A Phase 1 / 2, Open-Label, Multi-Arm Trial to Investigate the Safety, Tolerability, Pharmacokinetics, Biological, and Clinical Activity of AGEN1884 in Combination With AGEN2034 in Subjects With Metastatic or Locally Advanced Solid Tumors, and Expansion Into Select Solid Tumors
Overview
- Phase
- Phase 1
- Status
- Completed
- Sponsor
- Agenus Inc.
- Enrollment
- 154
- Locations
- 47
- Primary Endpoint
- Objective Response Rate (ORR), as determined by IERC, in the analysis population
Overview
Brief Summary
This is a Phase 1/2, open-label study of AGEN1884 in combination with AGEN2034 in subjects with locally advanced, recurrent and/or metastatic solid tumors including cervical cancer. AGEN2034 is a novel, fully human monoclonal immunoglobulin G4 (IgG4) antibody, designed to block program cell death-1 (PD-1). AGEN1884 is a novel, fully human monoclonal immunoglobulin G1 (IgG1) antibody, designed to block cytotoxic T-lymphocyte antigen-4 (CTLA-4).
Detailed Description
The trial consists of 2 phases:
- Phase 1: Dose escalation
- Phase 2: Expansion in advanced cervical cancer
Phase 1: Dose Escalation:
The enrollment to the Phase 1 portion of the study is completed. The trial will consist of a 3+3 dose escalation that will evaluate different combination dose levels (CDL) of AGEN1884 and AGEN2034 in subjects with locally advanced, recurrent and/or metastatic solid tumors.
Subjects may be enrolled to the following CDL cohorts:
- CDL1 - AGEN1884 1 mg/kg every 6 weeks + AGEN2034 1 mg/kg every 2 weeks (starting CDL)
- CDL2 - AGEN1884 1 mg/kg every 6 weeks + AGEN2034 3 mg/kg every 2 weeks (maximum planned CDL)
- CDL-1 - AGEN1884 0.3 mg/kg every 6 weeks + AGEN2034 1 mg/kg every 2 weeks (potential de-escalation CDL)
Combination Dose Level 1 (CDL1) will be the first to be tested. Dose escalation will continue until the maximum planned CDL (CDL2) is shown to be safe or the maximum tolerated dose (MTD) is reached. The MTD is defined as the CDL below which ≥ 33% of subjects develop dose-limiting toxicities (DLT). The decision to escalate to the next cohort will be made by a Safety Monitoring Committee (SMC), based on safety assessments after all subjects of a cohort reached the end of the DLT observation period of 21 days. Should ≥2 DLTs be observed in CDL1, the SMC may open enrollment to CDL-1. The SMC will also select the CDL for Phase 2.
Each subject will receive the combination treatment for a maximum of 24 months or until confirmed disease progression, unacceptable toxicity, or any criterion for withdrawal from the trial or the investigational medicinal products (IMPs) occur. Subjects who do not complete the DLT observation period of 21 days after the first dose, for reasons other than a DLT will be replaced. Additional subjects will be backfilled, concurrently with the 3+3 dose escalation schema at the lower cleared CDL, to ensure that each cohort enrolls at least 10 subjects. These additional subjects at each dose level will have the purpose of generating additional safety, PK, and receptor occupancy (RO) data, and will not undergo formal DLT observation.
The SMC selected CDL2 (AGEN1884 1 mg/kg every 6 weeks + AGEN2034 3 mg/kg every 2 weeks) as the Recommended Phase 2 dose (RP2D).
Phase 2: Expansion in Select Tumors
To further characterize safety and efficacy, the following expansion cohort will be enrolled:
Advanced cervical cancer In Phase 2, the RP2D of AGEN2034 and AGEN1884 will be administered for a maximum of 2 years or until confirmed progression, unacceptable toxicity, or any criterion for stopping the study drugs or withdrawal from the trial occurs.
