Solid Tumors, Advanced Malignancies, Metastatic Cancer
Conditions
Keywords
Solid tumors, NSCLC, CRC
Brief summary
This is an open-label, Phase 1/2 study in subjects with advanced or metastatic solid tumors. The study has three separate treatment groups where separate epigenetic agents are evaluated with an immunotherapy combination. Treatment Group A will evaluate the DNA methyltransferase inhibitor azacitidine in combination with the programmed death receptor-1 (PD-1) inhibitor pembrolizumab and the indoleamine 2,3-dioxygenase (IDO-1) inhibitor epacadostat; Treatment Group B will evaluate the bromodomain and extra-terminal (BET) inhibitor INCB057643 with pembrolizumab and epacadostat; and Treatment Group C will evaluate the lysine-specific demethylase 1A (LSD1) inhibitor INCB059872 with pembrolizumab and epacadostat. The study will be divided into 2 parts (Part 1 and 2). Part 1 is a dose-escalation assessment to evaluate the safety and tolerability of the combination therapies. Once the recommended doses have been determined, subjects with previously treated NSCLC, microsatellite-stable colorectal cancer (CRC), head and neck squamous cell carcinoma, urothelial carcinoma, and melanoma will be enrolled into expansion cohorts in Part 2.
Interventions
DRUGAzacitidine
Five doses of azacitidine will be administered by subcutaneous injection or intravenously (IV) over Days 1 to 7 in Cycles 1 through 6.
DRUGPembrolizumab
Pembrolizumab will be administered in a 30-minute IV infusion every 3 weeks on Day 1 of each 21-day cycle.
DRUGEpacadostat
Epacadostat tablets will be administered orally twice daily.
DRUGINCB057643
INCB057643 will be orally self- administered once daily beginning on Cycle 1 Day 1 and continuously thereafter in 21-day cycles.
DRUGINCB059872
INCB059872 will be orally self- administered once daily OR every other day beginning on Cycle 1 Day 1 and continuously thereafter in 21-day cycles.
Sponsors
Incyte Corporation
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Willingness to provide written informed consent for the study. * Willingness to undergo a pretreatment and on-treatment tumor biopsy to obtain tumor tissue. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. * Part 1: Subjects with histologically or cytologically confirmed advanced or metastatic solid tumors that have failed prior standard therapy (disease progression; subject refusal or intolerance is also allowable). * Part 2: \*Note: Subjects must have failed available therapies that are known to confer clinical benefit as indicated below, unless they are ineligible, intolerant, or refused standard treatment. * Subjects with histologically or cytologically confirmed NSCLC: * Metastatic (Stage IV) or recurrent NSCLC (according to American Joint Committee on Cancer 7th edition guidelines) who have had disease progression after available therapies for advanced or metastatic disease that are known to confer clinical benefit, been intolerant to treatment, or refused standard treatment. * Prior systemic regimens must include previously approved therapies, including a platinum-containing chemotherapy regimen; a tyrosine kinase inhibitor for tumors with driver mutations; and checkpoint inhibitors where approved. * Must have disease progression on a prior PD-1-pathway targeted agent. * Subjects with recurrent (unresectable) or metastatic CRC: * Have histologically confirmed microsatellite stable (MSS) CRC. * Stage IV MSS CRC (according to American Joint Committee on Cancer 7th edition guidelines) who have had disease progression after available therapies for advanced or metastatic disease that are known to confer clinical benefit, been intolerant to treatment, or refused standard treatment. * Prior systemic regimens must include previously approved therapies, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; an anti-VEGF therapy (if no contraindication); and if negative for KRAS, NRAS, and BRAF mutations and no contraindication, an anti-epidermal growth factor receptor (EGFR) therapy; and progressed after the last administration of approved therapy. * Subjects with HNSCC: * Histologically confirmed squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. * Carcinomas of the nasopharynx, salivary gland, or nonsquamous cell histology are excluded. * Must have received prior treatment with a platinum-based therapy * Must have had documented disease progression while on a prior PD-1 pathway-targeted agent. * Subjects with melanoma: * Histologically or cytologically confirmed melanoma. * Unresectable Stage III or Stage IV melanoma, as per American Joint Committee on Cancer staging system not amenable to local therapy. * Subjects with urothelial carcinoma: * Histologically or cytologically confirmed urothelial carcinoma of the renal pelvis, ureter, urinary bladder, or urethra that is transitional cell or mixed transitional/nontransitional (predominantly transitional) cell type. * Stage IV locally advanced or metastatic urothelial carcinoma (according to American Joint Committee on Cancer 7th edition guidelines) with documented disease progression while on a PD-1 pathway targeted therapy.
