Solid Tumor
Conditions
Keywords
solid tumors, colorectal cancer, pancreatic ductal adenocarcinoma, non-small cell lung cancer, PD-1, PD-L1, epacadostat, IDO inhibitor
Brief summary
This was an open-label, nonrandomized, Phase 1/2 study designed to determine the safety, tolerability, and efficacy of epacadostat when given in combination with pembrolizumab and 7 different chemotherapy regimens described as Treatment Groups A through G below (see Study Drug and Background Therapies, Dose, and Mode of Administration). Phase 1 consisted of a 3 + 3 + 3 design intended to determine the MTD or PAD of epacadostat when given in combination with pembrolizumab and chemotherapy; efficacy was also explored. Phase 2 was designed to enroll efficacy expansion cohorts to further evaluate the safety, tolerability, and efficacy of epacadostat at the MTD or PAD (as selected in Phase 1) when given in combination with pembrolizumab and chemotherapy. Each efficacy expansion cohort was to enroll participants with 1 specific type of advanced or metastatic solid tumor. Additional cohorts (ie, the mandatory biopsy cohorts) were designed to evaluate changes in the tumor microenvironment in participants with any advanced or metastatic solid tumor who had progressed on previous therapy with a PD-1 or a PD-L1 inhibitor. No participants were enrolled in any Phase 2 efficacy expansion cohort, or in any Phase 2 mandatory biopsy cohort receiving Treatment A, B, F, or G. Phase 2 mandatory biopsy cohort participants received Treatments C, D, or E (ie, were included in Treatment Groups C, D, or E). Participants were assigned to a treatment group based on the chemotherapy regimen most appropriate for their tumor type.
Interventions
DRUGEpacadostat
Epacadostat oral twice-daily continuous daily dosing at the protocol-defined dose.
DRUGPembrolizumab
Pembrolizumab
DRUGOxaliplatin
Oxaliplatin
DRUGLeucovorin
Leucovorin
DRUG5-Fluorouracil
5-Fluorouracil
DRUGGemcitabine
Gemcitabine
DRUGnab-Paclitaxel
nab-Paclitaxel
DRUGCarboplatin
Carboplatin
DRUGPaclitaxel
Paclitaxel
DRUGPemetrexed
Pemetrexed
DRUGCyclophosphamide
Cyclophosphamide
DRUGCisplatin
Cisplatin
DRUGInvestigator's choice of platinum agent
Investigator's choice of platinum agent: carboplatin or cisplatin
Sponsors
Incyte Corporation
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed diagnosis of selected advanced or metastatic solid tumors. * Presence of measurable disease per RECIST v1.1. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
Exclusion criteria
* Laboratory and medical history parameters not within the Protocol-defined range. * Receipt of anticancer medications or investigational drugs within the Protocol-defined intervals before the first administration of study drug. * Previous radiotherapy within 2 weeks of starting study therapy. * Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. * Has not recovered to ≤ Grade 1 from toxic effects of previous therapy and/or complications from previous surgical intervention before starting study therapy. * Receipt of a live vaccine within 30 days of planned start of study therapy. * Active infection requiring systemic therapy. * Subjects who have any active or inactive autoimmune disease or syndrome. * Women who are pregnant or breastfeeding.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phases 1 & 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Up to 21 months | A TEAE is any AE either reported for the first time or worsening of a pre-existing event after first dose of epacadostat, pembrolizumab, or chemotherapy. Serious adverse event is defined as an event that meets 1 of the following criteria: is fatal or life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability, incapacity, or a substantial disruption of a person's ability to conduct normal life functions, constitutes a congenital anomaly or birth defect,is a medically important event that may jeopardize the participant or may require medical or surgical intervention to prevent 1 of the outcomes listed above. |
| Phases 1 and 2: Number of Participants With Dose Limiting Toxicities (DLTs) | 28 days | A DLT was defined as the occurrence of any of the protocol-specified toxicities occurring up to and including Day 28 for the cohorts where mFOLFOX6 and nab-paclitaxel/gemcitabine are administered and Day 21 for all other chemotherapy regimens in Phase 1, except those with a clear alternative explanation (eg, disease progression) or transient (≤ 72 hours) abnormal laboratory values without associated clinically significant signs or symptoms based on investigator determination. |
| Phases 1 and 2: Objective Response Rate (ORR) | Up to Week 18 | 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 Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. |
Countries
United States
Participant flow
Recruitment details
The study was conducted at 9 study sites in the US. Phases 1 and 2 each consisted of Treatment Groups A-G, and every patient in the same group in Phases 1 and 2 received the same dose of epacadostat (100 mg BID oral), pembrolizumab (200 mg IV), and the respective chemotherapy regimens. Data analysis and summarization were performed by treatment group, by combining data of the same group in Phases 1 and 2.
