Study of Epacadostat (INCB024360) Alone and In Combination With Pembrolizumab (MK-3475) With Chemotherapy and Pembrolizumab Without Chemotherapy in Participants With Advanced Solid Tumors (MK-3475-434)

Study Overview
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Brief Summary
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This is an open-label, non-randomized, Phase I study of epacadostat (INCB024360) alone and in combination with pembrolizumab with chemotherapy and pembrolizumab without chemotherapy in participants with advanced solid tumors. The primary objective of the trial is to evaluate the safety and tolerability of epacadostat administered alone and in combination with pembrolizumab with and without chemotherapy. With protocol amendment 02 (26-April-2019), treatment with epacadostat was stopped in the Epacad+Pembro+Cisplatin+Pemetrexed, Epacad+Pembro+Carboplatin+Pemetrexed, and Epacad+Pembro+Carboplatin+Paclitaxel study arms.

Official Title
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A Phase I Study of INCB024360 (Epacadostat) Alone, INCB024360 in Combination With Pembrolizumab (MK-3475), and INCB024360 and Pembrolizumab in Combination With Chemotherapy in Patients With Advanced Solid Tumors (KEYNOTE-434)

Conditions
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Neoplasms, Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: Epacadostat 25 mg
* Drug: Epacadostat 100 mg
* Biological: pembrolizumab 200 mg
* Drug: Cisplatin 75 mg/m^2
* Drug: Carboplatin Area Under the Curve (AUC) 5
* Drug: Pemetrexed 500 mg/m^2
* Drug: Paclitaxel 200 mg/m^2
* Drug: Carboplatin AUC 6


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For Part A: Has a histologically-confirmed metastatic or locally advanced solid tumor that has failed to respond to standard therapy, progressed despite standard therapy, or for which standard therapy does not exist. For Part B: Has a histologically-confirmed or cytologically confirmed diagnosis of non-small cell lung carcinoma (NSCLC) stage IIIB/IV, be naïve to systemic therapy, and have confirmation that epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK)-directed therapy is not indicated. Cohort 1 and 2 must have a histological or cytological diagnosis of non-squamous cancer. Has at least one measurable lesion by computed tomography or magnetic resonance imaging per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 Has Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 Has a life expectancy of ≥3 months Females must not be pregnant (negative urine or serum human chorionic gonadotropin test within 72 hours of study start) Women of childbearing potential and male participants must agree to use adequate contraception during the study through 120 days after the last dose of study medication For Part A: Has provided tissue for programmed cell death ligand 1 (PD-L1)/ Indoleamine 2,3-dioxygenase 1 (IDO1) expression evaluation from an archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. For Part B submission of tissue is optional. Exclusion Criteria: Has received prior therapy with an anti-Programmed cell death protein (PD)-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) agents (including ipilimumab or any other antibody/drug specifically targeting T-cell co-stimulation or checkpoint pathways), or IDO1 inhibitor Is currently participating or has participated in a study with an investigational compound or device within 4 weeks, or 5 times half-life of the investigational compound, whichever is longer, of initial dosing on this study For Part A: Has had chemotherapy, targeted small molecule therapy, radiotherapy, major surgery, or biological cancer therapy (including monoclonal antibodies) within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to the first dose of study medication, or who has not recovered (≤ Grade 1 or baseline) from adverse events due