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).
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 Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
154
AGEN1884 + AGEN2034 according to protocol design
Objective Response Rate (ORR), as determined by IERC, in the analysis population
per RECIST 1.1
Time frame: Evaluated throughout the protocol, up to 2 years.
Safety and Tolerability of AGEN2034 and AGEN1884
Frequency, severity, and duration of TEAEs and laboratory abnormalities, using NCI CTCAE v4.03.
Time frame: From the time of the first dose to the end of follow-up (up to 2 years after the last dose).
Maximum drug concentration observed postdose at steady-state (Cmax-ss)
Serum AGEN2034 and AGEN1884 concentrations measured throughout the study.
Time frame: Pre-dose through 3 months after last dose.
Minimum observed concentration at steady-state (Cmin-ss)
Serum AGEN2034 and AGEN1884 concentrations measured throughout the study.
Time frame: 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)
Serum AGEN2034 and AGEN1884 concentrations measured throughout the study.
Time frame: 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-∞))
Serum AGEN2034 and AGEN1884 concentrations measured throughout the study.
Time frame: Pre-dose through 3 months after last dose.
Time to maximum observed concentration (tmax)
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Comprehensive Care and Research Center
Goodyear, Arizona, United States
City of Hope National Medical Center
Duarte, California, United States
University of Miami
Miami, Florida, United States
BRCR Medical Center, Inc
Plantation, Florida, United States
Augusta University
Augusta, Georgia, United States
Cancer Treatment Centers of America
Zion, Illinois, United States
Ochsner Cancer Institute
New Orleans, Louisiana, United States
West Michigan Cancer Center
Kalamazoo, Michigan, United States
University of Oklahoma
Oklahoma City, Oklahoma, United States
Chattanooga's Program In Women's Oncology
Chattanooga, Tennessee, United States
...and 37 more locations
Serum AGEN2034 and AGEN1884 concentrations measured throughout the study.
Time frame: Pre-dose through 3 months after last dose.
Terminal disposition rate constant (λz)
Serum AGEN2034 and AGEN1884 concentrations measured throughout the study.
Time frame: Pre-dose through 3 months after last dose.
Terminal elimination half-life (t1/2)
Serum AGEN2034 and AGEN1884 concentrations measured throughout the study.
Time frame: Pre-dose through 3 months after last dose.
Systemic clearance (CL)
Serum AGEN2034 and AGEN1884 concentrations measured throughout the study.
Time frame: Pre-dose through 3 months after last dose.
Volume of distribution (Vd)
Serum AGEN2034 and AGEN1884 concentrations measured throughout the study.
Time frame: Pre-dose through 3 months after last dose.
Immunogenicity of AGEN2034 and AGEN1884
Serum AGEN2034 and AGEN1884 ADA concentrations and serum AGEN2034 and AGEN1884 concentrations measured throughout the study.
Time frame: Pre-dose through 3 months after last dose.
Objective Response Rate (ORR), as determined by investigator
per RECIST 1.1
Time frame: Evaluated throughout the protocol, up to 2 years.
Duration of Response (DOR)
per RECIST 1.1, as determined by an IERC and investigator, defined as time from first observation of response to first observation of documented disease progression (or death within 12 weeks after last tumor assessment). Subjects without an event at analysis cutoff date will be censored on date of last tumor assessment.
Time frame: Time from first observation of response to first observation of documented disease progression, up to 3 years.
Disease Control Rate (DCR)
defined as proportion of subjects with complete response (CR), partial response (PR), or stable disease (SD) for at least 12 weeks.
Time frame: Duration of the trial, up to 3 years.
Duration of Stable Disease (SD)
measured from the start of treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started, including baseline measurements.
Time frame: Duration of the trial, up to 3 years.
Time to Response
defined as the time from the first dose date to first observation of confirmed response.
Time frame: Duration of the treatment phase of the trial, up to 2 years.
Progression-free Survival (PFS)
defined as time from first treatment administration to first observation of documented disease progression (or death within 12 weeks after last tumor assessment), per RECIST 1.1, as determined by an IERC and investigator. Subjects without an event at analysis cutoff date will be censored on date of last tumor assessment.
Time frame: Duration of the treatment phase of the trial, up to 2 years.
Overall Survival Rate (OS)
defined as time from start of treatment to death. For subjects who are still alive at time of data cutoff for trial analysis or who are lost to follow-up, survival will be censored at the last recorded date that the subject is known to be alive as of the cutoff date for analysis.
Time frame: Duration of the treatment phase of the trial, up to 2 years.