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

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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:
Information provided by (Responsible Party):
Incyte Corporation

Study Description
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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.

Condition or disease Intervention/treatment Phase
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 Drug: INCB001158 Drug: Pembrolizumab Phase 1 Phase 2

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 Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 260 participants
Allocation: Non-Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : September 14, 2016
Actual Primary Completion Date : August 31, 2020
Actual Study Completion Date : August 15, 2022

Resource links provided by the National Library of Medicine


Arms and Interventions
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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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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: INCB001158
Arginase Inhibitor
Other Name: CB-1158

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

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

Drug: Pembrolizumab
PD-1 Inhibitor
Other Name: Keytruda


Outcome Measures
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Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.

  2. Recommended Phase 2 Dose (RP2D) of INCB001158 in Combination With Pembrolizumab [ Time Frame: 12 Weeks ]
    INCB001158 was dosed orally BID

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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)

  8. 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.

  9. 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.

  10. 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.

  11. 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.


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02903914


Locations
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Sponsors and Collaborators
Incyte Corporation
Investigators
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Study Director: Emil Kuriakose, MD Calithera Biosciences, Inc
Study Director: Sven Gogov, MD Incyte Corporation
  Study Documents (Full-Text)

Documents provided by Incyte Corporation:
Study Protocol  [PDF] November 10, 2020
Statistical Analysis Plan  [PDF] February 21, 2021

More Information
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Responsible Party: Incyte Corporation
ClinicalTrials.gov Identifier: NCT02903914    
Other Study ID Numbers: INCB 01158-101
Mk3475 Keynote 741 ( Other Identifier: Merck )
First Posted: September 16, 2016    Key Record Dates
Results First Posted: September 30, 2021
Last Update Posted: February 24, 2023
Last Verified: February 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Incyte Corporation:
Immuno-Oncology
Checkpoint Inhibitors
Tumor Metabolism
Programmed cell death protein-1 (PD-1) inhibitor
Programmed death ligand 1 (PD-L1) inhibitor
Solid Tumors
RCC
MEL
 NSCLC
Arginase
Arginase Inhibitor
INCB001158 (CB-1158)
SCCHN
GEJ
Immune Therapy
Additional relevant MeSH terms:
Layout table for MeSH terms
Carcinoma, Renal Cell
Mesothelioma
Neoplasms
Neoplasms by Site
Urologic Neoplasms
Urogenital Neoplasms
Female Urogenital Diseases
Female Urogenital Diseases and Pregnancy Complications
Urogenital Diseases
Urologic Diseases
Male Urogenital Diseases
Adenocarcinoma
 Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Kidney Neoplasms
Kidney Diseases
Adenoma
Neoplasms, Mesothelial
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action