Pre-assignment details
A total of 70 participants were enrolled in the study. Study enrollment was permanently discontinued on 25 Oct 2018 as a strategic decision. At the time of data cut-off date of 25 Jan 2019, 11 participants were ongoing on treatment. . Phase 2 consisted of efficacy expansion and Mandatory biopsy cohorts. Phase 2 Efficacy expansion cohorts did not open for enrollment. Phase 2/Mandatory biopsy cohorts opened for enrollment and only groups C, D and E enrolled participants prior to study termination
Participants by arm
| Arm | Count |
|---|---|
| Group A: Epa + Pembrolizumab + mFOLFOX6 Epacadostat (Epa) oral twice-daily (BID) continuous daily dosing at the protocol-defined dose in combination with pembrolizumab administered intravenously (IV) in combination with mFOLFOX6 (oxaliplatin IV + leucovorin IV + 5-fluorouracil (5-FU) IV. | 9 |
| Group B: Epa + Pembrolizumab + Nab-Paclitaxel and Gemcitabine Epa (100 mg) oral BID continuous daily dosing at the protocol-defined dose in combination with pembrolizumab (200 mg) IV in combination with nab-paclitaxel IV and gemcitabine IV. | 9 |
| Group C: Epa + Pembrolizumab + Paclitaxel and Carboplatin Epa (100 mg) oral BID continuous daily dosing at the protocol-defined dose in combination with pembrolizumab (200 mg) in combination with paclitaxel IV and carboplatin IV. | 11 |
| Group D: Epa + Pembrolizumab + Pemetrexed and Platinum Agent Epa (100 mg) oral BID continuous daily dosing at the protocol-defined dose in combination with pembrolizumab (200 mg) IV in combination with pemetrexed IV and Investigator's choice of platinum agent: carboplatin IV or cisplatin IV. | 9 |
| Group E: Epa + Pembrolizumab + Cyclophosphamide Epa (100 mg)oral BID continuous daily dosing at the protocol-defined dose in combination with pembrolizumab (200 mg) IV in combination with cyclophosphamide PO. | 13 |
| Group F: Epa + Pembrolizumab + Gemcitabine and Platinum Agent Epa (100 mg) oral BID continuous daily dosing at the protocol-defined dose in combination with pembrolizumab (200 mg) IV in combination with gemcitabine IV and Investigator's choice of platinum agent: carboplatin IV or cisplatin IV. | 8 |
| Group G: Epa + Pembrolizumab + 5-FU and Platinum Agent Epa (100 mg) oral BID continuousdaily dosing at the protocol-defined dose in combination with pembrolizumab (200 mg) IV in combination with 5-FU IV and Investigator's choice of platinum agent: carboplatin IV or cisplatin IV. | 11 |
| Total | 70 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Death | 6 | 6 | 4 | 1 | 5 | 2 | 2 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 0 | 0 | 1 | 1 |
| Overall Study | Progressive Disease | 0 | 0 | 2 | 2 | 1 | 1 | 1 |
| Overall Study | Reason was not specified, | 2 | 2 | 2 | 3 | 3 | 3 | 6 |
| Overall Study | Study Terminated by the Sponsor | 0 | 0 | 0 | 1 | 2 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 2 | 2 | 2 | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Group G: Epa + Pembrolizumab + 5-FU and Platinum Agent | Group F: Epa + Pembrolizumab + Gemcitabine and Platinum Agent | Group E: Epa + Pembrolizumab + Cyclophosphamide | Group D: Epa + Pembrolizumab + Pemetrexed and Platinum Agent | Group C: Epa + Pembrolizumab + Paclitaxel and Carboplatin | Group B: Epa + Pembrolizumab + Nab-Paclitaxel and Gemcitabine | Group A: Epa + Pembrolizumab + mFOLFOX6 |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 58.3 years STANDARD_DEVIATION 12.54 | 59.4 years STANDARD_DEVIATION 12.24 | 60.3 years STANDARD_DEVIATION 12.01 | 62.0 years STANDARD_DEVIATION 10.21 | 58.2 years STANDARD_DEVIATION 12.96 | 63.7 years STANDARD_DEVIATION 12.11 | 46.0 years STANDARD_DEVIATION 14.98 | 55.8 years STANDARD_DEVIATION 8.03 |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 67 Participants | 10 Participants | 8 Participants | 13 Participants | 7 Participants | 11 Participants | 9 Participants | 9 Participants |
| Race/Ethnicity, Customized Ethnicity Not Reported | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Ethnicity Unknown | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 3 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Black/African-American | 6 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian/Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Other | 5 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Race White/Caucasian | 55 Participants | 8 Participants | 6 Participants | 10 Participants | 8 Participants | 9 Participants | 7 Participants | 7 Participants |
