Epacadostat + Pembrolizumab for Sarcoma

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: MAOIs, UGT1A9 inhibitors

Disqualifiers: Active infection, 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: 8

Duration: 24 weeks

30 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to test any good and bad effects of the combination therapy of epacadostat and pembrolizumab and to determine how well the combination therapy works in the treatment of patients with sarcoma.

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, you cannot participate if you are taking certain medications like Monoamine Oxidase Inhibitors (MAOIs) or UGT1A9 inhibitors within 21 days before screening. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination Epacadostat and Pembrolizumab for treating sarcoma?

The combination of Epacadostat and Pembrolizumab has shown promising results in other cancers like melanoma and squamous cell carcinoma of the head and neck, suggesting potential benefits in sarcoma. Pembrolizumab alone has shown some activity in advanced sarcomas, and Epacadostat may enhance this effect by altering the tumor environment to boost the immune response. ^{1 2 3 4 5}

Is the combination of Epacadostat and Pembrolizumab safe for humans?

The combination of Epacadostat and Pembrolizumab has been studied for safety in patients with advanced solid tumors. In these studies, the treatment was generally well tolerated, although some patients experienced serious side effects like dehydration, low sodium levels, and autoimmune encephalitis. No treatment-related deaths were reported. ^{1 2 6 7 8}

How is the drug combination of Epacadostat and Pembrolizumab different from other sarcoma treatments?

This drug combination is unique because it combines Epacadostat, an IDO1 inhibitor that helps the immune system recognize and attack cancer cells, with Pembrolizumab, a PD-1 inhibitor that prevents cancer cells from hiding from the immune system. This approach is novel for sarcoma, a cancer with limited treatment options, and aims to enhance the immune response against the tumor. ^{1 2 3 4 9}

Research Team

Sandra D'Angelo, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

Adults with advanced sarcoma who have tried at least one other treatment can join this trial. They must be in good health otherwise, able to consent, and willing to follow the study plan. A biopsy is needed unless it's too risky. Those without standard treatment options or refusing standard chemo are also eligible.

Inclusion Criteria

I am 18 years old or older.

My organs are working well enough for treatment.

You need to agree to have a tissue sample taken from your tumor before treatment begins. If it's too risky or impossible to do so, the principal investigator may decide to exempt you from this requirement.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Epacadostat 100mg twice daily and Pembrolizumab 200mg every 3 weeks

24 weeks

8 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Epacadostat
• Pembrolizumab

Trial Overview The trial tests a combo of two drugs: Epacadostat, which blocks an enzyme that cancers use to hide from the immune system, and Pembrolizumab, an immunotherapy drug already used for some cancers. The goal is to see if together they work better for sarcoma.

Participant Groups

Group I: Vascular Sarcoma Subtypes Experimental Treatment 2 Interventions

Including angiosarcoma and Epithelioid Hemangioendothelioma (EHE). Epacadostat 100mg Twice daily Continuously days 1-21 of each 3 week cycle Oral Pembrolizumab 200mg Every 3 weeks Day 1 of each 3 week cycle IV infusion

Group II: UPS, Liposarcoma or pleomorphic liposarcoma Experimental Treatment 2 Interventions

Undifferentiated Pleomorphic Sarcoma (UPS) or Liposarcoma (dedifferentiated or pleomorphic liposarcoma) Epacadostat 100mg Twice daily Continuously days 1-21 of each 3 week cycle Oral Pembrolizumab 200mg Every 3 weeks Day 1 of each 3 week cycle IV infusion

Group III: Other Experimental Treatment 2 Interventions

Epacadostat 100mg Twice daily Continuously days 1-21 of each 3 week cycle Oral Pembrolizumab 200mg Every 3 weeks Day 1 of each 3 week cycle IV infusion

Group IV: Leiomyosarcoma Experimental Treatment 2 Interventions

Epacadostat 100mg Twice daily Continuously days 1-21 of each 3 week cycle Oral Pembrolizumab 200mg Every 3 weeks Day 1 of each 3 week cycle IV infusion

Epacadostat is already approved in United States for the following indications:

Approved in United States as Epacadostat for:

• None approved; Orphan designation for stage IIB-IV melanoma

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

M.D. Anderson Cancer Center

Collaborator

Trials

3,107

Recruited

1,813,000+

Incyte Corporation

Industry Sponsor

Trials

408

Recruited

66,800+

Steven Stein

Incyte Corporation

Chief Medical Officer since 2015

MD from University of Witwatersrand

Hervé Hoppenot

Incyte Corporation

Chief Executive Officer since 2014

MBA from ESSEC Business School

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Findings from Research

In a phase II study involving 30 patients with advanced sarcoma, the combination of epacadostat (an IDO1 inhibitor) and pembrolizumab showed limited antitumor activity, with a best objective response rate of only 3.3%.

