Arginase Inhibitor INCB001158 as a Single Agent and in Combination With Immune Checkpoint Therapy in Patients With Advanced/Metastatic Solid Tumors

Phase 1

Completed

Conditions: Lung Cancer
Renal Cell Carcinoma (RCC)
Mesothelioma
Metastatic Cancer
Solid Tumors
Colorectal Cancer (CRC)
Bladder Cancer
UC (Urothelial Cancer)
Gastric Cancer
Head and Neck Cancer

Interventions: Drug: INCB001158
Drug: Pembrolizumab

Registration Number: NCT02903914

Lead Sponsor: Incyte Corporation

Brief Summary: This study is an open-label Phase 1/Phase 2 evaluation of INCB001158 as a single agent and in combination with immune checkpoint therapy in patients with advanced/metastatic solid tumors.

Detailed Description: This study is an open-label Phase 1 evaluation of INCB001158 as a single agent and in combination with immune checkpoint therapy in patients with advanced/metastatic solid tumors.

Single Agent INCB001158:

Patients with advanced/metastatic solid tumors will be enrolled into escalating monotherapy dose cohorts to determine the Recommended Phase 2 Dose (RP2D) of INCB001158. Additional patients with NSCLC, Colorectal Cancer (CRC), and other tumors including SCCHN, RCC, Gastric, Bladder and Melanoma will be enrolled at the single agent RP2D.

Combination Treatment:

Patients with advanced/metastatic NSCLC, Melanoma, Urothelial, Microsatellite Instability (MSI)/ Microsatellite Stable (MSS) CRC, Gastric, SCCHN and Mesothelioma will be enrolled into separate cohorts of combination therapy (INCB001158 and Pembrolizumab) to determine the RP2D.

In the dose expansion phase, additional patients with NSCLC, Melanoma, Urothelial, MSI/MSS CRC, Gastric, SCCHN and Mesothelioma will be treated with the combination of INCB001158 and Pembrolizumab at the RP2D.

All patients will be assessed for safety, pharmacokinetics, biomarkers and tumor response.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 260

Inclusion Criteria

Must be age 18 or older
Ability to provide written informed consent in accordance with federal, local, and institutional guidelines
Histological or cytological diagnosis of metastatic cancer or locally advanced cancer that is not amenable to local therapy
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1
Life Expectancy of at least 3 months
Adequate hepatic, renal (moderately impaired renal function in cohort 1c only), cardiac, and hematologic function
Measurable disease by RECISTv1.1 criteria
Resolution of treatment-related toxicities
Willingness to avoid pregnancy or fathering children
Prior anti-PD-1 treatment for combination dose expansion cohorts 1c, 3a - 3d

Exclusion Criteria

Currently pregnant or lactating
Unable to receive oral medications
Unable to receive oral or IV hydration
Intolerance to prior anti-PD-1/PD-L1 therapy
Prior anti-PD-1 treatment for combination dose expansion cohorts 1c, 3e - 3h
Prior severe hypersensitivity reaction to another monoclonal antibody (mAb)
Any other current or previous malignancy within 3 years except protocol allowed malignancies
Chemotherapy, Tyrosine Kinase Inhibitor therapy, radiation therapy or hormonal therapy within 2 weeks
Immunotherapy or biological therapy, or investigational agent within 3 weeks (Note: some cohort exceptions allow anti-PD-1 therapy)
Active known or suspected exclusionary autoimmune disease
Any condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other systemic immunosuppressive medications within 2 weeks
Concomitant therapy with valproic acid/valproate-containing therapies
Concomitant therapy with allopurinol and other xanthine oxidase inhibitors
History of known risks factors for bowel perforation
Symptomatic ascites or pleural effusion
Major surgery within 28 days before Cycle 1 Day 1
Active infection requiring within 2 weeks prior to first dose of study drug
Patients who have HIV, Hepatitis B or C
Conditions that could interfere with treatment or protocol-related procedures
Active, non-stable brain metastases or CNS disease
Known deficiencies or suspected defect in the urea cycle
Received live-virus vaccination within 30 days (seasonal flu vaccine allowed if non-live virus)
NSCLC with EGFR or ALK mutation

