NeoplasmsPhase 1NCT02862457
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)
A Phase 1 study testing Epacadostat 25 mg, Epacadostat 100 mg and pembrolizumab 200 mg in people with Neoplasms and Carcinoma, Non-Small-Cell Lung, run by Merck Sharp & Dohme LLC.
Trial 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. Read more about this study
- Who is it for?
- Ages 20 years and older
- Conditions the study is for
- Neoplasms, Carcinoma, Non-Small-Cell Lung
- What is being tested?
- Epacadostat 25 mg, Epacadostat 100 mg and pembrolizumab 200 mg
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 34 participants
- Where
- No sites listed yet
- Study dates
- 23 Aug 2016to 20 Nov 2020
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 20 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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
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- 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
About this study
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)
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
- Being tested
- Epacadostat 25 mg, Epacadostat 100 mg, pembrolizumab 200 mg, Cisplatin 75 mg/m^2, Carboplatin Area Under the Curve (AUC) 5
- 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
- Medical subject headings
- Neoplasms, Carcinoma, Non-Small-Cell Lung
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Epacadostat 25 mgDrug
Also called INCB024360
Oral administration
Epacadostat 100 mgDrug
Also called INCB024360
Oral administration
pembrolizumab 200 mgBiological
Also called MK-3475, KEYTRUDA®
Intravenous (IV) infusion
Cisplatin 75 mg/m^2Drug
Also called Platinol®, Platinol-AQ®
IV infusion
Carboplatin Area Under the Curve (AUC) 5Drug
Also called Paraplatin®
IV infusion
Pemetrexed 500 mg/m^2Drug
Also called Alimta®
IV infusion
Paclitaxel 200 mg/m^2Drug
Also called Taxol®, Abraxane®, Onxol®
IV infusion
Carboplatin AUC 6Drug
Also called Paraplatin®
IV infusion
| Study group | Role | What they receive |
|---|---|---|
| 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). Receives: 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). Receives: 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). Receives: 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). Receives: 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. Receives: 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. Receives: 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. Receives: Drug: Epacadostat 100 mg; Biological: pembrolizumab 200 mg; Drug: Paclitaxel 200 mg/m^2; Drug: Carboplatin AUC 6 |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: Up to approximately 38.5 months
Secondary outcomes (9)
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.
Measured: 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
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.
Measured: 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
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.
Measured: 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
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.
Measured: Cycle 1 (28-day cycle): Days 1, 5, and 12 at predose
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.
Measured: Cycle 1 (28-day cycle): Days 1, 5, and 12 at predose and 0.5, 1, 2, 4, 6, 8 and 10 hours postdose
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.
Measured: 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
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.
Measured: 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
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.
Measured: Predose prior to the Cycles 1, 2, 4, 6, and 8 infusion
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.
Measured: Predose prior to the Cycles 1, 2, 4, 6, and 8 infusion
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Aug 2016 (estimated)
- Study start23 Aug 2016
- Primary completion20 Nov 2020
- Study completion20 Nov 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for NeoplasmsStudies of the same condition, open and under way.
- More trials run by Merck Sharp & Dohme LLCThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 34 participants (actual)
Sponsor and investigators
- Lead sponsor
- Merck Sharp & Dohme LLC
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Medical Director, Study director, Merck Sharp & Dohme LLC
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02862457
- Sponsor's protocol ID
- 3475-434
- Other IDs
- MK-3475-434, 163423
- Status last verified
- Aug 2022
- First submitted
- 3 Aug 2016
- Last updated
- 19 Aug 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
Publications
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.
PubMed 38530565Doi 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.
