Neoplasms, Carcinoma, Non-Small-Cell Lung
Conditions
Keywords
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), PDL1, PDL2
Brief summary
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.
Interventions
DRUGEpacadostat 25 mg
Oral administration
DRUGEpacadostat 100 mg
Oral administration
BIOLOGICALpembrolizumab 200 mg
Intravenous (IV) infusion
IV infusion
DRUGCarboplatin Area Under the Curve (AUC) 5
IV infusion
IV infusion
IV infusion
IV infusion
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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) | Up to Day 7 for Part A Cohort 1; up to Day 21 for Part A Cohort 2 and Part B | 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. |
| Number of Participants Who Experienced At Least One Adverse Event (AE) | Up to approximately 39.7 months | 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. |
| Number of Participants Who Discontinued Study Treatment Due to An Adverse Event (AE) | Up to approximately 38.5 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Trough Concentration (Ctrough) of Epacadostat in Part A | Cycle 1 (28-day cycle): Days 1, 5, and 12 at predose | 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. |
| Terminal Half-Life (t1/2) of Epacadostat in Part A | Cycle 1 (28-day cycle): Days 1, 5, and 12 at predose and 0.5, 1, 2, 4, 6, 8 and 10 hours postdose | 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. |
| Maximum Concentration (Cmax) of Pembrolizumab in Part A Cycle 1 | 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 | 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. |
| Maximum Concentration (Cmax) of Epacadostat in Part A | Cycle 1 (28-day cycle): Days 1, 5, and 12 at predose and 0.5, 1, 2, 4, 6, 8 and 10 hours postdose | 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. |
| Trough Concentration (Ctrough) of Pembrolizumab in Part A Cycles 1, 2, 4, 6, and 8 | Predose prior to the Cycles 1, 2, 4, 6, and 8 infusion | 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. |
| Trough Concentration (Ctrough) of Pembrolizumab in Part B Cycles 1, 2, 4, 6, and 8 | Predose prior to the Cycles 1, 2, 4, 6, and 8 infusion | 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. |
| Maximum Concentration (Cmax) of Pembrolizumab in Part B Cycle 1 | 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 | 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. |
| Time to Maximum Concentration (Tmax) of Epacadostat in Part A | Cycle 1 (28-day cycle): Days 1, 5, and 12 at predose and 0.5, 1, 2, 4, 6, 8 and 10 hours postdose | 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. |
| Area Under the Concentration-Time Curve From Zero to the Time of the Last Measurable Concentration (AUC0-t) of Epacadostat in Part A | Cycle 1 (28-day cycle): Days 1, 5, and 12 at predose and 0.5, 1, 2, 4, 6, 8 and 10 hours postdose | 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. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Part A Cohort 1: Epacadostat 25 mg 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). | 3 |
| Part A Cohort 1: Epacadostat 100 mg 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). | 3 |
| Part A Cohort 2: Epacadostat 25 mg+Pembrolizumab 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). | 3 |
| Part A Cohort 2: Epacadostat 100 mg+Pembrolizumab 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). | 6 |
| Part B Cohort 1: Pembrolizumab+Cisplatin+Pemetrexed 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. | 7 |
| Part B Cohort 2: Pembrolizumab+Carboplatin+Pemetrexed 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. | 6 |
