A Phase 1/2 Study of INCB001158 in Combination With Chemotherapy in Subjects With Solid Tumors

Study Overview
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Brief Summary
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The purpose of this open-label nonrandomized Phase 1/2 study is to evaluate INCB001158 in combination with chemotherapy in participants with advanced/metastatic solid tumors.

Official Title
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A Phase 1/2 Study to Evaluate the Safety, Tolerability, and Efficacy of INCB001158 in Combination With Chemotherapy, in Subjects With Advanced or Metastatic Solid Tumors

Conditions
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Biliary Tract Cancer (BTC), Colorectal Cancer (CRC), Endometrial Cancer, Gastroesophageal Cancer (GC), Ovarian Cancer, Solid Tumors

Intervention / Treatment
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* Drug: INCB001158
* Drug: Oxaliplatin
* Drug: Leucovorin
* Drug: 5-Fluorouracil
* Drug: Gemcitabine
* Drug: Cisplatin
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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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. Baseline archival tumor specimen available or willingness to undergo a pretreatment tumor biopsy to obtain the specimen. Resolution of treatment-related toxicities. Adequate hepatic, renal, cardiac, and hematologic function. Additional cohort-specific criteria may apply. Exclusion Criteria: Subjects who participated in any other study in which receipt of an investigational study drug or device occurred within 28 days or 5 half-lives (whichever is longer) prior to first dose. Has received a prior monoclonal antibody within 4 weeks or 5 half-lives (whichever is shorter) before administration of study drug. Has had prior chemotherapy or targeted small molecule therapy within 2 weeks before administration of study treatment. Has received prior approved radiotherapy within 14 days of study therapy. Has had known additional malignancy that is progressing or requires active treatment, or history of other malignancy within 2 years of study entry. Has an active autoimmune disease that has required systemic treatment in past 2 years. Has an active infection requiring systemic therapy. Has known active CNS metastases and/or carcinomatous meningitis. Women who are pregnant or breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Group A<br>INCB001158 + FOLFOX | Drug: INCB001158<br>* Phase 1: INCB001158 administered orally twice daily at the protocol-defined dose. Phase 2: INCB001158 administered orally twice daily at the recommended dose from Phase 1.<br>* Other names: Arginase inhibitor;Drug: Oxaliplatin<br>* Oxaliplatin administered intravenously at the protocol-defined dose and schedule.<br>Drug: Leucovorin<br>* Leucovorin at the protocol-defined dose and regimen.<br>Drug: 5-Fluorouracil<br>* 5-Fluorouracil at the protocol-defined dose and regimen.<br>|
| Experimental: Treatment Group B<br>INCB001158 + gemcitabine/cisplatin | Drug: INCB001158<br>* Phase 1: INCB001158 administered orally twice daily at the protocol-defined dose. Phase 2: INCB001158 administered orally twice daily at the recommended dose from Phase 1.<br>* Other names: Arginase inhibitor;Drug: Gemcitabine<br>* Gemcitabine at the protocol-defined dose and regimen.<br>Drug: Cisplatin<br>* Cisplatin at the protocol-defined dose and regimen.<br>|
| Experimental: Treatment Group C<br>INCB001158 + paclitaxel | Drug: INCB001158<br>* Phase 1: INCB001158 administered orally twice daily at the protocol-defined dose. Phase 2: INCB001158 administered orally twice daily at the recommended dose from Phase 1.<br>* Other names: Arginase inhibitor;Drug: Paclitaxel<br>* Paclitaxel at the protocol-defined dose and regimen.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phases 1 and 2: Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related, that occurred after a participant provided informed consent. Abnormal laboratory values or test results occurring after informed consent constituted AEs only if they induced clinical signs or symptoms, were considered clinically meaningful, required therapy (e.g., hematologic abnormality that required transfusion), or required changes in the study drug(s). A TEAE was defined as any AE either reported for the first time or the worsening of a pre-existing event after the first dose of study drug. | up to 1385 days | 
| Phase 1: Number of Participants With Any Dose-limiting Toxicity (DLT) | A DLT was defined as the occurrence of any protocol-defined toxicity occurring up to and including Day 28, except those with a clear alternative explanation (e.g., disease progression) or transient (≤72 hours) abnormal laboratory values without associated clinically significant signs or symptoms based on investigator determination. All DLTs were assessed by the investigator using Common Terminology Criteria for Adverse Events (CTCAE) v4.03 criteria. | up to Day 28 | 
| Recommended Phase 2 Dose (RP2D) of INCB001158 When Given in Combination With Each Chemotherapy Regimen | The RP2D of the combination of INCB001158 and chemotherapy in 21-day (for gemcitabine/cisplatin) or 28-day (for mFOLFOX6 or paclitaxel) treatment cycles in participants with advanced or metastatic solid tumors was determined. After the dose escalation was completed, the INCB001158 dose level that was pharmacologically active and tolerable in combination with each chemotherapy regimen (i.e., maximum tolerated dose or lower) was determined to be the RP2D. The RP2D was then further assessed in tumor expansion cohorts in Phase 2. | up to Day 580 | 
