A Study of Epacadostat in Combination With Pembrolizumab and Chemotherapy in Participants With Advanced or Metastatic Solid Tumors (ECHO-207/KEYNOTE-723)

Study Overview
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Brief Summary
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This was an open-label, nonrandomized, Phase 1/2 study designed to determine the safety, tolerability, and efficacy of epacadostat when given in combination with pembrolizumab and 7 different chemotherapy regimens described as Treatment Groups A through G below (see Study Drug and Background Therapies, Dose, and Mode of Administration). Phase 1 consisted of a 3 + 3 + 3 design intended to determine the MTD or PAD of epacadostat when given in combination with pembrolizumab and chemotherapy; efficacy was also explored. Phase 2 was designed to enroll efficacy expansion cohorts to further evaluate the safety, tolerability, and efficacy of epacadostat at the MTD or PAD (as selected in Phase 1) when given in combination with pembrolizumab and chemotherapy. Each efficacy expansion cohort was to enroll participants with 1 specific type of advanced or metastatic solid tumor. Additional cohorts (ie, the mandatory biopsy cohorts) were designed to evaluate changes in the tumor microenvironment in participants with any advanced or metastatic solid tumor who had progressed on previous therapy with a PD-1 or a PD-L1 inhibitor. No participants were enrolled in any Phase 2 efficacy expansion cohort, or in any Phase 2 mandatory biopsy cohort receiving Treatment A, B, F, or G. Phase 2 mandatory biopsy cohort participants received Treatments C, D, or E (ie, were included in Treatment Groups C, D, or E). Participants were assigned to a treatment group based on the chemotherapy regimen most appropriate for their tumor type.

Official Title
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A Phase 1/2, Open-Label, Safety, Tolerability, and Efficacy Study of Epacadostat in Combination With Pembrolizumab and Chemotherapy in Subjects With Advanced or Metastatic Solid Tumors (ECHO-207/KEYNOTE-723)

Conditions
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Solid Tumor

Intervention / Treatment
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* Drug: Epacadostat
* Drug: Pembrolizumab
* Drug: Oxaliplatin
* Drug: Leucovorin
* Drug: 5-Fluorouracil
* Drug: Gemcitabine
* Drug: nab-Paclitaxel
* Drug: Carboplatin
* Drug: Paclitaxel
* Drug: Pemetrexed
* Drug: Cyclophosphamide
* Drug: Carboplatin
* Drug: Cisplatin
* Drug: 5-Fluorouracil
* Drug: Investigator's choice of platinum agent


