Immunotherapy + Chemotherapy for Sarcoma

Recruiting at 169 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: National Cancer Institute (NCI)

Must not be taking: Steroids, Anthracyclines

Disqualifiers: Pregnancy, Interstitial lung disease, others

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This phase II trial compares the effect of immunotherapy (pembrolizumab) plus chemotherapy (doxorubicin) to chemotherapy (doxorubicin) alone in treating patients with undifferentiated pleomorphic sarcoma (UPS) or a related poorly differentiated sarcoma that has spread from where it first started (primary site) to other places in the body (metastatic) or that cannot be removed by surgery (unresectable). Doxorubicin is in a class of medications called anthracyclines. Doxorubicin damages the cell's DNA and may kill tumor cells. It also blocks a certain enzyme needed for cell division and DNA repair. A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Adding immunotherapy (pembrolizumab) to the standard chemotherapy (doxorubicin) may help patients with metastatic or unresectable UPS or a related poorly differentiated sarcoma live longer without having disease progression.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on daily corticosteroids, you must finish tapering off before starting the study treatment.

What data supports the effectiveness of the drug doxorubicin in treating sarcoma?

Research shows that doxorubicin is one of the most active drugs for treating sarcomas, often used in combination with other agents like ifosfamide. However, its effectiveness can be limited by resistance mechanisms, such as the activation of the insulin-like growth factor-I receptor, which can reduce the drug's ability to kill cancer cells. ^{1 2 3 4 5}

What safety data exists for the combination of immunotherapy and chemotherapy, specifically involving doxorubicin, for sarcoma treatment?

Doxorubicin, a chemotherapy drug, is known to cause side effects like heart damage (cardiotoxicity), low white blood cell counts (myelosuppression), hair loss (alopecia), nausea, and vomiting. Liposomal formulations of doxorubicin, which are designed to reduce these side effects, have shown lower risks of heart damage and myelosuppression compared to conventional doxorubicin. However, they may increase the risk of a skin condition called palmar-plantar erythrodysesthesia (PPE). ^{6 7 8 9 10}

What makes the combination of Doxorubicin and Pembrolizumab unique for treating sarcoma?

The combination of Doxorubicin and Pembrolizumab is unique because it pairs a standard chemotherapy drug (Doxorubicin) with an immunotherapy drug (Pembrolizumab), which has shown modest activity on its own, to potentially enhance treatment efficacy and safety in advanced soft-tissue sarcoma. ^{1 5 6 11 12}

Research Team

Seth M Pollack

Principal Investigator

ECOG-ACRIN Cancer Research Group

Eligibility Criteria

This trial is for adults over 18 with specific aggressive sarcomas, like undifferentiated pleomorphic sarcoma or malignant fibrous histiocytoma, that have spread and can't be surgically removed. Women must have started menstruating to participate.

Inclusion Criteria

My diagnosis is undifferentiated spindle cell sarcoma.

My cancer is a type of sarcoma known as myxofibrosarcoma or is poorly differentiated.

My condition is a type of sarcoma with large cells.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive doxorubicin and pembrolizumab or doxorubicin alone. Treatment repeats every 21 days for 6 cycles, with pembrolizumab continuing for up to 2 years in the absence of disease progression or unacceptable toxicity.

6 cycles (18 weeks) for doxorubicin, up to 2 years for pembrolizumab

Every 21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up occurs every 3 months for 2 years, then every 6 months for up to 10 years.

Up to 10 years

Every 3 months for 2 years, then every 6 months

Treatment Details

Interventions

• Doxorubicin (Anti-tumor antibiotic)
• Pembrolizumab (Monoclonal Antibodies)

Trial Overview The study compares the effects of combining immunotherapy (pembrolizumab) with chemotherapy (doxorubicin) versus using chemotherapy alone on patients with certain advanced sarcomas to see if it improves survival without disease progression.

Participant Groups

Group I: Arm A (doxorubicin and pembrolizumab Experimental Treatment 6 Interventions

Patients receive doxorubicin IV over 3-10 minutes or up to 3 hours on day 1 of each cycle. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA scan, standard imaging scans and blood sample collection throughout the study.

Group II: Arm B (doxorubicin) Active Control 5 Interventions

Patients receive doxorubicin IV over 3-10 minutes or up to 3 hours on day 1 of each cycle. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. At time of disease progression, patients may begin receiving pembrolizumab alone IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days for 2 years in the absence of additional progression or unacceptable toxicity. Patients also undergo ECHO or MUGA scan, standard imaging scans and blood sample collection throughout the study.

Doxorubicin is already approved in Canada, Japan for the following indications:

Approved in Canada as Doxorubicin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Lymphomas
• Leukemias
• Multiple myeloma
• Kaposi's sarcoma
• Soft tissue sarcomas

Approved in Japan as Doxorubicin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Lymphomas
• Leukemias
• Multiple myeloma
• Kaposi's sarcoma
• Soft tissue sarcomas

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

The maximum tolerated dose (MTD) for the combination of ifosfamide and doxorubicin was determined to be ifosfamide at 12 g/m2 and doxorubicin at 60 mg/m2, with significant side effects like severe leukopenia and thrombopenia observed at higher doses.

The treatment regimen resulted in a 55% overall response rate in patients with untreated sarcomas, with a median survival of two years, suggesting that while the treatment has notable toxicity, it also offers substantial antitumor activity and potential for improved survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I multicenter study of combined high-dose ifosfamide and doxorubicin in the treatment of advanced sarcomas. Swiss Group for Clinical Research (SAKK). Leyvraz, S., Bacchi, M., Cerny, T., et al.[2020]

Lutein combined with doxorubicin (DOX) significantly inhibited the proliferation of S180 sarcoma cells in vitro, leading to increased cell apoptosis and reduced expression of growth-related proteins, indicating a potential mechanism for enhanced anti-cancer effects.

In vivo studies showed that the lutein-DOX combination therapy not only reduced tumor growth and size more effectively than DOX alone but also decreased the cytotoxicity and inflammatory response associated with DOX, suggesting a safer therapeutic option for sarcoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of lutein and doxorubicin combinatorial therapy on S180 cell proliferation and tumor growth. Luan, RL., Wang, PC., Yan, MX., et al.[2019]

Doxorubicin, a common chemotherapy drug, shows limited survival benefits for patients with localized or metastatic soft tissue sarcoma, despite causing some tumor responses.

Activation of the insulin-like growth factor-I receptor (IGF-I-R) in sarcoma cells can lead to resistance against doxorubicin, suggesting that targeting IGF-I-R may improve the effectiveness of chemotherapy in treating soft tissue sarcoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Insulin-like growth factor-I receptor activation blocks doxorubicin cytotoxicity in sarcoma cells. Beech, DJ., Perer, E., Helms, J., et al.[2014]

Doxorubicin and ifosfamide are the primary chemotherapy drugs used for treating sarcomas, while dacarbazine has limited effectiveness, highlighting the need for improved drug combinations.

New chemotherapy agents like gemcitabine and ET-743 have shown promise in certain sarcoma sub-types, and targeted therapies along with antiangiogenic treatments are beginning to demonstrate positive results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Chemotherapy of sarcomas: optimization of existing drugs and new molecules]. Fayette, J., Blay, JY.[2006]

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 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]

The combination regimen of doxorubicin (DOX), ifosfamide (IFF), and dacarbazine (DTIC) demonstrated significant activity against previously untreated inoperable or metastatic sarcoma, with a partial response rate of 44% among evaluable patients.

The treatment was associated with acceptable toxicity, primarily myelosuppression, but no serious cardiac or renal toxicity was observed, suggesting a favorable safety profile for further evaluation in larger studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Doxorubicin, ifosfamide, and dacarbazine (AID) with mesna uroprotection for advanced untreated sarcoma: a phase I study. Elias, AD., Antman, KH.[2013]

Pegylated-liposomal doxorubicin (PLD) has shown the potential for long-term disease remission in a patient with high-grade metastatic soft tissue sarcoma after previous treatments with free doxorubicin failed, highlighting its efficacy in difficult cases.

PLD has a better safety profile than free doxorubicin, with reduced risks of cardiotoxicity and other side effects, making it a favorable option for patients requiring chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term cure of soft tissue sarcoma with pegylated-liposomal doxorubicin after doxorubicin and ifosfamide failure. Savani, M., Murugan, P., Skubitz, KM.[2022]

Paeonol (Pae) has been shown to protect against doxorubicin (Dox)-induced cardiotoxicity in both rat models and primary cardiomyocytes by enhancing mitochondrial fusion and restoring cardiac function.

The protective mechanism involves the PKCε-Stat3-Mfn2 signaling pathway, where Pae activates Stat3 to promote Mfn2-mediated mitochondrial fusion, without compromising the anticancer efficacy of Dox.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paeonol protects against doxorubicin-induced cardiotoxicity by promoting Mfn2-mediated mitochondrial fusion through activating the PKCε-Stat3 pathway. Ding, M., Shi, R., Fu, F., et al.[2023]

This study analyzed over 7.5 million reports from the FDA Adverse Event Reporting System and found that conventional doxorubicin (DOX) has a higher incidence of adverse events compared to liposomal formulations, particularly in terms of myelosuppression and cardiotoxicity.

Liposomal DOX, especially the PEGylated version, showed lower reporting odds ratios for serious side effects like myelosuppression and cardiotoxicity, but a higher risk for palmar-plantar erythrodysesthesia (PPE), indicating the need for careful monitoring when using these formulations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of the adverse event profiles of conventional and liposomal formulations of doxorubicin using the FDA adverse event reporting system. Fukuda, A., Tahara, K., Hane, Y., et al.[2022]

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]

In a study involving 29 patients with advanced soft-tissue sarcoma, the combination of paclitaxel, doxorubicin, and filgrastim resulted in a partial response rate of 22.2%, indicating limited efficacy compared to single-agent doxorubicin.

The treatment regimen was associated with significant side effects, including grade 3 anemia in three patients and grade 3-4 neutropenia in 20 patients, highlighting safety concerns despite the lack of increased effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel (Taxol) plus doxorubicin plus filgrastim in advanced sarcoma: a phase II study. Sandler, A., Fox, S., Meyers, T., et al.[2019]

References

1. England pubmed.ncbi.nlm.nih.gov

Phase I multicenter study of combined high-dose ifosfamide and doxorubicin in the treatment of advanced sarcomas. Swiss Group for Clinical Research (SAKK). [2020]

2. Italy pubmed.ncbi.nlm.nih.gov

Effect of lutein and doxorubicin combinatorial therapy on S180 cell proliferation and tumor growth. [2019]

3. Greece pubmed.ncbi.nlm.nih.gov

Insulin-like growth factor-I receptor activation blocks doxorubicin cytotoxicity in sarcoma cells. [2014]

4. France pubmed.ncbi.nlm.nih.gov

[Chemotherapy of sarcomas: optimization of existing drugs and new molecules]. [2006]

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

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

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

Doxorubicin, ifosfamide, and dacarbazine (AID) with mesna uroprotection for advanced untreated sarcoma: a phase I study. [2013]

8. England pubmed.ncbi.nlm.nih.gov

Long-term cure of soft tissue sarcoma with pegylated-liposomal doxorubicin after doxorubicin and ifosfamide failure. [2022]

9. Egypt pubmed.ncbi.nlm.nih.gov

Paeonol protects against doxorubicin-induced cardiotoxicity by promoting Mfn2-mediated mitochondrial fusion through activating the PKCε-Stat3 pathway. [2023]

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

Comparison of the adverse event profiles of conventional and liposomal formulations of doxorubicin using the FDA adverse event reporting system. [2022]

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

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

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

Paclitaxel (Taxol) plus doxorubicin plus filgrastim in advanced sarcoma: a phase II study. [2019]