| Phase 2: Objective Response Rate (ORR) | ORR was defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR), as determined by investigator assessment of radiographic disease as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1). CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to <10 millimeters (mm). PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. Analysis was conducted by cohort (tumor type) in Phase 2 because different tumor types could have different response criteria or different background response rates. | up to 1385 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: ORR | ORR was defined as the percentage of participants with a confirmed best overall response of CR or PR, as determined by investigator assessment of radiographic disease as per RECIST v1.1. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to <10 mm. PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the Baseline sum diameters, no new lesions, and no progression of non-target lesions. | up to 580 days | 
| Phases 1 and 2: Duration of Response | DOR was defined as the time from initial objective response (CR or PR) (as determined by investigator assessment of radiographic disease assessment per RECIST v1.1) until the earliest date of disease progression or death due to any cause, if it occurred sooner than disease progression. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to <10 mm. PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. PD: progression of a target or non-target lesion or presence of a new lesion. | up to 368 days | 
| Phases 1 and 2: Disease Control Rate | DCR was defined as the percentage of participants with an overall response of CR, PR, or stable disease (SD), as determined by investigator assessment of radiographic disease as per RECIST v1.1, for at least 8 weeks. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to <10 mm. PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. PD: progression of a target or non-target lesion or presence of a new lesion. SD: no change in target lesions to qualify for CR, PR, or PD. | up to 1385 days | 
| Phases 1 and 2: Progression-free Survival | According to RECIST 1.1, PFS was defined as the length of time from the date of the first dose study of drug until the earliest date of disease progression, as determined by investigator assessment of radiographic disease per RECIST v1.1, or death due to any cause, if it occurred sooner than progression. | up to 1385 days | 
| Cmin of INCB001158 in Participants Treated With INCB001158 in Combination With Chemotherapy on Cycle 2 Day 1 Following Repeated Dose Administration | Cmin was defined as the minimum observed plasma concentration over the dose interval. Extensive sample collection was used for the first 12 participants enrolled in each chemotherapy regimen. Sparse sample collection was used for the 13th participant enrolled and onward. | Day 1 of Cycle 2: predose; 0.5, 1, 2, 4, 6, and 8-10 hours post-dose for extensive sample collection. Day 1 of Cycle 2: predose; 1 and 4 hours post-dose for sparse sample collection | 
| Cmax of INCB001158 in Participants Treated With INCB001158 in Combination With Chemotherapy Following the First Dose on Cycle 1 Day 1 and on Cycle 2 Day 1 Following Repeated Dose Administration | Cmax was defined as the maximum observed plasma concentration over the dose interval. Extensive sample collection was used for the first 12 participants enrolled in each chemotherapy regimen. Sparse sample collection was used for the 13th participant enrolled and onward. | Day 1 of Cycles 1 and 2: predose; 0.5, 1, 2, 4, 6, and 8-10 hours post-dose for extensive sample collection. Day 1 of Cycles 1 and 2: predose; 1 and 4 hours post-dose for sparse sample collection | 
| Tmax of INCB001158 in Participants Treated With INCB001158 in Combination With Chemotherapy Following the First Dose on Cycle 1 Day 1 and on Cycle 2 Day 1 Following Repeated Dose Administration | tmax was defined as the time to the maximum concentration. Extensive sample collection was used for the first 12 participants enrolled in each chemotherapy regimen. Sparse sample collection was used for the 13th participant enrolled and onward. | Day 1 of Cycles 1 and 2: predose; 0.5, 1, 2, 4, 6, and 8-10 hours post-dose for extensive sample collection. Day 1 of Cycles 1 and 2: predose; 1 and 4 hours post-dose for sparse sample collection | 
| AUC0-t of INCB001158 in Participants Treated With INCB001158 in Combination With Chemotherapy Following the First Dose on Cycle 1 Day 1 and on Cycle 2 Day 1 Following Repeated Dose Administration | AUC0-t was defined as the area under the plasma concentration-time curve from time = 0 to the last measurable concentration at time = t. Extensive sample collection was used for the first 12 participants enrolled in each chemotherapy regimen. Sparse sample collection was used for the 13th participant enrolled and onward. | Day 1 of Cycles 1 and 2: predose; 0.5, 1, 2, 4, 6, and 8-10 hours post-dose for extensive sample collection. Day 1 of Cycles 1 and 2: predose; 1 and 4 hours post-dose for sparse sample collection | 
| Tlast of INCB001158 in Participants Treated With INCB001158 in Combination With Chemotherapy Following the First Dose on Cycle 1 Day 1 and on Cycle 2 Day 1 Following Repeated Dose Administration | tlast was defined as the time of the last sample collected from which a concentration was measured. Extensive sample collection was used for the first 12 participants enrolled in each chemotherapy regimen. Sparse sample collection was used for the 13th participant enrolled and onward. | Day 1 of Cycles 1 and 2: predose; 0.5, 1, 2, 4, 6, and 8-10 hours post-dose for extensive sample collection. Day 1 of Cycles 1 and 2: predose; 1 and 4 hours post-dose for sparse sample collection | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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INCB001158, arginase inhibitor, oxaliplatin, leucovorin, 5 fluorouracil, gemcitabine, cisplatin, paclitaxel, solid tumors, colorectal cancer, biliary tract cancer, gastroesophageal cancer, endometrial cancer, ovarian cancer