Pembrolizumab + Local Chemotherapy for Sarcoma

Recruiting at 9 trial locations

Overseen By Charlotte Ariyan, MD, PhD

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Other malignancy, CNS metastases, 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: Unknown

Duration: 6 months

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment approach for sarcoma, a cancer affecting connective tissues like muscles and bones. Researchers are testing whether combining pembrolizumab with two chemotherapy drugs, melphalan and dactinomycin, delivered directly to an affected arm or leg, can safely delay disease progression. People with advanced or spreading sarcoma who have tried at least one other therapy and qualify for pembrolizumab and isolated limb infusion (a procedure targeting treatment to a limb) may be suitable for this study. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important advancements in sarcoma treatment.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you are on systemic immunosuppressive therapy or certain other treatments, you may need to discuss this with the trial team.

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

Research shows that pembrolizumab is generally well-tolerated for advanced cancers. Patients with advanced soft-tissue sarcoma have used it, and it maintains a manageable safety profile. Common side effects include tiredness and skin reactions.

Studies indicate that dactinomycin is effective and safe for certain cancers. However, if it leaks from a vein during treatment, it can harm nearby tissues. This known risk can be managed with careful administration.

Isolated limb infusion (ILI) delivers high doses of chemotherapy to a limb, reducing exposure to the rest of the body. It has been used safely in patients with advanced limb sarcoma. Some patients may experience side effects like swelling and temporary pain in the treated limb.

Melphalan, another chemotherapy drug in this trial, is safe in high doses for certain treatments. Side effects can include nausea and low blood cell counts, but these are usually temporary.

Overall, these treatments have been studied and are generally considered safe when used correctly. Trials focus on safety to ensure any side effects are understood and managed. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment combination for sarcoma because it integrates pembrolizumab, an immunotherapy, with localized chemotherapy methods. Unlike traditional systemic chemotherapy that affects the whole body, isolated limb infusion (ILI) delivers chemotherapy directly to the tumor in the limb, potentially reducing side effects. Pembrolizumab works by unleashing the immune system to attack cancer cells, which is different from standard chemotherapies like doxorubicin that directly kill cancer cells. This combination aims to enhance effectiveness while minimizing systemic toxicity, offering a promising new approach for difficult-to-treat extremity sarcomas.

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

Research has shown that pembrolizumab, a type of immunotherapy, can benefit patients with soft tissue sarcoma. Specifically, it increased the time patients live without the disease by 15% when combined with standard treatments. In this trial, participants with advanced or metastatic extremity sarcoma will receive pembrolizumab alongside isolated limb infusion (ILI). ILI delivers chemotherapy directly to an arm or leg and has demonstrated good results; one study found that 85% of patients responded well to this treatment. Together, these treatments aim to be more effective against advanced sarcoma, offering a potentially strong option for those affected. ^{6 7 8 9 10}

Who Is on the Research Team?

Edmund Bartlett, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

This trial is for individuals aged 12 or older with advanced sarcoma in an arm or leg, who have tried at least one systemic therapy or declined standard care. They must be able to consent, follow the protocol, and have adequate organ function. Pregnant women, those planning pregnancy, and patients with certain health conditions like active infections or uncontrolled illnesses are excluded.

Inclusion Criteria

I am a candidate for pembrolizumab treatment.

For female patients of childbearing potential, negative serum pregnancy test at screening visit and within 72 h prior to the first dose of study medication.

My blood and organ tests are within the required ranges for treatment.