to a previously administered treatment For Part B: Has received radiotherapy within 7 days of the first dose of trial treatment or radiation therapy to the lung that is >30 Gray (Gy) within 6 months of the first dose of study medication Is expected to require any other form of systemic or localized anti-neoplastic therapy while in study Has active central nervous system (CNS) metastases and/or carcinomatous meningitis Has symptomatic ascites or pleural effusion Has an active autoimmune disease that has required systemic treatment Is receiving systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 1 week prior to the first dose of study medication Has an active infection requiring systemic therapy Has history of (noninfectious) pneumonitis that required systemic steroids or current pneumonitis/interstitial lung disease Has received a live vaccine within 4 weeks prior to the first dose of study medication Has a known hypersensitivity to the components of the trial treatment or another monoclonal antibody For Part B: Has a known sensitivity to any component of cisplatin, carboplatin, paclitaxel, or pemetrexed. For Part B: Is on chronic systemic steroids with the exception of use of bronchodilators, inhaled steroids, or local steroid injections For Part B cohort 1 and 2: Is unable to interrupt aspirin or other nonsteroidal ant-inflammatory drugs (NSAIDs), other than an aspirin dose ≤1.3 g per day, for a 5-day period (8-day period for long-acting agents, such as piroxicam). For Part B cohort 1 and 2: Is unable or unwilling to take folic acid or vitamin B12 supplementation Is Human Immunodeficiency Virus (HIV)-positive (HIV 1/2 antibodies) Has known history of or is positive for active Hepatitis B (Hepatitis B surface antigen reactive) or has active Hepatitis C (Hepatitis C virus ribonucleic acid) Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial Is pregnant or breastfeeding, or expecting to conceive or father children during the study through 120 days after the last dose of study medication Has received monoamine oxidase inhibitors (MAOIs) within the 3 weeks before the first dose of study medication Has any history of Serotonin Syndrome after receiving serotonergic drugs Has presence of a gastrointestinal condition that may affect drug absorption

Ages Eligible for Study
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Minimum Age: 20 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: Part A Cohort 1: epacadostat 25 mg<br>Participants received 25 mg of epacadostat orally twice daily (BID) alone on Days 1-5 of Cycle 1 (28-day cycle) with a washout on Days 6 and 7. On Day 8 participants received a one-time intravenous (IV) infusion of 200 mg pembrolizumab while continuing to receive 25 mg of epacadostat BID on Days 8-28. For each 21-day cycle thereafter, participants received a one-time IV infusion of 200 mg pembrolizumab on Day 1 and received 25 mg of epacadostat BID on Days 1-21 for up to 35 cycles (approximately 2 years). | Drug: Epacadostat 25 mg<br>* Oral administration<br>* Other names: INCB024360;Biological: pembrolizumab 200 mg<br>* Intravenous (IV) infusion<br>* Other names: KEYTRUDA®;|
| Experimental: Part A Cohort 1: epacadostat 100 mg<br>Participants received 100 mg of epacadostat orally BID alone on Days 1-5 of Cycle 1 (28-day cycle) with a washout on Days 6 and 7. On Day 8 participants received a one-time IV infusion of 200 mg pembrolizumab while continuing to receive 100 mg of epacadostat BID on Days 8-28. For each 21-day cycle thereafter, participants received a one-time IV infusion of 200 mg pembrolizumab on Day 1 and received 100 mg of epacadostat BID on Days 1-21 for up to 35 cycles (approximately 2 years). | Drug: Epacadostat 100 mg<br>* Oral administration<br>* Other names: INCB024360;Biological: pembrolizumab 200 mg<br>* Intravenous (IV) infusion<br>* Other names: KEYTRUDA®;|
