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.

Study Overview

• Status: Not yet recruiting
• Conditions: Clear Cell Renal Cell Carcinoma; Stage III Renal Cell Cancer AJCC v8; Stage IV Renal Cell Cancer AJCC v8; Stage II Renal Cell Cancer AJCC v8
• Intervention / Treatment: Other: Questionnaire Administration; Procedure: Computed Tomography; Procedure: Biospecimen Collection; Procedure: Nephrectomy; Biological: Balstilimab; Biological: Botensilimab

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 16
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (botensilimab, balstilimab); Patients receive botensilimab 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 CT throughout the study.

Other: Questionnaire Administration; Ancillary studies; Procedure: Computed Tomography; Undergo CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Diagnostic CAT Scan; Diagnostic CAT Scan Service Type; Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Sample Collection; Procedure: Nephrectomy; Undergo nephrectomy; Biological: Balstilimab; Given IV; Other Names: AGEN2034; AGEN 2034; AGEN-2034; Biological: Botensilimab; Given IV; Other Names: AGEN1181; AGEN 1181; AGEN-1181; Anti-CTLA-4 Monoclonal Antibody AGEN1181

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients successfully completing neoadjuvant treatment and undergoing planned definitive surgical resection of primary tumor (radical or partial nephrectomy) without significant treatment related delays	The intervention will be considered feasible if at least 80% of enrolled patients (13 out of 16) successfully undergo planned radical or partial nephrectomy following treatment.	Up to 1 year post-surgery
Incidence and severity of treatment-related adverse events	Will be analyzed descriptively using frequencies and proportions, stratified by severity according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.	Up to 30 days after last dose of study treatment
Incidence and severity of surgical complications	Will be summarized using the Clavien-Dindo Classification.	Up to 30 days after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate (ORR)	Will be defined as the proportion of patients achieving a complete response or partial response of the primary tumor as defined by RECIST 1.1 criteria. ORR will be summarized as a proportion with a 95% confidence interval (CI) using the Clopper-Pearson method (exact binomial CIs), and analyses conducted on both the intention-to-treat and per-protocol populations.	After neoadjuvant treatment, assessed up to 1 year post-nephrectomy
Major pathologic response (MPR) rate	Will be defined as the proportion of patients with < 10% viable tumor cells. MPR rate will be determined through centralized pathology review of the surgical specimen, summarized as proportions with 95% CIs using Clopper-Pearson method, and a descriptive comparison between response categories will be presented.	Up to 1 year post-surgery
Partial pathologic rate (PPR) rate	Will be defined as the proportion of patients with < 50% viable tumor cells in the tumor bed of the resected specimen, will be assessed. PPR rate will be determined through centralized pathology review of the surgical specimen, summarized as proportions with 95% CIs using Clopper-Pearson method, and a descriptive comparison between response categories will be presented.	Up to 1 year post-surgery
Rates of distant metastasis	Will be defined as proportion of patients experiencing distant metastatic disease. Will be summarized as proportions with 95% CIs.	Up to 1 year post-surgery
Rates of local recurrence	Will be defined as proportion of patients experiencing local recurrence after treatment. Will be summarized as proportions with 95% CIs.	Up to 1 year post-surgery
Disease-free survival (DFS)	DFS will be analyzed using the Kaplan-Meier method for medians and survival curves, with subgroup comparisons by log-rank tests and hazard ratios estimated using Cox proportional hazards models.	From surgery to the first documented evidence of disease recurrence (local, regional, or distant metastasis) or death from any cause, assessed up to 1 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in immune biomarkers	Single-cell ribonucleic acid sequencing will be performed on tumor tissue to evaluate changes within the tumor microenvironment. Will be analyzed using paired t-tests or Wilcoxon signed-rank tests for non-normally distributed data, and multivariable models will be used to explore correlations between these changes and clinical endpoints (e.g., ORR, MPR).	At baseline and after treatment, assessed up to 1 year
Systemic immune activation markers	Peripheral blood mononuclear cell analysis will be conducted. Changes will be analyzed using paired t-tests or Wilcoxon signed-rank tests for non-normally distributed data, and multivariable models will be used to explore correlations between these changes and clinical endpoints (e.g., ORR, MPR).	At baseline and after treatment, assessed up to 1 year
T-cell clonality and diversity	T-cell receptor sequencing will be used to evaluate tumor and blood samples. Data will be summarized descriptively, with changes in clonality indices assessed using paired statistical tests, while associations between TCR clonality and clinical outcomes (e.g., ORR, DFS) will be explored using logistic or Cox regression models.	At pre and post treatment, assessed up to 1 year
Immune cell subset analysis	Immunofluorescence immunohistochemistry will be employed to assess immune cell subsets, including CD8+, CD4+, and Treg populations, within the tumor microenvironment. Data will be summarized descriptively, with changes assessed using paired statistical tests, while associations between immune cell subsets and clinical outcomes (e.g., ORR, DFS) will be explored using logistic or Cox regression models.	At pre and post treatment, assessed up to 1 year
Soluble biomarkers, including KIM-1, and other renal injury markers	Will be measured in blood samples. Will be analyzed using paired t-tests or non-parametric equivalents.	At baseline, before surgery, and post-treatment, will be assessed up to 1 year
Circulating tumor deoxyribonucleic acid levels	Will be analyzed to assess dynamic changes and their correlation with treatment response and disease progression. Linear mixed-effects models for longitudinal changes, and their correlations with clinical outcomes (e.g., DFS, ORR, MPR) will be explored using Spearman or Pearson correlation coefficients.	At pre-and post-treatment, assessed up to 1 year

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Adanma Anji Ayanambakkam Attanathi, Yale University Cancer Center LAO

Study record dates

Study Major Dates

• Study Start (Estimated): August 21, 2026
• Primary Completion (Estimated): August 30, 2027
• Study Completion (Estimated): August 30, 2027

Study Registration Dates

• First Submitted: April 7, 2026
• First Submitted That Met QC Criteria: April 7, 2026
• First Posted (Actual): April 8, 2026

Study Record Updates

• Last Update Posted (Actual): May 15, 2026
• Last Update Submitted That Met QC Criteria: May 14, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Urologic Neoplasms; Carcinoma; Kidney Neoplasms; Carcinoma, Renal Cell; Investigative Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Surgical Procedures, Operative; Urologic Surgical Procedures; Urogenital Surgical Procedures; Specimen Handling; balstilimab; Nephrectomy
• Other Study ID Numbers: NCI-2026-02194 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); UM1CA186689 (U.S. NIH Grant/Contract); 10743 (Other Identifier: CTEP)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No