Exclusion criteria
* Laboratory parameters not within the protocol-defined range. * Receipt of anticancer medications or investigational drugs within a defined interval before the first administration of study drug. * Has not recovered from toxic effects of prior therapy to ≤ Grade 1. * Active or inactive autoimmune disease or syndrome. * Active infection requiring systemic therapy. * Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. * History or presence of an abnormal ECG that, in the investigator's opinion, is clinically meaningful. * Has received a live vaccine within 30 days of planned start of study therapy. * Prior receipt of an IDO inhibitor. * Subjects with uncontrolled type I or type II diabetes mellitus (defined as HgbA1c \> 8). * Prior receipt of a BET inhibitor (Treatment Group B only). * Subjects with a history of bleeding related to cancer under study requiring a medical intervention (eg, embolization procedure, RBC transfusion, or hospitalization) within 30 days of study enrollment (Treatment Groups B and C only). * Clinically significant bleeding within 14 days of Cycle 1 Day 1 (Treatment Groups B and C only). * Prior receipt of an LSD1 inhibitor including INCB059872 (Treatment Group C only).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1 and 2 : Number of Participants With Treatment Emergent Adverse Events | Baseline through 42-49 days after end of treatment, estimated up to 27 months (24 months with 100 day FU period). | A treatment-emergent AE was defined as an event occurring after exposure to at least 1 dose of study drug. A treatment-related AE was defined as an event with a definite, probable, or possible causality to study medication. A serious AE is an event resulting in death, hospitalization, persistent or significant disability/incapacity, or is life threatening, a congenital anomaly/birth defect or requires medical or surgical intervention to prevent 1 of the outcomes above. The intensity of an AE was graded according to the National Cancer Institute common terminology criteria for adverse events (NCI-CTCAE) version 4.03: Grade 1 (Mild); Grade 2 (Moderate); Grade 3 (Severe); Grade 4 (life-threatening). |
| Part 1 and 2: Objective Response Rate Based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Every 9 weeks for the duration of study participation; estimated minimum of 6 months. | 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. CR is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. A participant was considered as an objective responder if the participant had a best overall response of CR or PR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Parts 1 and 2: Percentage of Responders Determined by Immunohistochemistry | Baseline to Week 5/6 or week 8/9 | Responder is defined as an increase in the number of tumor-infiltrating lymphocytes or the ratio of CD8+ lymphocytes to T regulatory cells infiltrating tumor post-treatment versus pretreatment with pembrolizumab and epacadostat in combination with azacitidine. |
| Parts 1 and 2: Progression-free Survival Based on RECIST v1.1. | Every 9 weeks from date of randomization until the date of first documented progression or date of death from any cause whichever came first, assessed up to 24 months | Defined as the time from date of first dose of study drug until the earliest date of disease progression per RECIST v1.1, or death due to any cause, if occurring sooner than progression. |
| Parts 1 and 2: Duration of Response Based on RECIST v1.1 | Every 9 weeks from date of randomization until the date of first documented progression or date of death from any cause whichever came first, assessed up to 24 months | Defined as the time from earliest date of disease response until the earliest date of disease progression per RECIST v1.1, or death due to any cause, if occurring sooner than progression. |
Countries
Spain, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 8 study sites in United States, 2 sites in UK and 1 site in Spain.
Pre-assignment details
A total of 70 participants were enrolled in the study. Study enrollment was permanently discontinued on 15-Feb-2019 as a strategic decision. No patients were enrolled in Treatment Group B and Treatment Group C.
