Safety, Pharmacokinetics, and Pharmacodynamics of Escalating Oral Doses of the Arginase Inhibitor INCB001158 (formerly known as CB-1158) as a Single Agent and in Combination with Immune Checkpoint Therapy in Patients with Advanced/Metastatic Solid Tumors

1. Age * 18 years
2. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1
3. Adequate organ function as indicated by the laboratory values in
* Absolute neutrophil count (ANC) *1.500/mcL
* Platelets * 100,000 / mcL
* Hemoglobin * 9 g/dL (5,59 mmol/l)
* Creatinine Clearance * 50 mL/min (calculated using the formula of Cockcroft and Gault)
* Serum total bilirubin OR Direct bilirubin (for patients with Gilbert Syndrome and total bilirubin levels >1.5 ULN) * 1.5 X ULN OR * ULN
* AST (SGOT) and ALT (SGPT) * 2.5 X ULN
* International Normalized Ratio (INR) or Prothrombin Time (PT) * 1.5 X ULN- Does not apply to patients receiving therapeutic anticoagulation
4. Measurable Disease: At least one tumor lesion/lymph node that meets the RECIST v1.1 criteria for being *measurable*.
Resolution of all treatment-related toxicities, except alopecia, anemia, or endocrinopathies managed by hormone replacement, from any previous cancer therapy to * Grade 1 or to values within those required for eligibility on this study prior to the first dose of study treatment.;Part 2 specific inclusion criteria:
Histologically or cytologically proven diagnosis of :
* advanced/metastatic NSCLC (squamous or non-squamous) in patients who have disease progression after treatment with all available therapies known to confer clinical benefit (Part 2a)
* advanced/metastatic CRC in patients who have disease progression after treatment with all available therapies known to confer clinical benefit (Part 2b)
* advanced/metastatic tumors including gastric cancer, cancer of the GEJ, UCC, RCC, melanoma, or SCCHN in patients who have disease progression after treatment with all available therapies known to confer clinical benefit. Other advanced/metastatic solid tumors (e.g., those demonstrated or expected to have high infiltration with arginase-positive cells) may be allowed based on the discretion of the Medical Monitor (Part 2c);Part 3 (pembrolizumab expansion cohorts) specific inclusion criteria:
Part 3a: Non-small cell lung cancer (NSCLC) * PD/SD on anti-PD-1/PD-L1 therapy
1. Histological or cytological diagnosis of locally advanced unresectable or metastatic NSCLC that does not harbor an activating EGFR or ALK mutation
2. Prior progression on or after platinum-based chemotherapy or refused/ineligible to receive platinum-based chemotherapy.
3. Received an anti-PD-1/PD-L1 agent in a prior line of therapy for advanced/metastatic disease and EITHER:
a. Had documented radiological disease progression (per Investigator assessment, preferably with confirmation of PD after 4 weeks) while receiving anti-PD-1/PD-L1 therapy in the most recent line of therapy, OR
b. Had documented stable disease (per Investigator assessment) for * 24 weeks while receiving pembrolizumab therapy in the most recent line of therapy;Part 3b: Melanoma * PD/SD on anti-PD-1/PD-L1 therapy
1. Histological or cytological diagnosis of locally advanced unresectable or metastatic melanoma
2. Received an anti-PD-1/PD-L1 agent in the most recent prior line of therapy for advanced/metastatic disease and EITHER:
a. Had documented radiological disease progression (per Investigator assessment, preferably with confirmation of PD after 4 weeks) while receiving anti-PD-1/PD-L1 therapy in the most recent line of therapy, OR
b. Had documented stable disease (per Investigator assessment) for * 24 weeks while receiving pembrolizumab therapy in the most recent line of therapy;Part 3c: Urothelial cell carcinoma (UCC) * PD/SD on anti-PD-1/PD-L1 therapy
1. Histological or cytological diagnosis of locally advanced unresectable or metastatic UCC
2. Received an anti-PD-1/PD-L1 agent in the most recent prior line of therapy for advanced/metastatic disease and EITHER:
a. Had documented radiological disease progression (per Investigator assessment, preferably with confirmation of PD after 4 weeks) while receiving anti-PD-1/PD-L1 therapy in the most recent line of therapy, OR
b. Had documented stable disease (per Investigator assessment) for * 24 weeks while receiving pembrolizumab therapy in the most recent line of therapy;Part 3d: Mismatch repair deficient and/or microsatellite instability-high (MSI-H) colorectal cancer (CRC) * PD/SD on anti-PD-1/PD-L1 therapy
1. Histological or cytological diagnosis of locally advanced unresectable or metastatic CRC demonstrated to be mismatch repair deficient or microsatellite instability-high.
