A Phase 1 Study of BMS-936558 Plus Sunitinib or Pazopanib in Subjects with Metastatic Renal Cell Carcinoma (CA209-016)
Research Hypothesis: BMS-936558 and sunitinib or pazopanib can be given safely in combination to subjects with metastatic renal cell carcinoma (mRCC). Primary Objective: To assess the overall safety and tolerability of BMS-936558 plus sunitinib or pazopanib, in order to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose(RP2D) of BMS-936558 plus sunitinib or pazopanib in subjects with mRCC.
Target Population a) Male and Females age greater than or equal to 18 years of age b) Subjects with histological confirmation of RCC with a clear-cell component (dose escalation or dose expansion) or non-clear-cell RCC, limited to papillary, chromophobe or unclassified histology (dose escalation only) c) Advanced or metastatic disease d) Measurable disease as defined by RECIST 1.1 criteria e) In the dose-escalation cohorts, subjects must have received at least one prior systemic treatment regimen in the advanced/metastatic setting (at least one prior cytokine, anti-angiogenic or mTOR inhibitor). f) In the dose-expansion cohorts, subjects must not have received any prior systemic therapy in the advanced/metastatic setting g) Favorable or intermediate-risk MSKCC prognostic score (0 - 1 of 3 risk factors for pre-treated patients in the dose-escalation part, 0 - 2 of 5 risk factors for treatmentnaÃ¯ve patients in the dose-expansion part) h) Karnofsky Performance Status (KPS) greater than or equal to 80% i) Tumor tissue (archival or recent acquisition) must be available (block or 10 - 15 unstained slides of FFPE tissue) for correlative studies. 3) Age and Reproductive Status a) Women of childbearing potential (WOCBP) and men must be using an acceptable method of contraception to avoid pregnancy throughout the study and for up to 18 weeks after the last dose of investigational product in such a manner that the risk of pregnancy is minimized. b) WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of investigational product. c) Women must not be breastfeeding Exclusion Criteria 1) Target Disease Exceptions a) Active CNS metastases (including evidence of cerebral edema by CT scan or MRI, progression from prior imaging study, any requirement for steroids to control clinical symptoms relating to CNS metastases, or the presence of clinical symptoms relating to CNS metastases) within 30 days of study enrollment. Subjects with known metastases must have a baseline imaging scan within 30 days of randomization. 2) Medical History and Concurrent Diseases a) Any active or recent history of a known or suspected autoimmune disease or recent history of a syndrome that required systemic corticosteroids or immunosuppressive medications except for syndromes which would not be expected to recur in the absence of an external trigger. Subjects with vitiligo or type I diabetes mellitus are permitted to enroll b) Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). c) Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV RNA) indicating acute or chronic infection d) Subjects who received prior sunitinib or pazopanib and required permanent discontinuation due to toxicity or required dose reduction or delay during the first 12 weeks of therapy due to toxicity e) Subjects who received both prior sunitinib and pazopanib f) Ongoing symptomatic cardiac dysrhythmias, uncontrolled atrial fibrillation, or prolongation of the Fridericia corrected QT (QTcF) interval defined as greater than 450 msec for males and greater than 470 msec for females g) History of any of the following cardiovascular conditions within 12 months of enrollment: cardiac angioplasty or stenting, myocardial infarction, unstable angina, coronary artery by-pass graft surgery, symptomatic peripheral vascular disease, class III or IV congestive heart failure, as defined by the New York Heart Association h) History of cerebrovascular accident including transient ischemic attack within the past 12 months i) History of pulmonary embolism or deep venous thrombosis (DVT) within the past 6 months j) Poorly controlled hypertension (SBP greater than 140 mmHg or DBP greater than 90 mmHg), despite antihypertensive therapy k) Evidence of active bleeding or bleeding susceptibility; or medically significant hemorrhage within prior 30 days l) History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months m) Serious, non-healing wound, ulcer, or bone fracture n) Prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-CLTA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways o) Any requirement for anti-coagulation p) Receiving concomitant strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, nefazodone, telithromycin, voriconazole) and/or inducers(eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. John's Wort) q) Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of sunitinib or pazopanib (eg, malabsorptive disorder, ulcerative disease, uncontrolled nausea, vomiting, diarrhea, or small bowel resection) r) Major surgery (eg, nephrectomy, hip or spine surgery) less than 4 weeks prior to administration of study drug. Minor surgery (eg, biopsy or chest tube placement)less than 2 weeks prior to administration of study drug s) Anti-cancer therapy less than 21 days (28 days for bevacizumab) prior to administration of study drug. Palliative, focal radiation therapy, immunosuppressive doses of systemic corticosteroids ( greater than 10 mg/day prednisone equivalents) or any other immunosuppressive agents less than 14 days prior to administration of study drug t) Presence of toxicities attributed to prior anti-cancer therapy other than alopecia that have not resolved to grade 1 or baseline before administration of study drug u) Any known medical condition that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results 3) Physical and Laboratory Test Findings a) WBC less than 2,000/mm3 b) Neutrophils less than 1,500/mm3 c) Platelets less than 100,000/mm3 d) AST or ALT greater than 3 x ULN e) Total Bilirubin greater than 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin less than 3.0 mg/dL) f) Cardiac ejection fraction less than LLN g) Serum creatinine greater than 1.5 X upper limit of normal (ULN) or creatinine clearance less than 40 mL/min (measured or calculated by Cockroft-Gault formula) 4) Allergies and Adverse Drug Reaction a) Known allergic/hypersensitivity reaction to any of the components of study treatments b) History of severe hypersensitivity reaction to any monoclonal antibody 5) Sex and Reproductive Status a) Sexually active fertile men not using effective birth control if their partners are WOCBP. 6) Other Exclusion Criteria a) Prisoners or subjects who are involuntarily incarcerated b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness
The trial will include 2 parallel treatment arms: BMS-936558 plus sunitinib (Arm S) and BMS-936558 plus pazopanib (Arm P). The study will be conducted in 2 parts (dose escalation and dose expansion). Subjects must have received at least one prior systemic therapy regimen in the advanced/metastatic setting to be eligible for the dose-escalation part of the study, while subjects must be treatment-naÃ¯ve to be eligible for the dose-expansion part of the study. Subjects participating in the dose-escalation phase who received prior pazopanib will be assigned to receive BMS-936558 plus sunitinib, while subjects who received prior sunitinib will be assigned to receive BMS-936558 plus pazopanib. Subjects who have not received prior sunitinib or pazopanib may enroll on either dose-escalation arm and will be assigned to these arms in an alternating fashion when both arms are open. Following determination of the MTD of BMS-936558 in combination with each agent, 2 separate expansion cohorts including only treatment-naÃ¯ve subjects will be enrolled so that 24 subjects in total are treated at the MTD of each treatment arm. Each treatment cycle will be 6 weeks in duration, with BMS-936558 dosed on Days 1 and 22 and anti-angiogenic therapy dosed according to the approved product label for sunitinib (50 mg daily; 4 weeks on, 2 weeks off) and pazopanib (800 mg daily). Disease assessments will take place every 6 weeks (Â± 1 week) from the first dose of study drug for the first 4 assessments, and then every 12 weeks (Â± 1 week) until disease progression. Subjects will be treated until unacceptable toxicity, disease progression, or withdrawal of informed consent. Thirty six subjects (18 subjects per arm) are expected to be treated in the dose-escalation part of the study. Additional subjects will receive treatment in the dose-expansion part, so that 24 total subjects are treated at the MTD for each treatment arm.
09/16/2014 04:03 AM