Clinical trial NCT05529316: A Study of Botensilimab (AGEN1181) for the Treatment of Advanced Melanoma
Official title: A Multicohort, Open Label, Phase 2 Study of Botensilimab (AGEN1181) for Treatment of Advanced Melanoma Refractory to Prior Checkpoint Inhibitor Therapy
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Advanced Melanoma
Keywords: Open-label
Monotherapy
Combination Therapy
Anti-PD-1
Anti-PD-L1
Anti-CTLA-4
Immunotherapy
Lead sponsor: Agenus Inc.
Sponsor class: INDUSTRY
First posted: 2022-09-07
Enrollment: 174
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study is an open-label, 2-part, Phase 2, multicenter study to evaluate the efficacy, safety, tolerability, and pharmacokinetic profiles of botensilimab as monotherapy and in combination with balstilimab in participants with advanced cutaneous melanoma refractory to checkpoint inhibitor therapy.

Detailed description: This Phase 2 study will enroll up to approximately 220 evaluable adult participants with a histologically confirmed diagnosis of either Stage III (unresectable) or Stage IV cutaneous melanoma and who have had prior treatments with anti-programmed death (ligand) 1 \[PD-(L)1\].

This study will consist of 2 parts. Part 1 consists of 2 cohorts (Cohorts A and B) that will receive botensilimab monotherapy. In Cohort A, participants refractory to PD-(L)1 will receive botensilimab. In Cohort B, participants refractory to PD-(L)1 and cytotoxic T-lymphocyte antigen 4 (CTLA-4) will receive botensilimab. Part 2 consists of Cohorts A and B that will receive botensilimab combination therapy. In Cohort A, participants refractory to PD-(L)1 will receive botensilimab in combination with balstilimab. In Cohort B, participants refractory to PD-(L)1 and CTLA-4 will receive botensilimab in combination with balstilimab.

Eligibility criteria: Inclusion Criteria:

To participate in the study, participants must meet all the following inclusion criteria:

Cohort A only:

1. Prior treatment with anti-PD-(L)1 therapy (for example, 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.
2. Progression must be either on treatment with anti-PD-(L)1 regimen or ≤ 12 weeks from last anti-PD-(L)1 dose in metastatic setting or ≤ 24 weeks from completion of therapy in adjuvant/ neoadjuvant setting.
3. For Part 2 only, no intervening anti-cancer therapy between the last course of anti-PD-(L)1 treatment and the first dose of study treatment except for local measures (for example, surgical excision, biopsy, focal radiation therapy), or BRAF ± MEK inhibition when applicable in BRAF mutant participants.

Cohort B only:

1. Prior treatment with first-generation anti-CTLA-4 therapy (for example, ipilimumab or tremelimumab) and prior treatment with anti-PD-(L)1 for at least 6 weeks.
2. Progression on most recent anti-neoplastic therapy.
3. For Part 2 only, no more than 3 prior lines of therapy in the advanced setting for BRAF mutant and no more than 2 prior lines of therapy in the advanced setting in the BRAF wild type.

Cohorts A and B:

1. Voluntarily agree to participate by giving signed, dated, and written informed consent prior to any study-specific procedures.
2. Histological confirmation of Stage III (unresectable) or Stage IV cutaneous melanoma, per the American Joint Committee on Cancer 8th edition staging system.
3. Measurable disease on baseline imaging per RECIST 1.1 criteria.
4. BRAF V600 mutation status or consent to BRAF V600 mutation testing per local institutional standards during the screening period.
5. Life expectancy ≥ 3 months.
6. Eastern Cooperative Oncology Group performance status of 0 or 1.
7. Adequate organ function is defined as the following laboratory values within 21 days of Cycle 1 Day 1 (C1D1):

   1. Neutrophils \> 1500/microliter (μL) (stable off any growth factor within 4 weeks of first study treatment administration).
   2. Platelets \> 100 × 10\^3/μL (transfusion to achieve this level is not permitted within 2 weeks of first study treatment administration).
   3. Hemoglobin \> 8.0 grams/deciliter (g/dL) (transfusion to achieve this level is not permitted within 2 weeks of first study treatment administration).
   4. Creatinine clearance ≥ 45 milliliters/minute (measured or calculated using modification of diet in renal disease).
   5. Aspartate aminotransferase/alanine aminotransferase \< 3.0 × upper limit of normal (ULN).
   6. Total bilirubin \< 1.5 × ULN, or \< 3.0 × ULN for participants with Gilbert syndrome.
   7. Albumin ≥ 3.0 g/dL.
   8. International normalized ratio or prothrombin time ≤ 1.5 × ULN and activated partial thromboplastin time ≤ 1.5 × ULN (unless participant is receiving anticoagulant therapy).
8. Participant must provide a 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.
9. 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. 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. Note: Abstinence is acceptable if this is the established and preferred contraception for the participant.
10. In Part 1, male participants 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 participants 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. Males with pregnant partners must agree to use a condom; no additional method of contraception is required for the pregnant partner.

