Doxorubicin Plus Dual Checkpoint Blockade for Soft Tissue Sarcomas

NCT04028063 | Active Not Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: 19-0554.ccNCI-2020-00728
• Study Type: interventional
• Target: 65
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Metastatic Soft Tissue Sarcoma; Advanced Soft Tissue Sarcoma

Outcome Measures

Primary Outcomes (1)

• Determine the progression-free survival rate

  Determine the progression-free survival rate at 6 months of combination therapy with doxorubicin, AGEN1884, and AGEN2034 in anthracycline-naïve patients with advanced or metastatic soft tissue sarcomas.

  6 months

Secondary Outcomes (4)

• Determine the overall response rate

  3 years

• Determine the clinical benefit rate

  3 years

• Determine the duration of response

  3 years

• Determine the incidence of adverse events

  3 years

Other Outcomes (1)

• Measure changes in tumor-infiltrating and circulating immune cells

  3 years

Study Arms (5)

Part 1: Stage 1, Safety Lead-In

EXPERIMENTAL

The safety lead-in will enroll 6 participants. Balstilimab 300mg flat q3 weeks up to 2 years; Zalifrelimab 1mg/kg q6 weeks x 4; Doxorubicin 75mg/m2 q3 weeks x 2, starts at C2 The participants will complete a dose-limiting toxiciy (DLT) observation period of 9 weeks.

Drug: Balstilimab; Drug: Zalifrelimab; Drug: Doxorubicin

Part 1: Stage 2, Expansion

EXPERIMENTAL

Balstilimab 300mg flat q3 weeks up to 2 years; Zalifrelimab 1mg/kg q6 weeks up to 2 years; Doxorubicin 75mg/m2 q3 weeks x 6

Drug: Balstilimab; Drug: Zalifrelimab; Drug: Doxorubicin

Part 2: Stage 2, Dose 1

EXPERIMENTAL

Doxorubicin 60mg/m2 q3 weeks x 6 doses Botensilimab 75mg q6 weeks up to two years

Drug: Doxorubicin; Drug: Botensilimab

Stage 2, Dose 2

EXPERIMENTAL

Doxorubicin 75mg/m2 q3 weeks x 6 doses Botensilimab 75mg q6 weeks up to two years

Drug: Doxorubicin; Drug: Botensilimab

Stage 2, Dose 3 Combination of Doxorubicin with Botensilimab and Balstilimab

EXPERIMENTAL

Doxorubicin 75mg/m2 q3 weeks x 6 doses Botensilimab 75mg flat q6 weeks up to 2 years Balstilimab 450mg q3 weeks up to 2 years

Drug: Balstilimab; Drug: Doxorubicin; Drug: Botensilimab

Interventions

Balstilimab DRUG

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.

Also known as: AGEN2034

Part 1: Stage 1, Safety Lead-In; Part 1: Stage 2, Expansion; Stage 2, Dose 3 Combination of Doxorubicin with Botensilimab and Balstilimab

Zalifrelimab DRUG

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.

Also known as: AGEN1884

Part 1: Stage 1, Safety Lead-In; Part 1: Stage 2, Expansion

Doxorubicin DRUG

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%.

Also known as: Lipodox, Doxil

Part 1: Stage 1, Safety Lead-In; Part 1: Stage 2, Expansion; Part 2: Stage 2, Dose 1; Stage 2, Dose 2; Stage 2, Dose 3 Combination of Doxorubicin with Botensilimab and Balstilimab

Botensilimab DRUG

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.

Also known as: AGEN1181

Part 2: Stage 2, Dose 1; Stage 2, Dose 2; Stage 2, Dose 3 Combination of Doxorubicin with Botensilimab and Balstilimab

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Part One:
• Provision to sign and date the consent form.
• Stated willingness to comply with all study procedures and be available for the duration of the study.
• Be male or female aged 18-100 years at the time of signing informed consent.
• Have a histological diagnosis of advanced or metastatic soft tissue sarcoma (STS) (by local pathology review), not curable by surgery, for which treatment with doxorubicin is deemed appropriate by the investigator.
• Has one of the following histologies:
• synovial sarcoma,
• malignant peripheral nerve sheath tumors,
• dedifferentiated, pleomorphic or myxoid/round cell liposarcoma,
• uterine or soft tissue leiomyosarcoma,
• malignant phylloides tumor,
• high grade undifferentiated pleomorphic sarcomas (HGUPS/MFH),
• myxofibrosarcoma,
• fibrosarcoma,
• angiosarcoma,

You may not qualify if:

• Part One:
• Prior therapy with anthracycline or checkpoint inhibitors.
• Hypersensitivity to doxorubicin or any excipients.
• Patients may not be receiving any other investigational agents (within 4 weeks prior to Cycle 1, Day 1).
• Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to Cycle 1, Day 1 or has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
• Patient has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to Cycle 1, Day 1 or has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier. Subjects with ≤ Grade 2 neuropathy or alopecia are an exception to this criterion and may qualify for the study. Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
• Additional known malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, or squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in situ cervical cancer.
• Patients with underlying immune deficiency, chronic infections including HIV, hepatitis, or tuberculosis (TB) or autoimmune disease.
• Patients with underlying hematologic issues including bleeding diathesis, such as known previous GI bleeding requiring intervention within the past 6 months. Newly diagnosed pulmonary emboli or deep venous thrombosis must be clinically stable on anticoagulation regimen for ≥ 2 weeks as of Cycle 1 Day 1.
• Has known history of non-infectious pneumonitis that required oral corticosteroid therapy for resolution within 12 months prior to study entry, or evidence by imaging or symptoms of active non-infectious pneumonitis.
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis or leptomeningeal disease. Subjects with previously treated brain metastases may participate provided they are stable based on the following: 1) MRI brain obtained during screening evaluations shows no radiographic evidence of progression or new lesions, 2) any neurologic symptoms have returned to baseline, 3) no requirement for steroids for at least 28 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability. Patients without a known history of brain metastases do not require screening brain MRI prior to study enrollment.
• Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
• Any uncontrolled, intercurrent illness including but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia
• Prolonged QTc interval on Screening EKG \>475 ms.

Sponsors & Collaborators

• University of Colorado, Denver: lead
• Agenus Inc.: collaborator

Study Sites (1)

University of Colorado Hospital

Aurora, Colorado, 80045, United States

Location

MeSH Terms

Conditions

Sarcoma

Interventions

balstilimab; Doxorubicin; liposomal doxorubicin

Condition Hierarchy (Ancestors)

Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms

Intervention Hierarchy (Ancestors)

Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates

Study Officials

• Breelyn Wilky, MD

  University of Colorado, Denver

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: July 17, 2019
• First Posted: July 22, 2019
• Study Start: January 28, 2020
• Primary Completion (Estimated): April 7, 2027
• Study Completion (Estimated): December 31, 2027
• Last Updated: April 20, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)