A Study of the Safety, Tolerability, and Efficacy of Epacadostat Administered in Combination With Nivolumab in Select Advanced Cancers (ECHO-204)

Phase 1

Completed

Conditions: Ovarian Cancer
Head and Neck Cancer
Lung Cancer
Melanoma
B-cell Malignancies
Colorectal Cancer (CRC)
Lymphoma
Glioblastoma

Interventions: Drug: Nivolumab
Drug: Epacadostat
Drug: Chemotherapy

Registration Number: NCT02327078

Lead Sponsor: Incyte Corporation

Brief Summary: This is a Phase 1/2, open label study. Phase 1 consists of 2 parts. Part 1 is a dose-escalation assessment of the safety and tolerability of epacadostat administered with nivolumab in subjects with select advanced solid tumors and lymphomas. Part 2 will evaluate the safety and tolerability of epacadostat in combination with nivolumab and chemotherapy in subjects with squamous cell carcinoma of head and neck (SCCHN) and non-small cell lung cancer (NSCLC).

Phase 2 will include expansion cohorts in 7 tumor types, including melanoma, NSCLC, SCCHN, colorectal cancer, ovarian cancer, glioblastoma and diffuse large B-cell lymphoma (DLBCL).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 307

Inclusion Criteria

Male or female subjects, age 18 years or older
Subjects with histologically or cytologically confirmed NSCLC, MEL (including I/O relapsed MEL or I/O refractory MEL), CRC, SCCHN, ovarian cancer, recurrent B cell NHL or HL, or glioblastoma
Presence of measurable disease by RECIST v1.1 for solid tumors or Cheson criteria for B cell NHL (including DLBCL) or HL. For subjects with glioblastoma, presence of measurable disease is not required.
Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1
Fresh baseline tumor biopsies (defined as a biopsy specimen taken since completion of the most recent prior chemotherapy regimen) are required for all cohorts except glioblastoma

Exclusion Criteria

Laboratory and medical history parameters not within Protocol-defined range
Currently pregnant or breastfeeding
Subjects who have received prior immune checkpoint inhibitors or an IDO inhibitor (except select Phase 2 cohorts evaluating I/O relapsed or I/O refractory MEL). Subjects who have received experimental vaccines or other immune therapies should be discussed with the medical monitor to confirm eligibility
Untreated central nervous system (CNS) metastases or CNS metastases that have progressed
Subjects with any active or inactive autoimmune process
Evidence of interstitial lung disease or active, noninfectious pneumonitis
Subjects with any active or inactive autoimmune process
Ocular MEL