Exclusion Criteria:

To participate in the study, participants must meet none of the following exclusion criteria:

Cohort A:

1. Received prior anti-CTLA-4 therapy.

Cohort B:

1. Received prior Fc-engineered or Fc-enhanced anti-CTLA-4 therapy (for example, BMS-96218, BMS-986288, HBM4003, XTX101, CTLA-4 targeting bispecific or other approaches such as ONC-392).

Cohorts A and B:

1. Ocular, uveal, or mucosal melanoma.
2. 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.
3. Any history of CTCAE Grade ≥ 3 immune-mediated toxicity (excluding endocrinopathies and non-necrotizing/bullous rash) from prior checkpoint inhibition.
4. Refractory ascites require 2 or more therapeutic paracentesis in the last 4 weeks or ≥ 4 within the last 90 days prior to study entry.
5. Bowel obstruction within the past 3 months or an impending bowel obstruction.
6. Clinically significant (that is, 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.
7. Active brain metastases or leptomeningeal metastases with the following exceptions:

   1. Treated brain metastases require a) surgical resection, or b) stereotactic radiosurgery. These participants 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 magnetic resonance imaging is within screening window. Whole-brain radiation is not allowed.
   2. Untreated isolated brain metastases that are too small for treatment by surgical resection or stereotactic radiosurgery (for example, 1-2 millimeters) and/or of uncertain etiology are potentially eligible but need to be discussed with and approved by the study Medical Monitor.
8. Concurrent malignancy (present during screening) requiring treatment or history of prior malignancy active within 2 years prior to the first dose of study treatment (that is, participants 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 participant has no evidence of disease). Participants 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.
9. Incomplete resolution of clinically significant adverse events related to most recent therapy/intervention prior to enrollment.
10. 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. A booster shot is not required but also must be administered \> 7 days from C1D1 or \> 7 days from future cycle on study.
11. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
12. Any evidence of current interstitial lung disease (ILD) or pneumonitis or a prior history of ILD or non-infectious pneumonitis requiring high-dose glucocorticoids.
13. History of allogeneic organ transplant.
14. Psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.
15. Participants with a condition requiring systemic treatment with either corticosteroids (\> 10 milligrams \[mg\] 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.
16. Active autoimmune disease or history of autoimmune disease that required systemic treatment within 2 years before starting study treatment (that is, with use of disease-modifying agents or immunosuppressive drugs).
17. 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 participants participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating Investigator.
18. A WOCBP who is pregnant or breastfeeding or WOCBP who are not willing to employ effective birth control from screening to 90 days after the last dose of botensilimab (whichever is later).
19. Previous SARS-CoV-2 infection within 10 days for mild or asymptomatic infections or 20 days for severe/critical illness prior to C1D1.
20. Uncontrolled infection with human immunodeficiency virus (HIV). Participants on stable highly active antiretroviral therapy with undetectable viral load and normal cluster of differentiation 4 counts for at least 6 months prior to study entry are eligible. Serological testing for HIV at screening is not required.
21. Known to be positive for hepatitis B virus (HBV) surface antigen, or any other positive test for HBV indicating acute or chronic infection. Participants 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.
22. Known active hepatitis C virus (HCV) as determined by positive serology and confirmed by polymerase chain reaction (PCR). Participants 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.
23. Dependence on total parenteral nutrition.

