What side effects are associated with this type of intervention?

The most common treatments for Soft Tissue Sarcoma (STS), particularly those involving chemotherapy combined with dual immune checkpoint blockade, have a range of side effects. Doxorubicin, a common chemotherapy agent, can cause myelosuppression, alopecia, mucositis, and cardiotoxicity. Immune checkpoint inhibitors, such as anti-CTLA-4 (e.g., ipilimumab) and anti-PD-1 (e.g., nivolumab), are associated with immune-related adverse events including colitis, pneumonitis, hepatitis, endocrinopathies, and skin reactions. Combining these treatments may increase the risk of both chemotherapy-related and immune-related toxicities.

What prior FDA approvals exist?

The FDA has approved several treatments for Soft Tissue Sarcoma (STS), including chemotherapy agents like doxorubicin, which is a cornerstone in the treatment of various STS subtypes. Additionally, immune checkpoint inhibitors such as pembrolizumab (anti-PD-1) have shown efficacy in certain STS subtypes, particularly when combined with other agents. While dual checkpoint blockade (anti-CTLA-4 and anti-PD-1) is being actively studied, it has not yet received FDA approval specifically for STS. However, the combination of these immunotherapies with chemotherapy represents a promising area of research aimed at enhancing anti-tumor immune responses in STS patients.

What other types of research exist?

Promising novel alternatives for Soft Tissue Sarcoma patients in 2024 include: 1) Pembrolizumab (anti-PD-1) combined with Axitinib (VEGFR inhibitor), which has shown efficacy in various sarcomas. 2) Nivolumab (anti-PD-1) combined with Ipilimumab (anti-CTLA-4), which has demonstrated benefits in other cancers and is being explored in sarcomas. 3) Tazemetostat (EZH2 inhibitor) for patients with specific genetic mutations. 4) Adoptive T-cell therapies, such as TIL (tumor-infiltrating lymphocytes) therapy, which are being investigated for their potential in STS.

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Monoclonal Antibodies

Doxorubicin + Dual Checkpoint Blockade for Soft Tissue Sarcoma

Phase 2

Recruiting

Led By Breelyn Wilky, MD

Research Sponsored by University of Colorado, Denver

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

ECOG performance status of 0 or 1 (See Appendix B for scale definitions).

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.

Must not have

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

Prior therapy with anthracycline or checkpoint inhibitors

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 3 years

Awards & highlights

No Placebo-Only Group

Summary

This trial tests a combination of chemotherapy and immune-boosting drugs in cancer patients. The goal is to see if this combination works better than chemotherapy alone by helping the body's natural defenses fight cancer more effectively. Combination therapies of chemotherapy and immunotherapy have shown promising results in initial studies, with potential synergistic effects enhancing anti-tumor immunity.

Who is the study for?

Adults aged 18-100 with advanced or metastatic soft tissue sarcoma, suitable for doxorubicin treatment, and who haven't had anthracyclines or checkpoint inhibitors before. They must have good organ function, an ECOG status of 0 or 1, be willing to undergo biopsies and use effective contraception. Exclusions include prior certain treatments, immune deficiencies, active infections/autoimmune diseases, CNS metastases not stable/treated within a month.

What is being tested?

The trial is testing the effectiveness of doxorubicin combined with two immunotherapy drugs (AGEN1884 and AGEN2034) in treating soft tissue sarcomas. It's an open-label Phase II study where all participants receive the same treatment without randomization. The main goal is to see if this combo improves progression-free survival at six months compared to historical data from doxorubicin alone.

What are the potential side effects?

Potential side effects may include reactions related to the immune system such as inflammation in different organs due to dual checkpoint blockade therapy; typical chemotherapy-related issues like nausea and hair loss from doxorubicin; fatigue; increased risk of infection; blood disorders; and possible infusion reactions.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I am fully active or restricted in physically strenuous activity but can do light work.

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My soft tissue sarcoma cannot be cured by surgery and doxorubicin is considered suitable for me.

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I am between 18 and 100 years old.

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I have had at most one treatment for metastatic sarcoma and no treatments with anthracyclines or checkpoint inhibitors.

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I am between 18 and 100 years old.

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My sarcoma cannot be removed by surgery and doxorubicin is considered suitable for me.

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I am fully active or restricted in physically strenuous activity but can do light work.

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I have or will get a central venous catheter placed for treatment.

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I have had at most one treatment for my metastatic sarcoma and no treatments with anthracyclines or checkpoint inhibitors.

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I have or will get a central venous catheter placed for treatment.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I haven't had cancer antibody treatment in the last 4 weeks or have recovered from its side effects.

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I have previously been treated with anthracycline or checkpoint inhibitors.

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I have an immune deficiency or a chronic infection like HIV, hepatitis, or TB.

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I have had lung inflammation treated with steroids in the last year.

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I haven't needed systemic treatment for an autoimmune disease in the last 2 years.

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I do not have any uncontrolled illnesses like infections or heart problems.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 3 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~3 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and 3 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Determine the progression-free survival rate

Secondary study objectives

Determine the clinical benefit rate

Determine the duration of response

Determine the incidence of adverse events

+1 more

Other study objectives

Measure changes in tumor-infiltrating and circulating immune cells

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

5Treatment groups

Experimental Treatment

Group I: Stage 2, Dose 3 Combination of Doxorubicin with Botensilimab and BalstilimabExperimental Treatment3 Interventions

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

Group II: Stage 2, Dose 2Experimental Treatment2 Interventions

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

Group III: Part 2: Stage 2, Dose 1Experimental Treatment2 Interventions

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

Group IV: Part 1: Stage 2, ExpansionExperimental Treatment3 Interventions

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

Group V: Part 1: Stage 1, Safety Lead-InExperimental Treatment3 Interventions

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.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Balstilimab

2023

Completed Phase 1

~20

Doxorubicin

2012

Completed Phase 3

~8030

0 / 16Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

The most common treatments for Soft Tissue Sarcoma (STS) include chemotherapy and immune checkpoint inhibitors. Chemotherapy agents like Doxorubicin work by disrupting DNA replication in rapidly dividing cancer cells, leading to cell death. Immune checkpoint inhibitors, such as anti-CTLA-4 (AGEN1884) and anti-PD-1 (AGEN2034), enhance the immune system's ability to attack cancer cells by blocking proteins that inhibit immune responses. Combining these therapies aims to increase the effectiveness of treatment by directly killing cancer cells and boosting the immune system's capacity to target and eliminate the tumor. This dual approach is particularly important for STS patients as it may improve treatment outcomes and survival rates.