For the Phase 2 portion of the trial, an Independent Data Monitoring Committee (IDMC) will be established to evaluate safety and efficacy and an IERC will be established to adjudicate tumor response.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- Female
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •To be eligible for participation in this trial the subject must:
- •Voluntarily agree to participate by giving written informed consent. (Participation in pharmacogenomics testing is optional.)
- •Be ≥18 years of age.
- •Phase 1: Male or female having a histologically or cytologically confirmed diagnosis of a locally advanced, recurrent, and/or metastatic solid tumor for which no standard therapy is available or standard therapy has failed.
- •I. Female having (1) a histologically or cytologically confirmed diagnosis of squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix, and (2) locally advanced, recurrent, and/or metastatic disease at the time of enrollment. Histologic confirmation of the original primary tumor is required via pathology report.
- •Note: The following cervical tumors are not eligible: minimal deviation/adenoma malignum, gastric type adenocarcinoma, clear cell carcinoma, and mesonephric carcinoma.
- •II. Has cervical cancer and has relapsed after a platinum-based treatment (first line) regimen for locally advanced, recurrent, and/or metastatic disease; Note: Subjects who only received platinum-based chemotherapy concurrently with primary radiation (e.g., weekly cisplatin) or adjuvant chemotherapy following completion of radiation therapy (e.g., paclitaxel and carboplatin for ≤4 cycles) and progressed within 6 months after treatment completion will be eligible as this systemic therapy will be considered first line.
- •Measurable Disease:
- •Phase 1: Have objective evidence of disease; the presence of measurable disease is not required.
- •Phase 2: Have measurable disease on imaging based on RECIST version 1.
Exclusion Criteria
- Not provided
Arms & Interventions
AGEN1884 + AGEN2034
AGEN1884 in combination with AGEN2034 in subjects with Subjects with Metastatic or Locally Advanced Solid Tumors, and Expansion into Select Solid Tumors (cervical)
Intervention: AGEN1884 + AGEN2034 (Drug)
Outcomes
Primary Outcomes
Objective Response Rate (ORR), as determined by IERC, in the analysis population
Time Frame: Evaluated throughout the protocol, up to 2 years.
per RECIST 1.1
Secondary Outcomes
- Safety and Tolerability of AGEN2034 and AGEN1884(From the time of the first dose to the end of follow-up (up to 2 years after the last dose).)
- Systemic clearance (CL)(Pre-dose through 3 months after last dose.)
- Volume of distribution (Vd)(Pre-dose through 3 months after last dose.)
- Duration of Stable Disease (SD)(Duration of the trial, up to 3 years.)
- Minimum observed concentration at steady-state (Cmin-ss)(Pre-dose through 3 months after last dose.)
- Time to maximum observed concentration (tmax)(Pre-dose through 3 months after last dose.)
- Terminal disposition rate constant (λz)(Pre-dose through 3 months after last dose.)
- Duration of Response (DOR)(Time from first observation of response to first observation of documented disease progression, up to 3 years.)
- Progression-free Survival (PFS)(Duration of the treatment phase of the trial, up to 2 years.)
- Maximum drug concentration observed postdose at steady-state (Cmax-ss)(Pre-dose through 3 months after last dose.)
- Area under the drug concentration-time curve within time span t1 to t2 at steady-state (AUC(τ1-τ2)-ss)(Pre-dose through 3 months after last dose.)
- Area under the drug concentration-time curve from time zero to time t (AUC(0-t)), area under the drug concentration-time curve from time zero to infinity (AUC(0-∞))(Pre-dose through 3 months after last dose.)
- Terminal elimination half-life (t1/2)(Pre-dose through 3 months after last dose.)
- Immunogenicity of AGEN2034 and AGEN1884(Pre-dose through 3 months after last dose.)
- Objective Response Rate (ORR), as determined by investigator(Evaluated throughout the protocol, up to 2 years.)
- Disease Control Rate (DCR)(Duration of the trial, up to 3 years.)
- Time to Response(Duration of the treatment phase of the trial, up to 2 years.)
- Overall Survival Rate (OS)(Duration of the treatment phase of the trial, up to 2 years.)