| Experimental: Part A Cohort 2: epacadostat 25 mg+pembrolizumab<br>For each 21-day cycle, participants received a one-time IV infusion of 200 mg pembrolizumab on Day 1 and received 25 mg of epacadostat orally BID on Days 1-21 for up to 35 cycles (approximately 2 years). | Drug: Epacadostat 25 mg<br>* Oral administration<br>* Other names: INCB024360;Biological: pembrolizumab 200 mg<br>* Intravenous (IV) infusion<br>* Other names: KEYTRUDA®;|
| Experimental: Part A Cohort 2: epacadostat 100 mg+pembrolizumab<br>For each 21-day cycle, participants received a one-time IV infusion of 200 mg pembrolizumab on Day 1 and received 100 mg of epacadostat orally BID on Days 1-21 for up to 35 cycles (approximately 2 years). | Drug: Epacadostat 100 mg<br>* Oral administration<br>* Other names: INCB024360;Biological: pembrolizumab 200 mg<br>* Intravenous (IV) infusion<br>* Other names: KEYTRUDA®;|
| Experimental: Part B Cohort 1: pembrolizumab+cisplatin+pemetrexed<br>For each 21-day cycle, participants received a one-time IV infusion of 200 mg pembrolizumab on Day 1 and 100 mg of epacadostat orally BID on Days 1-21 for up to 35 cycles (approximately 2 years). For the first 4 cycles, participants also received a one-time IV infusion of 75 mg/m^2 cisplatin and 500 mg/m^2 pemetrexed on Day 1. Treatment with epacadostat was stopped with protocol amendment 02. | Drug: Epacadostat 100 mg<br>* Oral administration<br>* Other names: INCB024360;Biological: pembrolizumab 200 mg<br>* Intravenous (IV) infusion<br>* Other names: KEYTRUDA®;Drug: Cisplatin 75 mg/m^2<br>* IV infusion<br>* Other names: Platinol-AQ®;Drug: Pemetrexed 500 mg/m^2<br>* IV infusion<br>* Other names: Alimta®;|
| Experimental: Part B Cohort 2: pembrolizumab+carboplatin+pemetrexed<br>For each 21-day cycle, participants received a one-time IV infusion of 200 mg pembrolizumab on Day 1 and 100 mg of epacadostat orally BID on Days 1-21 for up to 35 cycles (approximately 2 years). For the first 4 cycles, participants also received a one-time IV infusion of Area Under the Curve (AUC) 5 carboplatin and 500 mg/m^2 pemetrexed on Day 1. Treatment with epacadostat was stopped with protocol amendment 02. | Drug: Epacadostat 100 mg<br>* Oral administration<br>* Other names: INCB024360;Biological: pembrolizumab 200 mg<br>* Intravenous (IV) infusion<br>* Other names: KEYTRUDA®;Drug: Carboplatin Area Under the Curve (AUC) 5<br>* IV infusion<br>* Other names: Paraplatin®;Drug: Pemetrexed 500 mg/m^2<br>* IV infusion<br>* Other names: Alimta®;|
| Experimental: Part B Cohort 3: pembrolizumab+carboplatin+paclitaxel<br>For each 21-day cycle, participants received a one-time IV infusion of 200 mg pembrolizumab on Day 1 and 100 mg of epacadostat orally BID on Days 1-21 for up to 35 cycles (approximately 2 years). For the first 4 cycles, participants also received a one-time IV infusion of AUC 6 carboplatin and 200 mg/m^2 paclitaxel on Day 1. Treatment with epacadostat was stopped with protocol amendment 02. | Drug: Epacadostat 100 mg<br>* Oral administration<br>* Other names: INCB024360;Biological: pembrolizumab 200 mg<br>* Intravenous (IV) infusion<br>* Other names: KEYTRUDA®;Drug: Paclitaxel 200 mg/m^2<br>* IV infusion<br>* Other names: Onxol®;Drug: Carboplatin AUC 6<br>* IV infusion<br>* Other names: Paraplatin®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing Dose-Limiting Toxicities (DLTs) According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v.4.0) | A DLT was defined as the occurrence of any treatment-emergent adverse event occurring up to and including Study Day 7 for Part A Cohort 1 or Day 21 for Part A Cohort 2 and Part B. The following criteria defined DLTs: Grade (G) 4 thrombocytopenia; G4 neutropenia (despite optimal supportive care in Part B) lasting >1 week; febrile neutropenia (only if considered clinically significant in Part B); G4 toxicity; G3 laboratory abnormality lasting >1 week: G3 toxicity