2. Received an anti-PD-1/PD-L1 agent in the most recent prior line of therapy for advanced/metastatic disease and EITHER:
a. Had documented radiological disease progression (per Investigator assessment, preferably with confirmation of PD after 4 weeks) while receiving anti-PD-1/PD-L1 therapy in the most recent line of therapy, OR
b. Had documented stable disease (per Investigator assessment) for * 24 weeks while receiving pembrolizumab therapy in the most recent line of therapy;Part 3e: Microsatellite stable (MSS) colorectal cancer (CRC) * Checkpoint inhibitor naive
1. Histological or cytological diagnosis of locally advanced unresectable or metastatic CRC demonstrated to lack mismatch repair deficiency and microsatellite instability (low or high).
2. Received at least one prior fluoropyrimidine-containing systemic therapy for advanced/metastatic CRC
3. Has not received prior anti-PD-1/PD-L1, anti-CTLA4, or other checkpoint inhibitor or immune co-stimulator (e.g., anti-OX-40, anti-41BB, etc.);Part 3f: Gastric/gastro-esophageal (GE) junction cancer * Checkpoint inhibitor naive
1. Histological or cytological diagnosis of locally advanced unresectable or metastatic gastric or GEJ cancer
2. Received at least two prior systemic therapies for advanced/metastatic disease; prior regimens must have included a platinum and a fluoropyrimidine
3. Human epidermal growth factor receptor 2 (HER-2/neu) negative, or, if HER2/neu positive, must have previously received treatment with trastuzumab
4. Has not received prior anti-PD-1/PD-L1, anti-CTLA4, or other checkpoint inhibitor or immune co-stimulator (e.g., anti-OX-40, anti-41BB, etc.);Part 3g: Squamous cell carcinoma of the head and neck (SCCHN) * Checkpoint inhibitor naive
1. Histological or cytological diagnosis of recurrent or metastatic SCCHN
2. Had disease progression EITHER:
a. While receiving or after platinum-containing chemotherapy administered for recurrent or metastatic SCCHN, OR
b. Following platinum-containing chemotherapy administered as part of induction, concurrent, or adjuvant therapy.
3. Has not received prior anti-PD-1/PD-L1, anti-CTLA4, or other checkpoint inhibitor or immune co-stimulator (e.g., anti-OX-40, anti-41BB, etc.).;Part 3h: Mesothelioma * Checkpoint inhibitor naive
1. Histological or cytological diagnosis of locally advanced incurable or metastatic malignant pleural mesothelioma
2. Has failed or was unable to received standard therapy for malignant pleural mesothelioma
3. Has not received prior anti-PD-1/PD-L1, anti-CTLA4, or other checkpoint inhibitor or immune co-stimulator (e.g., anti-OX-40, anti-41BB, etc.)

1. Any other current or previous malignancy within the past three years except a) adequately treated basal cell or squamous cell skin cancer, b) carcinoma in situ of the cervix, c) prostate cancer with stable prostate specific antigen (PSA) levels for 3 years, d) or other neoplasm that, in the opinion of the Principal Investigator and with the agreement of the Medical Monitor, will not interfere with study-specific endpoints.
2. Cytotoxic chemotherapy, tyrosine kinase inhibitor (or other targeted anti-cancer agent), radiation therapy, or hormonal therapy within 14 days or 5 half-lives, whichever is longer, prior to Cycle 1 Day 1 (42 days for nitrosoureas or mitomycin C).
3. Immunotherapy or biological therapy (e.g., monoclonal antibodies) within 21 days prior to Cycle 1 Day 1
* EXCEPTION: Washout of anti-PD-1 therapy is NOT required in the Part 3 Expansion Cohorts.
