A MULTICOHORT, OPEN LABEL, PHASE 2 STUDY OF BOTENSILIMAB (AGEN1181) FOR TREATMENT OF ADVANCED MELANOMA REFRACTORY TO PRIOR CHECKPOINT INHIBITOR THERAPY

Trial ID: 2022-500652-37-00
Protocol: C-800-23
Sponsor: Agenus Inc.

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Diseases & Conditions

Metastatic malignant melanoma

Objectives

The primary objective of this study is to evaluate the **clinical efficacy** of botensilimab, both as a monotherapy and in combination with balstilimab, in patients with advanced melanoma that is refractory to prior checkpoint inhibitor therapy. This is clinically relevant as it aims to provide insights into potential treatment options for a patient population with limited therapeutic alternatives.

Secondary objectives include:

Evaluating the clinical efficacy of botensilimab as monotherapy and in combination with balstilimab in delaying the time until disease progression.
Assessing the duration of response (DOR) in patients who exhibit an objective disease response to botensilimab, both as monotherapy and in combination with balstilimab.
Evaluating the overall survival (OS) of patients treated with botensilimab as monotherapy and in combination with balstilimab.

Participants

The clinical trial involves a total of **88 participants** diagnosed with **advanced melanoma** that is refractory to prior checkpoint inhibitor therapy. The study population includes both male and female subjects, aged 18 years and older, with a confirmed diagnosis of Stage III (unresectable) or Stage IV cutaneous melanoma, as per the AJCC 8th edition staging system. Participants were selected based on their prior treatment history, including previous exposure to anti-PD-L1 and anti-CTLA-4 therapies, and their progression status on these treatments. The trial includes individuals with a life expectancy of at least 3 months and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants are required to have adequate organ function and measurable disease per RECIST 1.1 criteria. The trial population is characterized by a willingness to comply with study requirements and provide informed consent. Lifestyle considerations such as diet and physical activity are not specified, but participants must adhere to contraceptive measures if applicable. The study does not specify any particular lifestyle habits or restrictions beyond the medical and treatment history criteria outlined.

Plans and Procedures

The clinical trial is a **Phase II** study designed to evaluate the clinical efficacy of **botensilimab** as monotherapy and in combination with **balstilimab** in patients with advanced melanoma refractory to prior checkpoint inhibitor therapy. The trial is structured as a multicohort, open-label study, with an estimated duration from October 2022 to March 2025. Participants will be randomly assigned to different cohorts based on their prior treatment history and specific inclusion criteria. The study will involve a series of visits, starting with a screening visit to confirm eligibility, followed by regular follow-up visits to monitor treatment response and safety, and concluding with an end-of-study visit to assess overall outcomes.

Participants will be involved in the study for a maximum treatment period of 24 months, depending on the cohort assignment and treatment response. The study visits are designed to ensure comprehensive monitoring of the participants' health status and treatment efficacy. The inclusion visit will involve detailed assessments to confirm the diagnosis of advanced melanoma and ensure compliance with the eligibility criteria, such as prior treatment with anti-PD-L1 therapy and measurable disease per RECIST 1.1 criteria. Follow-up visits will occur at regular intervals to evaluate the objective response rate, progression-free survival, duration of response, and overall survival time.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The primary endpoint of the study is the objective response rate, while secondary endpoints include progression-free survival, duration of response, and overall survival. The trial aims to provide valuable insights into the efficacy of botensilimab and balstilimab in treating advanced melanoma, potentially offering new therapeutic options for patients with this challenging condition.

Treatment

The clinical trial involves the administration of **botensilimab**, a **solution for infusion** developed by Agenus Inc. This experimental medication is a **human IgG1k monoclonal antibody against CTLA4**, also known by its sponsor product code AGEN1181. Botensilimab is administered via **intravenous infusion**. The dosing regimen includes a maximum daily dose of 150 mg, with a total maximum dose of 600 mg over a treatment period of up to 3 weeks. The medication is not formulated for pediatric use and is not classified as an orphan drug. Participant compliance with the dosing schedule will be monitored throughout the trial.

In combination with botensilimab, the trial also evaluates **balstilimab**, another **solution for infusion** from Agenus Inc. Balstilimab is a **human IgG4 monoclonal antagonist antibody directed against programmed cell death protein 1 (PD-1)**, with the sponsor product code AGEN2034. This medication is also administered via **intravenous infusion**. The dosing schedule for balstilimab allows for a maximum daily dose of 450 mg, with a total maximum dose of 14,400 mg over a treatment period of up to 24 weeks. Similar to botensilimab, balstilimab is not intended for pediatric use and is not designated as an orphan drug. Compliance with the administration protocol will be closely monitored to ensure adherence to the study's requirements.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified for use in this study. The primary objective of the trial is to assess the clinical efficacy of botensilimab as a monotherapy and in combination with balstilimab in patients with advanced melanoma refractory to prior checkpoint inhibitor therapy.

