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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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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 / Treatment
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* Drug: INCB001158
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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*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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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