PubMed 32564277
Study at a glance
From the registry record, last updated by the sponsor on 19 Aug 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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)
- ClinicalTrials.gov ID
- NCT02862457
- Acronym / sponsor ID
- 3475-434
- 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
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 34 participants (actual)
- Lead sponsor
- Merck Sharp & Dohme LLCIndustry (pharma, biotech, devices)
- Study start
- 23 Aug 2016 (actual)
- Primary completion
- 20 Nov 2020 (actual)
- Study completion
- 20 Nov 2020 (actual)
- First posted
- 11 Aug 2016 (estimated)
- Results
- Posted 11 Jan 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 7
| Arm | Type | Receives |
|---|---|---|
| Part A Cohort 1: epacadostat 25 mg | Experimental | Drug: Epacadostat 25 mg, Biological: pembrolizumab 200 mgParticipants 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). |
| Part A Cohort 1: epacadostat 100 mg | Experimental | Drug: Epacadostat 100 mg, Biological: pembrolizumab 200 mgParticipants 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). |
| Part A Cohort 2: epacadostat 25 mg+pembrolizumab | Experimental | Drug: Epacadostat 25 mg, Biological: pembrolizumab 200 mgFor 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). |
| Part A Cohort 2: epacadostat 100 mg+pembrolizumab | Experimental | Drug: Epacadostat 100 mg, Biological: pembrolizumab 200 mgFor 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). |
| Part B Cohort 1: pembrolizumab+cisplatin+pemetrexed | Experimental | Drug: Epacadostat 100 mg, Biological: pembrolizumab 200 mg, Drug: Cisplatin 75 mg/m^2, Drug: Pemetrexed 500 mg/m^2For 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. |
| Part B Cohort 2: pembrolizumab+carboplatin+pemetrexed | Experimental | Drug: Epacadostat 100 mg, Biological: pembrolizumab 200 mg, Drug: Carboplatin Area Under the Curve (AUC) 5, Drug: Pemetrexed 500 mg/m^2For 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. |
| Part B Cohort 3: pembrolizumab+carboplatin+paclitaxel | Experimental | Drug: Epacadostat 100 mg, Biological: pembrolizumab 200 mg, Drug: Paclitaxel 200 mg/m^2, Drug: Carboplatin AUC 6For 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. |
Who may qualify
- Ages
- 20 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- 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
Key exclusion criteria (24 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Epacadostat 25 mgAlso: INCB024360Oral administration | Drug | Part A Cohort 1: epacadostat 25 mg, Part A Cohort 2: epacadostat 25 mg+pembrolizumab |
| Epacadostat 100 mgAlso: INCB024360Oral administration | Drug | 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 mgAlso: MK-3475, KEYTRUDA®Intravenous (IV) infusion | Biological | 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^2Also: Platinol®, Platinol-AQ®IV infusion | Drug | Part B Cohort 1: pembrolizumab+cisplatin+pemetrexed |
| Carboplatin Area Under the Curve (AUC) 5Also: Paraplatin®IV infusion | Drug | Part B Cohort 2: pembrolizumab+carboplatin+pemetrexed |
| Pemetrexed 500 mg/m^2Also: Alimta®IV infusion | Drug | Part B Cohort 1: pembrolizumab+cisplatin+pemetrexed, Part B Cohort 2: pembrolizumab+carboplatin+pemetrexed |
| Paclitaxel 200 mg/m^2Also: Taxol®, Abraxane®, Onxol®IV infusion | Drug | Part B Cohort 3: pembrolizumab+carboplatin+paclitaxel |
| Carboplatin AUC 6Also: Paraplatin®IV infusion | Drug | Part B Cohort 3: pembrolizumab+carboplatin+paclitaxel |
Primary outcome
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)
Time frame: 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)
Time frame: 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)
Time frame: 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.
9 secondary outcomes
Maximum Concentration (Cmax) of Epacadostat in Part A
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
Time to Maximum Concentration (Tmax) of Epacadostat in Part A
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
Area Under the Concentration-Time Curve From Zero to the Time of the Last Measurable Concentration (AUC0-t) of Epacadostat in Part A
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
Trough Concentration (Ctrough) of Epacadostat in Part A
Time frame: Cycle 1 (28-day cycle): Days 1, 5, and 12 at predose
Terminal Half-Life (t1/2) of Epacadostat in Part A
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
Maximum Concentration (Cmax) of Pembrolizumab in Part A Cycle 1
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
Maximum Concentration (Cmax) of Pembrolizumab in Part B Cycle 1
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
Trough Concentration (Ctrough) of Pembrolizumab in Part A Cycles 1, 2, 4, 6, and 8
Time frame: Predose prior to the Cycles 1, 2, 4, 6, and 8 infusion
Trough Concentration (Ctrough) of Pembrolizumab in Part B Cycles 1, 2, 4, 6, and 8
Time frame: Predose prior to the Cycles 1, 2, 4, 6, and 8 infusion
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Aug 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 38530565Yamamoto 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.
- Derived from this study: PubMed 32564277Doi 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.
- Individual participant dataSharing planned: Yes. http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Medical Director study director
Merck Sharp & Dohme LLC
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Epacadostat 25 mg, Epacadostat 100 mg and pembrolizumab 200 mg in people with Neoplasms and Carcinoma, Non-Small-Cell Lung, run by Merck Sharp & Dohme LLC.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Aug 2022. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 11 Jan 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome 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) (time frame: Up to Day 7 for Part A Cohort 1; up to Day 21 for Part A Cohort 2 and Part B). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02862457, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Aug 2022.