| Part B Cohort 3: Pembrolizumab+Carboplatin+Paclitaxel 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. | 6 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Death | 1 | 3 | 2 | 3 | 0 | 2 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Part A Cohort 1: Epacadostat 25 mg | Part A Cohort 1: Epacadostat 100 mg | Part A Cohort 2: Epacadostat 25 mg+Pembrolizumab | Part A Cohort 2: Epacadostat 100 mg+Pembrolizumab | Part B Cohort 1: Pembrolizumab+Cisplatin+Pemetrexed | Part B Cohort 2: Pembrolizumab+Carboplatin+Pemetrexed | Part B Cohort 3: Pembrolizumab+Carboplatin+Paclitaxel | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 63.7 years STANDARD_DEVIATION 7.8 | 71.0 years STANDARD_DEVIATION 4.6 | 62.0 years STANDARD_DEVIATION 12.2 | 67.5 years STANDARD_DEVIATION 3.2 | 57.9 years STANDARD_DEVIATION 7.3 | 68.0 years STANDARD_DEVIATION 3.8 | 61.0 years STANDARD_DEVIATION 13.4 | 63.9 years STANDARD_DEVIATION 8.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 3 Participants | 3 Participants | 6 Participants | 7 Participants | 6 Participants | 6 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 3 Participants | 3 Participants | 6 Participants | 7 Participants | 6 Participants | 6 Participants | 34 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 2 Participants | 1 Participants | 1 Participants | 3 Participants | 1 Participants | 12 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 1 Participants | 5 Participants | 6 Participants | 3 Participants | 5 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 3 / 3 | 2 / 3 | 3 / 6 | 0 / 7 | 2 / 6 | 1 / 6 |
| other Total, other adverse events | 3 / 3 | 2 / 3 | 3 / 3 | 6 / 6 | 7 / 7 | 6 / 6 | 6 / 6 |
| serious Total, serious adverse events | 0 / 3 | 2 / 3 | 2 / 3 | 1 / 6 | 1 / 7 | 2 / 6 | 2 / 6 |
Outcome results
Primary
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.
Time frame: Up to Day 7 for Part A Cohort 1; up to Day 21 for Part A Cohort 2 and Part B
Population: All participants in Parts A and B who received ≥1 dose of study treatment and who completed all safety evaluations in the pre-specified time frame for DLT analysis
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A Cohort 1: Epacadostat 25 mg | 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) | 0 Participants |
| Part A Cohort 1: Epacadostat 100 mg | 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) | 0 Participants |
| Part A Cohort 2: Epacadostat 25 mg+Pembrolizumab | 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) | 0 Participants |
| Part A Cohort 2: Epacadostat 100 mg+Pembrolizumab | 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) | 1 Participants |
| Part B Cohort 1: Pembrolizumab+Cisplatin+Pemetrexed | 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) | 1 Participants |
| Part B Cohort 2: Pembrolizumab+Carboplatin+Pemetrexed | 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) | 2 Participants |
| Part B Cohort 3: Pembrolizumab+Carboplatin+Paclitaxel | 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) | 2 Participants |
Primary
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.
Time frame: Up to approximately 38.5 months
Population: All participants who received ≥1 dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A Cohort 1: Epacadostat 25 mg | Number of Participants Who Discontinued Study Treatment Due to An Adverse Event (AE) | 0 Participants |
| Part A Cohort 1: Epacadostat 100 mg | Number of Participants Who Discontinued Study Treatment Due to An Adverse Event (AE) | 1 Participants |
| Part A Cohort 2: Epacadostat 25 mg+Pembrolizumab | Number of Participants Who Discontinued Study Treatment Due to An Adverse Event (AE) | 0 Participants |
| Part A Cohort 2: Epacadostat 100 mg+Pembrolizumab | Number of Participants Who Discontinued Study Treatment Due to An Adverse Event (AE) | 1 Participants |
| Part B Cohort 1: Pembrolizumab+Cisplatin+Pemetrexed | Number of Participants Who Discontinued Study Treatment Due to An Adverse Event (AE) | 0 Participants |
| Part B Cohort 2: Pembrolizumab+Carboplatin+Pemetrexed | Number of Participants Who Discontinued Study Treatment Due to An Adverse Event (AE) | 3 Participants |
| Part B Cohort 3: Pembrolizumab+Carboplatin+Paclitaxel | Number of Participants Who Discontinued Study Treatment Due to An Adverse Event (AE) | 3 Participants |
Primary
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.
