A Phase 1/2, Open-Label, Multiple Ascending Dose Trial to Investigate the Safety, Tolerability, Pharmacokinetics, Biological, and Clinical Activity of AGEN2034 in Subjects With Metastatic or Locally Advanced Solid Tumors, With Expansion to Second Line Cervical Cancer
Overview
- Phase
- Phase 1
- Status
- Completed
- Sponsor
- Agenus Inc.
- Enrollment
- 211
- Locations
- 44
- Primary Endpoint
- Phase 1: Number of Participants Experiencing Treatment-emergent Adverse Events (TEAEs)
Overview
Brief Summary
This is a 2-part trial: a Phase 1, open-label, dose-escalation study in participants with metastatic or locally advanced solid tumors, with a consecutive Phase 2 expansion to evaluate efficacy in participants with recurrent, unresectable, or metastatic (advanced) cervical cancer that has progressed after a platinum-based treatment regimen.
Detailed Description
Phase 1: Dose Escalation
Phase 1 will consist of a standard 3+3 dose escalation with the following escalating dose levels and schedules:
Part A1: 1, 3, and 10 milligrams/kilogram (mg/kg) administered every 2 weeks
Part A2: 6 and 10 mg/kg every 3 weeks
Each participant will stay on the dose level and schedule assigned at trial entry. Participants will receive AGEN2034 for a maximum of 2 years or until confirmed progression, unacceptable toxicity, or any criterion for stopping the study drug or withdrawal from the trial occurs.
A Safety Monitoring Committee (SMC) will assess safety; decide on dose-escalation and opening of backfill enrollment; define the recommended Phase 2 dose (RP2D); and determine opening of the Phase 2 cohorts.
In Part A1, the first participant of each cohort will be observed for 16 days (that is, ≥48 hours after second dose) for occurrence of dose-limiting toxicity (DLT) before the second participant is administered trial medication. Thereafter, within each cohort, consecutively enrolled participants may initiate treatment ≥48 hours after the prior enrolled participant-initiated treatment. Dose escalation will continue until the maximum tolerated dose (MTD) is reached or the maximum planned dose level (10.0 mg/kg) is shown to be safe. The MTD is defined as the dose below which ≥2 DLTs are observed.
Once Part A1 is completed, enrollment to Part A2 will begin. If <2 DLTs are observed in Part A1 at the maximum planned dose of 10 mg/kg every 2 weeks, open enrollment to Part A2 will begin with enrollment of 10 participants at 6 mg/kg every 3 weeks, followed by open enrollment of 10 participants at 10 mg/kg every 3 weeks. If ≥2 DLTs are observed in Part A1, at the maximum planned dose in Part A1, the standard 3+3 dose escalation will resume with Part A2 where consecutively enrolled participants in dose escalation may initiate treatment ≥48 hours after the prior enrolled participant-initiated treatment.
For cohorts in dose escalation, concurrent with the 3+3 dose escalation schema, additional participants will be backfilled to lower dose levels to ensure that each cohort enrolls a total of 10 participants. Participants enrolled to backfill cohorts may be enrolled simultaneously, without sequential dosing (that is, not required to wait 48 hours between 2 participants). These additional participants at each dose level will have the purpose of generating additional safety, pharmacokinetics, and receptor occupancy data, and will not undergo formal DLT observation.
Phase 2: Dose Expansion
To further characterize safety and efficacy, participants with recurrent, unresectable, or metastatic cervical cancer will be enrolled in Phase 2 and receive the RP2D of AGEN2034 (3 mg/kg every 2 weeks) for a maximum of 2 years or until confirmed progression, unacceptable toxicity, or any criterion for stopping the study drug or withdrawal from the trial occurs.
An SMC will assess safety, and an Independent Data Monitoring Committee will evaluate safety and efficacy.
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
- •Voluntarily agree to participate by giving written informed consent. Participation in pharmacogenomics testing is optional.
- •Be ≥18 years of age.
- •Diagnosis and prior systemic treatment:
- •Phase 1: Have a histologically or cytologically confirmed diagnosis of a metastatic or locally advanced solid tumor for which no standard therapy is available or standard therapy has failed.
- •Phase 2: I. Have (1) a histologically or cytologically confirmed diagnosis of squamous-cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix, and (2) metastatic, locally advanced, and/or unresectable 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 advanced (recurrent, unresectable, or metastatic) disease; Note: Participants who have received \>1 prior systemic treatment regimen for their advanced or metastatic disease will be eligible in the following cases: Participant receiving chemotherapy concurrently with primary radiation (for example, weekly cisplatin) or participant receiving adjuvant chemotherapy following completion of radiation therapy (for example, paclitaxel and carboplatin for ≤4 cycles) and progressed within 6 months after treatment completion.
- •Measurable disease - based on investigator assessment
- •Phase 1: Have objective evidence of disease; the presence of measurable disease is not required.
- •Phase 2: Have measurable disease on imaging based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Note: Participants must have at least one "target lesion" to be used to assess response, as defined by RECIST 1.
