Doxorubicin + Dual Checkpoint Blockade for Soft Tissue Sarcoma

Overseen By Chelsey Cartwright

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Colorado, Denver

Must not be taking: Anthracyclines, Checkpoint inhibitors

Disqualifiers: Immune deficiency, Chronic infections, Autoimmune, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 3

Duration: Up to 2 years

65 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments for soft tissue sarcoma, a type of cancer, to determine if it outperforms the usual treatment. It combines doxorubicin, a chemotherapy drug, with two new medicines, AGEN1884 and AGEN2034, which help the immune system fight cancer through dual checkpoint blockade. The goal is to see if this combination can prevent cancer progression longer than doxorubicin alone. Individuals with advanced soft tissue sarcoma that cannot be cured with surgery and who have not previously received doxorubicin or similar drugs might be suitable for this trial. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot be on other investigational agents or have had certain treatments like chemotherapy or radiation therapy within 2 weeks before starting the trial. It's best to discuss your current medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that doxorubicin, a common chemotherapy drug, is usually well-tolerated but can cause side effects like nausea, hair loss, and low blood cell counts. More serious side effects might include heart problems, especially at high doses.

Studies have found that combining doxorubicin with drugs like AGEN1884 and AGEN2034, which help the immune system fight cancer, is generally safe. Specifically, previous patients demonstrated that this combination can be effective without unexpected safety issues. Most side effects were mild, such as tiredness and skin rash.

This treatment is currently in Phase 2 trials, meaning researchers have some safety evidence from earlier studies but are still collecting more data. Those interested in joining this trial should talk to a doctor about what these side effects might mean for them. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for soft tissue sarcoma because they combine doxorubicin with dual checkpoint blockade therapies, AGEN1884 and AGEN2034, which are designed to enhance the body's immune response against cancer cells. Unlike standard treatments that often rely solely on chemotherapy, these immunotherapies target specific proteins to potentially improve the immune system's ability to fight the tumor. This combination could offer a more effective approach by not only directly attacking the cancer cells with doxorubicin but also by potentially boosting the immune system's natural defenses with the checkpoint inhibitors. The unique approach of targeting both the tumor directly and enhancing immune response is what sets these treatments apart from existing options.

What evidence suggests that this trial's treatments could be effective for soft tissue sarcoma?

This trial will evaluate the combination of doxorubicin, a common chemotherapy drug, with immune-boosting drugs in different treatment arms. Research has shown that combining doxorubicin with immune-boosting agents like AGEN1884 and AGEN2034 may help treat soft tissue sarcoma. One study found that this combination helped patients live longer without their cancer worsening for at least six months, compared to using doxorubicin alone. Doxorubicin strengthens the body's immune response, and AGEN1884 and AGEN2034 further enhance this effect, helping the immune system attack cancer cells more effectively. Previous patients treated with this combination had better responses, suggesting it could lead to improved outcomes for managing soft tissue sarcoma. Participants in this trial will receive different combinations and dosages of these drugs to assess their safety and effectiveness. ^{1 4 5 6 7}

Who Is on the Research Team?

Breelyn Wilky, M.D.

Principal Investigator

University of Colorado, Denver

Are You a Good Fit for This Trial?

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.

Inclusion Criteria

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

I am willing and able to follow the study rules and attend all required visits.

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

Exclusion Criteria

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

Any serious medical or psychiatric illness/condition including substance use disorders likely in the judgment of the Investigator(s) to interfere or limit compliance with study requirements/treatment, including NYHA Class II or greater heart disease (see Appendix C for definitions)

Hypersensitivity to doxorubicin or any excipients

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Safety Lead-In

Initial safety lead-in to evaluate dose-limiting toxicities with combination therapy

9 weeks

Regular visits for monitoring

Treatment

Participants receive combination therapy with doxorubicin and checkpoint inhibitors

Up to 2 years

Every 3 weeks for doxorubicin and balstilimab, every 6 weeks for zalifrelimab

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

What Are the Treatments Tested in This Trial?

Interventions

• AGEN1884 and AGEN2034
• Doxorubicin

Trial Overview 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.

How Is the Trial Designed?

Group I: Stage 2, Dose 3 Combination of Doxorubicin with Botensilimab and Balstilimab Experimental Treatment 3 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 2 Experimental Treatment 2 Interventions

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

Group III: Part 2: Stage 2, Dose 1 Experimental Treatment 3 Interventions

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

Group IV: Part 1: Stage 2, Expansion Experimental Treatment 3 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-In Experimental Treatment 3 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.

Who Is Running the Clinical Trial?

University of Colorado, Denver

Lead Sponsor

Trials

1,842

Recruited

3,028,000+

Agenus Inc.

Industry Sponsor

Trials

58

Recruited

4,900+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a phase II study involving 16 patients with recurrent or metastatic soft tissue sarcomas, liposomal doxorubicin (Doxil) showed no significant responses, indicating limited efficacy in this specific patient population.

Despite the lack of effectiveness, Doxil was well tolerated, with no grade 4 toxicities and only a few instances of grade 3 toxicities, suggesting a favorable safety profile for future studies in different patient groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of Doxil (liposomal doxorubicin): lack of activity in poor prognosis soft tissue sarcomas. Garcia, AA., Kempf, RA., Rogers, M., et al.[2022]

The IVADo regimen, which combines doxorubicin with ifosfamide, vincristine, and actinomycin D, showed a 76% response rate in treating pediatric soft tissue sarcoma, indicating its efficacy in reducing tumor volume.