Exclusion Criteria

You are not eligible if you have any of the following: - Another cancer that needs to be treated - Physical conditions that make you unable to receive ILI treatment, as determined by your doctor - History of allergic reaction to pembrolizumab or any of its components - Active infection that requires treatment or congestive heart failure in the last 6 months - Known active brain metastases, except for those previously treated and stable - Significant immunosuppression, such as primary immunodeficiency, opportunistic infection, or use of immunosuppressive therapy within 7 days before enrollment - Active infections with HIV, hepatitis B or C, or tuberculosis - History or evidence of autoimmune disease that has required systemic treatment in the past 2 years - Pregnant or breastfeeding, planning to become pregnant, or planning to father a child during the study and for 4 months after the last dose of pembrolizumab - Not willing to use contraception during the study and for 4 months after the last dose of pembrolizumab (if of childbearing potential) - Received cancer treatment or major surgery within 14 days before the start of the study or has not recovered from treatment-related adverse events - Currently participating in another study involving investigational drugs or devices, or participated in such a study within 3 weeks of starting this study - Known psychiatric or substance abuse disorders that would interfere with participation in the study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pembrolizumab in combination with melphalan and dactinomycin via isolated limb infusion (ILI)

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Dactinomycin
• Isolated Limb Infusion
• Melphalan
• Pembrolizumab

Trial Overview The study tests pembrolizumab combined with chemotherapy drugs melphalan and dactinomycin delivered via isolated limb infusion (ILI) directly to the affected limb. The goal is to see if this approach safely delays disease progression compared to current treatments.

How Is the Trial Designed?

Group I: Participants with Sarcoma Experimental Treatment 3 Interventions

Advanced/metastatic extremity sarcoma eligible for pembrolizumab and isolated limb infusion (ILI)

Dactinomycin is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Cosmegen for:

• Rhabdomyosarcoma
• Ewing sarcoma
• Wilms tumor
• Troophoblastic neoplasm

Approved in European Union as Actinomycin D for:

• Rhabdomyosarcoma
• Ewing sarcoma
• Wilms tumor
• Troophoblastic neoplasm

Approved in Canada as Cosmegen for:

• Rhabdomyosarcoma
• Ewing sarcoma
• Wilms tumor
• Troophoblastic neoplasm

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Published Research Related to This Trial

In a study of 20 patients with bulky cutaneous melanoma, low-dose TNFalpha combined with melphalan in hyperthermic isolated limb perfusion resulted in a complete tumor response in 70% of cases and a partial response in 25%.

The treatment demonstrated a low risk of systemic toxicity (less than 5% leakage) and mild locoregional toxicity in 95% of patients, indicating it is a safe and effective option for managing in-transit metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hyperthermic isolated limb perfusion with low-dose tumor necrosis factor-alpha and melphalan for bulky in-transit melanoma metastases. Rossi, CR., Foletto, M., Mocellin, S., et al.[2019]

Hyperthermic isolated limb perfusion using tasonermin and melphalan has shown promising efficacy in treating undifferentiated spindle-cell sarcoma, leading to a partial response and complete pathological remission in a 65-year-old female patient after treatment.

This approach is effective in preserving limb function while treating advanced sarcomas, suggesting that it should be considered as part of a multimodal treatment strategy for localized limb sarcomas in specialized medical centers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant Hypertermic Isolated Limb Perfusion in Treatment of Undifferentiated Spindle Cell Sarcoma of Lower Limb with Achieved Complete Pathologic Response. Vočka, M., Špaček, M., Matějovský, Z., et al.[2019]

Hyperthermic isolated limb perfusion (HILP) and isolated limb infusion (ILI) with melphalan are effective treatment options for in-transit melanoma and advanced extremity sarcoma, indicating their role in regional chemotherapy.

Future research should focus on patient selection, refining techniques for consistent results with manageable toxicity, and developing new strategies and agents to enhance treatment efficacy and inform systemic therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Future directions in regional treatment strategies for melanoma and sarcoma. Beasley, GM., Ross, MI., Tyler, DS.[2013]

Hyperthermic isolated limb perfusion (HILP) and isolated limb infusion (ILI) with melphalan are effective treatment options for in-transit melanoma of the extremity, focusing on maximizing drug delivery while managing toxicity.