excluding nausea or vomiting controlled within 72 hours, rash in the absence of desquamation, no mucosal involvement, does not require systemic steroids, and resolves to G1 by the next scheduled dose of pembrolizumab or 14 days; G2 or higher episcleritis, uveitis, or iritis; unable to receive 75% of epacadostat or 1 dose of pembrolizumab during the DLT observation period because of toxicity, even if the toxicity does not meet DLT criteria; or >2 week delay in initiating Cycle 2 due to toxicity. | Up to Day 7 for Part A Cohort 1; up to Day 21 for Part A Cohort 2 and Part B | 
| Number of Participants Who Experienced At Least One Adverse Event (AE) | An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event. The number of participants who experienced an AE was reported for each arm. | Up to approximately 39.7 months | 
| Number of Participants Who Discontinued Study Treatment Due to An Adverse Event (AE) | An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event. The number of participants who discontinued due to an AE was reported for each arm. | Up to approximately 38.5 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Concentration (Cmax) of Epacadostat in Part A | Cmax was the maximum observed concentration of epacadostat in plasma for epacadostat administered alone (Cohort 1) and epacadostat administered with pembrolizumab (Cohort 2). Per protocol, Cmax for Cohort 1 was measured on Days 1, 5, and 12 and Cmax for Cohort 2 was measured on Day 5 only. Blood samples were collected pre-dose and post-dose at multiple time points up to 12 days during Cycle 1 (28-day cycle). Cmax is presented as a geometric mean with a percent geometric coefficient of variation. | Cycle 1 (28-day cycle): Days 1, 5, and 12 at predose and 0.5, 1, 2, 4, 6, 8 and 10 hours postdose | 
| Time to Maximum Concentration (Tmax) of Epacadostat in Part A | Tmax was the time required to reach the maximum concentration of epacadostat in plasma for epacadostat administered alone (Cohort 1) and epacadostat administered with pembrolizumab (Cohort 2). Per protocol, Tmax for Cohort 1 was measured on Days 1, 5, and 12 and Tmax for Cohort 2 was measured on Day 5 only. Blood samples were collected pre-dose and post-dose at multiple time points up to 12 days during Cycle 1 (28-day cycle). Tmax is presented as a Median with a full range. | Cycle 1 (28-day cycle): Days 1, 5, and 12 at predose and 0.5, 1, 2, 4, 6, 8 and 10 hours postdose | 
| Area Under the Concentration-Time Curve From Zero to the Time of the Last Measurable Concentration (AUC0-t) of Epacadostat in Part A | AUC0-t was defined as the AUC from zero to the time of the last measurable concentration of epacadostat in plasma for epacadostat administered alone (Cohort 1) and epacadostat administered with pembrolizumab (Cohort 2). Per protocol, AUC0-t for Cohort 1 was measured on Days 1, 5, and 12 and AUC0-t for Cohort 2 was measured on Day 5 only. Blood samples were collected pre-dose and post-dose at multiple time points up to 12 days during Cycle 1 (28-day cycle). AUC0-t is presented as a geometric mean with a percent geometric coefficient of variation. | Cycle 1 (28-day cycle): Days 1, 5, and 12 at predose and 0.5, 1, 2, 4, 6, 8 and 10 hours postdose | 
| Trough Concentration (Ctrough) of Epacadostat in Part A | Ctrough was the lowest concentration of epacadostat in plasma just before the next dose for epacadostat administered alone (Cohort 1) and epacadostat administered with pembrolizumab (Cohort 2). Per protocol, Ctrough for Cohort 1 was measured on Days 1, 5, and 12 and Ctrough for Cohort 2 was measured on Day 5 only. Blood samples were collected pre-dose at multiple time points up to 12 days during Cycle 1 (28-day cycle). Ctrough is presented as a geometric mean with a percent geometric coefficient of variation. | Cycle 1 (28-day cycle): Days 1, 5, and 12 at predose | 