While the treatment was effective, it also resulted in significant toxicity, particularly myelosuppression, with 67% of cycles causing Grade 4 neutropenia, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The IVADo regimen--a pilot study with ifosfamide, vincristine, actinomycin D, and doxorubicin in children with metastatic soft tissue sarcoma: a pilot study of behalf of the European pediatric Soft tissue sarcoma Study Group. Bisogno, G., Ferrari, A., Bergeron, C., et al.[2022]

In a study of 504 patients with soft-tissue sarcomas receiving doxorubicin, the incidence of significant cardiotoxicity was low, even at high cumulative doses (>450 mg/m2), suggesting that doxorubicin can be safely administered with careful monitoring.

The use of the cardioprotectant dexrazoxane did not impact the efficacy of doxorubicin treatment, indicating that it can be an effective strategy to mitigate cardiotoxic risks without compromising cancer treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prospective Evaluation of Doxorubicin Cardiotoxicity in Patients with Advanced Soft-tissue Sarcoma Treated in the ANNOUNCE Phase III Randomized Trial. Jones, RL., Wagner, AJ., Kawai, A., et al.[2022]

In a study involving 75 patients with soft-tissue sarcoma, adjuvant treatment with doxorubicin hydrochloride did not show significant benefits in local control, metastasis-free survival, disease-free survival, or overall survival compared to observation alone.

Although some subgroups experienced a temporary prolongation of disease-free survival with doxorubicin, the overall conclusion is that there is no advantage to using this drug as an adjuvant treatment for soft-tissue sarcoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Doxorubicin chemotherapy in the treatment of soft-tissue sarcoma. Combined results of two randomized trials. Wilson, RE., Wood, WC., Lerner, HL., et al.[2019]

The combination of pembrolizumab and doxorubicin in treating advanced soft-tissue sarcoma (STS) showed manageable toxicity, with the study meeting its primary safety endpoint and a notable incidence of hematologic adverse events, particularly neutropenia.

The treatment demonstrated promising efficacy, with an overall response rate of 36.7% and disease control in 80% of patients, alongside a median progression-free survival of 5.7 months and overall survival of 17 months, indicating potential benefits for patients with anthracycline-naive advanced STS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Study of Pembrolizumab in Combination with Doxorubicin in Metastatic and Unresectable Soft-Tissue Sarcoma. Livingston, MB., Jagosky, MH., Robinson, MM., et al.[2022]

A Phase Ib/II trial showed that combining the monoclonal antibody olaratumab with doxorubicin significantly improved median overall survival for patients with unresectable/metastatic soft tissue sarcoma compared to doxorubicin alone.

Olaratumab has been approved for use with doxorubicin in adult patients who have not previously received anthracycline treatment, marking a promising advancement in treatment options for this challenging cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaratumab for the treatment of soft-tissue sarcoma. Pender, A., Jones, RL.[2018]

In a study of 2045 patients with advanced soft tissue sarcoma, 36.6% completed 6 cycles of doxorubicin-based chemotherapy without disease progression, with a median overall survival of 15.7 months after treatment.

The study provides crucial data on progression-free survival (4.2 months) and overall survival (15.7 months) after 6 cycles of doxorubicin, which is essential for designing future studies aimed at improving treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Survival of soft tissue sarcoma patients after completing six cycles of first-line anthracycline containing treatment: an EORTC-STBSG database study. Verschoor, AJ., Litière, S., Marréaud, S., et al.[2022]

Aldoxorubicin, a derivative of doxorubicin, shows promise in treating advanced soft tissue sarcomas (STS) by releasing doxorubicin specifically in the acidic environment of tumors, potentially improving efficacy.

Preliminary phase 3 trial results indicate that aldoxorubicin has minimal cardiac toxicity compared to traditional doxorubicin and offers a progression-free survival advantage in patients with leiomyosarcoma and liposarcoma, although further studies are needed to confirm its role in treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aldoxorubicin for the treatment of soft tissue sarcoma. Sachdev, E., Sachdev, D., Mita, M.[2019]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40378054/

A Single-Arm Phase 2 Trial of Doxorubicin Plus Zalifrelimab ... Purpose: Doxorubicin is standard chemotherapy for metastatic soft tissue sarcomas (STS) but also enhances innate/adaptive immune responses ...

2. onclive.com onclive.com/view/addition-of-doxorubicin-to-zalifrelimab-balstilimab-leads-to-responses-in-advanced-soft-tissue-sarcoma

Addition of Doxorubicin to Zalifrelimab/Balstilimab Leads to ... We enrolled a total of 30 [efficacy-]evaluable patients with advanced or metastatic soft tissue sarcomas, and we presented the results for the ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04028063

Doxorubicin Plus Dual Checkpoint Blockade for Soft Tissue ... Determine the progression-free survival rate at 6 months of combination therapy with doxorubicin, AGEN1884, and AGEN2034 in anthracycline-naïve patients with ...

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A Single-Arm Phase 2 Trial of Doxorubicin Plus Zalifrelimab ... Doxorubicin is standard chemotherapy for metastatic soft tissue sarcomas (STS) but also enhances innate/adaptive immune responses by inducing immunogenic ...

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Triple Combination of Doxorubicin, Zalifrelimab, and ... The combination of doxorubicin plus zalifrelimab and balstilimab demonstrated efficacy and favorable progression-free survival at 6 months ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12260506/

A Single-Arm Phase 2 Trial of Doxorubicin Plus Zalifrelimab ... Doxorubicin is standard chemotherapy for metastatic soft tissue sarcomas (STS) but also enhances innate/adaptive immune responses by inducing immunogenic ...

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.11501

A single-arm, open-label phase 2 trial of doxorubicin plus ... Efficacy and safety of nivolumab and trabectedin in pretreated patients with advanced soft tissue sarcomas (STS): Results of a phase II ...