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

Trial Summary

What is the purpose of this trial?

The purpose of this study is to find out whether giving the study drug pembrolizumab in combination with the chemotherapy drugs melphalan and dactinomycin, delivered directly to the affected arm or leg using a technique called isolated limb infusion (ILI), is a safe treatment that can delay the time before your disease gets worse (progresses).

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.

What data supports the effectiveness of the treatment Pembrolizumab + Local Chemotherapy for Sarcoma?

Research shows that hyperthermic isolated limb perfusion (HILP) with melphalan, a component of the treatment, achieves high response rates in sarcomas and can prevent limb amputation in over 80% of cases. Additionally, isolated limb infusion (ILI) with melphalan and dactinomycin is a common treatment for advanced extremity sarcoma, suggesting potential effectiveness of the combined approach. ^{1 2 3 4 5}

Is the combination of Pembrolizumab and local chemotherapy safe for treating sarcoma?

The combination of hyperthermic isolated limb perfusion (HILP) with melphalan and tumor necrosis factor-alpha (TNF-alpha) has been used safely in treating soft tissue sarcomas and melanoma, with no major complications during the procedure, although one patient experienced limb issues post-surgery. This suggests that the treatment can be safely applied with proper precautions. ^{1 6 7 8 9}

How is the treatment with Pembrolizumab and local chemotherapy unique for sarcoma?

This treatment combines Pembrolizumab, an immunotherapy drug that helps the immune system attack cancer cells, with local chemotherapy techniques like isolated limb infusion (ILI) and hyperthermic isolated limb perfusion (HILP) using melphalan and dactinomycin. This approach is unique because it targets the tumor directly in the limb, potentially reducing the need for amputation and improving drug delivery to the cancer cells. ^{1 4 10 11 12}

Research Team

Edmund Bartlett, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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) 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]

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]

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]

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]

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 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]

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]

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 (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]

References

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

Future directions in regional treatment strategies for melanoma and sarcoma. [2013]

2. Germany pubmed.ncbi.nlm.nih.gov

[Regional chemotherapy--perfusion of the extremities]. [2016]

3. United States 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. [2013]

4. France 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]. [2017]

5. Spain 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]. [2013]

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

Hyperthermic isolated limb perfusion with low-dose tumor necrosis factor-alpha and melphalan for bulky in-transit melanoma metastases. [2019]

7. Czech Republic 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. [2019]

8. Greece 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. [2019]

9. England 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. [2021]

10. England 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. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Current uses of isolated limb perfusion in the clinic and a model system for new strategies. [2023]

12. United States 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. [2008]