Time frame: Up to approximately 39.7 months
Population: All participants who received ≥1 dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A Cohort 1: Epacadostat 25 mg | Number of Participants Who Experienced At Least One Adverse Event (AE) | 3 Participants |
| Part A Cohort 1: Epacadostat 100 mg | Number of Participants Who Experienced At Least One Adverse Event (AE) | 2 Participants |
| Part A Cohort 2: Epacadostat 25 mg+Pembrolizumab | Number of Participants Who Experienced At Least One Adverse Event (AE) | 3 Participants |
| Part A Cohort 2: Epacadostat 100 mg+Pembrolizumab | Number of Participants Who Experienced At Least One Adverse Event (AE) | 6 Participants |
| Part B Cohort 1: Pembrolizumab+Cisplatin+Pemetrexed | Number of Participants Who Experienced At Least One Adverse Event (AE) | 7 Participants |
| Part B Cohort 2: Pembrolizumab+Carboplatin+Pemetrexed | Number of Participants Who Experienced At Least One Adverse Event (AE) | 6 Participants |
| Part B Cohort 3: Pembrolizumab+Carboplatin+Paclitaxel | Number of Participants Who Experienced At Least One Adverse Event (AE) | 6 Participants |
Secondary
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.
Time frame: Cycle 1 (28-day cycle): Days 1, 5, and 12 at predose and 0.5, 1, 2, 4, 6, 8 and 10 hours postdose
Population: The analysis population consisted of all participants in Part A that contributed blood samples for analysis of AUC 0-t. Per protocol, AUC0-t was only measured on Day 5 for Part A Cohort 2.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A Cohort 1: Epacadostat 25 mg | Area Under the Concentration-Time Curve From Zero to the Time of the Last Measurable Concentration (AUC0-t) of Epacadostat in Part A | Day 5 | 1060 nM•hour | Geometric Coefficient of Variation 24 |
| Part A Cohort 1: Epacadostat 25 mg | Area Under the Concentration-Time Curve From Zero to the Time of the Last Measurable Concentration (AUC0-t) of Epacadostat in Part A | Day 1 | 855 nM•hour | Geometric Coefficient of Variation 13 |
| Part A Cohort 1: Epacadostat 25 mg | Area Under the Concentration-Time Curve From Zero to the Time of the Last Measurable Concentration (AUC0-t) of Epacadostat in Part A | Day 12 | 1020 nM•hour | Geometric Coefficient of Variation 27.3 |
| Part A Cohort 1: Epacadostat 100 mg | Area Under the Concentration-Time Curve From Zero to the Time of the Last Measurable Concentration (AUC0-t) of Epacadostat in Part A | Day 12 | 4710 nM•hour | Geometric Coefficient of Variation 17.9 |
| Part A Cohort 1: Epacadostat 100 mg | Area Under the Concentration-Time Curve From Zero to the Time of the Last Measurable Concentration (AUC0-t) of Epacadostat in Part A | Day 1 | 4250 nM•hour | Geometric Coefficient of Variation 7.1 |
| Part A Cohort 1: Epacadostat 100 mg | Area Under the Concentration-Time Curve From Zero to the Time of the Last Measurable Concentration (AUC0-t) of Epacadostat in Part A | Day 5 | 4670 nM•hour | Geometric Coefficient of Variation 22.7 |
| Part A Cohort 2: Epacadostat 25 mg+Pembrolizumab | Area Under the Concentration-Time Curve From Zero to the Time of the Last Measurable Concentration (AUC0-t) of Epacadostat in Part A | Day 5 | 1260 nM•hour | Geometric Coefficient of Variation 8.8 |
| Part A Cohort 2: Epacadostat 100 mg+Pembrolizumab | Area Under the Concentration-Time Curve From Zero to the Time of the Last Measurable Concentration (AUC0-t) of Epacadostat in Part A | Day 5 | 3950 nM•hour | Geometric Coefficient of Variation 38.8 |
Secondary
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.
