Epacadostat + Sirolimus for Advanced Cancers

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose and ensure the safety of a new treatment combination for individuals with advanced cancers. It tests epacadostat (an IDO inhibitor) and sirolimus together, specifically targeting those with advanced solid tumors or non-small cell lung cancer (NSCLC) that have not responded to previous treatments. Ideal participants are adults who have experienced progression after at least one round of systemic therapy for their cancer. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment combination.

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.

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

Research shows that the combination of Epacadostat and Sirolimus is under study for its safety in treating advanced cancers. Previous studies found that this combination can prevent cancer progression in about 33% of patients.

The trial is in an early phase, focusing primarily on the treatment's safety for participants. At this stage, researchers aim to determine the right dose that patients can tolerate without severe side effects. While the treatment is still under evaluation, researchers closely monitor for any side effects.

Early phase trials like this one assess whether patients can tolerate the treatment and determine the optimal dose to avoid serious issues. So far, the combination of Epacadostat and Sirolimus has been manageable for participants, with some reporting stable conditions. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of epacadostat and sirolimus for advanced cancers because it targets the immune system in a new way. Epacadostat works by inhibiting an enzyme called IDO1, which can suppress the immune system's ability to fight cancer cells. Sirolimus, on the other hand, is an mTOR inhibitor that can help regulate cell growth. This combination could potentially enhance the immune response against tumors, making it different from traditional chemotherapy or targeted therapies that attack cancer cells directly. By using this unique approach, there's hope for more effective control of cancer growth with potentially fewer side effects.

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

This trial will evaluate the combination of Epacadostat and Sirolimus for advanced cancers. Research has shown that combining Epacadostat, which blocks the IDO1 enzyme, with Sirolimus might help fight advanced cancers by boosting the immune system. Studies found that using these drugs together prevented cancer growth or spread in about 33% of patients for some time. By blocking IDO1, the body may better recognize and attack cancer cells. While more research is needed, early results are promising for patients with advanced solid tumors. ^{1 3 4 6 7}

Who Is on the Research Team?

Chao Huang, MD

Principal Investigator

KUMC

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

Citations

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Epacadostat (INCB24360) in Combination With Sirolimus ... Preclinical findings suggest that IDO1 is critical for cancers to evade immune surveillance and can be exploited for cancer immunotherapy. Sirolimus is an oral ...

2. ascopubs.org ascopubs.org/doi/abs/10.1200/JCO.2022.40.16_suppl.2575

Phase I study of epacadostat in combination with sirolimus ... SE produced stable disease as best response in 33% of patients. Research using the combination of SE as an immunomodulatory therapy in patients ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.e14589

Pharmacokinetics (PK) of epacadostat in combination with ... We initiated a phase I trial to test the safety and tolerability of SE combination in patients (pts) with advanced solid tumors and performed PK studies.

4. withpower.com withpower.com/trial/phase-1-carcinoma-non-small-cell-lung-1-2018-96e64

Epacadostat + Sirolimus for 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, ...

5. jto.org jto.org/article/S1556-0864(23)01967-6/pdf

EP11.02-02 Phase I Study of Epacadostat in ... Conclusions: Nivolumab maintenance following platinum- based chemotherapy did not show clinical benefits after EGFR-TKI failure in patients with EGFR-mutant ...

6. asco.org asco.org/abstracts-presentations/ABSTRACT374478

Phase I study of epacadostat in combination with sirolimus ... SE produced stable disease as best response in 33% of patients. Research using the combination of SE as an immunomodulatory therapy in patients with lung cancer ...

7. clinconnect.io clinconnect.io/trials/NCT03217669

Epacadostat (INCB24360) in Combination With Sirolimus in This clinical trial is investigating the combination of two medications, Epacadostat (INCB24360) and Sirolimus, for adults with advanced solid tumors, ...