NCT04028063

Doxorubicin Plus Dual Checkpoint Blockade for Soft Tissue Sarcomas

An Open-Label, Phase II Efficacy Trial of Doxorubicin in Combination With Dual Checkpoint Blockade Using Zalifrelimab (AGEN1884) or Botensilimab (AGEN1181) With Balstilimab (AGEN2034) for Advanced or Metastatic Soft Tissue Sarcomas

• Status: Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 65 (estimated)
• Sponsor: University of Colorado, Denver · Academic / Other
• Sex: All
• Age: 18 Years – 100 Years
• Healthy volunteers: Not accepted

Summary

This is an open-label, non-randomized, single-institution, single arm Phase II study conducted using a Simon two-stage design with an additional safety lead-in. The overall objective is to determine the efficacy of combination doxorubicin with dual checkpoint blockade with anti-CTLA-4 antibody AGEN1884 and anti-PD-1 antibody AGEN2034. The investigators will estimate the progression-free survival rate at 6 months (PFS6mo) of doxorubicin plus AGEN1884/AGEN2034 in comparison to historical PFS6mo with doxorubicin monotherapy, calculated as the mean from two large randomized Phase 3 clinical trials.

Detailed description

The primary endpoint for the study is PFS6mo by RECIST 1.1. The sample size calculation is based on a Simon Two-Stage design with incorporation of early stopping rules for safety and futility (See section 9 for statistical considerations). The Investigators will enroll up to 35 patients on the study to obtain 28 evaluable patients for the primary endpoint. Safety of the combination will be evaluated after the first six patients complete the DLT observation period of 9 weeks. This lengthy DLT period is designed to capture safety and toxicity profile, understanding that immune-related toxicities from checkpoint inhibitors may not emerge immediately. This will also ensure adequate evaluation of potential cardiac and hepatic toxicity from combination doxorubicin and checkpoint inhibitor therapy. If two or more patients experience DLT in the initial safety lead-in cohort, the regimen will be declared intolerable. Any patients who do not complete study therapy through the 9-week DLT observation period for any reasons other than toxicity will be replaced for safety lead-in assessment. If fewer than two patients experience DLT, the investigators will proceed to expansion to complete enrollment of 15 patients in Stage 1. Following enrollment of stage one, accrual will pause for analysis of efficacy. If 6 or fewer of the 15 patients are progression-free at 6 months, the investigators will halt the study for futility. If 7 or more patients are free from progression, then the investigators will proceed with enrollment of 13 additional patients to complete stage 2. the investigators are powered to detect improvement in 6-month PFS rate to 63.4% with the combination over the 43.4% historical PFS6mo.

Conditions

• Metastatic Soft Tissue Sarcoma
• Advanced Soft Tissue Sarcoma

Interventions

Type	Name	Description
DRUG	Balstilimab	Balstilimab (AGEN2034) is a human monoclonal antibody that targets programmed cell death 1 (PD-1). Engagement of PD-1 by its ligands, programmed death ligand (PD-L1) and PD-L2, leads to signal transduction that inhibits important aspects of T cell function including proliferation, cytokine production and cytolytic activity. Balstilimab (AGEN2034) potently inhibits PD-1 binding to PD- L1 and PD- L2 and is intended to reverse the immunosuppressive effects of this signaling pathway in the context of tumor immuno-surveillance by T cells. Balstilimab (AGEN2034) is intended for development as a treatment for advanced malignancies as a single agent or in combinations.
DRUG	Zalifrelimab	Zalifrelimab (AGEN1884) is a fully human monoclonal immunoglobulin G1 κ subclass (IgG1κ) antibody that specifically recognizes cytotoxic T lymphocyte-associated protein 4 (CTLA-4, also known as CD152). Zalifrelimab (AGEN1884) is being developed as a monotherapy for cancer indications with potential for future development in combination with other immunotherapies.
DRUG	Doxorubicin	Doxorubicin is the standard of care first-line therapy for most subtypes of metastatic soft tissue sarcomas. Doxorubicin monotherapy administered at 75 mg/m2 has resulted in objective response rate of 14%, and median progression-free survival of 4.6 months, and another study reported progression-free survival at 6 months of 46.3%, with a median PFS of 5.8 months, and best objective response rate of 19%.
DRUG	Botensilimab	Botensilimab (AGEN1181) is a novel, human, fragment-crystallizable (Fc)-engineered immunoglobulin G1 (IgG1) anti-CTLA-4 antibody designed to exploit a novel mechanism by which increased Fc engagement enhances antigen-specific effector T cell responses.

Timeline

• Start date: 2020-01-28
• Primary completion: 2027-04-07
• Completion: 2027-12-31
• First posted: 2019-07-22
• Last updated: 2026-01-27

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study