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Phase 1 Part 1 Epacadostat 25mg BID +Nivolumab	Epacadostat	Epacadostat 25mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab administered intravenously (IV) at 3mg/kg Q2W
Phase 1 Part 1 Epacadostat 100mg BID +Nivolumab	Epacadostat	Epacadostat 100mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab administered intravenously (IV) at 3mg/kg Q2W.
Phase 1 Part 1 Epacadostat 300mg BID +Nivolumab	Epacadostat	Epacadostat 300mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab administered intravenously (IV) at 3mg/kg Q2W.
Phase 1 Part 2 Epacadostat 100mg BID +Nivolumab +5-FU/Platinum	Chemotherapy	Epacadostat 100mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 360mg Q3W and 5-FU/Platinum( Carboplatin or Cisplatin+5-Fluorouracil) administered intravenously (IV).
Phase 1 Part 2 Epacadostat 100mg BID +Pemetrexed/Platinum	Epacadostat	Epacadostat 100mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 360 mg Q3W and Pemetrexed/Platinum (Carboplatin orCisplatin+Pemetrexed) administered intravenously (IV).
Phase 1 Part 2 Epacadostat 100mg BID +Pemetrexed/Platinum	Chemotherapy	Epacadostat 100mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 360 mg Q3W and Pemetrexed/Platinum (Carboplatin orCisplatin+Pemetrexed) administered intravenously (IV).
Phase 1 Part 2 Epacadostat 100mg BID +Paclitaxel/Platinum	Epacadostat	Epacadostat 100mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 360 mg Q3W and Paclitaxel/Platinum(Carboplatin+Cisplatin+Paclitaxel)administered intravenously (IV).
Phase 1 Part 2 Epacadostat 100mg BID +Paclitaxel/Platinum	Chemotherapy	Epacadostat 100mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 360 mg Q3W and Paclitaxel/Platinum(Carboplatin+Cisplatin+Paclitaxel)administered intravenously (IV).
Phase 1 Part 1 Epacadostat 25mg BID +Nivolumab	Nivolumab	Epacadostat 25mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab administered intravenously (IV) at 3mg/kg Q2W
Phase 1 Part 1 Epacadostat 50mg BID +Nivolumab	Nivolumab	Epacadostat 50mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab administered intravenously (IV) at 3mg/kg Q2W
Phase 1 Part 1 Epacadostat 50mg BID +Nivolumab	Epacadostat	Epacadostat 50mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab administered intravenously (IV) at 3mg/kg Q2W
Phase 1 Part 1 Epacadostat 100mg BID +Nivolumab	Nivolumab	Epacadostat 100mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab administered intravenously (IV) at 3mg/kg Q2W.
Phase 1 Part 1 Epacadostat 300mg BID +Nivolumab	Nivolumab	Epacadostat 300mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab administered intravenously (IV) at 3mg/kg Q2W.
Phase 1 Part 2 Epacadostat 100mg BID +Nivolumab +5-FU/Platinum	Epacadostat	Epacadostat 100mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 360mg Q3W and 5-FU/Platinum( Carboplatin or Cisplatin+5-Fluorouracil) administered intravenously (IV).
Phase 1 Part 2 Epacadostat 100mg BID +Nivolumab +5-FU/Platinum	Nivolumab	Epacadostat 100mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 360mg Q3W and 5-FU/Platinum( Carboplatin or Cisplatin+5-Fluorouracil) administered intravenously (IV).
Phase 2 Epacadostat 100mg BID + Nivolumab	Nivolumab	Epacadostat 100mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 240mg Q2W or 480 mg Q4W based on tumor type administered intravenously (IV).
Phase 2 Epacadostat 100mg BID + Nivolumab	Epacadostat	Epacadostat 100mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 240mg Q2W or 480 mg Q4W based on tumor type administered intravenously (IV).
Phase 2 Epacadostat 300mg BID + Nivolumab	Nivolumab	Epacadostat 300mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 240mg Q2W administered intravenously (IV).
Phase 2 Epacadostat 300mg BID + Nivolumab	Epacadostat	Epacadostat 300mg oral twice daily (BID) continuous daily dosing in combination with Nivolumab 240mg Q2W administered intravenously (IV).