Participants by arm
| Arm | Count |
|---|---|
| Treatment Group A :100mg of INCB24360 In Treatment Group A, subjects will receive the DNMT inhibitor azacitidine in combination with the PD-1 inhibitor pembrolizumab and the IDO1 inhibitor epacadostat at 100mg. Due to early termination of study subjects from dose escalation and dose expansion are combined. | 62 |
| Treatment Group A :300mg of INCB24360 In Treatment Group A, subjects will receive the DNMT inhibitor azacitidine in combination with the PD-1 inhibitor pembrolizumab and the IDO1 inhibitor epacadostat at 300mg. | 8 |
| Treatment Group B :INCB057643+Pembrolizumab+Epacadostat In Treatment Group B, subjects will receive INCB057643 in combination with the PD-1 inhibitor pembrolizumab and the IDO1 inhibitor epacadostat at 100mg. | 0 |
| Treatment Group C :INCB059872+Pembrolizumab+Epacadostat In Treatment Group C, subjects will receive INCB059872 in combination with the PD-1 inhibitor pembrolizumab and the IDO1 inhibitor epacadostat at 100mg. | 0 |
| Total | 70 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 33 | 3 | 0 | 0 |
| Overall Study | Lost to Follow-up | 3 | 1 | 0 | 0 |
| Overall Study | Other Unspecified | 2 | 0 | 0 | 0 |
| Overall Study | Progressive Disease | 9 | 1 | 0 | 0 |
| Overall Study | Study Terminated by Sponsor | 4 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 11 | 3 | 0 | 0 |
Baseline characteristics
| Characteristic | Treatment Group A :300mg of INCB24360 | Treatment Group A :100mg of INCB24360 | Total | Treatment Group C :INCB059872+Pembrolizumab+Epacadostat | Treatment Group B :INCB057643+Pembrolizumab+Epacadostat |
|---|---|---|---|---|---|
| Age, Continuous | 53.0 years STANDARD_DEVIATION 11.31 | 57.0 years STANDARD_DEVIATION 11.92 | 56.5 years STANDARD_DEVIATION 11.84 | — | — |
| Race/Ethnicity, Customized American-Indian/Alaska Native | 0 Participants | 0 Participants | 0 Participants | — | — |
| Race/Ethnicity, Customized Asian | 0 Participants | 2 Participants | 2 Participants | — | — |
| Race/Ethnicity, Customized Black/African-American | 0 Participants | 3 Participants | 3 Participants | — | — |
| Race/Ethnicity, Customized Hispanic or Latino Hispanic or Latino | 2 Participants | 4 Participants | 6 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Hispanic or Latino Not Hispanic or Latino | 6 Participants | 54 Participants | 60 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Hispanic or Latino Unknown | 0 Participants | 4 Participants | 4 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian/Pacific Islander | 0 Participants | 0 Participants | 0 Participants | — | — |
| Race/Ethnicity, Customized Other | 3 Participants | 1 Participants | 4 Participants | — | — |
| Race/Ethnicity, Customized White/Caucasian | 5 Participants | 56 Participants | 61 Participants | — | — |
| Sex: Female, Male Female | 4 Participants | 19 Participants | 23 Participants | — | — |
| Sex: Female, Male Male | 4 Participants | 43 Participants | 47 Participants | — | — |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 41 / 62 | 4 / 8 |
| other Total, other adverse events | 59 / 62 | 8 / 8 |
| serious Total, serious adverse events | 28 / 62 | 3 / 8 |
Outcome results
Primary
Part 1 and 2 : Number of Participants With Treatment Emergent Adverse Events
A treatment-emergent AE was defined as an event occurring after exposure to at least 1 dose of study drug. A treatment-related AE was defined as an event with a definite, probable, or possible causality to study medication. A serious AE is an event resulting in death, hospitalization, persistent or significant disability/incapacity, or is life threatening, a congenital anomaly/birth defect or requires medical or surgical intervention to prevent 1 of the outcomes above. The intensity of an AE was graded according to the National Cancer Institute common terminology criteria for adverse events (NCI-CTCAE) version 4.03: Grade 1 (Mild); Grade 2 (Moderate); Grade 3 (Severe); Grade 4 (life-threatening).
Time frame: Baseline through 42-49 days after end of treatment, estimated up to 27 months (24 months with 100 day FU period).