| Terminal Half-Life (t1/2) of Epacadostat in Part A | t1/2 was the time required to divide the epacadostat concentration by two after reaching pseudo-equilibrium. Plasma t1/2 was measured for epacadostat administered alone (Cohort 1) and epacadostat administered with pembrolizumab (Cohort 2). Per protocol, t1/2 for Cohort 1 was measured on Days 1, 5, and 12 and t1/2 for Cohort 2 was measured on Day 5 only. Blood samples were collected pre-dose and post-dose at multiple time points up to 12 days during Cycle 1 (28-day cycle). t1/2 is presented as a geometric mean with a percent geometric coefficient of variation. | Cycle 1 (28-day cycle): Days 1, 5, and 12 at predose and 0.5, 1, 2, 4, 6, 8 and 10 hours postdose | 
| Maximum Concentration (Cmax) of Pembrolizumab in Part A Cycle 1 | Cmax was the maximum observed concentration of pembrolizumab in serum for participants that received either dose regimen in Part A for Cohort 1 combined, Cohort 2 combined, and Cohorts 1+2 combined. Per protocol, the analysis for the Cmax of pembrolizumab was performed in Cycle 1 only. Blood samples were collected predose and postdose within 30 minutes post pembrolizumab infusion during Cycle 1 (21-day pembrolizumab treatment cycle starting at Day 8 of Cycle 1). Cmax is presented as a geometric mean with a percent geometric coefficient of variation. | Cycle 1 (21-day pembrolizumab treatment cycle starting at Day 8 of Cycle 1): Day 1 predose and postdose within 30 minutes after the end of pembrolizumab infusion | 
| Maximum Concentration (Cmax) of Pembrolizumab in Part B Cycle 1 | Cmax was the maximum observed concentration of pembrolizumab in serum for participants that received either dose regimen in Part B for Cohort 1, Cohort 2, Cohort 3, and Cohorts 1+2+ 3 combined. Per protocol, the analysis for the Cmax of pembrolizumab was performed in Cycle 1 only. Blood samples were collected predose and postdose within 30 minutes post pembrolizumab infusion during Cycle 1 (21-day pembrolizumab treatment cycle starting at Day 8 of Cycle 1). Cmax is presented as a geometric mean with a percent geometric coefficient of variation. | Cycle 1 (21-day pembrolizumab treatment cycle starting at Day 8 of Cycle 1): Day 1 predose and postdose within 30 minutes after the end of pembrolizumab infusion | 
| Trough Concentration (Ctrough) of Pembrolizumab in Part A Cycles 1, 2, 4, 6, and 8 | Ctrough was the lowest concentration of pembrolizumab in serum just before the next dose for participants that received either dose regimen in Part A for Cohort 1 combined, Cohort 2 combined, and Cohorts 1+2 combined. Per protocol, blood sampling for Ctrough was taken at predose prior to the Cycle 1, 2, 4, 6, and 8 infusion. Cycle 1 length was 28 days (21-day pembrolizumab treatment cycle starting at Day 8 of Cycle 1). Cycle 2, 4, 6, and 8 length was 21 days. Ctrough is presented as a geometric mean with a percent geometric coefficient of variation. | Predose prior to the Cycles 1, 2, 4, 6, and 8 infusion | 
| Trough Concentration (Ctrough) of Pembrolizumab in Part B Cycles 1, 2, 4, 6, and 8 | Ctrough was the lowest concentration of pembrolizumab in serum just before the next dose for participants that received either dose regimen in Part B for Cohort 1, Cohort 2, Cohort 3, and Cohorts 1+2+3 combined. Per protocol, blood sampling for Ctrough was taken at pre-dose prior to the Cycle 1, 2, 4, 6, and 8 infusion. Cycle 1 length was 28 days (21-day pembrolizumab treatment cycle starting at Day 8 of Cycle 1). Cycle 2, 4, 6, and 8 length was 21 days. Ctrough is presented as a geometric mean with a percent geometric coefficient of variation. | Predose prior to the Cycles 1, 2, 4, 6, and 8 infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PDL1, Advanced Solid Tumors, PD-1, PD1, Programmed Cell Death-1, Programmed Cell Death 1, Programmed Cell Death-Ligand 1 (PD-L1), Programmed Cell Death-Ligand 2 (PD-L2), PDL2