Primary Outcome Measures

Name	Time	Method
Phase 2: Progression Free Survival (PFS)	From first dose up end of the study (up to approximately 6 years)	PFS is defined as the time from randomization to the first documented progressive disease per RECIST v1.1 or death due to any cause, whichever occurs first.
Phase 1, Part 2: Number of Participants With Dose Limiting Toxicities (DLTs)	Day 42	A DLT was defined as occurrence of any treatment-emergent adverse event (TEAE) in Phase 1 Parts 1 and 2. DLT included all TEAE of specified grades such as 1) Hematologic toxicities - any Grade 4 thrombocytopenia or neutropenia, anemia, febrile neutropenia, ≥ Grade 3 hemolysis, thrombocytopenia and 2) Nonhematologic toxicities - Grade 4 AE, nausea, vomiting, or diarrhea, electrolyte abnormality, ≥ Grade 3 aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin elevation, Grade 2 AST/ALT with symptomatic liver inflammation, AST or ALT \> 3 × upper limit of normal (ULN) and concurrent total bilirubin \> 2 × ULN without initial findings of cholestasis, and any other ≥ Grade 3 toxicity. A TEAE is any AE either reported for the first time or worsening of a pre-existing event after first dose of study drug and up to 100 days after last dose of study drug.
Phase 1, Part 1: Number of Participants With Dose Limiting Toxicities (DLTs)	Day 42	A DLT was defined as occurrence of any treatment-emergent adverse event (TEAE) in Phase 1 Parts 1 and 2. DLT included all TEAE of specified grades such as 1) Hematologic toxicities - any Grade 4 thrombocytopenia or neutropenia, anemia, febrile neutropenia, ≥ Grade 3 hemolysis, thrombocytopenia and 2) Nonhematologic toxicities - Grade 4 AE, nausea, vomiting, or diarrhea, electrolyte abnormality, ≥ Grade 3 aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin elevation, Grade 2 AST/ALT with symptomatic liver inflammation, AST or ALT \> 3 × upper limit of normal (ULN) and concurrent total bilirubin \> 2 × ULN without initial findings of cholestasis, and any other ≥ Grade 3 toxicity. A TEAE is any AE either reported for the first time or worsening of a pre-existing event after first dose of study drug and up to 100 days after last dose of study drug.
Phase 1, Parts 1 and 2: Number of Participants With At Least One Treatment-Emergent Adverse Event (TEAE)	up to approximately 39 months	An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (e.g., a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A TEAE is any AE either reported for the first time or worsening of a pre-existing event after first dose of study drug and up to 100 days after last dose of study drug.
Phase 2: Objective Response Rate (ORR) in Participants With Select Solid Tumors Per Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 for Participants With Solid Tumors and Per Cheson Criteria for Participants With DLBCL	From first dose up end of the study (up to approximately 6 years)	ORR was defined as the percentage of participants having a complete response (CR) or partial response (PR) as determined by investigator assessment of radiographic disease per RECIST v1.1. CR per RECIST v 1.1 was defined as disappearance of all target lesions. PR per RECIST v 1.1 was defined as At least a 30% decrease in the sum of diameters (SOD) of target lesions, taking as reference the Baseline sum diameters. Data is reported as per dose received by the participants with a particular cancer type. CR per Cheson criteria was defined as complete disappearance of all detectable clinical evidence of disease and disease-related symptoms. PR per Cheson criteria was defined as at least a 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses.
Phase 2: Overall Survival (OS) Rate of Proportion With Glioblastoma	Month 9	OS rate is defined as the proportion of participants alive 9 months after the start of treatment.