Efficacy

The clinical trial aims to assess the efficacy of **botensilimab** as monotherapy and in combination with **balstilimab** for the treatment of advanced melanoma refractory to prior checkpoint inhibitor therapy. Efficacy will be primarily evaluated using the Objective Response Rate (ORR) as assessed by the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1). Secondary endpoints include Progression-Free Survival (PFS), Duration of Response (DOR), and Overall Survival (OS). PFS is defined as the time from enrollment until disease progression or death, quantified as a rate at 6 and 12 months. DOR is defined as the time from the first objective response until progression of disease or death, quantified as median DOR. OS is defined as the time from enrollment until death, quantified as median OS.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Cohort A only: Prior treatment with anti-programmed cell death protein (ligand) 1 (anti-PD-L1) therapy (e.g., pembrolizumab or nivolumab) for at least 6 weeks, and radiologic progression confirmed by 2 scans at least 4 weeks apart, or if symptomatic due to progressive malignancy, then 1 scan showing progression is sufficient.
Cohorts A and B: Measurable disease per RECIST 1.1 criteria.
Cohorts A and B: BRAF V600 mutation status or consent to BRAF V600 mutation testing per local institutional standards during screening period.
Cohorts A and B: Life expectancy ≥ 3 months.
Cohorts A and B: Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
Cohorts A and B: Adequate organ function defined as the following laboratory values within 21 days of Cycle 1 Day 1 (C1D1): a. Neutrophils > 1500/μL (stable off any growth factor within 4 weeks of first study treatment administration). b. Platelets > 100 × 103/μL (transfusion to achieve this level is not permitted within 2 weeks of first study treatment administration). c. Hemoglobin > 8.0 g/dL (transfusion to achieve this level is not permitted within 2 weeks of first study treatment administration). d. Creatinine clearance ≥ 45 mL/min (measured or calculated using modification of diet in renal disease [MDRD]). e. Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) < 3.0 × upper limit of normal (ULN). f. Total bilirubin < 1.5 × ULN, or < 3.0 × ULN for patients with Gilbert syndrome. g. Albumin ≥ 3.0 g/dL. h. International normalized ratio (INR) or prothrombin time ≤ 1.5 × ULN and activated partial thromboplastin time ≤ 1.5 × ULN (unless patient is receiving anticoagulant therapy).
Cohorts A and B: Patients must provide formalin-fixed paraffin-embedded tumor tissue sample from the most recent biopsy of a tumor lesion, obtained within 90 days from signing informed consent form. If recent tumor tissue is unavailable or inadequate, a fresh biopsy will be required, unless the Sponsor agrees that it is not safe/feasible.
Cohorts A and B: Women of childbearing potential (WOCBP) must have a negative urine or serum pregnancy test at screening (within 72 hours of first dose of study medication) and prior to study drug administration. Non-childbearing potential is defined as: a. ≥ 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 a follicle-stimulating hormone value in the postmenopausal range upon pre-study (screening) evaluation. c. Status is post-hysterectomy, bilateral oophorectomy, or tubal ligation. In Part 1, WOCBP must agree to use highly effective contraceptive measures starting with the Screening Visit through 3 months after the last dose of study treatment. In Part 2, WOCBP must agree to use highly effective contraceptive measures starting with the Screening Visit through 5 months after the last dose of study treatment.
Cohorts A and B: In Part 1, male patients with a female partner(s) of childbearing potential must agree to use highly effective contraceptive measures throughout the study starting with the Screening Visit through 3 months after the last dose of study treatment is received. In Part 2, male patients with a female partner(s) of childbearing potential must agree to use highly effective contraceptive measures throughout the study starting with the Screening Visit through 5 months after the last dose of study treatment is received. Male patients with pregnant partners must agree to use a condom; no additional method of contraception is required for the pregnant partner.
Cohort A only: Progression must be either on treatment with anti-PD-L1 regimen or ≤ 12 weeks from last anti-PD-L1 dose in metastatic setting or ≤ 24 weeks from completion of therapy in adjuvant/neoadjuvant setting.
Cohort A only: For Part 2 only, no intervening anti-cancer therapy between the last course of anti-PDL1 treatment and the first dose of study treatment except for local measures (eg, surgical excision, biopsy, focal radiation therapy), or BRAF ± MEK inhibition when applicable in BRAF mutant patients.
Cohort B only: Prior treatment with first generation anti-CTLA-4 therapy (e.g., ipilimumab or tremelimumab), and prior treatment with anti-PD-L1 for at least 6 weeks.
Cohort B only: Progression on most recent anti-neoplastic therapy.
Cohort B only: For Part 2 only, no more than 3 prior lines of therapy in the metastatic setting for BRAF mutation and no more than 2 prior lines of therapy in the metastatic setting in the BRAF wild type.
Cohorts A and B: Voluntarily agree to participate by giving signed, dated, and written informed consent prior to any study-specific procedures.
Cohorts A and B: ≥ 18 years of age.
Cohorts A and B: Histological confirmation of Stage III (unresectable) or Stage IV cutaneous melanoma, as per the AJCC 8th edition staging system.
Cohorts A and B: Willing and able to comply with the requirements of the protocol