Study & Design

Study Type: INTERVENTIONAL

Study Design: FACTORIAL

Arm && Interventions

Group	Intervention	Description
INCB00158 was administered as monotherapy at 50mg twice daily	INCB001158	Monotherapy Part 1a: INCB001158 administered orally in patients with advanced/metastatic solid tumors. Escalating doses will be explored to determine the recommended phase 2 dose (RP2D).
INCB00158 was administered in combination with pembroluzimab at 100mg twice daily	INCB001158	Part 3a: INCB001158 and Pembrolizumab the combination RP2D in patients with advanced/metastatic NSCLC (EGFR and ALK negative) with disease progression on anti-PD-1 therapy or prolonged stable disease on Pembrolizumab in the immediate prior line of therapy.
INCB00158 was administered in combination with pembroluzimab at 100mg twice daily	Pembrolizumab	Part 3a: INCB001158 and Pembrolizumab the combination RP2D in patients with advanced/metastatic NSCLC (EGFR and ALK negative) with disease progression on anti-PD-1 therapy or prolonged stable disease on Pembrolizumab in the immediate prior line of therapy.
INCB00158 was administered as monotherapy at 75mg twice daily	INCB001158	Monotherapy Part 2a: INCB001158 administered orally at the RP2D in patients with advanced/metastatic NSCLC (EGFR and Anaplastic Lymphoma Kinase (ALK) negative) previously treated with Standard of Care (SOC).
INCB00158 was administered as monotherapy at 100mg twice daily	INCB001158	Monotherapy Part 2b: INCB001158 administered orally at the RP2D in patients with advanced/metastatic CRC previously treated with SOC.
INCB00158 was administered in combination with pembroluzimab at 50mg twice daily	INCB001158	Monotherapy Part 2d: INCB001158 administered orally at the RP2D in patients with any tumor types in Parts 2a, 2b, or 2c.
INCB00158 was administered as monotherapy at 150mg twice daily	INCB001158	Monotherapy Part 2c: INCB001158 administered orally at the RP2D in patients with Bladder Cancer, Gastric or Gastroesophageal Junction (GEJ) Cancer, Renal Cell Cancer (RCC), Squamous Cell Carcinoma of the Head and Neck (SCCHN), Urothelial Cell Cancer (UCC), or Melanoma, previously treated with SOC.
INCB00158 was administered in combination with pembroluzimab at 75mg twice daily	INCB001158	Combination Part 1b: INCB001158 and Pembrolizumab administered in patients with advanced/metastatic NSCLC, Melanoma, Urothelial Cell Cancer, MSI CRC, MSS CRC, Gastric or Gastroesophageal Junction (GEJ) Cancer, SCCHN and Mesothelioma. Multiple dose levels will be explored to determine the recommended phase 2 dose (RP2D).
INCB00158 was administered in combination with pembroluzimab at 75mg twice daily	Pembrolizumab	Combination Part 1b: INCB001158 and Pembrolizumab administered in patients with advanced/metastatic NSCLC, Melanoma, Urothelial Cell Cancer, MSI CRC, MSS CRC, Gastric or Gastroesophageal Junction (GEJ) Cancer, SCCHN and Mesothelioma. Multiple dose levels will be explored to determine the recommended phase 2 dose (RP2D).
INCB001158 50 mg BID in combination with pembrolizumab	Pembrolizumab	Part C: evaluated a reduced dose of INCB001158 50 mg BID in combination with pembrolizumab with patients with moderately impaired renal function.
INCB001158 50 mg BID in combination with pembrolizumab	INCB001158	Part C: evaluated a reduced dose of INCB001158 50 mg BID in combination with pembrolizumab with patients with moderately impaired renal function.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Any Treatment-emergent Adverse Event (TEAE)	up to study completion (up to approximately 3.5 years)	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 treatment(s). A TEAE was defined as any adverse event that started or worsened after the first dose of study drug.