Time frame: Cycle 1 (28-day cycle): Days 1, 5, and 12 at predose and 0.5, 1, 2, 4, 6, 8 and 10 hours postdose
Population: The analysis population consisted of all participants in Part A that contributed blood samples for analysis of Cmax. Per protocol, Cmax was only measured on Day 5 for Part A Cohort 2.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A Cohort 1: Epacadostat 25 mg | Maximum Concentration (Cmax) of Epacadostat in Part A | Day 5 | 269 nM | Geometric Coefficient of Variation 19.3 |
| Part A Cohort 1: Epacadostat 25 mg | Maximum Concentration (Cmax) of Epacadostat in Part A | Day 1 | 327 nM | Geometric Coefficient of Variation 15.9 |
| Part A Cohort 1: Epacadostat 25 mg | Maximum Concentration (Cmax) of Epacadostat in Part A | Day 12 | 294 nM | Geometric Coefficient of Variation 43.8 |
| Part A Cohort 1: Epacadostat 100 mg | Maximum Concentration (Cmax) of Epacadostat in Part A | Day 12 | 1200 nM | Geometric Coefficient of Variation 27 |
| Part A Cohort 1: Epacadostat 100 mg | Maximum Concentration (Cmax) of Epacadostat in Part A | Day 1 | 1060 nM | Geometric Coefficient of Variation 19.7 |
| Part A Cohort 1: Epacadostat 100 mg | Maximum Concentration (Cmax) of Epacadostat in Part A | Day 5 | 1100 nM | Geometric Coefficient of Variation 36.8 |
| Part A Cohort 2: Epacadostat 25 mg+Pembrolizumab | Maximum Concentration (Cmax) of Epacadostat in Part A | Day 5 | 371 nM | Geometric Coefficient of Variation 10.7 |
| Part A Cohort 2: Epacadostat 100 mg+Pembrolizumab | Maximum Concentration (Cmax) of Epacadostat in Part A | Day 5 | 852 nM | Geometric Coefficient of Variation 74 |
Secondary
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.
Time frame: 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
Population: The analysis population consisted of all participants in Part A that contributed blood samples for analysis of Cmax. Per protocol, the Cmax of pembrolizumab for Part A was planned to be measured using data combined for Cohort 1 and Cohort 2 for the 200 mg pembrolizumab dose regimen irrespective of epacadostat dose received.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A Cohort 1: Epacadostat 25 mg | Maximum Concentration (Cmax) of Pembrolizumab in Part A Cycle 1 | 80.0 µg/mL | Geometric Coefficient of Variation 12.3 |
| Part A Cohort 1: Epacadostat 100 mg | Maximum Concentration (Cmax) of Pembrolizumab in Part A Cycle 1 | 73.8 µg/mL | Geometric Coefficient of Variation 25.7 |
| Part A Cohort 2: Epacadostat 25 mg+Pembrolizumab | Maximum Concentration (Cmax) of Pembrolizumab in Part A Cycle 1 | 76.2 µg/mL | Geometric Coefficient of Variation 21.1 |
Secondary
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.
Time frame: 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
Population: The analysis population consisted of all participants in Part B that contributed blood samples for analysis of Cmax.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A Cohort 1: Epacadostat 25 mg | Maximum Concentration (Cmax) of Pembrolizumab in Part B Cycle 1 | 73.8 µg/mL | Geometric Coefficient of Variation 25 |
| Part A Cohort 1: Epacadostat 100 mg | Maximum Concentration (Cmax) of Pembrolizumab in Part B Cycle 1 | 64.3 µg/mL | Geometric Coefficient of Variation 32.1 |
| Part A Cohort 2: Epacadostat 25 mg+Pembrolizumab | Maximum Concentration (Cmax) of Pembrolizumab in Part B Cycle 1 | 65.3 µg/mL | Geometric Coefficient of Variation 22.4 |
| Part A Cohort 2: Epacadostat 100 mg+Pembrolizumab | Maximum Concentration (Cmax) of Pembrolizumab in Part B Cycle 1 | 68.0 µg/mL | Geometric Coefficient of Variation 26 |
Secondary
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.
