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

Safety, Pharmacokinetics, and Pharmacodynamics of Escalating Oral Doses of the Arginase Inhibitor INCB001158 (Formerly Known as CB1158) as a Single Agent and in Combination With Immune Checkpoint Therapy in Patients With Advanced/Metastatic Solid Tumors

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.

Study Overview

• Status: Completed
• Conditions: Head and Neck Cancer; Gastric Cancer; Lung Cancer; Metastatic Cancer; Mesothelioma; Bladder Cancer; Solid Tumors; Renal Cell Carcinoma (RCC); Colorectal Cancer (CRC); UC (Urothelial Cancer)
• Intervention / Treatment: Drug: Pembrolizumab; Drug: INCB001158

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.

• Study Type: Interventional
• Enrollment (Actual): 260
• Phase: Phase 1

Contacts and Locations

Study Locations

• Italy
  • Milan, Italy, 20132
    • Ospedale San Raffaele
  • Siena, Italy, 53100
    • Oncologica Azienda Ospedaliera Universitaria Senese
• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • NKI
  • Nijmegen, Netherlands, HP 452
    • Radboudumc
• Spain
  • Barcelona, Spain, 8035
    • Hospital Universitari Vall d'Hebron
  • Barcelona, Spain, 8908
    • Institut Catala d'Oncologia
  • Madrid, Spain, 28050
    • START Madrid-HM CIOCC
• United States
  • Alabama
    • Mobile, Alabama, United States, 36604
      • University of South Alabama
  • Arizona
    • Scottsdale, Arizona, United States, 85258
      • Honor Health/Pinnacle Oncology Hematology
    • Tucson, Arizona, United States, 85719
      • University of Arizona
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • DFCI
    • Boston, Massachusetts, United States, 02215
      • BIDMC
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute at Tennessee Oncology
  • Texas
    • Houston, Texas, United States, 77230
      • MD Anderson
    • Houston, Texas, United States, 77230-1402
      • MD Anderson
    • San Antonio, Texas, United States, 78229
      • START

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

*Additional cohort specific criteria may apply

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Factorial Assignment
• Masking: None (Open Label)

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: INCB00158 was administered as monotherapy at 50mg twice daily; 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).	Drug: INCB001158; Arginase Inhibitor; Other Names: CB-1158
Experimental: INCB00158 was administered as monotherapy at 75mg twice daily; 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).	Drug: INCB001158; Arginase Inhibitor; Other Names: CB-1158
Experimental: INCB00158 was administered as monotherapy at 100mg twice daily; Monotherapy Part 2b: INCB001158 administered orally at the RP2D in patients with advanced/metastatic CRC previously treated with SOC.	Drug: INCB001158; Arginase Inhibitor; Other Names: CB-1158
Experimental: INCB00158 was administered as monotherapy at 150mg twice daily; 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.	Drug: INCB001158; Arginase Inhibitor; Other Names: CB-1158
Experimental: INCB00158 was administered in combination with pembroluzimab at 50mg twice daily; Monotherapy Part 2d: INCB001158 administered orally at the RP2D in patients with any tumor types in Parts 2a, 2b, or 2c.	Drug: INCB001158; Arginase Inhibitor; Other Names: CB-1158
Experimental: INCB00158 was administered in combination with pembroluzimab at 75mg twice daily; 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).	Drug: Pembrolizumab; PD-1 Inhibitor; Other Names: Keytruda; Drug: INCB001158; Arginase Inhibitor; Other Names: CB-1158
Experimental: INCB00158 was administered in combination with pembroluzimab at 100mg twice daily; 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.	Drug: Pembrolizumab; PD-1 Inhibitor; Other Names: Keytruda; Drug: INCB001158; Arginase Inhibitor; Other Names: CB-1158
Experimental: INCB001158 50 mg BID in combination with pembrolizumab; Part C: evaluated a reduced dose of INCB001158 50 mg BID in combination with pembrolizumab with patients with moderately impaired renal function.	Drug: Pembrolizumab; PD-1 Inhibitor; Other Names: Keytruda; Drug: INCB001158; Arginase Inhibitor; Other Names: CB-1158