4. Treatment with an unapproved investigational therapeutic agent within 21 days (or 5 half-lives for small molecule agents) prior to Cycle 1 Day 1
* EXCEPTION: Washout of anti-PD-1 therapy is NOT required in the Part 3 Expansion Cohorts.
5. Has a diagnosis of immunodeficiency or any condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other systemic immunosuppressive medications within 14 days prior to the first dose of study treatment. Inhaled steroids and adrenal replacement steroid doses < 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease.;Disease-specific Exclusion Criteria:;For Part 3:
1. Intolerance to prior anti-PD-1/PD-L1 therapy including 1) discontinuation due to immune-related toxicity or, 2) immune-related toxicities that that required intensive or prolonged immunosuppression (including, high-dose IV corticosteroids, > 2 mo of immunosuppressive corticosteroids (i.e., equivalent of >10mg oral prednisone daily) or the addition of potent immunosuppression to corticosteroids (e.g., mycophenolate mofetil/CellCept or infliximab) to manage.
2. Prior severe hypersensitivity (* Grade 3) to pembrolizumab and/or any of its excipients or prior severe hypersensitivity reaction to any other monoclonal antibody (mAb).
3. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
4. Has a history of interstitial lung disease.
5. Has received transfusion of blood products (including platelets or red blood cells) or administration of colony stimulating factors (including G-CSF, GM-CSF or recombinant erythropoietin) within 2 weeks prior to study Day 1.
6. Active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
7. Concomitant therapy with allopurinol and other xanthine oxidase inhibitors
8. Exclusion criterion deleted in Protocol Amendment 2-EU.
9. Patients with symptomatic ascites or pleural effusion requiring intermittent paracentesis or thoracocentesis. A patient who is clinically stable following treatment for these conditions (including therapeutic thoraco- or para-centesis) is eligible.
10. Unable to receive medications per os (PO)
11. Unstable/inadequate cardiac function:
* Myocardial infarction or symptomatic ischemia within the last 6 months
* Uncontrolled or clinically significant conduction abnormalities (e.g., ventricular tachycardia on antiarrhythmics are excluded; 1st degree AV block or asymptomatic LAFB/RBBB are eligible)
* Congestive heart failure (New York Heart Association class III to IV)
12. Known or suspected defect in the function of the urea cycle, including a known deficiency of carbamoyl phosphate synthetase I, ornithine transcarbamylase, argininosuccinate synthetase, argininosuccinate lyase, N-acetyl glutamate synthetase, or arginase.
13. Major surgery within 2 months prior to first dose of study treatment
14. Infection requiring parenteral antibiotics, antivirals, or antifungals within two weeks prior to first dose of study treatment
15. Patient is known to be positive for Human Immunodeficiency Virus (HIV), Hepatitis B or Hepatitis C.
16. Refractory nausea and vomiting, uncontrolled diarrhea, malabsorption, significant small bowel resection or gastric bypass surgery, use of feeding tubes or other situation that may preclude adequate absorption
17. Serious psychiatric or medical conditions that could interfere with treatment or protocol-related procedures
18. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
Note: Patients with brain metastases or CNS disease are permitted, but must have completed treatment and either (1) have no evidence of active CNS disease for at least 4 weeks prior to the first dose OR (2) have stable CNS lesions, defined as not requiring intrathecal chemotherapy for at least 6 weeks or systemic steroid treatment to prevent CNS complications for at least 3 weeks prior to first dose. Patients with CNS disease must also have a Screening head CT or MRI demonstrating stable disease compared to their most recent CNS evaluation. This exception does not apply to patients with carcinomatous meningitis who are excluded regardless of clinical stability.
19. Patients in whom oral and/or IV fluid hydration are contraindicated
20. Patients who are pregnant or lactating
21. Has received a live-virus vaccination within 30 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted.
22. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the Patient*s participation for the full duration of the trial, or is not in the best interest of the Patient to participate, in the opinion of the treating investigator.
For Part 3a: NSCLC
1. Documented activating mutations in EGFR or ALK.