Clinical trial NCT02862457: 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)
Official title: A Phase I Study of INCB024360 (Epacadostat) Alone, INCB024360 in Combination With Pembrolizumab (MK-3475), and INCB024360 and Pembrolizumab in Combination With Chemotherapy in Patients With Advanced Solid Tumors (KEYNOTE-434)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
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
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2016-08-11
Enrollment: 34
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: 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)
timeFrame: Up to Day 7 for Part A Cohort 1; up to Day 21 for Part A Cohort 2 and Part B
measure: Number of Participants Who Experienced At Least One Adverse Event (AE)
timeFrame: Up to approximately 39.7 months
measure: Number of Participants Who Discontinued Study Treatment Due to An Adverse Event (AE)
timeFrame: Up to approximately 38.5 months
Secondary outcomes:
measure: Maximum Concentration (Cmax) of Epacadostat in Part A
timeFrame: Cycle 1 (28-day cycle): Days 1, 5, and 12 at predose and 0.5, 1, 2, 4, 6, 8 and 10 hours postdose
measure: Time to Maximum Concentration (Tmax) of Epacadostat in Part A
timeFrame: Cycle 1 (28-day cycle): Days 1, 5, and 12 at predose and 0.5, 1, 2, 4, 6, 8 and 10 hours postdose
measure: Area Under the Concentration-Time Curve From Zero to the Time of the Last Measurable Concentration (AUC0-t) of Epacadostat in Part A
timeFrame: Cycle 1 (28-day cycle): Days 1, 5, and 12 at predose and 0.5, 1, 2, 4, 6, 8 and 10 hours postdose
measure: Trough Concentration (Ctrough) of Epacadostat in Part A
timeFrame: Cycle 1 (28-day cycle): Days 1, 5, and 12 at predose
measure: Terminal Half-Life (t1/2) of Epacadostat in Part A
timeFrame: Cycle 1 (28-day cycle): Days 1, 5, and 12 at predose and 0.5, 1, 2, 4, 6, 8 and 10 hours postdose
measure: Maximum Concentration (Cmax) of Pembrolizumab in Part A Cycle 1
timeFrame: 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
measure: Maximum Concentration (Cmax) of Pembrolizumab in Part B Cycle 1
timeFrame: 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
measure: Trough Concentration (Ctrough) of Pembrolizumab in Part A Cycles 1, 2, 4, 6, and 8
timeFrame: Predose prior to the Cycles 1, 2, 4, 6, and 8 infusion
measure: Trough Concentration (Ctrough) of Pembrolizumab in Part B Cycles 1, 2, 4, 6, and 8
timeFrame: Predose prior to the Cycles 1, 2, 4, 6, and 8 infusion
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.