The treatment was well tolerated, with 23% of patients experiencing grade 3 treatment-related adverse events, but no significant changes in tumor expression of PD-L1 or IDO1 were observed, suggesting that the IDO1 inhibition may not have been sufficient.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase II Study of Epacadostat and Pembrolizumab in Patients with Advanced Sarcoma. Kelly, CM., Qin, LX., Whiting, KA., et al.[2023]

In a trial involving 62 patients with advanced solid tumors, the combination of epacadostat (an IDO1 inhibitor) and pembrolizumab (a PD-1 inhibitor) was generally well tolerated, with no maximum tolerated dose reached and only 11% of patients discontinuing due to treatment-related adverse events.

The combination therapy showed promising antitumor activity, with 55% of melanoma patients and responses observed in other cancer types, indicating potential effectiveness across various advanced solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Epacadostat Plus Pembrolizumab in Patients With Advanced Solid Tumors: Phase I Results From a Multicenter, Open-Label Phase I/II Trial (ECHO-202/KEYNOTE-037). Mitchell, TC., Hamid, O., Smith, DC., et al.[2023]

In a phase 3 trial involving 706 patients with unresectable stage III or IV melanoma, the combination of epacadostat and pembrolizumab did not show any significant improvement in progression-free survival or overall survival compared to pembrolizumab alone.

The most common serious side effects were similar between the two groups, with no treatment-related deaths reported, indicating that the combination therapy was generally safe but ineffective in enhancing treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study. Long, GV., Dummer, R., Hamid, O., et al.[2020]

In a phase 2 study involving 86 patients with advanced soft-tissue or bone sarcoma, pembrolizumab demonstrated some efficacy, particularly in undifferentiated pleomorphic sarcoma (40% response rate) and dedifferentiated liposarcoma (20% response rate), although the overall response rate did not meet the primary endpoint.

The treatment was associated with some serious adverse events, including immune-related conditions like adrenal insufficiency and pneumonitis, highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. Tawbi, HA., Burgess, M., Bolejack, V., et al.[2022]

A new compound, referred to as compound 3, has shown superior inhibitory potency against the IDO1 enzyme compared to the existing IDO1 inhibitor epacadostat, indicating its potential as a more effective treatment in oncology immunotherapy.

Compound 3 also demonstrated improved pharmacokinetic properties, including better oral exposure and bioavailability, while maintaining comparable antitumor efficacy in preclinical models, suggesting it could be a promising lead for developing more effective IDO1 inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design, synthesis, biological evaluation of urea substituted 1,2,5-oxadiazole-3-carboximidamides as novel indoleamine 2,3-dioxygenase-1 (IDO1) inhibitors. Ye, K., Wang, K., Wang, T., et al.[2023]

In a phase 2 study involving 98 patients with rare and ultra-rare sarcomas, pembrolizumab showed an objective response rate of 6.2% at week 12, indicating some activity in these difficult-to-treat cancers.

The treatment was associated with manageable toxicity, with the most common severe adverse events being anemia and liver enzyme increases, and no deaths were linked to the drug itself, suggesting it may be a safe option for selected sarcoma histotypes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in patients with rare and ultra-rare sarcomas (AcSé Pembrolizumab): analysis of a subgroup from a non-randomised, open-label, phase 2, basket trial. Blay, JY., Chevret, S., Le Cesne, A., et al.[2023]

References

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

A Phase II Study of Epacadostat and Pembrolizumab in Patients with Advanced Sarcoma. [2023]

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

Epacadostat Plus Pembrolizumab in Patients With Advanced Solid Tumors: Phase I Results From a Multicenter, Open-Label Phase I/II Trial (ECHO-202/KEYNOTE-037). [2023]

3. England pubmed.ncbi.nlm.nih.gov

Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study. [2020]

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

Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. [2022]

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

Epacadostat Shows Value in Two SCCHN Trials. [2021]

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

The safety and tolerability of epacadostat alone and in combination with pembrolizumab in patients with advanced solid tumors: results from a first-in-Japanese phase I study (KEYNOTE-434). [2022]

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

Phase 1 study of epacadostat in combination with atezolizumab for patients with previously treated advanced nonsmall cell lung cancer. [2021]

8. France pubmed.ncbi.nlm.nih.gov

Design, synthesis, biological evaluation of urea substituted 1,2,5-oxadiazole-3-carboximidamides as novel indoleamine 2,3-dioxygenase-1 (IDO1) inhibitors. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab in patients with rare and ultra-rare sarcomas (AcSé Pembrolizumab): analysis of a subgroup from a non-randomised, open-label, phase 2, basket trial. [2023]