Arginase Inhibitor INCB001158 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.

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.

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