Time frame: Cycle 1 (28-day cycle): Days 1, 5, and 12 at predose and 0.5, 1, 2, 4, 6, 8 and 10 hours postdose
Population: The analysis population consisted of all participants in Part A that contributed blood samples for analysis of t1/2. Per protocol, t1/2 was only measured on Day 5 for Part A Cohort 2.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A Cohort 1: Epacadostat 25 mg | Terminal Half-Life (t1/2) of Epacadostat in Part A | Day 5 | 3.01 hours | Geometric Coefficient of Variation 70.6 |
| Part A Cohort 1: Epacadostat 25 mg | Terminal Half-Life (t1/2) of Epacadostat in Part A | Day 1 | 3.94 hours | — |
| Part A Cohort 1: Epacadostat 25 mg | Terminal Half-Life (t1/2) of Epacadostat in Part A | Day 12 | 4.27 hours | Geometric Coefficient of Variation 86 |
| Part A Cohort 1: Epacadostat 100 mg | Terminal Half-Life (t1/2) of Epacadostat in Part A | Day 12 | 2.43 hours | Geometric Coefficient of Variation 16.1 |
| Part A Cohort 1: Epacadostat 100 mg | Terminal Half-Life (t1/2) of Epacadostat in Part A | Day 1 | 2.55 hours | Geometric Coefficient of Variation 40.9 |
| Part A Cohort 1: Epacadostat 100 mg | Terminal Half-Life (t1/2) of Epacadostat in Part A | Day 5 | 2.82 hours | Geometric Coefficient of Variation 45.1 |
| Part A Cohort 2: Epacadostat 25 mg+Pembrolizumab | Terminal Half-Life (t1/2) of Epacadostat in Part A | Day 5 | 2.62 hours | Geometric Coefficient of Variation 9.7 |
| Part A Cohort 2: Epacadostat 100 mg+Pembrolizumab | Terminal Half-Life (t1/2) of Epacadostat in Part A | Day 5 | 3.77 hours | Geometric Coefficient of Variation 21.9 |
Secondary
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.
Time frame: Cycle 1 (28-day cycle): Days 1, 5, and 12 at predose and 0.5, 1, 2, 4, 6, 8 and 10 hours postdose
Population: The analysis population consisted of all participants in Part A that contributed blood samples for analysis of Tmax. Per protocol, Tmax was only measured on Day 5 for Part A Cohort 2.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part A Cohort 1: Epacadostat 25 mg | Time to Maximum Concentration (Tmax) of Epacadostat in Part A | Day 5 | 2.00 hours |
| Part A Cohort 1: Epacadostat 25 mg | Time to Maximum Concentration (Tmax) of Epacadostat in Part A | Day 1 | 2.00 hours |
| Part A Cohort 1: Epacadostat 25 mg | Time to Maximum Concentration (Tmax) of Epacadostat in Part A | Day 12 | 2.00 hours |
| Part A Cohort 1: Epacadostat 100 mg | Time to Maximum Concentration (Tmax) of Epacadostat in Part A | Day 12 | 2.00 hours |
| Part A Cohort 1: Epacadostat 100 mg | Time to Maximum Concentration (Tmax) of Epacadostat in Part A | Day 1 | 2.00 hours |
| Part A Cohort 1: Epacadostat 100 mg | Time to Maximum Concentration (Tmax) of Epacadostat in Part A | Day 5 | 2.00 hours |
| Part A Cohort 2: Epacadostat 25 mg+Pembrolizumab | Time to Maximum Concentration (Tmax) of Epacadostat in Part A | Day 5 | 2.00 hours |
| Part A Cohort 2: Epacadostat 100 mg+Pembrolizumab | Time to Maximum Concentration (Tmax) of Epacadostat in Part A | Day 5 | 2.00 hours |
Secondary
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.
