Epacadostat + Sirolimus for Advanced Cancers

Recruiting at 1 trial location

Overseen By Kerry Hepler

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Chao Huang

Must not be taking: IDO inhibitors, PI3K/AKT/mTOR agents

Disqualifiers: Autoimmune diseases, Brain metastases, Hepatitis, others

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

Compensation: Varies

Number of Visits: 9

15 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a small phase I study with dose escalation and dose expansion cohorts. The former cohort will need up to 12 subjects with advanced solid tumor to define feasibility and recommended phase 2 dose (RP2D); the latter up to 10 subjects to further define safety. Study subjects will be adults with advanced solid tumor (dose escalation) and advanced non-small cell lung cancer (NSCLC) who progressed on at least one first-line systemic therapy (dose expansion).

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot participate if you are using certain investigational agents, immunosuppressive treatments, or medications that affect specific enzymes like CYP3A4 and UGT1A9. It's best to discuss your current medications with the study team.

What data supports the effectiveness of the drug combination of Epacadostat and Sirolimus for advanced cancers?

Epacadostat, an IDO1 enzyme inhibitor, has shown promising antitumor activity when combined with other drugs like pembrolizumab in advanced melanoma, suggesting potential benefits in altering the tumor environment to help the immune system fight cancer. ^{1 2 3 4 5}

What makes the drug combination of Epacadostat and Sirolimus unique for treating advanced cancers?

The combination of Epacadostat and Sirolimus is unique because Epacadostat is a potent inhibitor of the IDO1 enzyme, which helps tumors evade the immune system, while Sirolimus is an immunosuppressant that can modulate immune responses. This combination aims to create a more favorable immune environment to fight cancer, which is different from standard treatments that may not target these specific pathways. ^{1 2 4 6 7}

Research Team

Chao Huang, MD

Principal Investigator

KUMC

Eligibility Criteria

Adults with advanced solid tumors, specifically those with non-small cell lung cancer (NSCLC) that has worsened after first-line treatment. Participants must be over 18, have adequate organ function, and not have any health issues or treatments that could affect the study's results. They should not be pregnant or nursing and must agree to use contraception.

Inclusion Criteria

No known allergy or reaction to any component of either study drug formulation

Not pregnant or nursing

I haven't taken MAOI drugs in the last 21 days.

Exclusion Criteria

I have been treated with an IDO inhibitor.

I have been treated with drugs targeting PI3K, AKT, or mTOR for my cancer.

You have had or currently have an abnormal ECG that the doctor thinks is important.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Sirolimus Lead-in

Participants receive a loading dose of sirolimus on day -7 and maintenance dose starting day -6

1 week

1 visit (in-person)

Dose Escalation

Traditional 3 + 3 dose escalation design with sirolimus and epacadostat to determine the recommended phase 2 dose

28 days

Weekly visits (in-person)

Dose Expansion

Once RP2D is defined, 10 NSCLC patients will be enrolled to further define safety

up to 12 months

Every 8 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Epacadostat
• Sirolimus

Trial Overview The trial is testing Epacadostat in combination with Sirolimus on patients with advanced malignancies. It includes a dose escalation phase to determine safe dosage levels followed by a dose expansion phase to further assess safety for NSCLC patients who've had prior therapy.

Participant Groups

Group I: Sirolimus/Epacadostat Dose Expansion Experimental Treatment 2 Interventions

Once recommended phase 2 dose (RP2D) is defined, a total of 10 non-small cell lung cancer (NSCLC) patients who meet eligibility will be enrolled in the dose expansion cohort. Treatment will be sirolimus RP2D once daily and epacadostat RP2D twice daily (BID). Sirolimus lead-in phase: loading dose on day -7 and maintenance dose starting day -6. On Cycle 1 Day 1, epacadostat 300mg BID will be added.

Group II: Sirolimus/Epacadostat Dose Escalation Experimental Treatment 2 Interventions

Traditional 3 + 3 dose escalation design. Starting doses: sirolimus 3milligrams (mg) loading/1mg maintenance and epacadostat 300mg twice daily (BID). If 0 in 3 subjects develops dose limiting toxicity (DLT), next 3 subjects will be treated at dose level 2 (DL2): sirolimus 6mg loading/2mg maintenance and epacadostat 300mg BID. If 1 subject in dose level 1 (DL1) develops DLT, 3 additional subjects will be enrolled in DL1. If 2 or more subjects in a total of 6 subjects, or 2 or more subjects in the initial 3 subjects develop DLT, the next 3 subjects will be treated at dose level -1 (DL-1): 3mg loading/1mg sirolimus + epacadostat 100mg BID. If only 1 subject in a total of 6 develops DLT, dose escalation to DL2 will be made for the next 3 subjects. Same algorithm will apply to DL2 except no further dose escalation/de-escalation will be made. Sirolimus lead-in phase: loading dose on day -7 and maintenance dose starting day -6. On Cycle 1 Day 1, epacadostat 300mg BID will be added.

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?

Chao Huang

Lead Sponsor

Trials

1

Recruited

20+

University of Kansas Medical Center

Collaborator

Trials

527

Recruited

181,000+

Findings from Research

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 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 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 I study involving 142 patients with advanced solid tumors, the combination of itacitinib (a JAK1 inhibitor) with epacadostat or parsaclisib was found to be safe, with manageable adverse events, although no significant clinical responses were observed in the epacadostat group.

While some patients showed a partial response to the combination of itacitinib and parsaclisib, the overall clinical activity was limited, and the treatment did not significantly enhance immune activation in the tumor microenvironment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exploring the safety, effect on the tumor microenvironment, and efficacy of itacitinib in combination with epacadostat or parsaclisib in advanced solid tumors: a phase I study. Naing, A., Powderly, JD., Nemunaitis, JJ., et al.[2022]

References

1. 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]

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

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

Phase 1/2 study of epacadostat in combination with ipilimumab in patients with unresectable or metastatic melanoma. [2020]

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

Exploring the safety, effect on the tumor microenvironment, and efficacy of itacitinib in combination with epacadostat or parsaclisib in advanced solid tumors: a phase I study. [2022]

6. 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]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Development of a novel formulation method to prepare liposomal Epacadostat. [2021]