Neoadjuvant Efficacy and Safety of Botensilimab and Balstilimab in dMMR and pMMR Tumors: A Pan-Tumor Basket Study

Trial ID: 2023-505756-21-00
Sponsor: Netherlands Cancer Institute

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Diseases & Conditions

Mismatch repair cancer syndrome

Objectives

The primary objective of this study is to evaluate the **efficacy** of the combination of botensilimab and balstilimab in patients with dMMR and pMMR tumors. The efficacy is measured by the major pathologic response rate, defined as ≤ 10% viable tumor remaining in the surgical resection of the tumor bed following neoadjuvant therapy. This is clinically relevant as it aims to determine the potential of these agents in reducing tumor viability pre-surgery, which could improve surgical outcomes and long-term prognosis for patients with these tumor types. Additionally, the study includes a safety run-in cohort to assess the safety and feasibility of pre-operative administration of botensilimab and balstilimab in dMMR and pMMR tumors of any origin.

Secondary objectives include: - Assessing survival and the correlation of pathologic response with survival. - Evaluating the pathologic response rate. - Determining the radiological response rate. - Assessing post-surgical outcomes and infectious complications following neoadjuvant immunotherapy.

Participants

The clinical trial involves a study population comprising both **male** and **female** participants, aged 18 years and older, with non-metastatic **dMMR** and **pMMR** cancers. The specific types of cancers include, but are not limited to, colorectal cancer, oesophageal cancer, gastric cancer, duodenal and small bowel cancer, endometrial cancer, breast cancer, prostate cancer, and sarcoma. Participants are required to have a **WHO performance status** of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial does not include a vulnerable population. The selection criteria necessitate that participants are eligible for study biopsy and meet specific laboratory test criteria. Lifestyle considerations such as diet and physical activity are not specified. The sponsor has not provided information regarding the total number of participants in the trial.

Plans and Procedures

The clinical trial is designed to evaluate the **efficacy** and safety of **botensilimab** in combination with **balstilimab** in patients with various tumor types, including but not limited to colorectal cancer, esophageal cancer, gastric cancer, and sarcoma. This trial is a **randomized**, **double-blind**, and **controlled** study, conducted over an estimated duration from September 2023 to September 2028. The primary objective is to determine the major pathologic response rate, defined as less than 10% viable tumor remaining in the surgical resection of the tumor bed following neoadjuvant therapy. Secondary endpoints include pathologic complete response, event-free survival, disease-free survival, overall survival, and radiological response according to RECIST 1.1.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, cancer type, and laboratory test results. Eligible participants must have a WHO performance status of 0 or 1 and meet specific laboratory criteria. The trial includes a safety run-in phase with two cohorts of 10 patients each to assess the safety and feasibility of the treatment in both dMMR and pMMR tumors. Following the screening, participants will receive treatment on day 1 and day 22, with surgery scheduled at week 8. Pre- and post-treatment samples will be collected for exploratory analyses, and participants will undergo additional imaging studies, including a CT scan and optionally a PET-CT scan.

The expected length of participant involvement is approximately 8 weeks, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent. Participants are required to adhere to contraceptive measures during and after the study, with specific guidelines for both women of childbearing potential and men. The trial aims to investigate changes in the tumor microenvironment and identify potential biomarkers or targets for future immuno-oncology combinations.

Treatment

The clinical trial involves the administration of **Botensilimab**, a **solution for infusion** developed by Agenus Inc. Botensilimab is a **human IgG1k monoclonal antibody** targeting CTLA4, classified under the origin of "Protein - Other." The pharmaceutical form is a solution for infusion, administered via **intravenous infusion**. The maximum daily dose is 50 mg, with a total maximum dose of 100 mg over a treatment period of 4 weeks. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.

Additionally, the trial includes the administration of **Balstilimab**, also a **solution for infusion** from Agenus Inc. Balstilimab is an **anti-PD1 human monoclonal antibody**, specifically a human IgG4 monoclonal antagonist antibody directed against programmed cell death protein 1 (PD-1). It is administered intravenously, with a maximum daily dose of 450 mg and a total maximum dose of 900 mg over a 4-week treatment period. The dosing schedule is carefully monitored to maintain participant compliance and ensure the integrity of the trial data.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are utilized in this study. The focus remains on evaluating the efficacy and safety of the combination of Botensilimab and Balstilimab in the specified tumor cohorts. The trial's primary objective is to assess the major pathologic response rate, defined as ≤ 10% viable tumor remaining in the surgical resection of the tumor bed following neoadjuvant therapy.