Time frame: Cycle 1 (28-day cycle): Days 1, 5, and 12 at predose
Population: The analysis population consisted of all participants in Part A that contributed blood samples for analysis of Ctrough. Per protocol, Ctrough was only measured on Day 5 for Part A Cohort 2.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A Cohort 1: Epacadostat 25 mg | Trough Concentration (Ctrough) of Epacadostat in Part A | Day 5 | NA nM | — |
| Part A Cohort 1: Epacadostat 25 mg | Trough Concentration (Ctrough) of Epacadostat in Part A | Day 1 | NA nM | — |
| Part A Cohort 1: Epacadostat 25 mg | Trough Concentration (Ctrough) of Epacadostat in Part A | Day 12 | NA nM | — |
| Part A Cohort 1: Epacadostat 100 mg | Trough Concentration (Ctrough) of Epacadostat in Part A | Day 12 | 95.4 nM | Geometric Coefficient of Variation 31.8 |
| Part A Cohort 1: Epacadostat 100 mg | Trough Concentration (Ctrough) of Epacadostat in Part A | Day 1 | NA nM | — |
| Part A Cohort 1: Epacadostat 100 mg | Trough Concentration (Ctrough) of Epacadostat in Part A | Day 5 | 87.7 nM | Geometric Coefficient of Variation 21.7 |
| Part A Cohort 2: Epacadostat 25 mg+Pembrolizumab | Trough Concentration (Ctrough) of Epacadostat in Part A | Day 5 | NA nM | — |
| Part A Cohort 2: Epacadostat 100 mg+Pembrolizumab | Trough Concentration (Ctrough) of Epacadostat in Part A | Day 5 | 106.0 nM | Geometric Coefficient of Variation 64.1 |
Secondary
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.
Time frame: Predose prior to the Cycles 1, 2, 4, 6, and 8 infusion
Population: The analysis population consisted of all participants in Part A that contributed blood samples for analysis of Ctrough. Per protocol, the Ctrough of pembrolizumab for Part A was planned to be measured using data combined for Cohort 1 and Cohort 2 for the 200 mg pembrolizumab dose regimen irrespective of epacadostat dose received.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A Cohort 1: Epacadostat 25 mg | Trough Concentration (Ctrough) of Pembrolizumab in Part A Cycles 1, 2, 4, 6, and 8 | Cycle 6 | 28.5 µg/mL | Geometric Coefficient of Variation 25.3 |
| Part A Cohort 1: Epacadostat 25 mg | Trough Concentration (Ctrough) of Pembrolizumab in Part A Cycles 1, 2, 4, 6, and 8 | Cycle 4 | 24.5 µg/mL | Geometric Coefficient of Variation 31.3 |
| Part A Cohort 1: Epacadostat 25 mg | Trough Concentration (Ctrough) of Pembrolizumab in Part A Cycles 1, 2, 4, 6, and 8 | Cycle 1 | NA µg/mL | — |
| Part A Cohort 1: Epacadostat 25 mg | Trough Concentration (Ctrough) of Pembrolizumab in Part A Cycles 1, 2, 4, 6, and 8 | Cycle 2 | 17.3 µg/mL | Geometric Coefficient of Variation 26.6 |
| Part A Cohort 1: Epacadostat 25 mg | Trough Concentration (Ctrough) of Pembrolizumab in Part A Cycles 1, 2, 4, 6, and 8 | Cycle 8 | 38.2 µg/mL | — |