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Exclusion Criteria

Cohort A only: Received prior anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4) therapy.
Cohorts A and B: Active autoimmune disease or history of autoimmune disease that required systemic treatment within 2 years before starting treatment (i.e., with use of disease-modifying agents or immunosuppressive drugs).
Cohorts A and B: History or current evidence of any condition, co-morbidity, therapy, any active infections, or laboratory abnormality that might confound the results of the study, interfere with the patient’s participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating Investigator.
Cohort B only: Received prior Fc-engineered or Fc-enhanced anti-CTLA-4 therapy (e.g., BMS-96218, BMS-986288, HBM4003, XTX101, CTLA-4 targeting bispecific or other approaches such as ONC-392).
Cohorts A and B: Ocular, uveal, or mucosal melanoma.
Cohorts A and B: Any persistent toxicities (Common Terminology Criteria for Adverse Events [CTCAE] Grade ≥ 2) from prior cancer therapy, excluding endocrinopathies stable on medication, stable neuropathy, and alopecia.
Cohorts A and B: Any history of CTCAE Grade ≥ 3 immune-mediated toxicity (excluding endocrinopathies and non-necrotizing/bullous rash) from prior checkpoint inhibition.
Cohorts A and B: Refractory ascites defined as requiring 2 or more therapeutic paracentesis in the last 4 weeks or ≥ 4 within the last 90 days prior to study entry.
Cohorts A and B: Bowel obstruction within the past 3 months or an impending bowel obstruction.
Cohorts A and B: 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 ≥ III), or serious uncontrolled cardiac arrhythmia requiring medication.
Cohorts A and B: Active brain metastases or leptomeningeal metastases with the following exceptions: a. Treated brain metastases require a) surgical resection, or b) stereotactic radiosurgery. These patients must be off steroids ≥ 10 days prior to randomization for the purpose of managing their brain metastases. Repeat brain imaging following surgical resection or stereotactic radiosurgery is not required if their last brain MRI is within screening window. Whole-brain radiation is not allowed. b. Untreated isolated brain metastases that are too small for treatment by surgical resection or stereotactic radiosurgery (e.g., 1-2 mm) and/or of uncertain etiology are potentially eligible but need to be discussed with and approved by the study Medical Monitor.
Cohorts A and B: Concurrent malignancy (present during screening) requiring treatment or history of prior malignancy active within 2 years prior to the first dose of study treatment (i.e., patients with a history of prior malignancy are eligible if treatment was completed at least 2 years before the first dose of study treatment and the patient has no evidence of disease). Patients with history of prior early-stage basal/squamous cell skin cancer, low-risk prostate cancer eligible for active surveillance or noninvasive or in situ cancers who have undergone definitive treatment at any time are also eligible.
Cohorts A and B: A WOCBP who is pregnant or breastfeeding.
Cohorts A and B: Previous SARS-CoV-2 infection within 10 days for mild or asymptomatic infections or 20 days for severe/critical illness prior to C1D1.
Cohorts A and B: Uncontrolled infection with HIV. Patients on stable highly active antiretroviral therapy (HAART) with undetectable viral load and normal CD4 counts for at least 6 months prior to study entry are eligible. Serological testing for HIV at screening is not required.
Cohorts A and B: Known to be positive for hepatitis B virus (HBV) surface antigen, or any other positive test for HBV indicating acute or chronic infection. Patients who are receiving or who have received anti-HBV therapy and have undetectable HBV DNA for at least 6 months prior to study entry are eligible. Serological testing for HBV at screening is not required.
Cohorts A and B: Known active hepatitis C virus (HCV) as determined by positive serology and confirmed by polymerase chain reaction (PCR). Patients on or who have received antiretroviral therapy are eligible provided they are virus-free by PCR for at least 6 months prior to study entry. Serological testing for HCV at screening is not required.
Cohorts A and B: Incomplete resolution of clinically significant AEs related to most recent therapy/intervention prior to enrollment.
Cohorts A and B: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine or booster < 7 days before C1D1. For vaccines requiring more than 1 dose, the full series should be completed prior to C1D1, when feasible. Booster shot not required but also must be administered > 7 days from C1D1 or > 7 days from future cycle on study.
Cohorts A and B: Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
Cohorts A and B: Any evidence of current interstitial lung disease (ILD) or pneumonitis or a prior history of ILD or non-infectious pneumonitis requiring high-dose glucocorticoids.
Cohorts A and B: History of allogeneic organ transplant.
Cohorts A and B: Psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.
Cohorts A and B: Patients with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) within 14 days or another immunosuppressive medication within 30 days of the first dose of study treatment. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
Cohorts A and B: Dependence on total parenteral nutrition.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Belgium	Not Recruiting	01 Oct 2022	10
France	Not Recruiting	01 Oct 2022	30
Germany	Not Recruiting	01 Oct 2022	25
Italy	Not Recruiting	01 Oct 2022	25
Spain	Not Recruiting	01 Oct 2022	30