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 treatment(s). A TEAE was defined as any adverse event that started or worsened after the first dose of study drug.	up to study completion (up to approximately 3.5 years)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recommended Phase 2 Dose (RP2D) of INCB001158	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.	12 weeks
RP2D of INCB001158 in Combination With Pembrolizumab	INCB001158 was dosed orally BID.	12 weeks
Objective Response Rate (ORR)	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.	Until disease progression/study discontinuation (up to approximately 5 years)
Percentage of Participants With the Indicated Best Overall Response (BOR)	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.	Until disease progression/study discontinuation (up to approximately 5 years)
Duration of Response (DOR)	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.	Until disease progression/study discontinuation (up to approximately 5 years)
Progression-free Survival (PFS)	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.	Until disease progression/study discontinuation (up to approximately 5 years)
Cmax of INCB001158 Following Single Escalating Doses for Part 1A	Cmax was defined as the maximum observed concentration of INCB001158.	Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose
Tmax of INCB001158 Following Single Escalating Doses for Part 1A	tmax was defined as the time of the maximum observed concentration of INCB001158.	Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose
AUC0-t of INCB001158 Following Single Escalating Doses for Part 1A	AUC0-t was defined as the area under the concentration-time curve from dosing (time 0) of INCB001158 to time t.	Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose
AUC0-inf of INCB001158 Following Single Escalating Doses for Part 1A	AUC0-inf was defined as the area under the concentration-time curve from dosing (time 0) of INCB001158 extrapolated to infinity.	Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose
t1/2 of INCB001158 Following Single Escalating Doses for Part 1A	t1/2 was defined as the half-life of INCB001158.	Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose
CL/F of INCB001158 Following Single Escalating Doses for Part 1A	CL/F was defined as the apparent oral dose clearance of INCB001158.	Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose
Vz/F of INCB001158 Following Single Escalating Doses for Part 1A	Vz/F was defined as the apparent volume of distribution of INCB001158.	Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose
Cmax of INCB001158 Following Multiple Escalating Doses for Part 1A	Cmax was defined as the maximum observed concentration of INCB001158.	Cycle 1 Day 15: predose; 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose
Tmax of INCB001158 Following Multiple Escalating Doses for Part 1A	tmax was defined as the time of the maximum observed concentration of INCB001158.	Cycle 1 Day 15: predose; 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose
AUC0-t of INCB001158 Following Multiple Escalating Doses for Part 1A	AUC0-t was defined as the area under the concentration-time curve from dosing (time 0) of INCB001158 to time t.	Cycle 1 Day 15: predose; 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose
AUC0-tau of INCB001158 Following Multiple Escalating Doses for Part 1A	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.	Cycle 1 Day 15: predose; 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose
t1/2 of INCB001158 Following Multiple Escalating Doses for Part 1A	t1/2 was defined as the half-life of INCB001158.	Cycle 1 Day 15: predose; 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose
CL/F of INCB001158 Following Multiple Escalating Doses for Part 1A	CL/F was defined as the apparent oral dose clearance of INCB001158.	Cycle 1 Day 15: predose; 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose
Vz/F of INCB001158 Following Multiple Escalating Doses for Part 1A	Vz/F was defined as the apparent volume of distribution of INCB001158.	Cycle 1 Day 15: predose; 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose
Cmax of INCB001158 in the Fed and Fasted States Following Multiple Doses for Part 1A to Assess the Effect of Food	Cmax was defined as the maximum observed concentration of INCB001158.	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 of INCB001158 in the Fed and Fasted States Following Multiple Doses for Part 1A to Assess the Effect of Food	tmax was defined as the time of the maximum observed concentration of INCB001158.	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 of INCB001158 in the Fed and Fasted States Following Multiple Doses for Part 1A to Assess the Effect of Food	AUC was defined as the area under the concentration-time curve of INCB001158.	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 of INCB001158 for Capsules Versus Tablets for Part 2D to Assess the Effect of Formulation	Cmax was defined as the maximum observed concentration of INCB001158.	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 of INCB001158 for Capsules Versus Tablets for Part 2D to Assess the Effect of Formulation	tmax was defined as the time of the maximum observed concentration of INCB001158.	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 of INCB001158 for Capsules Versus Tablets for Part 2D to Assess the Effect of Formulation	AUC0-t was defined as the area under the concentration-time curve from dosing (time 0) of INCB001158 to time t.	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 of INCB001158 for Capsules Versus Tablets for Part 2D to Assess the Effect of Formulation	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.	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 of INCB001158 in Participants With Renal Impairment (Part 1C) and Normal Renal Function (Part 1A)	Cmax was defined as the Maximum observed concentration of INCB001158.	Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, 8, 12, and 24 (Part 1A only) hours post-dose.
Tmax of INCB001158 in Participants With Renal Impairment (Part 1C) and Normal Renal Function (Part 1A)	tmax was defined as the time of the maximum observed concentration of INCB001158.	Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, 8, 12, and 24 (Part 1A only) hours post-dose.
AUC0-8h of INCB001158 in Participants With Renal Impairment (Part 1C) and Normal Renal Function (Part 1A)	AUC0-8h was defined as the area under the concentration-time curve from dosing (time 0) of INCB001158 to 8 hours post-dose.	Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, and 8 hours post-dose

Collaborators and Investigators

• Sponsor: Incyte Corporation
• Investigators: Study Director: Sven Gogov, MD, Incyte Corporation; Study Director: Emil Kuriakose, MD, Calithera Biosciences, Inc

Study record dates

Study Major Dates

• Study Start (Actual): September 14, 2016
• Primary Completion (Actual): April 30, 2020
• Study Completion (Actual): August 15, 2022

Study Registration Dates

• First Submitted: September 9, 2016
• First Submitted That Met QC Criteria: September 13, 2016
• First Posted (Estimated): September 16, 2016

Study Record Updates

• Last Update Posted (Actual): August 5, 2025
• Last Update Submitted That Met QC Criteria: August 1, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: NSCLC; Solid Tumors; SCCHN; GEJ; Immune Therapy; RCC; Tumor Metabolism; Immuno-Oncology; Checkpoint Inhibitors; Arginase; Programmed cell death protein-1 (PD-1) inhibitor; Programmed death ligand 1 (PD-L1) inhibitor; MEL; Arginase Inhibitor; INCB001158 (CB-1158)
• Additional Relevant MeSH Terms: Urogenital Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Adenoma; Neoplasms, Mesothelial; Urologic Neoplasms; Carcinoma; Kidney Neoplasms; Mesothelioma; Carcinoma, Renal Cell; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Pembrolizumab
• Other Study ID Numbers: INCB 01158-101; Mk3475 Keynote 741 (Other Identifier: Merck); 2017-002903-82 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No