| Part A Cohort 1: Epacadostat 100 mg | Trough Concentration (Ctrough) of Pembrolizumab in Part A Cycles 1, 2, 4, 6, and 8 | Cycle 4 | 41.8 µg/mL | Geometric Coefficient of Variation 21.1 |
| Part A Cohort 1: Epacadostat 100 mg | Trough Concentration (Ctrough) of Pembrolizumab in Part A Cycles 1, 2, 4, 6, and 8 | Cycle 1 | NA µg/mL | — |
| Part A Cohort 1: Epacadostat 100 mg | Trough Concentration (Ctrough) of Pembrolizumab in Part A Cycles 1, 2, 4, 6, and 8 | Cycle 2 | 17.9 µg/mL | Geometric Coefficient of Variation 33.5 |
| Part A Cohort 1: Epacadostat 100 mg | Trough Concentration (Ctrough) of Pembrolizumab in Part A Cycles 1, 2, 4, 6, and 8 | Cycle 6 | 51.0 µg/mL | Geometric Coefficient of Variation 17.4 |
| Part A Cohort 1: Epacadostat 100 mg | Trough Concentration (Ctrough) of Pembrolizumab in Part A Cycles 1, 2, 4, 6, and 8 | Cycle 8 | 47.9 µg/mL | Geometric Coefficient of Variation 13.9 |
| Part A Cohort 2: Epacadostat 25 mg+Pembrolizumab | Trough Concentration (Ctrough) of Pembrolizumab in Part A Cycles 1, 2, 4, 6, and 8 | Cycle 8 | 45.2 µg/mL | Geometric Coefficient of Variation 16.1 |
| Part A Cohort 2: Epacadostat 25 mg+Pembrolizumab | Trough Concentration (Ctrough) of Pembrolizumab in Part A Cycles 1, 2, 4, 6, and 8 | Cycle 6 | 39.8 µg/mL | Geometric Coefficient of Variation 37.5 |
| Part A Cohort 2: Epacadostat 25 mg+Pembrolizumab | Trough Concentration (Ctrough) of Pembrolizumab in Part A Cycles 1, 2, 4, 6, and 8 | Cycle 1 | NA µg/mL | — |
| Part A Cohort 2: Epacadostat 25 mg+Pembrolizumab | Trough Concentration (Ctrough) of Pembrolizumab in Part A Cycles 1, 2, 4, 6, and 8 | Cycle 4 | 35.0 µg/mL | Geometric Coefficient of Variation 36 |
| Part A Cohort 2: Epacadostat 25 mg+Pembrolizumab | Trough Concentration (Ctrough) of Pembrolizumab in Part A Cycles 1, 2, 4, 6, and 8 | Cycle 2 | 17.6 µg/mL | Geometric Coefficient of Variation 29.6 |
Secondary
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.
Time frame: Predose prior to the Cycles 1, 2, 4, 6, and 8 infusion
Population: The analysis population consisted of all participants in Part B that contributed blood samples for analysis of Ctrough.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A Cohort 1: Epacadostat 25 mg | Trough Concentration (Ctrough) of Pembrolizumab in Part B Cycles 1, 2, 4, 6, and 8 | Cycle 6 | 53.8 µg/mL | Geometric Coefficient of Variation 29.5 |
| Part A Cohort 1: Epacadostat 25 mg | Trough Concentration (Ctrough) of Pembrolizumab in Part B Cycles 1, 2, 4, 6, and 8 | Cycle 2 | 16.6 µg/mL | Geometric Coefficient of Variation 27.6 |
| Part A Cohort 1: Epacadostat 25 mg | Trough Concentration (Ctrough) of Pembrolizumab in Part B Cycles 1, 2, 4, 6, and 8 | Cycle 8 | 65.4 µg/mL | Geometric Coefficient of Variation 18.6 |
| Part A Cohort 1: Epacadostat 25 mg | Trough Concentration (Ctrough) of Pembrolizumab in Part B Cycles 1, 2, 4, 6, and 8 | Cycle 4 | 37.8 µg/mL | Geometric Coefficient of Variation 20.2 |
