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
- Conditions
- advanced/metastatic malignant solid tumors10027476
- Registration Number
- NL-OMON48697
- Lead Sponsor
- Incyte Corporation
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Withdrawn
- Sex
- Not specified
- Target Recruitment
- 12
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 recei
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
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>The primary endpoint is the safety of INCB001158 as monotherapy and as combi<br /><br>therapy with pembrolizumab.<br /><br><br /><br>The following safety analyzes will be evaluated for all patients in each<br /><br>treatment combination:<br /><br>Undesirable events (AEs) and changes in laboratory values, vital signs and<br /><br>physical examinations.</p><br>
- Secondary Outcome Measures
Name Time Method <p>The secondary endpoints are efficacy.<br /><br><br /><br>The following efficacy analyzes will be evaluated for all patients in each<br /><br>treatment combination:<br /><br>-On the basis of an evaluation of AEs, pharmacokinetics (PK), pharmacodynamics<br /><br>and indications for clinical activity;<br /><br>-Determined via standard RECIST criteria (except for pleural mesothelioma,<br /><br>which will be evaluated using adjusted RECIST criteria) [total response rate<br /><br>(ORR), best overall response (BOR), duration of response (duration of response,<br /><br>DOR), and progression-free survival (PFS)] and immune-related RECIST (ir RECY)<br /><br>criteria (irORR, irBOR, irDOR and irPFS);<br /><br>-A non-compartmental analysis method will be used to analyze the plasma<br /><br>concentration of INCB001158.</p><br>