINE:

Patients receive botensilimab intravenously (IV) over 30 minutes on day 1 of weeks 1 and 7 and balstilimab IV over 30 minutes on day 1 of weeks 1, 3, 5, 7, 9, and 11 in the absence of disease progression or unacceptable toxicity. Patients undergo nephrectomy 12-16 weeks from the initiation of neoadjuvant therapy. Additionally, patients undergo blood sample collection and computed tomography (CT) throughout the study.

After completion of study treatment, patients are followed every 3 months for up to 1 year post-nephrectomy.

Inclusion Criteria:

• Patients must have biopsy-confirmed, non-metastatic, high-risk renal cell carcinoma (RCC) with a clear cell component, defined as clinical stage T2N0, T3N0, T4N0, or any T stage with N1 disease (i.e., T2a-T4NanyM0 or TanyN1M0), and no evidence of metastatic disease
• Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of botensilimab in combination with balstilimab in patients < 18 years of age, children are excluded from this study
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (or Karnofsky ≥ 60%)
• Patients must be considered suitable for curative-intent surgical resection of RCC, including radical or partial nephrectomy, as determined by the urology team and the treating physician according to standard clinical guidelines
• Absolute neutrophil count ≥ 1,000/mcL
• Platelets ≥ 100,000/mcL
• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SGPT]) ≤ 3 x institutional ULN
• Glomerular filtration rate (GFR) 50 mL/min/1.73 m^2
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. Also including a prior history of renal cell carcinoma
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class II or better
• Patients must be scheduled to undergo either partial or radical nephrectomy as part of treatment plan
• The effects of botensilimab and balstilimab on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and 4 months after completion of treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of botensilimab and balstilimab administration. All patients of childbearing potential must undergo a blood or urine pregnancy test within 14 days prior to receiving the first dose of botensilimab and balstilimab to confirm they are not pregnant. If dosing is delayed beyond this window, the pregnancy test must be repeated to ensure results remain current
• Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants
• Availability of pre-treatment archival slides or tissue blocks is required for inclusion in the study

Exclusion Criteria:

• Patients who have suspected or proven metastatic renal cell carcinoma
• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia
• Patients who are receiving any other investigational agents
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to botensilimab or balstilimab
• Patients with uncontrolled intercurrent illness or any other significant condition(s) that would make participation in this protocol unreasonably hazardous
• Pregnant women are excluded from this study because botensilimab and balstilimab are agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with botensilimab or balstilimab, breastfeeding should be discontinued if the mother is treated with botensilimab or balstilimab
• Patients without a clear cell component in their baseline kidney biopsy or non-clear cell renal cell carcinoma (RCC) are excluded from this study
• Patients who have received prior treatment for RCC, including surgery, radiation, thermos-ablation or systemic therapy including immune checkpoint inhibitors, or VEGF tyrosine kinase inhibitors (TKIs)
• Patients who have received prior treatment with an anti-PD-1, anti-programmed cell death protein ligand 1 (PD-L1), anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways
• Patients who have undergone major surgery within 28 days prior to the start of the study
• Patients with any active or recent history of a known or suspected autoimmune disease or recent history of a syndrome that required systemic corticosteroids (> 10 mg daily prednisone equivalent) or immunosuppressive medications within 14 days prior to first dose of study drug; the exception would be for syndromes which would not be expected to recur in the absence of an external trigger. Inhaled steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
• Patients with vitiligo or type I diabetes mellitus or residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement are permitted to enroll