- •Tumors within a previously irradiated field will be designated as "non-target" lesions unless progression is documented or a biopsy is obtained to confirm persistence at least 90 days following completion of radiation therapy. Note: Measurable disease by RECIST 1.1 must be confirmed by independent central radiologic review prior to first dose. Participants without centrally confirmed measurable disease at baseline will not be eligible for this trial.
- •Have a life expectancy of at least 3 months and an Eastern Cooperative Oncology Group performance status of 0 or
Exclusion Criteria
- •Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks before the first dose of treatment.
- •Has an inadequate washout period prior to first dose of study drug defined as:
- •Received systemic cytotoxic chemotherapy or biological therapy within 3 weeks before first dose,
- •Received radiation therapy within 3 weeks before first dose, or
- •Had major surgery within 4 weeks before first dose.
- •Has received prior therapy with:
- •Any antibody/drug targeting T-cell co-regulatory proteins (immune checkpoints) such as anti-PD-1, anti-programmed cell death ligand 1, or anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibodies
- •For Phase 2: \>1 systemic treatment regimen for the advanced (recurrent, unresectable, or metastatic) cervical cancer for which the participant is considered for the study Note: In Phase 1, prior treatment with a CTLA-4 antibody is permissible for participants with metastatic melanoma.
- •Has persisting toxicity related to prior therapy of National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 (NCI CTCAE) Grade \>1 severity.
- •Note: Sensory neuropathy or alopecia of Grade ≤2 is acceptable.
Arms & Interventions
Monotherapy
Dose of 3 mg/kg intravenous (IV) every 2 weeks for up to 24 months.
Intervention: AGEN2034 (Drug)
Outcomes
Primary Outcomes
Phase 1: Number of Participants Experiencing Treatment-emergent Adverse Events (TEAEs)
Time Frame: Up to 3 years
An adverse event (AE) was any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product, which did not necessarily have a causal relationship with the treatment. TEAEs were AEs with onset dates during the on-treatment period, or the worsening of an event during the on-treatment period. A summary of all Serious Adverse Events and Other Adverse Events (nonserious), regardless of causality, is located in the 'Reported Adverse Events' Section.
Phase 1: Number of Participants Experiencing Dose-limiting Toxicities (DLTs) for Balstilimab
Time Frame: 21 days
A DLT was defined as any treatment-related toxicity that was National Cancer Institute Common Terminology Criteria for Adverse Event Grade ≥3, confirmed by the safety monitoring committee to be relevant for the study drug treatment, and that occurred during the first 3 weeks of balstilimab treatment in the dose escalation portion of the study (DLT evaluation period).
Phase 2: Objective Response Rate (ORR) as Determined by an Independent Endpoint Review Committee (IERC)
Time Frame: Up to 3 years
ORR was defined as percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR), as determined by an IERC per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). BOR was defined as the best response recorded from the start of the study treatment until the end of treatment. CR was defined as disappearance of all target lesions, and PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Secondary Outcomes
- Phase 1: Receptor Occupancy of Circulating T Cells(4 hours after the first dose (Cycle 1 Day 1) and immediately prior to the second dose (Cycle 2 Day 1) (2-3 weeks/cycle))
- Phase 2: Cmax of Balstilimab(Day 1 (Pre-dose up to 24 hours post dose) of Cycle 1 and Cycle 2 (2 weeks/cycle) (up to 2 weeks))
- Phase 2: Duration of Response (DOR)(Up to 3 years)
- Phase 2: Time to Response (TTR) as Determined by an IERC(Up to 3 years)
- Phase 1: Maximum Observed Concentration (Cmax) of Balstilimab(Day 1 (Pre-dose up to 24 hours post dose) of Cycle 1 and Cycle 2 (2-3 weeks/cycle) (up to 3 weeks))
- Phase 1: Area Under the Drug Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUC0-last) of Balstilimab(Day 1 (Pre-dose up to 24 hours post dose) of Cycle 1 and Cycle 2 (2-3 weeks/cycle) (up to 3 weeks))
- Phase 2: ORR as Determined by the Investigator(Up to 3 years)
- Phase 1: Number of Participants With Serum Anti-drug Antibodies (ADAs) for Balstilimab(Up to 2.5 years)
- Phase 2: Number of Participants Experiencing TEAEs(Up to 3 years)
- Phase 2: Number of Participants With Serum ADAs for Balstilimab(Up to 2.5 years)
- Phase 2: Progression-free Survival (PFS)(Up to 3 years)
- Phase 2: AUC0-last of Balstilimab(Day 1 (Pre-dose up to 24 hours post dose) of Cycle 1 and Cycle 2 (2 weeks/cycle) (up to 2 weeks))
- Phase 2: Disease Control Rate (DCR) as Determined by an IERC(Up to 3 years)
- Phase 2: Tumor Control Rate (TCR) as Determined by an IERC(Up to 3 years)
- Phase 2: Overall Survival (OS)(Up to 3 years)