| Sex: Female, Male Female | 36 Participants | 4 Participants | 5 Participants | 10 Participants | 4 Participants | 6 Participants | 4 Participants | 3 Participants |
| Sex: Female, Male Male | 34 Participants | 7 Participants | 3 Participants | 3 Participants | 5 Participants | 5 Participants | 5 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 6 / 9 | 6 / 9 | 4 / 11 | 1 / 9 | 6 / 13 | 2 / 8 | 3 / 11 | 28 / 70 |
| other Total, other adverse events | 9 / 9 | 8 / 9 | 11 / 11 | 9 / 9 | 13 / 13 | 8 / 8 | 10 / 11 | 68 / 70 |
| serious Total, serious adverse events | 5 / 9 | 5 / 9 | 5 / 11 | 3 / 9 | 6 / 13 | 4 / 8 | 6 / 11 | 34 / 70 |
Outcome results
Primary
Phases 1 & 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs
A TEAE is any AE either reported for the first time or worsening of a pre-existing event after first dose of epacadostat, pembrolizumab, or chemotherapy. Serious adverse event is defined as an event that meets 1 of the following criteria: is fatal or life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability, incapacity, or a substantial disruption of a person's ability to conduct normal life functions, constitutes a congenital anomaly or birth defect,is a medically important event that may jeopardize the participant or may require medical or surgical intervention to prevent 1 of the outcomes listed above.
Time frame: Up to 21 months
Population: The safety population included all participants enrolled in the study who received at least 1 dose of epacadostat, pembrolizumab, or an applicable chemotherapy regimen.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group A: Epa + Pembrolizumab + mFOLFOX6 | Phases 1 & 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | TEAE | 9 Participants |
| Group A: Epa + Pembrolizumab + mFOLFOX6 | Phases 1 & 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAE | 5 Participants |
| Group B: Epa + Pembrolizumab + Nab-Paclitaxel and Gemcitabine | Phases 1 & 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | TEAE | 9 Participants |
| Group B: Epa + Pembrolizumab + Nab-Paclitaxel and Gemcitabine | Phases 1 & 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAE | 5 Participants |
| Group C: Epa + Pembrolizumab + Paclitaxel and Carboplatin | Phases 1 & 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | TEAE | 11 Participants |
| Group C: Epa + Pembrolizumab + Paclitaxel and Carboplatin | Phases 1 & 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAE | 3 Participants |
| Group D: Epa + Pembrolizumab + Pemetrexed and Platinum Agent | Phases 1 & 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | TEAE | 9 Participants |
| Group D: Epa + Pembrolizumab + Pemetrexed and Platinum Agent | Phases 1 & 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAE | 6 Participants |
| Group E: Epa + Pembrolizumab + Cyclophosphamide | Phases 1 & 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | TEAE | 13 Participants |
| Group E: Epa + Pembrolizumab + Cyclophosphamide | Phases 1 & 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAE | 4 Participants |
| Group F: Epa + Pembrolizumab + Gemcitabine and Platinum Agent | Phases 1 & 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | TEAE | 8 Participants |
| Group F: Epa + Pembrolizumab + Gemcitabine and Platinum Agent | Phases 1 & 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAE | 6 Participants |
| Group G: Epa + Pembrolizumab + 5-FU and Platinum Agent | Phases 1 & 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAE | 5 Participants |
| Group G: Epa + Pembrolizumab + 5-FU and Platinum Agent | Phases 1 & 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | TEAE | 11 Participants |
Primary
Phases 1 and 2: Number of Participants With Dose Limiting Toxicities (DLTs)
A DLT was defined as the occurrence of any of the protocol-specified toxicities occurring up to and including Day 28 for the cohorts where mFOLFOX6 and nab-paclitaxel/gemcitabine are administered and Day 21 for all other chemotherapy regimens in Phase 1, except those with a clear alternative explanation (eg, disease progression) or transient (≤ 72 hours) abnormal laboratory values without associated clinically significant signs or symptoms based on investigator determination.
