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

Trial Summary

What is the purpose of this trial?

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.

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.

What data supports the effectiveness of the drug Doxorubicin + Dual Checkpoint Blockade for Soft Tissue Sarcoma?

Research shows that doxorubicin is a standard first-line treatment for soft tissue sarcoma, but its effectiveness is limited. A study combining doxorubicin with another drug, olaratumab, showed improved survival, suggesting that combining doxorubicin with other treatments might enhance its effectiveness. ^{1 2 3 4 5}

Is the combination of Doxorubicin and Dual Checkpoint Blockade safe for humans?

Doxorubicin, a common chemotherapy drug, has been associated with heart-related side effects (cardiotoxicity) in some patients with soft tissue sarcoma. However, a derivative called Aldoxorubicin shows promise with minimal heart-related side effects, though more studies are needed to confirm its safety. ^{2 3 5 6 7}

What makes the drug combination of Doxorubicin, AGEN1884, and AGEN2034 unique for treating soft tissue sarcoma?

This treatment combines doxorubicin, a standard chemotherapy drug for soft tissue sarcoma, with AGEN1884 and AGEN2034, which are immune checkpoint inhibitors. This combination aims to enhance the body's immune response against cancer cells, potentially offering a novel approach compared to traditional chemotherapy alone. ^{1 3 4 5 8}

Research Team

Breelyn Wilky, M.D.

Principal Investigator

University of Colorado, Denver

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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 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]

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]

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]

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]

References

1. England 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. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Doxorubicin chemotherapy in the treatment of soft-tissue sarcoma. Combined results of two randomized trials. [2019]

3. United States 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. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Olaratumab for the treatment of soft-tissue sarcoma. [2018]

5. England pubmed.ncbi.nlm.nih.gov

A phase II study of Doxil (liposomal doxorubicin): lack of activity in poor prognosis soft tissue sarcomas. [2022]

6. United States 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. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Aldoxorubicin for the treatment of soft tissue sarcoma. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Phase II Study of Pembrolizumab in Combination with Doxorubicin in Metastatic and Unresectable Soft-Tissue Sarcoma. [2022]