Secondary Outcome Measures

Name	Time	Method
Recommended Phase 2 Dose (RP2D) of INCB001158	12 weeks	The RP2D was determined by a traditional 3+3 dose-escalation design of single-agent INCB001158 in participants with advanced/metastatic solid tumors at doses of 50, 75, 100, or 150 mg.
RP2D of INCB001158 in Combination With Pembrolizumab	12 weeks	INCB001158 was dosed orally BID.
Objective Response Rate (ORR)	Until disease progression/study discontinuation (up to approximately 5 years)	ORR was defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1) as the percentage of participants with a confirmed best overall response of complete response (CR) or partial response (PR) at any post-Baseline visits prior to first disease progression and alternative cancer therapy use. 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. Pleural mesothelioma was evaluated using modified RECIST criteria. Confidence intervals were calculated based on the exact method for binomial distributions (Clopper Pearson). Two participants evaluable for PFS were not evaluable for response.
Percentage of Participants With the Indicated Best Overall Response (BOR)	Until disease progression/study discontinuation (up to approximately 5 years)	BOR was evaluated 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. Stable disease (SD): no change in target lesions to qualify for CR, PR, or progressive disease (PD). PD: progression of a target or non-target lesion or presence of a new lesion. Missing: participant had a missing BOR because there were no post-Baseline tumor assessments. Pleural mesothelioma was evaluated using modified RECIST criteria.
Duration of Response (DOR)	Until disease progression/study discontinuation (up to approximately 5 years)	DOR was defined as the number of months from the date of the first documentation of an objective response (CR or PR per RECIST v1.1) to the date of the first documentation of disease progression or death, whichever occurred first. 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. Pleural mesothelioma will be evaluated using modified RECIST criteria. Kaplan-Meier (KM) product-limit estimates with a log-log transformation were used for 95% confidence interval calculation.
Progression-free Survival (PFS)	Until disease progression/study discontinuation (up to approximately 5 years)	PFS was defined as the length of time between the date of the first dose and the earlier of death or progressive disease as assessed by RECIST v1.1. Pleural mesothelioma was evaluated using modified RECIST criteria. Participants enrolled in Part 1c had renal impairment. These participants received INCB001158 50 mg + pembrolizumab, which was half the recommended Phase 2 dose of INCB001158. In renally impaired participants, the 50 mg dose has comparable exposure to 100 mg in participants with normal renal function. It was pre-specified to combine Part 1c and Part 3 participants for efficacy analysis based on planned comparable dosing according to renal function.
Cmax of INCB001158 Following Single Escalating Doses for Part 1A	Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose	Cmax was defined as the maximum observed concentration of INCB001158.
Tmax of INCB001158 Following Single Escalating Doses for Part 1A	Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose	tmax was defined as the time of the maximum observed concentration of INCB001158.
AUC0-t of INCB001158 Following Single Escalating Doses for Part 1A	Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose	AUC0-t was defined as the area under the concentration-time curve from dosing (time 0) of INCB001158 to time t.
AUC0-inf of INCB001158 Following Single Escalating Doses for Part 1A	Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose	AUC0-inf was defined as the area under the concentration-time curve from dosing (time 0) of INCB001158 extrapolated to infinity.
t1/2 of INCB001158 Following Single Escalating Doses for Part 1A	Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose	t1/2 was defined as the half-life of INCB001158.
CL/F of INCB001158 Following Single Escalating Doses for Part 1A	Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose	CL/F was defined as the apparent oral dose clearance of INCB001158.
Vz/F of INCB001158 Following Single Escalating Doses for Part 1A	Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose	Vz/F was defined as the apparent volume of distribution of INCB001158.
Cmax of INCB001158 Following Multiple Escalating Doses for Part 1A	Cycle 1 Day 15: predose; 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose	Cmax was defined as the maximum observed concentration of INCB001158.
Tmax of INCB001158 Following Multiple Escalating Doses for Part 1A	Cycle 1 Day 15: predose; 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose	tmax was defined as the time of the maximum observed concentration of INCB001158.
AUC0-t of INCB001158 Following Multiple Escalating Doses for Part 1A	Cycle 1 Day 15: predose; 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose	AUC0-t was defined as the area under the concentration-time curve from dosing (time 0) of INCB001158 to time t.
AUC0-tau of INCB001158 Following Multiple Escalating Doses for Part 1A	Cycle 1 Day 15: predose; 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose	AUC0-tau was defined as the area under the concentration-time curve from dosing (time 0) of INCB001158 to the end of the dosing period.
t1/2 of INCB001158 Following Multiple Escalating Doses for Part 1A	Cycle 1 Day 15: predose; 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose	t1/2 was defined as the half-life of INCB001158.