Research is ongoing to understand resistance mechanisms to melphalan and explore the addition of modulators to enhance treatment efficacy, with promising preclinical results for temozolomide as a potential alternative.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current clinical and research approaches to optimizing regional chemotherapy: novel strategies generated through a better understanding of drug pharmacokinetics, drug resistance, and the development of clinically relevant animal models. Beasley, GM., Kahn, L., Tyler, DS.[2008]

Hyperthermic isolated limb perfusion with tumor necrosis factor-α and melphalan (TM-HILP) shows high response rates in treating synovial sarcomas (SS), with a response rate of 74% similar to the overall soft tissue sarcoma cohort (76%).

The study found that SS tumors were more commonly located distally and were smaller than other soft tissue sarcomas, but there was no significant difference in treatment response based on tumor location, although proximal tumors had a higher rate of complete resections (R0 status).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The pathologic response of resected synovial sarcomas to hyperthermic isolated limb perfusion with melphalan and TNF-α: a comparison with the whole group of resected soft tissue sarcomas. Schwindenhammer, B., Podleska, LE., Kutritz, A., et al.[2021]

Induction chemotherapy using isolated limb perfusion (ILP) with melphalan and tumor necrosis factor-α before limb-conserving surgery did not show significant differences in local recurrence or distant metastasis-free survival compared to standard surgery followed by routine post-operative radiotherapy, based on a study of 124 patients.

Patients in the ILP cohort required significantly less post-operative radiotherapy (27%) compared to the standard cohort (82%), suggesting that ILP may reduce the need for additional radiation treatment after surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regional chemotherapy by isolated limb perfusion prior to surgery compared with surgery and post-operative radiotherapy for primary, locally advanced extremity sarcoma: a comparison of matched cohorts. Jakob, J., Smith, HG., Wilkinson, MJ., et al.[2022]

Hyperthermic isolated limb perfusion with TNF-alpha and melphalan (TM-HILP) was safely performed on 20 patients with inoperable melanoma and soft tissue sarcoma, with no major intra-operative complications reported, although one patient required amputation due to postoperative ischemic necrosis.

The treatment showed promising efficacy, with 62% of melanoma patients achieving a complete response, and all soft tissue sarcoma patients responding completely after tumor excision, indicating TM-HILP could be a viable option for advanced cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hyperthermic isolated limb perfusion for recurrent melanomas and soft tissue sarcomas: feasibility and reproducibility in a multi-institutional Hellenic collaborative study. Lasithiotakis, K., Economou, G., Gogas, H., et al.[2019]

Isolated limb perfusion using high doses of TNF-alpha combined with IFN-gamma and melphalan has shown a remarkable 91% complete remission rate in patients with malignant melanoma over a 4-year period.

This treatment also effectively prevents amputation in 87.5% of cases for irresectable soft tissue sarcoma, demonstrating its efficacy as a neoadjuvant therapy, while validating a dual targeting strategy that impacts both tumor blood vessels and cancer cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy of the tumor necrosis factor-alpha (rTNF-alpha) associated with interferon-gamma and chemotherapy in extracorporeal circulation in the limb in inoperable malignant melanoma, soft tissue sarcoma and epidermoid carcinoma. A 4-year experience]. Lejeune, F., Liénard, D., Eggermont, A., et al.[2017]

Isolated limb perfusion with TNFalpha and melphalan has a high response rate of 76% in treating locally advanced soft-tissue sarcomas, with 71% of patients avoiding amputation, demonstrating its efficacy in limb-threatening tumors.

Laboratory models have revealed that TNFalpha enhances the uptake of chemotherapy drugs like melphalan by tumors, increasing their effectiveness, and new treatment modalities, including gene therapy, are being developed based on these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current uses of isolated limb perfusion in the clinic and a model system for new strategies. Eggermont, AM., de Wilt, JH., ten Hagen, TL.[2023]

Hyperthermic isolated limb perfusion with TNF-alpha and melphalan (HILP-TM) resulted in a favorable response rate in nearly half of the sarcoma cases studied, with 48.8% classified as responders after treatment.