Secondary Outcome Measures

Name	Time	Method
Phase 2: Duration of Disease Control, Defined as CR, PR, and Stable Disease (SD)	From first dose up end of the study (up to approximately 6 years)	Duration of disease control is the time from the first dose to the first objective response of PD, or death, whichever occurs first, for participants who reported a best overall response of SD or better. PD was defined as at least a 20% increase in the SOD of target lesions. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the Baseline sum diameters.
Phase 1, Part 2: ORR Per RECIST v1.1 and for Participants With Advanced or Metastatic SCCHN and Advanced or Metastatic NSCLC	From first dose up end of the study (up to approximately 6 years)	ORR was defined as percentage of participants having CR or PR as determined by investigator assessment of radiographic disease per RECIST v1.1. CR per RECIST v 1.1 was defined as disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters (SOD) of target lesions, taking as reference the Baseline sum diameters.
Phase 1, Part 2: Duration of Response (DOR) for Participants With Advanced or Metastatic SCCHN and Advanced or Metastatic NSCLC	From first dose up end of the study (up to approximately 6 years)	DOR is defined as the time from the first overall response contributing to an objective response (CR or PR) to the earlier of the participant's death and first overall response of PD. CR was defined as disappearance of all target lesions. PR was defined as At least a 30% decrease in the SOD of target lesions, taking as reference the Baseline sum diameters. PD was defined as at least a 20% increase in the SOD of target lesions.
Phase 1, Part 1: ORR Per RECIST v1.1 for Participants With Solid Tumors; Per Cheson Criteria for Participants With B-cell NHL; and Per RANO and mRANO Criteria for Participants With GBM	From first dose up end of the study (up to approximately 6 years)	ORR was defined as percentage of participants having CR or PR as determined by investigator assessment of radiographic disease per RECIST v1.1. CR per RECIST v 1.1 was defined as disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters (SOD) of target lesions, taking as reference the Baseline sum diameters. Per Cheson criteria, CR: complete disappearance of all detectable clinical evidence of disease and disease-related symptoms. PR: at least a 50% decrease in SPD of up to 6 of the largest dominant nodes or nodal masses. Per RANO criteria, CR: Complete disappearance of all enhancing measurable and non-measurable disease sustained. PR: at least ≥50% decrease compared with baseline in the SOD of all measurable enhancing lesions sustained.
Phase 1, Part 2: PFS for Participants With Advanced or Metastatic SCCHN and Advanced or Metastatic NSCLC	From first dose up end of the study (up to approximately 6 years)	PFS is defined as the time from randomization to the first documented progressive disease or death due to any cause, whichever occurs first.
Phase 2: Safety and Tolerability Measured by the Number of Adverse Events (AEs), Serious Adverse Events (SAEs), and Fatal Treatment Emergent AEs	up to approximately 35 months	An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (e.g., a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A TEAE is any AE either reported for the first time or worsening of a pre-existing event after first dose of study drug and up to 100 days after last dose of study drug. Adverse events of grade 5 which result in death are called as fatal AEs.
Phase 2: Duration of Response	From first dose up end of the study (up to approximately 6 years)	DOR is defined as the time from the first overall response contributing to an objective response (CR or PR) to the earlier of the participant's death and first overall response of PD. CR was defined as disappearance of all target lesions. PR was defined as At least a 30% decrease in the sum of diameters (SOD) of target lesions, taking as reference the Baseline sum diameters. PD was defined as at least a 20% increase in the SOD of target lesions.

Trial Locations

Locations (23): Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
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Baltimore, Maryland, United States
Dana Farber Cancer Institute
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Boston, Massachusetts, United States
Duke University Medical Center
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Durham, North Carolina, United States
The University of Kansas Clinical Research Center
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Fairway, Kansas, United States
UCSF - University of California San Francisco
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San Francisco, California, United States
Vanderbilt University Medical Center
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Nashville, Tennessee, United States
UAB Comprehensive Cancer Center
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Birmingham, Alabama, United States
The Angeles Clinic and Research Institute
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Los Angeles, California, United States
Medical College of Wisconsin
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Milwaukee, Wisconsin, United States
University of Colorado Anschutz Medical Campus
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Aurora, Colorado, United States
USC Norris Cancer Center
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Los Angeles, California, United States
Columbia University, Herbert Irving Comprehensive Cancer Center
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New York, New York, United States
Lahey Hospital & Medical Center
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Burlington, Massachusetts, United States
NYU Cancer Center
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New York, New York, United States
University of Pittsburgh School of Medicine
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Pittsburgh, Pennsylvania, United States
MD Anderson Cancer Center
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Houston, Texas, United States
Texas Oncology Research
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Austin, Texas, United States
Utah Cancer Specialists
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Salt Lake City, Utah, United States
The Christie NHS Foundation Trust
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Manchester, United Kingdom
Huntsman Cancer Institute
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Salt Lake City, Utah, United States
Oxford University Hospitals NHS Trust
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Oxford, United Kingdom
Sanford Research
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North Sioux City, South Dakota, United States
Wake Forest Medical Center Boulevard
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Winston-Salem, North Carolina, United States