| Part A Cohort 1: Epacadostat 25 mg | Trough Concentration (Ctrough) of Pembrolizumab in Part B Cycles 1, 2, 4, 6, and 8 | Cycle 1 | NA µg/mL | — |
| Part A Cohort 1: Epacadostat 100 mg | Trough Concentration (Ctrough) of Pembrolizumab in Part B Cycles 1, 2, 4, 6, and 8 | Cycle 4 | 28.1 µg/mL | — |
| Part A Cohort 1: Epacadostat 100 mg | Trough Concentration (Ctrough) of Pembrolizumab in Part B Cycles 1, 2, 4, 6, and 8 | Cycle 6 | 40.5 µg/mL | — |
| Part A Cohort 1: Epacadostat 100 mg | Trough Concentration (Ctrough) of Pembrolizumab in Part B Cycles 1, 2, 4, 6, and 8 | Cycle 8 | 52.7 µg/mL | — |
| Part A Cohort 1: Epacadostat 100 mg | Trough Concentration (Ctrough) of Pembrolizumab in Part B Cycles 1, 2, 4, 6, and 8 | Cycle 2 | 17.4 µg/mL | Geometric Coefficient of Variation 36.6 |
| Part A Cohort 1: Epacadostat 100 mg | Trough Concentration (Ctrough) of Pembrolizumab in Part B Cycles 1, 2, 4, 6, and 8 | Cycle 1 | NA µg/mL | — |
| Part A Cohort 2: Epacadostat 25 mg+Pembrolizumab | Trough Concentration (Ctrough) of Pembrolizumab in Part B Cycles 1, 2, 4, 6, and 8 | Cycle 4 | 25.4 µg/mL | Geometric Coefficient of Variation 25.7 |
| Part A Cohort 2: Epacadostat 25 mg+Pembrolizumab | Trough Concentration (Ctrough) of Pembrolizumab in Part B Cycles 1, 2, 4, 6, and 8 | Cycle 1 | NA µg/mL | — |
| Part A Cohort 2: Epacadostat 25 mg+Pembrolizumab | Trough Concentration (Ctrough) of Pembrolizumab in Part B Cycles 1, 2, 4, 6, and 8 | Cycle 2 | 8.69 µg/mL | Geometric Coefficient of Variation 122 |
| Part A Cohort 2: Epacadostat 25 mg+Pembrolizumab | Trough Concentration (Ctrough) of Pembrolizumab in Part B Cycles 1, 2, 4, 6, and 8 | Cycle 6 | 21.5 µg/mL | Geometric Coefficient of Variation 130 |
| Part A Cohort 2: Epacadostat 25 mg+Pembrolizumab | Trough Concentration (Ctrough) of Pembrolizumab in Part B Cycles 1, 2, 4, 6, and 8 | Cycle 8 | 34.5 µg/mL | Geometric Coefficient of Variation 42.9 |
| Part A Cohort 2: Epacadostat 100 mg+Pembrolizumab | Trough Concentration (Ctrough) of Pembrolizumab in Part B Cycles 1, 2, 4, 6, and 8 | Cycle 6 | 38.6 µg/mL | Geometric Coefficient of Variation 73.5 |
| Part A Cohort 2: Epacadostat 100 mg+Pembrolizumab | Trough Concentration (Ctrough) of Pembrolizumab in Part B Cycles 1, 2, 4, 6, and 8 | Cycle 2 | 13.3 µg/mL | Geometric Coefficient of Variation 73.9 |
| Part A Cohort 2: Epacadostat 100 mg+Pembrolizumab | Trough Concentration (Ctrough) of Pembrolizumab in Part B Cycles 1, 2, 4, 6, and 8 | Cycle 1 | NA µg/mL | — |
| Part A Cohort 2: Epacadostat 100 mg+Pembrolizumab | Trough Concentration (Ctrough) of Pembrolizumab in Part B Cycles 1, 2, 4, 6, and 8 | Cycle 4 | 31.5 µg/mL | Geometric Coefficient of Variation 28.5 |
| Part A Cohort 2: Epacadostat 100 mg+Pembrolizumab | Trough Concentration (Ctrough) of Pembrolizumab in Part B Cycles 1, 2, 4, 6, and 8 | Cycle 8 | 50.3 µg/mL | Geometric Coefficient of Variation 39.6 |