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)

Merck Sharp & Dohme (MSD)

Status and phase: Completed; Phase 1

Conditions: Neoplasms; Carcinoma, Non-Small-Cell Lung

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

Study type: Interventional

Funder types: Industry

Identifiers

NCT02862457

3475-434

MK-3475-434 (Other Identifier)

163423 (Registry Identifier)

Details and patient eligibility

About

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.

Enrollment: 34 patients

Sex: All

Ages: 20+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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34 participants in 7 patient groups

Part A Cohort 1: epacadostat 25 mg

Experimental group

Description:

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).

Treatment:

Drug: Epacadostat 25 mg

Biological: pembrolizumab 200 mg

Part A Cohort 1: epacadostat 100 mg

Experimental group

Description:

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).

Treatment:

Drug: Epacadostat 100 mg

Biological: pembrolizumab 200 mg

Part A Cohort 2: epacadostat 25 mg+pembrolizumab

Experimental group

Description:

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).

Treatment:

Drug: Epacadostat 25 mg

Biological: pembrolizumab 200 mg

Part A Cohort 2: epacadostat 100 mg+pembrolizumab

Experimental group

Description:

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).

Treatment:

Drug: Epacadostat 100 mg

Biological: pembrolizumab 200 mg

Part B Cohort 1: pembrolizumab+cisplatin+pemetrexed

Experimental group

Description:

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.

Treatment:

Drug: Pemetrexed 500 mg/m^2

Drug: Cisplatin 75 mg/m^2

Drug: Epacadostat 100 mg

Biological: pembrolizumab 200 mg

Part B Cohort 2: pembrolizumab+carboplatin+pemetrexed

Experimental group

Description:

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.

Treatment:

Drug: Carboplatin Area Under the Curve (AUC) 5

Drug: Pemetrexed 500 mg/m^2

Drug: Epacadostat 100 mg

Biological: pembrolizumab 200 mg

Part B Cohort 3: pembrolizumab+carboplatin+paclitaxel

Experimental group

Description:

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.

Treatment:

Drug: Epacadostat 100 mg

Drug: Carboplatin AUC 6

Biological: pembrolizumab 200 mg

Drug: Paclitaxel 200 mg/m^2