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)

NCT02862457 | Completed Phase 1 Results

• 3 other identifiers: 3475-434MK-3475-434163423
• Study Type: interventional
• Target: 34
• Locations: 0 countries
• Sites: N/A

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

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

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (9)

• 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

• 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

• 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

• Trough Concentration (Ctrough) of Epacadostat in Part A

  Cycle 1 (28-day cycle): Days 1, 5, and 12 at predose

• 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

Study Arms (7)

Part A Cohort 1: epacadostat 25 mg

EXPERIMENTAL

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; Biological: pembrolizumab 200 mg

Part A Cohort 1: epacadostat 100 mg

EXPERIMENTAL

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; Biological: pembrolizumab 200 mg

Part A Cohort 2: epacadostat 25 mg+pembrolizumab

EXPERIMENTAL

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; Biological: pembrolizumab 200 mg

Part A Cohort 2: epacadostat 100 mg+pembrolizumab

EXPERIMENTAL

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; Biological: pembrolizumab 200 mg

Part B Cohort 1: pembrolizumab+cisplatin+pemetrexed

EXPERIMENTAL

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; Biological: pembrolizumab 200 mg; Drug: Cisplatin 75 mg/m^2; Drug: Pemetrexed 500 mg/m^2

Part B Cohort 2: pembrolizumab+carboplatin+pemetrexed

EXPERIMENTAL

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; Biological: pembrolizumab 200 mg; Drug: Carboplatin Area Under the Curve (AUC) 5; Drug: Pemetrexed 500 mg/m^2

Part B Cohort 3: pembrolizumab+carboplatin+paclitaxel

EXPERIMENTAL

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; Biological: pembrolizumab 200 mg; Drug: Paclitaxel 200 mg/m^2; Drug: Carboplatin AUC 6

Interventions

Epacadostat 25 mg DRUG

Oral administration

Also known as: INCB024360

Part A Cohort 1: epacadostat 25 mg; Part A Cohort 2: epacadostat 25 mg+pembrolizumab

Epacadostat 100 mg DRUG

Oral administration

Also known as: INCB024360

Part A Cohort 1: epacadostat 100 mg; 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

pembrolizumab 200 mg BIOLOGICAL

Intravenous (IV) infusion

Also known as: MK-3475, KEYTRUDA®

Part A Cohort 1: epacadostat 100 mg; Part A Cohort 1: epacadostat 25 mg; Part A Cohort 2: epacadostat 100 mg+pembrolizumab; Part A Cohort 2: epacadostat 25 mg+pembrolizumab; Part B Cohort 1: pembrolizumab+cisplatin+pemetrexed; Part B Cohort 2: pembrolizumab+carboplatin+pemetrexed; Part B Cohort 3: pembrolizumab+carboplatin+paclitaxel

Cisplatin 75 mg/m^2 DRUG

IV infusion

Also known as: Platinol®, Platinol-AQ®

Part B Cohort 1: pembrolizumab+cisplatin+pemetrexed

Carboplatin Area Under the Curve (AUC) 5 DRUG

IV infusion

Also known as: Paraplatin®

Part B Cohort 2: pembrolizumab+carboplatin+pemetrexed

Pemetrexed 500 mg/m^2 DRUG

IV infusion

Also known as: Alimta®

Part B Cohort 1: pembrolizumab+cisplatin+pemetrexed; Part B Cohort 2: pembrolizumab+carboplatin+pemetrexed

Paclitaxel 200 mg/m^2 DRUG

IV infusion

Also known as: Taxol®, Abraxane®, Onxol®

Part B Cohort 3: pembrolizumab+carboplatin+paclitaxel

Carboplatin AUC 6 DRUG

IV infusion

Also known as: Paraplatin®

Part B Cohort 3: pembrolizumab+carboplatin+paclitaxel

Eligibility Criteria

• Age: 20 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Related Publications (2)

• 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.

  PMID: 38530565 DERIVED

• 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.

  PMID: 32564277 DERIVED

MeSH Terms

Conditions

Neoplasms; Carcinoma, Non-Small-Cell Lung

Interventions

epacadostat; pembrolizumab; Cisplatin; Area Under Curve; Carboplatin; Pemetrexed; Paclitaxel; Albumin-Bound Paclitaxel

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Statistics as Topic; Epidemiologic Methods; Investigative Techniques; Pharmacokinetics; Metabolism; Pharmacological and Toxicological Phenomena; Physiological Phenomena; Public Health; Environment and Public Health; Coordination Complexes; Organic Chemicals; Guanine; Hypoxanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Dicarboxylic; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Diterpenes; Terpenes; Albumins; Proteins

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme LLC

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 3, 2016
• First Posted: August 11, 2016
• Study Start: August 23, 2016
• Primary Completion: November 20, 2020
• Study Completion: November 20, 2020
• Last Updated: August 19, 2022
• Results First Posted: January 11, 2022

Record last verified: 2022-08

Data Sharing

• IPD Sharing: Will share