Efficacy

The efficacy of the combination therapy of **Botensilimab** and **Balstilimab** in the clinical trial will be assessed primarily through the major pathologic response (MPR) rate. This is defined as having less than 10% residual viable tumor (RVT) in the resection specimen following neoadjuvant therapy. In cases where only in situ carcinoma or equivalent non-invasive residual tissue is found upon pathologic assessment, this will not be included in the RVT calculation. A complete resolution of invasive tumor cells, with only in situ or equivalent non-invasive tissue remaining, will be considered a pathologic complete response (pCR) to treatment.

Secondary endpoints include pathologic complete response (pCR), event-free survival, disease-free survival (DFS), overall survival (OS), and radiological response according to RECIST 1.1 criteria. Pathologic complete response is defined as no RVT in the primary tumor and locoregional lymph nodes. Event-free survival is measured from registration to the date of disease progression, recurrence, or death from any cause. Disease-free survival is defined as the time from surgery to disease recurrence, and overall survival is the time from registration until death from any cause.

Patients will receive treatment on day 1 and day 22, followed by surgery at week 8. Exploratory analyses will be conducted using pre- and post-treatment samples collected through biopsies. Additional assessments include an extra CT scan pre-operatively, with an optional PET-CT scan and feces collection. These analyses aim to investigate changes in the tumor microenvironment and identify potential biomarkers or targets for future immuno-oncology combinations.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Signed written informed consent
Patients at least 18 years of age
Non-metastatic dMMR and pMMR cancers either fitting within a specific basket or in the “other” cohort (e.g. sarcoma, cervical cancer, head and neck cancers, anal cancer, esophageal SCC)
Eligible for study biopsy
WHO performance status of 0 or 1
Screening laboratory tests must meet the following criteria and should be obtained within 7 days prior to randomization/registration: WBC > 2.0 x 10^9/L, ANC > 1.5x10^9/L, platelets > 100 x 10^9/L, Hemoglobin > 5.0mmol/L. Transfusion is allowed to obtain an adequate hemoglobin level. Liver function tests: total bilirubin < 1.5 upper limit of normal (ULN) (except for subjects with Gilbert syndrome, who can have total bilirubin <3.0 mg/dL); alkaline phosphatase <1.5ULN; transaminases (ASAT/ALAT) <3 x ULN; LDH < 1.5x ULN; Creatinine clearance (Cockcroft-Gault) of >45 ml/min, Albumin > 3.0 g/dL
Women of childbearing potential (WOCBP)* must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 20 weeks after the last dose of investigational drug; Non-childbearing potential is defined as: a. Postmenopausal: ≥ 50 years of age and has not had menses for greater than 1 year. b. Amenorrheic for ≥ 2 years without a hysterectomy and bilateral oophorectomy and afollicle-stimulating hormone value in the postmenopausal range upon prestudy( screening) evaluation. c. Status is post-hysterectomy, bilateral oophorectomy, or tubal ligation.
Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 7 days prior to registration
Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving the study treatment and who are sexually active with WOCBP (excluding azoospermic men) will be instructed to adhere to contraception for a period of 28 weeks after the last dose of investigational drug and are not allowed to donate sperm during that timeframe.
In case of pMMR tumors: no indication for neoadjuvant therapy according to standard of care, unless adjuvant treatment is considered a standard of care alternative

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Exclusion Criteria

Signs of distant metastases on imaging and physical examination
No intercurrent illnesses, including but not limited to infections, unstable angina pectoris
Underlying medical conditions that, in the investigator’s opinion, will make the administration of the study drug hazardous or obscure the interpretation of toxicity determination of adverse events
Positive test for hepatitis B virus surface antigen (HBsAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
History of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS);
Active autoimmune disease or a documented history of autoimmune disease, or other medical conditions requiring systemic steroid or immunosuppressive medications, except for subjects with vitiligo, diabetes mellitus type 1, hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis or resolved childhood asthma/atopy not requiring systemic treatment
Conditions requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
Live vaccines in the 4 weeks prior to inclusion
Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
Current pregnancy or breastfeeding
Clinical obstruction
Clinical symptoms or radiological suspicion of perforation
Previous treatment with immune checkpoint inhibitors targeting including but not limited to CTLA-4, PD-1 or PD-L1
Prior chemotherapy for any cancer
Radiotherapy prior to surgery for disease under study
Active malignancies other than disease under study within 3 years prior to inclusion, except for malignancies with a negligible recurrence rate (e.g. <10% in 5 years);
History of allergy to study drug components
History of severe hypersensitivity reaction to any monoclonal antibody
Specific for pMMR GEA cohort: Known DPD deficiency; refer local clinical guidance, for DPD status recommendation prior to starting treatment