CL/F of INCB001158 Following Multiple Escalating Doses for Part 1A	Cycle 1 Day 15: predose; 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose	CL/F was defined as the apparent oral dose clearance of INCB001158.
Vz/F of INCB001158 Following Multiple Escalating Doses for Part 1A	Cycle 1 Day 15: predose; 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose	Vz/F was defined as the apparent volume of distribution of INCB001158.
Cmax of INCB001158 in the Fed and Fasted States Following Multiple Doses for Part 1A to Assess the Effect of Food	Fasted: Cycle 1 Day 15: predose; 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose. Fed: Cycle 2 Day 8: predose; 0.5, 1, 2, 4, 6, and 8 hours post-dose	Cmax was defined as the maximum observed concentration of INCB001158.
Tmax of INCB001158 in the Fed and Fasted States Following Multiple Doses for Part 1A to Assess the Effect of Food	Fasted: Cycle 1 Day 15: predose; 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose. Fed: Cycle 2 Day 8: predose; 0.5, 1, 2, 4, 6, and 8 hours post-dose	tmax was defined as the time of the maximum observed concentration of INCB001158.
AUC of INCB001158 in the Fed and Fasted States Following Multiple Doses for Part 1A to Assess the Effect of Food	Fasted: Cycle 1 Day 15: predose; 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose. Fed: Cycle 2 Day 8: predose; 0.5, 1, 2, 4, 6, and 8 hours post-dose	AUC was defined as the area under the concentration-time curve of INCB001158.
Cmax of INCB001158 for Capsules Versus Tablets for Part 2D to Assess the Effect of Formulation	Tablet: Cycle 1 Day 15 (Tablet) and Cycle 2 Day 1 (Capsule): predose; 0.5, 1, 2, 4, 6, 8, and 10 hours post-dose	Cmax was defined as the maximum observed concentration of INCB001158.
Tmax of INCB001158 for Capsules Versus Tablets for Part 2D to Assess the Effect of Formulation	Tablet: Cycle 1 Day 15 (Tablet) and Cycle 2 Day 1 (Capsule): predose; 0.5, 1, 2, 4, 6, 8, and 10 hours post-dose	tmax was defined as the time of the maximum observed concentration of INCB001158.
AUC0-t of INCB001158 for Capsules Versus Tablets for Part 2D to Assess the Effect of Formulation	Tablet: Cycle 1 Day 15 (Tablet) and Cycle 2 Day 1 (Capsule): predose; 0.5, 1, 2, 4, 6, 8, and 10 hours post-dose	AUC0-t was defined as the area under the concentration-time curve from dosing (time 0) of INCB001158 to time t.
AUC0-tau of INCB001158 for Capsules Versus Tablets for Part 2D to Assess the Effect of Formulation	Tablet: Cycle 1 Day 15 (Tablet) and Cycle 2 Day 1 (Capsule): predose; 0.5, 1, 2, 4, 6, 8, and 10 hours post-dose	AUC0-tau was defined as the area under the concentration-time curve from dosing (time 0) of INCB001158 to the end of the dosing period.
Cmax of INCB001158 in Participants With Renal Impairment (Part 1C) and Normal Renal Function (Part 1A)	Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, 8, 12, and 24 (Part 1A only) hours post-dose.	Cmax was defined as the Maximum observed concentration of INCB001158.
Tmax of INCB001158 in Participants With Renal Impairment (Part 1C) and Normal Renal Function (Part 1A)	Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, 8, 12, and 24 (Part 1A only) hours post-dose.	tmax was defined as the time of the maximum observed concentration of INCB001158.
AUC0-8h of INCB001158 in Participants With Renal Impairment (Part 1C) and Normal Renal Function (Part 1A)	Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, and 8 hours post-dose	AUC0-8h was defined as the area under the concentration-time curve from dosing (time 0) of INCB001158 to 8 hours post-dose.

Trial Locations

Locations (19): Johns Hopkins
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Baltimore, Maryland, United States
BIDMC
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Boston, Massachusetts, United States
MD Anderson
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Houston, Texas, United States
Radboudumc
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Nijmegen, Netherlands
Henry Ford
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Detroit, Michigan, United States
Sarah Cannon Research Institute at Tennessee Oncology
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Nashville, Tennessee, United States
DFCI
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Boston, Massachusetts, United States
Georgetown
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Washington, District of Columbia, United States
Vanderbilt
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Nashville, Tennessee, United States
Ospedale San Raffaele
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Milan, Italy
NKI
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Amsterdam, Netherlands
Hospital Universitari Vall d'Hebron
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Barcelona, Spain
START Madrid-HM CIOCC
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Madrid, Spain
University of South Alabama
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Mobile, Alabama, United States
Honor Health/Pinnacle Oncology Hematology
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Scottsdale, Arizona, United States
University of Arizona
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Tucson, Arizona, United States
START
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San Antonio, Texas, United States
Institut Catala d'Oncologia
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Barcelona, Spain
Oncologica Azienda Ospedaliera Universitaria Senese
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Siena, Italy