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)

NCT ID: NCT02862457

Last Updated: 2022-08-19

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 34 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-08-23
• Study Completion Date: 2020-11-20

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.

Conditions

Neoplasms; Carcinoma, Non-Small-Cell Lung

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Epacadostat 100 mg

Intervention Type: DRUG

Oral administration

pembrolizumab 200 mg

Intervention Type: BIOLOGICAL

Intravenous (IV) infusion

Carboplatin Area Under the Curve (AUC) 5

Intervention Type: DRUG

IV infusion

Pemetrexed 500 mg/m^2

Intervention Type: DRUG

IV infusion

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).

Group Type: EXPERIMENTAL

Epacadostat 25 mg

Intervention Type: DRUG

Oral administration

pembrolizumab 200 mg

Intervention Type: BIOLOGICAL

Intravenous (IV) infusion

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).

Group Type: EXPERIMENTAL

Epacadostat 100 mg

Intervention Type: DRUG

Oral administration

pembrolizumab 200 mg

Intervention Type: BIOLOGICAL

Intravenous (IV) infusion

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).

Group Type: EXPERIMENTAL

Epacadostat 25 mg

Intervention Type: DRUG

Oral administration

pembrolizumab 200 mg

Intervention Type: BIOLOGICAL

Intravenous (IV) infusion

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).

Group Type: EXPERIMENTAL

Epacadostat 100 mg

Intervention Type: DRUG

Oral administration

pembrolizumab 200 mg

Intervention Type: BIOLOGICAL

Intravenous (IV) infusion

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.

Group Type: EXPERIMENTAL

Epacadostat 100 mg

Intervention Type: DRUG

Oral administration

pembrolizumab 200 mg

Intervention Type: BIOLOGICAL

Intravenous (IV) infusion

Cisplatin 75 mg/m^2

Intervention Type: DRUG

IV infusion

Pemetrexed 500 mg/m^2

Intervention Type: DRUG

IV infusion

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.

Group Type: EXPERIMENTAL

Epacadostat 100 mg

Intervention Type: DRUG

Oral administration

pembrolizumab 200 mg

Intervention Type: BIOLOGICAL

Intravenous (IV) infusion

Paclitaxel 200 mg/m^2

Intervention Type: DRUG

IV infusion

Carboplatin AUC 6

Intervention Type: DRUG

IV infusion

Interventions

Epacadostat 25 mg

Oral administration

Intervention Type: DRUG

Epacadostat 100 mg

Oral administration

Intervention Type: DRUG

pembrolizumab 200 mg

Intravenous (IV) infusion

Intervention Type: BIOLOGICAL

Cisplatin 75 mg/m^2

IV infusion

Intervention Type: DRUG

Carboplatin Area Under the Curve (AUC) 5

IV infusion

Intervention Type: DRUG

Pemetrexed 500 mg/m^2

IV infusion

Intervention Type: DRUG

Paclitaxel 200 mg/m^2

IV infusion

Intervention Type: DRUG

Carboplatin AUC 6

IV infusion

Intervention Type: DRUG

Other Intervention Names

INCB024360; INCB024360; MK-3475; KEYTRUDA®; Platinol®; Platinol-AQ®; Paraplatin®; Alimta®; Taxol®; Abraxane®; Onxol®; Paraplatin®

Eligibility Criteria

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

• Minimum Eligible Age: 20 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Director

Role: STUDY_DIRECTOR

Merck Sharp & Dohme LLC

References

Yamamoto N, Satouchi M, Doi T, Fujiwara Y, Yanagitani N, Kawa Y, Yoh K, Leopold L, Munteanu M, Sawada T, Han S, Noguchi K, Nishio M. KEYNOTE-434 part B: A phase 1 study evaluating the combination of epacadostat, pembrolizumab, and chemotherapy in Japanese patients with previously untreated advanced non-small-cell lung cancer. Invest New Drugs. 2024 Jun;42(3):261-271. doi: 10.1007/s10637-024-01422-6. Epub 2024 Mar 26.

Reference Type: DERIVED

PMID: 38530565 (View on PubMed)

Doi T, Fujiwara Y, Shitara K, Shimizu T, Yonemori K, Matsubara N, Ohno I, Kogawa T, Naito Y, Leopold L, Munteanu M, Yatsuzuka N, Han SR, Samkari A, Yamamoto N. The safety and tolerability of epacadostat alone and in combination with pembrolizumab in patients with advanced solid tumors: results from a first-in-Japanese phase I study (KEYNOTE-434). Invest New Drugs. 2021 Feb;39(1):152-162. doi: 10.1007/s10637-020-00942-1. Epub 2020 Jun 20.

Reference Type: DERIVED

PMID: 32564277 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

MK-3475-434

Identifier Type: OTHER

Identifier Source: secondary_id

163423

Identifier Type: REGISTRY

Identifier Source: secondary_id

3475-434

Identifier Type: -

Identifier Source: org_study_id