Population: The safety population includes all subjects enrolled in the study who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment Group A :100mg of INCB24360 | Part 1 and 2 : Number of Participants With Treatment Emergent Adverse Events | 62 Participants |
| Treatment Group A :300mg of INCB24360 | Part 1 and 2 : Number of Participants With Treatment Emergent Adverse Events | 8 Participants |
Primary
Part 1 and 2: Objective Response Rate Based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
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. CR is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. A participant was considered as an objective responder if the participant had a best overall response of CR or PR.
Time frame: Every 9 weeks for the duration of study participation; estimated minimum of 6 months.
Population: The response evaluable population includes all subjects enrolled in the study who received at least 1 dose of study drug, completed a baseline scan and have at least 1 post baseline scan, or has been on study for a minimum of 70 days of follow-up or who discontinued treatment. No participants enrolled in part 2 of the study due to early termination of study
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment Group A :100mg of INCB24360 | Part 1 and 2: Objective Response Rate Based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | 3 Participants |
| Treatment Group A :300mg of INCB24360 | Part 1 and 2: Objective Response Rate Based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | 1 Participants |
| Treatment Group B :INCB057643+Pembrolizumab+Epacadostat | Part 1 and 2: Objective Response Rate Based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | 0 Participants |
| Treatment Group C :INCB059872+Pembrolizumab+Epacadostat | Part 1 and 2: Objective Response Rate Based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | 0 Participants |
Secondary
Parts 1 and 2: Duration of Response Based on RECIST v1.1
Defined as the time from earliest date of disease response until the earliest date of disease progression per RECIST v1.1, or death due to any cause, if occurring sooner than progression.
Time frame: Every 9 weeks from date of randomization until the date of first documented progression or date of death from any cause whichever came first, assessed up to 24 months
Population: All subjects enrolled in the study who received at least 1 dose of study drug, completed a baseline scan and have at least 1 post baseline scan, or has been on study for a minimum of 70 days of follow-up or who discontinued treatment. No participants enrolled in part 2 of the study due to early termination of study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment Group A :100mg of INCB24360 | Parts 1 and 2: Duration of Response Based on RECIST v1.1 | 2.63 Months |
| Treatment Group A :300mg of INCB24360 | Parts 1 and 2: Duration of Response Based on RECIST v1.1 | 1.22 Months |
Secondary
Parts 1 and 2: Percentage of Responders Determined by Immunohistochemistry
Responder is defined as an increase in the number of tumor-infiltrating lymphocytes or the ratio of CD8+ lymphocytes to T regulatory cells infiltrating tumor post-treatment versus pretreatment with pembrolizumab and epacadostat in combination with azacitidine.
Time frame: Baseline to Week 5/6 or week 8/9
Population: All subjects enrolled in the study who received at least 1 dose of study drug, who had evaluable baseline and on treatment biopsies. No participants enrolled in part 2 of the study due to early termination of study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment Group A :100mg of INCB24360 | Parts 1 and 2: Percentage of Responders Determined by Immunohistochemistry | Intratumoral CD8+ T cells | 14 Participants |
| Treatment Group A :100mg of INCB24360 | Parts 1 and 2: Percentage of Responders Determined by Immunohistochemistry | CD8+:FoxP3+ ratios | 10 Participants |
Secondary
Parts 1 and 2: Progression-free Survival Based on RECIST v1.1.
Defined as the time from date of first dose of study drug until the earliest date of disease progression per RECIST v1.1, or death due to any cause, if occurring sooner than progression.
Time frame: Every 9 weeks from date of randomization until the date of first documented progression or date of death from any cause whichever came first, assessed up to 24 months
Population: All subjects enrolled in the study who received at least 1 dose of study drug, completed a baseline scan and have at least 1 post baseline scan, or has been on study for a minimum of 70 days of follow-up or who discontinued treatment. No participants enrolled in part 2 of the study due to early termination of study
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment Group A :100mg of INCB24360 | Parts 1 and 2: Progression-free Survival Based on RECIST v1.1. | 2.07 Months |
| Treatment Group A :300mg of INCB24360 | Parts 1 and 2: Progression-free Survival Based on RECIST v1.1. | 2.64 Months |