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

• ClinicalTrials.gov Identifier: NCT02903914
• Recruitment Status: Completed
• First Posted: September 16, 2016
• Results First Posted: September 30, 2021
• Last Update Posted: February 24, 2023
• Sponsor: Incyte Corporation
• Information provided by (Responsible Party): Incyte Corporation

Tracking Information

• First Submitted Date: September 9, 2016
• First Posted Date: September 16, 2016
• Results First Submitted Date: August 31, 2021
• Results First Posted Date: September 30, 2021
• Last Update Posted Date: February 24, 2023
• Actual Study Start Date: September 14, 2016
• Actual Primary Completion Date: August 31, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 31, 2021)

Determination of the Safety and Tolerability of INCB001158 as a Single Agent and in Combination With Pembrolizumab: Incidence of Adverse Events [ Time Frame: Up to 6 months ]

Evaluation of adverse events (AEs) and changes in laboratory values, vital signs, and physical examinations.

Original Primary Outcome Measures (submitted: September 13, 2016)

Safety and Tolerability of CB-1158 as a single agent and in combination with nivolumab: Incidence of Adverse Events [ Time Frame: Every 28 days from study start until disease progression or unacceptable toxicity, assessed for an expected average of 6 months ]

Evaluation of adverse events (AEs) and changes in laboratory values, vital signs, and physical examinations

Current Secondary Outcome Measures (submitted: August 31, 2021)

• Recommended Phase 2 Dose (RP2D) of INCB001158 [ Time Frame: 12 Weeks ]
  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.
• Recommended Phase 2 Dose (RP2D) of INCB001158 in Combination With Pembrolizumab [ Time Frame: 12 Weeks ]
  INCB001158 was dosed orally BID
• Overall Response Rate (ORR) Anti-tumor Activity of INCB001158 as Monotherapy and in Combination With Pembrolizumab for Patients With Advanced/Metastatic Solid Tumors [ Time Frame: Until disease progression/study discontinuation up to 24 months ]
  ORR assessment of anti-tumor activity per RECIST Criteria (v1.1) and immune-related RECIST (irRECIST) criteria.
• Best Overall Response (BOR) Anti-tumor Activity of INCB001158 as Monotherapy and in Combination With Pembrolizumab for Patients With Advanced/Metastatic Solid Tumors [ Time Frame: Until disease progression/study discontinuation up to 24 months ]
  BOR Assessment of anti-tumor activity per RECIST Criteria (v1.1) and immune-related RECIST (irRECIST) criteria.
• Duration of Response (DOR) Anti-tumor Activity of INCB001158 as Monotherapy and in Combination With Pembrolizumab for Patients With Advanced/Metastatic Solid Tumors [ Time Frame: Until disease progression/study discontinuation up to 24 months ]
  DOR Assessment of anti-tumor activity per RECIST Criteria (v1.1) and immune-related RECIST (irRECIST) criteria.
• Progression-free Survival (PFS) Anti-tumor Activity of INCB001158 as Monotherapy and in Combination With Pembrolizumab for Patients With Advanced/Metastatic Solid Tumors [ Time Frame: Until disease progression/study discontinuation up to 24 months ]
  DOR Assessment of anti-tumor activity per RECIST Criteria (v1.1) and immune-related RECIST (irRECIST) criteria.
• Pharmacokinetics: Cmax of INCB001158 [ Time Frame: Cycle 1 Day 1 (C1D1), C1D15, C2D! + 2, C4D1 ]
  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)
• Tmax Plasma Pharmacokinetic (PK) Profile of INCB001158 [ Time Frame: 12 Weeks ]
  Non-compartmental method of analysis will be used to analyze the plasma concentrations of INCB001158.
• AUCt Plasma Pharmacokinetic (PK) Profile of INCB001158 [ Time Frame: 12 Weeks ]
  Non-compartmental method of analysis will be used to analyze the plasma concentrations of INCB001158.
• AUC0-12 Plasma Pharmacokinetic (PK) Profile of INCB001158 [ Time Frame: 12 Weeks ]
  Non-compartmental method of analysis will be used to analyze the plasma concentrations of INCB001158.
• CL/F Plasma Pharmacokinetic (PK) Profile of INCB001158 [ Time Frame: 12 Weeks ]
  Non-compartmental method of analysis will be used to analyze the plasma concentrations of INCB001158.

Original Secondary Outcome Measures (submitted: September 13, 2016)

• Recommended Phase 2 Dose (RP2D) of CB-1158 [ Time Frame: 12 Weeks ]
  Up to 30 patients with solid tumors will be enrolled in Dose Escalation to determine the RP2D of CB-1158 as monotherapy.
• RP2D of CB-1158 with Nivolumab [ Time Frame: 12 Weeks ]
  Up to 24 patients with solid tumors will be enrolled in Dose Escalation to determine the RP2D of CB-1158 with Nivolumab
• Maximum plasma concentration of CB-1158 [ Time Frame: Every 28 days from study start until disease progression or unacceptable toxicity, assessed for an expected average of 6 months ]
  Non-compartmental method of analysis will be used to analyze the plasma concentrations of CB-1158

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Arginase Inhibitor INCB001158 as a Single Agent and in Combination With Immune Checkpoint Therapy in Patients With Advanced/Metastatic Solid Tumors
• Official Title: 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Factorial Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

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

Intervention

• Drug: INCB001158
  Arginase Inhibitor
  Other Name: CB-1158
• Drug: Pembrolizumab
  PD-1 Inhibitor
  Other Name: Keytruda

Study Arms

• 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).
  Intervention: Drug: INCB001158
• 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).
  Intervention: Drug: INCB001158
• 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.
  Intervention: Drug: INCB001158
• 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.
  Intervention: Drug: INCB001158
• 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.
  Intervention: Drug: INCB001158
• 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).
  Interventions:

  • Drug: INCB001158
  • Drug: Pembrolizumab
• 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.
  Interventions:

  • Drug: INCB001158
  • Drug: Pembrolizumab
• 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.
  Interventions:

  • Drug: INCB001158
  • Drug: Pembrolizumab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 2, 2020): 260
• Original Estimated Enrollment (submitted: September 13, 2016): 236
• Actual Study Completion Date: August 15, 2022
• Actual Primary Completion Date: August 31, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

*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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Italy, Netherlands, Spain, United States

Administrative Information

• NCT Number: NCT02903914
• Other Study ID Numbers: INCB 01158-101; Mk3475 Keynote 741 ( Other Identifier: Merck )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Incyte Corporation
• Original Responsible Party: Calithera Biosciences, Inc
• Current Study Sponsor: Incyte Corporation
• Original Study Sponsor: Calithera Biosciences, Inc
• Collaborators: Not Provided

Investigators

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

• PRS Account: Incyte Corporation
• Verification Date: February 2023