Clinical study to investigate the efficacy of botensilimab (AGEN1181) in patients with advanced melanoma refractory to prior checkpoint inhibitor therapy

Phase 1

Recruiting

Conditions: Advanced melanoma refractory to prior checkpoint inhibitor therapy
MedDRA version: 20.0Level: LLTClassification code: 10027481Term: Metastatic melanoma Class: 10029104
Therapeutic area: Diseases [C] - Neoplasms [C04]

Registration Number: CTIS2022-500652-37-00

Lead Sponsor: Agenus Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Recruiting

Sex: All

Target Recruitment: 208

Inclusion Criteria

01. 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., 02. 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., 03. 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., 04. 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., 05. Cohort B only: Progression on most recent anti-neoplastic therapy., 06. 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., 07. Cohorts A and B: Voluntarily agree to participate by giving signed, dated, and written informed consent prior to any study-specific procedures., 08. Cohorts A and B: = 18 years of age., 09. Cohorts A and B: Histological confirmation of Stage III (unresectable) or Stage IV cutaneous melanoma, as per the AJCC 8th edition staging system., 18. Cohorts A and B: Willing and able to comply with the requirements of the protocol, 10. Cohorts A and B: Measurable disease per RECIST 1.1 criteria., 11. Cohorts A and B: BRAF V600 mutation status or consent to BRAF V600 mutation testing per local institutional standards during screening period., 12. Cohorts A and B: Life expectancy = 3 months., 13. Cohorts A and B: Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1., 14. 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)., 15. 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., 16. Cohorts A and B: Women of childbe

Exclusion Criteria

01. Cohort A only: Received prior anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4) therapy., 08. 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., 09. 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., 10. 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., 20. Cohorts A and B: A WOCBP who is pregnant or breastfeeding., 21. 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., 22. 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., 23. 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., 24. 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., 11. Cohorts A and B: Incomplete resolution of clinically significant AEs related to most recent therapy/intervention prior to enrollment., 12. 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 fu

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To evaluate the clinical efficacy of botensilimab as monotherapy and in combination with balstilimab.;Secondary Objective: 1. To evaluate the clinical efficacy of botensilimab as monotherapy and in combination with balstilimab in delaying the time until disease progression., 2. To evaluate the duration of response (DOR) in patients with an objective disease response to botensilimab as monotherapy and in combination with balstilimab., 3. To evaluate the overall survival (OS) of patients treated with botensilimab as monotherapy and in combination with balstilimab.;Primary end point(s): 1. Objective response rate (ORR) as assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) criteria.

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s):1. Progression-free survival (PFS), defined as the time from enrollment until disease progression or death, whichever comes first, quantified as a rate at 6 and 12 months.;Secondary end point(s):2. Duration of response (DOR), defined as the time from first objective response until progression of disease or death, whichever comes first, quantified as median DOR.;Secondary end point(s):3. Overall survival (OS) time, defined as the time from enrollment until death, whichever comes first, quantified as median OS.