Primary outcomes:
measure: Objective Response Rate
timeFrame: First dose through up to 3 months
Secondary outcomes:
measure: Progression-free Survival
timeFrame: From first dose to first observation of documented disease progression (or death within 12 weeks of last tumor assessment) (up to 3 months)
measure: Duration Of Response
timeFrame: From first dose to first observation of documented disease progression (or death within 12 weeks of last tumor assessment) (up to 3 months)
measure: Overall Survival Time
timeFrame: First dose through up to 3 months
measure: Frequency of Treatment-emergent Adverse Events
timeFrame: First dose through up to 3 months
measure: Serum Botensilimab Anti-drug Antibodies
timeFrame: First study dose (pre-dose and 1 hour post-dose) through up to 3 months
measure: Serum Botensilimab Concentration
timeFrame: First study dose (pre-dose and 1 hour post-dose) through up to 3 months
measure: Serum Balstilimab Anti-drug Antibodies
timeFrame: First study dose (pre-dose and 1 hour post-dose) through up to 3 months
measure: Serum Balstilimab Concentration
timeFrame: First study dose (pre-dose and 1 hour post-dose) through up to 3 months
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Scottsdale Healthcare Hospitals DBA HonorHealth
state: Arizona
city: Fullerton
country: United States
facility: Virginia K. Crosson Cancer Center at St. Jude Medical Center
state: California
city: Santa Monica
country: United States
facility: Providence Saint John's Health Center
state: California
city: New Haven
country: United States
facility: Yale University School of Medicine - Yale Cancer Center
state: Connecticut
city: Washington
country: United States
facility: Georgetown University Medical Center
state: District of Columbia
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Hackensack
country: United States
facility: John Theurer Cancer Center at Hackensack University Medical Center
state: New Jersey
city: Jette
country: Belgium
facility: Universitair Ziekenhuis Brussel
city: Ijuí
country: Brazil
facility: Oncosite - Centro de Pesquisa Clinica Em Oncologia
city: Jaú
country: Brazil
facility: Centro de Pesquisas Clinicas da Fundação Doutor Amaral Carvalho
city: Porto Alegre
country: Brazil
facility: Centro Gaucho Integrado de Oncologia, Hematologia, Ensino e Pesquisa
city: Rio de Janeiro
country: Brazil
facility: INCA II - Instituto Nacional de Cancer Jose Alencar Gomes da Silva
city: São Paulo
country: Brazil
facility: Hospital Sirio Libanes
city: São Paulo
country: Brazil
facility: Real e Benemerita Associaçao Portuguesa de Beneficencia - A Beneficencia Portuguesa de Sao Paulo
city: São Paulo
country: Brazil
facility: Hospital A.C. Camargo Cancer Center
city: Amiens
country: France
facility: CHU Amiens Picardie - Hopital Sud
city: La Tronche
country: France
facility: CHU Grenoble-Alpes - Hopital Michallon
city: Lyon
country: France
facility: Centre Leon Berard
city: Nantes Cedex 1
country: France
facility: CHU de Nantes
city: Paris
country: France
facility: AP-HP Hopital Saint-Louis
city: Rennes
country: France
facility: Centre Eugene Marquis
city: Villejuif
country: France
facility: Gustave Roussy
city: Essen
country: Germany
facility: Universitaetsklinikum Essen
city: Hamburg
country: Germany
facility: Universitaetsklinikum Hamburg-Eppendorf
city: Heidelberg
country: Germany
facility: Universitaetsklinikum Heidelberg
city: Kiel
country: Germany
facility: University Hospital Schleswig-Holstein
city: Mainz
country: Germany
facility: Universitaetsmedizin der Johannes Gutenberg - Universitaet Mainz
city: Munchen
country: Germany
facility: Klinikum der Universitaet München
city: Tuebingen
country: Germany
facility: Universitaetsklinikum Tuebingen
city: Würzburg
country: Germany
facility: Universitaetsklinikum Würzburg
city: Meldola
country: Italy
facility: IRCCS Istituto Romagnolo per lo Studio dei Tumori Dino Amadori - IRST S.r.l.
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori IRCCS Fondazione G. Pascale
city: Siena
country: Italy
facility: Azienda Ospedaliero Universitaria Senese
city: Moscow
country: Russian Federation
facility: Blokhin National Medical Research Oncology Centre
city: Moscow
country: Russian Federation
facility: Branch Office of "Hadassah Medical Ltd"
city: Moscow
country: Russian Federation
facility: Moscow City Oncology Hospital #62
city: Saint Petersburg
country: Russian Federation
facility: LLC Medical Services
city: Saint Petersburg
country: Russian Federation
facility: Clinical Hospital Russian Railways - Medicine
city: Saint Petersburg
country: Russian Federation
facility: Petrov National Medical Research Center of Oncology
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Clinic Barcelona
city: Donostia
country: Spain
facility: Onkologikoa
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Maranon
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Macarena
city: Valencia
country: Spain
facility: Consorcio Hospital General Universitario de Valencia
city: Lausanne
country: Switzerland
facility: CHUV - Centre hospitalier universitaire vaudois
city: Zuerich
country: Switzerland
facility: Universitaetsspital Zuerich
city: London
country: United Kingdom
facility: Royal Marsden Foundation Trust
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
city: Middlesex
country: United Kingdom
facility: Mount Vernon Cancer Centre
Study officials:
affiliation: Agenus Inc.
name: Medical Director
role: STUDY_DIRECTOR
References: