Immunotherapy + Chemotherapy for Sarcoma

Recruiting at 230 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: National Cancer Institute (NCI)

Must not be taking: Steroids, Anthracyclines

Disqualifiers: Pregnancy, Interstitial lung disease, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: 24

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

365 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines whether adding immunotherapy (pembrolizumab) to the usual chemotherapy (doxorubicin) treats certain types of advanced sarcoma more effectively than chemotherapy alone. Sarcoma is a cancer that begins in the bones or soft tissues and can spread to other parts of the body. The trial aims to determine if this combination can halt cancer growth and extend patients' lives. Suitable participants have a confirmed diagnosis of dedifferentiated liposarcoma (DDLPS), undifferentiated pleomorphic sarcoma (UPS), or a similar poorly differentiated sarcoma that cannot be surgically removed or has metastasized. As a Phase 3 trial, this study represents the final step before FDA approval, offering patients a chance to contribute to potentially groundbreaking treatment advancements.

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.

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

Research has shown that using pembrolizumab with doxorubicin typically results in manageable side effects. However, there is a risk of blood-related side effects. One study found a significant chance of these issues with this combination.

Most patients tolerate pembrolizumab well, though some may experience immune-related side effects, such as fatigue or skin reactions. Doxorubicin, a common chemotherapy drug, can cause side effects like nausea, hair loss, and potential heart issues, which are usually monitored closely during treatment.

Overall, while risks exist with combining pembrolizumab and doxorubicin, proper care and monitoring can often manage them. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about combining doxorubicin with pembrolizumab for treating sarcoma because it brings a new approach to tackling this challenging cancer. Traditional treatments primarily use chemotherapy like doxorubicin alone, which targets and kills rapidly growing cancer cells. However, pembrolizumab, an immunotherapy drug, works by unleashing the immune system to recognize and attack cancer cells, offering a dual mechanism that could enhance effectiveness. This combination aims to not only halt tumor growth but also potentially improve long-term survival rates by engaging the body's natural defenses, something standard chemotherapy alone doesn’t achieve.

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

Research shows that using doxorubicin with pembrolizumab, which participants in Arm A of this trial will receive, may help treat certain sarcomas. Studies have found that about 19% of patients experienced tumor shrinkage or halted growth, meaning roughly one in five patients saw some improvement. On average, patients lived about 8.1 months without their cancer worsening. Pembrolizumab, an immunotherapy, helps the immune system attack cancer cells, while doxorubicin directly targets the cancer. This combination might help patients with advanced sarcoma live longer without disease progression. Participants in Arm B will receive doxorubicin alone, with the option to add pembrolizumab if the disease progresses. ^{3 4 5 6 7}

Who Is on the Research Team?

Seth M Pollack

Principal Investigator

ECOG-ACRIN Cancer Research Group

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Doxorubicin
• Pembrolizumab

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.

How Is the Trial Designed?

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 United States, European Union, Canada, Japan for the following indications:

Approved in United States as Adriamycin for:

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

Approved in European Union as Doxorubicin for:

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

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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 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]

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]

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]

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]

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]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/EDBK_432234

Immunotherapy in Sarcoma: Current Data and Promising ... ... efficacy of doxorubicin with pembrolizumab had promising results. The Pollack study showed an ORR of 19%, which is similar to pembrolizumab ...

2. aacrjournals.org aacrjournals.org/clincancerres/article/27/23/6424/675001/Phase-II-Study-of-Pembrolizumab-in-Combination

Phase II Study of Pembrolizumab in Combination with ... Doxorubicin is standard therapy for advanced soft-tissue sarcoma (STS) with minimal improvement in efficacy and increased toxicity with addition of other ...

3. frontiersin.org frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1504117/full

The outcomes and treatment strategies in metastatic soft ... This study was to investigate the efficacy and safety of immunotherapy-based therapy in metastatic STS.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT02888665

Pembrolizumab and Doxorubicin Hydrochloride in Treating ... This phase I/II trial studies the side effects and best dose of doxorubicin hydrochloride when given together with pembrolizumab and to see how well they work ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7489365/

Assessment of Doxorubicin and Pembrolizumab in Patients ... The objective response rate was 13% for phase 2 patients and 19% overall, with median progression-free survival of 8.1 months and median overall ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/34475102/

Phase II Study of Pembrolizumab in Combination with ... Conclusions: Combination pembrolizumab and doxorubicin has manageable toxicity and preliminary promising activity in treatment of patients with ...

7. jamanetwork.com jamanetwork.com/journals/jamaoncology/fullarticle/2770032

Assessment of Doxorubicin and Pembrolizumab in Patients ... The objective response rate was 13% for phase 2 patients and 19% overall, with median progression-free survival of 8.1 months and median overall ...