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 2; 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
• Genders Eligible for Study: All

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
Determination of the Safety and Tolerability of INCB001158 as a Single Agent and in Combination With Pembrolizumab: Incidence of Adverse Events	Evaluation of adverse events (AEs) and changes in laboratory values, vital signs, and physical examinations.	Up to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recommended Phase 2 Dose (RP2D) of INCB001158	RP2D was determined by a traditional 3+3 dose escalation design of single agent INCB001158 in patients with advanced/metastatic solid tumors at doses 50, 75, 100 or 150 mg.	12 Weeks
Recommended Phase 2 Dose (RP2D) of INCB001158 in Combination With Pembrolizumab	INCB001158 was dosed orally BID	12 Weeks
Overall Response Rate (ORR) Anti-tumor Activity of INCB001158 as Monotherapy and in Combination With Pembrolizumab for Patients With Advanced/Metastatic Solid Tumors	ORR assessment of anti-tumor activity per RECIST Criteria (v1.1) and immune-related RECIST (irRECIST) criteria.	Until disease progression/study discontinuation up to 24 months
Best Overall Response (BOR) Anti-tumor Activity of INCB001158 as Monotherapy and in Combination With Pembrolizumab for Patients With Advanced/Metastatic Solid Tumors	BOR Assessment of anti-tumor activity per RECIST Criteria (v1.1) and immune-related RECIST (irRECIST) criteria.	Until disease progression/study discontinuation up to 24 months
Duration of Response (DOR) Anti-tumor Activity of INCB001158 as Monotherapy and in Combination With Pembrolizumab for Patients With Advanced/Metastatic Solid Tumors	DOR Assessment of anti-tumor activity per RECIST Criteria (v1.1) and immune-related RECIST (irRECIST) criteria.	Until disease progression/study discontinuation up to 24 months
Progression-free Survival (PFS) Anti-tumor Activity of INCB001158 as Monotherapy and in Combination With Pembrolizumab for Patients With Advanced/Metastatic Solid Tumors	DOR Assessment of anti-tumor activity per RECIST Criteria (v1.1) and immune-related RECIST (irRECIST) criteria.	Until disease progression/study discontinuation up to 24 months
Pharmacokinetics: Cmax of INCB001158	Non-compartmental method of analysis will be used to analyze the plasma concentrations of INCB001158. in patients with CrCl 30-49 mL/min (Part 1c only) or CrCl ≥ 50 mL/min (Parts 1a, 1b, 2, and 3)	Cycle 1 Day 1 (C1D1), C1D15, C2D! + 2, C4D1
Tmax Plasma Pharmacokinetic (PK) Profile of INCB001158	Non-compartmental method of analysis will be used to analyze the plasma concentrations of INCB001158.	12 Weeks
AUCt Plasma Pharmacokinetic (PK) Profile of INCB001158	Non-compartmental method of analysis will be used to analyze the plasma concentrations of INCB001158.	12 Weeks
AUC0-12 Plasma Pharmacokinetic (PK) Profile of INCB001158	Non-compartmental method of analysis will be used to analyze the plasma concentrations of INCB001158.	12 Weeks
CL/F Plasma Pharmacokinetic (PK) Profile of INCB001158	Non-compartmental method of analysis will be used to analyze the plasma concentrations of INCB001158.	12 Weeks

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): August 31, 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 (Estimate): September 16, 2016

Study Record Updates

• Last Update Posted (Actual): February 24, 2023
• Last Update Submitted That Met QC Criteria: February 22, 2023
• Last Verified: February 1, 2023

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: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Kidney Neoplasms; Adenoma; Neoplasms, Mesothelial; Carcinoma, Renal Cell; Mesothelioma; Antineoplastic Agents; Antineoplastic Agents, Immunological; Pembrolizumab
• Other Study ID Numbers: INCB 01158-101; Mk3475 Keynote 741 (Other Identifier: Merck)

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 device product: No