Time frame: 28 days
Population: The safety population included all participants enrolled in the study who received at least 1 dose of epacadostat, pembrolizumab, or an applicable chemotherapy regimen.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group A: Epa + Pembrolizumab + mFOLFOX6 | Phases 1 and 2: Number of Participants With Dose Limiting Toxicities (DLTs) | 2 Participants |
| Group B: Epa + Pembrolizumab + Nab-Paclitaxel and Gemcitabine | Phases 1 and 2: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Group C: Epa + Pembrolizumab + Paclitaxel and Carboplatin | Phases 1 and 2: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Group D: Epa + Pembrolizumab + Pemetrexed and Platinum Agent | Phases 1 and 2: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Group E: Epa + Pembrolizumab + Cyclophosphamide | Phases 1 and 2: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Group F: Epa + Pembrolizumab + Gemcitabine and Platinum Agent | Phases 1 and 2: Number of Participants With Dose Limiting Toxicities (DLTs) | 3 Participants |
| Group G: Epa + Pembrolizumab + 5-FU and Platinum Agent | Phases 1 and 2: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
Primary
Phases 1 and 2: Objective Response Rate (ORR)
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 Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
Time frame: Up to Week 18
Population: The full analysis set included all participants enrolled in the study who received at least 1 dose of epacadostat and have at least 1 postbaseline assessment or who discontinued epacadostat.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group A: Epa + Pembrolizumab + mFOLFOX6 | Phases 1 and 2: Objective Response Rate (ORR) | Complete Response | 0 Participants |
| Group A: Epa + Pembrolizumab + mFOLFOX6 | Phases 1 and 2: Objective Response Rate (ORR) | Partial Response | 5 Participants |
| Group B: Epa + Pembrolizumab + Nab-Paclitaxel and Gemcitabine | Phases 1 and 2: Objective Response Rate (ORR) | Complete Response | 1 Participants |
| Group B: Epa + Pembrolizumab + Nab-Paclitaxel and Gemcitabine | Phases 1 and 2: Objective Response Rate (ORR) | Partial Response | 2 Participants |
| Group C: Epa + Pembrolizumab + Paclitaxel and Carboplatin | Phases 1 and 2: Objective Response Rate (ORR) | Complete Response | 0 Participants |
| Group C: Epa + Pembrolizumab + Paclitaxel and Carboplatin | Phases 1 and 2: Objective Response Rate (ORR) | Partial Response | 3 Participants |
| Group D: Epa + Pembrolizumab + Pemetrexed and Platinum Agent | Phases 1 and 2: Objective Response Rate (ORR) | Complete Response | 0 Participants |
| Group D: Epa + Pembrolizumab + Pemetrexed and Platinum Agent | Phases 1 and 2: Objective Response Rate (ORR) | Partial Response | 2 Participants |
| Group E: Epa + Pembrolizumab + Cyclophosphamide | Phases 1 and 2: Objective Response Rate (ORR) | Complete Response | 0 Participants |
| Group E: Epa + Pembrolizumab + Cyclophosphamide | Phases 1 and 2: Objective Response Rate (ORR) | Partial Response | 3 Participants |
| Group F: Epa + Pembrolizumab + Gemcitabine and Platinum Agent | Phases 1 and 2: Objective Response Rate (ORR) | Complete Response | 0 Participants |
| Group F: Epa + Pembrolizumab + Gemcitabine and Platinum Agent | Phases 1 and 2: Objective Response Rate (ORR) | Partial Response | 1 Participants |
| Group G: Epa + Pembrolizumab + 5-FU and Platinum Agent | Phases 1 and 2: Objective Response Rate (ORR) | Complete Response | 0 Participants |
| Group G: Epa + Pembrolizumab + 5-FU and Platinum Agent | Phases 1 and 2: Objective Response Rate (ORR) | Partial Response | 5 Participants |