Despite the presence of metallothioneins (MTs) in 70.7% of the tumors, their expression did not predict the response to HILP-TM, indicating that other factors may influence treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overexpression of the drug resistance-associated protein metallothionein does not correlate with response of sarcomas to isolated limb perfusion treatment. Grabellus, F., Sheu, SY., Tötsch, M., et al.[2013]

Hyperthermic isolated limb perfusion (HILP) using melphalan is effective for treating malignant melanoma, achieving complete response rates of 65-80% for in transit metastases and regional lymph node metastases.

Combining tumor necrosis factor (TNF) alpha with melphalan significantly enhances response rates in soft tissue sarcoma, allowing over 80% of patients to avoid limb amputation, although local recurrences in melanoma remain a challenge.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Regional chemotherapy--perfusion of the extremities]. Meyer, T., Göhl, J.[2016]

In a study of 30 patients with locally advanced extremity sarcoma and melanoma treated with hyperthermic isolated limb perfusion using melphalan and TNF-α, the limb salvage rate was 86.7%, successfully avoiding amputation in 26 cases.

The treatment showed a high overall response rate of 93.4%, with a median overall survival of 13.5 months, indicating that ILP-MT is both effective and safe for managing advanced limb tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Tumor necrosis factor α and melfalan-based hyperthermic isolated limb perfusion in locally advanced extremity soft tissue sarcomas and melanomas]. Alegre, JF., Duarte, M., Sureda González, M., et al.[2013]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10298874/

Isolated Limb Infusion for Limb-Threatening, Unresectable ... Overall response rate (ORR) was 85%, with 0% complete response (CR), rendering most with resectable disease 3–7 weeks after ILI, for a limb ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S0959804918308153

The effect of age on outcomes after isolated limb perfusion ... The overall response rate for all patients with melanoma was 82.4% with a limb salvage rate of 96.5%. Similarly, no significant differences in response rates ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4504423/

Isolated Limb Infusion in a Series of over 100 ... From 5/2007-1/2012, 76 patients successfully underwent initial ILI, and 28 following either previous hyperthermic isolated limb perfusion (HILP) or ILI. Seventy ...

4. jamanetwork.com jamanetwork.com/journals/jamasurgery/fullarticle/1107074

Limb Preservation With Isolated Limb Infusion for Locally ... Isolated limb infusion enables delivery of regional chemotherapy at almost 10-fold–greater concentrations than systemic chemotherapy and has the advantage of ...

5. annalsofoncology.org annalsofoncology.org/article/S0923-7534(19)47694-1/fulltext

Limb salvage with isolated perfusion for soft tissue sarcoma Conclusion. ILP with TNF-α and melphalan is an effective neo-adjuvant treatment with high response rates that can achieve limb salvage for most patients with ...

6. hemonc.org hemonc.org/w/images/7/7c/Dactinomycin.pdf

COSMEGEN® (dactinomycin for injection), for intravenous ... The safety and effectiveness of dactinomycin have been established in pediatric patients with. Wilms tumor, rhabdomyosarcoma, Ewing sarcoma, and metastatic ...

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2012/050682s029s030lbl.pdf

Cosmegen® for Injection (dactinomycin ... - accessdata.fda.gov Ewing's Sarcoma:​​ Outcomes in regional and metastatic disease for previously untreated patients administered COSMEGEN resulted in 31 of 44 patients (70%) ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6889215/

Impact of chemotherapy cycles and intervals on outcomes ... The present study shows that VDC/IE chemotherapy is well tolerated in adult patients with ES, chemotherapy of at least 12 cycles is associated with better EFS ...

9. mayoclinic.org mayoclinic.org/drugs-supplements/dactinomycin-intravenous-route/description/drg-20063277

Dactinomycin (intravenous route) - Side effects & uses If dactinomycin accidentally seeps out of the vein into which it is injected, it may severely damage some tissues and cause scarring. Tell your ...

10. recordatirarediseases.com recordatirarediseases.com/wp-content/uploads/2024/12/cosmegen-product-monograph-en.pdf

Cosmegen Product Monograph - Recordati Rare Diseases The International Agency on Research on Cancer has judged that dactinomycin is a positive carcinogen in animals. Local sarcomas were produced in mice and rats ...