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed diagnosis of selected advanced or metastatic solid tumors. Presence of measurable disease per RECIST v1.1. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Exclusion Criteria: Laboratory and medical history parameters not within the Protocol-defined range. Receipt of anticancer medications or investigational drugs within the Protocol-defined intervals before the first administration of study drug. Previous radiotherapy within 2 weeks of starting study therapy. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Has not recovered to ≤ Grade 1 from toxic effects of previous therapy and/or complications from previous surgical intervention before starting study therapy. Receipt of a live vaccine within 30 days of planned start of study therapy. Active infection requiring systemic therapy. Subjects who have any active or inactive autoimmune disease or syndrome. Women who are pregnant or breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Group A<br>Epacadostat + pembrolizumab + mFOLFOX6 (oxaliplatin, leucovorin, 5-fluorouracil) | Drug: Epacadostat<br>* Epacadostat oral twice-daily continuous daily dosing at the protocol-defined dose.<br>* Other names: INCB024360;Drug: Pembrolizumab<br>* Pembrolizumab<br>Drug: Oxaliplatin<br>* Oxaliplatin<br>Drug: Leucovorin<br>* Leucovorin<br>Drug: 5-Fluorouracil<br>* 5-Fluorouracil<br>|
| Experimental: Treatment Group B<br>Epacadostat + pembrolizumab + gemcitabine and nab-paclitaxel | Drug: Epacadostat<br>* Epacadostat oral twice-daily continuous daily dosing at the protocol-defined dose.<br>* Other names: INCB024360;Drug: Pembrolizumab<br>* Pembrolizumab<br>Drug: Gemcitabine<br>* Gemcitabine<br>Drug: nab-Paclitaxel<br>* nab-Paclitaxel<br>|
| Experimental: Treatment Group C<br>Epacadostat + pembrolizumab + carboplatin and paclitaxel | Drug: Epacadostat<br>* Epacadostat oral twice-daily continuous daily dosing at the protocol-defined dose.<br>* Other names: INCB024360;Drug: Pembrolizumab<br>* Pembrolizumab<br>Drug: Carboplatin<br>* Carboplatin<br>Drug: Paclitaxel<br>* Paclitaxel<br>|
| Experimental: Treatment Group D<br>Epacadostat + pembrolizumab + pemetrexed and investigators choice of platinum agent | Drug: Epacadostat<br>* Epacadostat oral twice-daily continuous daily dosing at the protocol-defined dose.<br>* Other names: INCB024360;Drug: Pembrolizumab<br>* Pembrolizumab<br>Drug: Pemetrexed<br>* Pemetrexed<br>Drug: Carboplatin<br>* Carboplatin<br>Drug: Cisplatin<br>* Cisplatin<br>Drug: Investigator's choice of platinum agent<br>* Investigator's choice of platinum agent: carboplatin or cisplatin<br>|
| Experimental: Treatment Group E<br>Epacadostat + pembrolizumab + cyclophosphamide | Drug: Epacadostat<br>* Epacadostat oral twice-daily continuous daily dosing at the protocol-defined dose.<br>* Other names: INCB024360;Drug: Pembrolizumab<br>* Pembrolizumab<br>Drug: Cyclophosphamide<br>* Cyclophosphamide<br>|
| Experimental: Treatment Group F<br>Epacadostat + pembrolizumab + gemcitabine and investigators choice of platinum agent | Drug: Epacadostat<br>* Epacadostat oral twice-daily continuous daily dosing at the protocol-defined dose.<br>* Other names: INCB024360;Drug: Pembrolizumab<br>* Pembrolizumab<br>Drug: Gemcitabine<br>* Gemcitabine<br>|
| Experimental: Treatment Group G<br>Epacadostat + pembrolizumab + investigators choice of platinum agent and 5-fluorouracil | Drug: Epacadostat<br>* Epacadostat oral twice-daily continuous daily dosing at the protocol-defined dose.<br>* Other names: INCB024360;Drug: Pembrolizumab<br>* Pembrolizumab<br>Drug: Carboplatin<br>* Carboplatin<br>Drug: Cisplatin<br>* Cisplatin<br>Drug: 5-Fluorouracil<br>* 5-FU<br>Drug: Investigator's choice of platinum agent<br>* Investigator's choice of platinum agent: carboplatin or cisplatin<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phases 1 & 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | A TEAE is any AE either reported for the first time or worsening of a pre-existing event after first dose of epacadostat, pembrolizumab, or chemotherapy. Serious adverse event is defined as an event that meets 1 of the following criteria: is fatal or life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability, incapacity, or a substantial disruption of a person's ability to conduct normal life functions, constitutes a congenital anomaly or birth defect,is a medically important event that may jeopardize the participant or may require medical or surgical intervention to prevent 1 of the outcomes listed above. | Up to 21 months | 
| Phases 1 and 2: Number of Participants With Dose Limiting Toxicities (DLTs) | A DLT was defined as the occurrence of any of the protocol-specified toxicities occurring up to and including Day 28 for the cohorts where mFOLFOX6 and nab-paclitaxel/gemcitabine are administered and Day 21 for all other chemotherapy regimens in Phase 1, except those with a clear alternative explanation (eg, disease progression) or transient (≤ 72 hours) abnormal laboratory values without associated clinically significant signs or symptoms based on investigator determination. | 28 days | 
| Phases 1 and 2: Objective Response Rate (ORR) | ORR was defined as the percentage of participants having a complete response (CR) or partial response (PR) as determined by investigator assessment of radiographic disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. | Up to Week 18 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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solid tumors, colorectal cancer, pancreatic ductal adenocarcinoma, non-small cell lung cancer, PD-1, PD-L1, epacadostat, IDO inhibitor