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A Phase 1 Study of BMS-936558 Plus Sunitinib or Pazopanib in Subjects with Metastatic Renal Cell Carcinoma
- 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.
- Secondary Objective
- To assess preliminary antitumor activity of BMS-936558 plus sunitinib or pazopanib in subjects with mRCC.
- Exploratory Objectives
- To evaluate pharmacodynamic and predictive biomarkers of BMS-936558 plus sunitinib or pazopanib in subjects with mRCC
- To characterize the pharmacokinetics of BMS-936558 in subjects with mRCC and to explore exposure-response with respect to safety, efficacy and biomarkers
- To assess the immunogenicity of BMS-936558
- To assess the overall survival (OS) in mRCC subjects receiving BMS-936558 in combination with sunitinib or pazopanib
- Signed Written Informed Consent
- Willing and able to provide informed consent
- Target Population
- Male and Females age ≥ 18 years of age
- 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)
- Advanced or metastatic disease
- Measurable disease as defined by RECIST 1.1 criteria (Appendix 4)
- 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)
- In the dose-expansion cohorts, subjects must not have received any prior systemic therapy in the advanced/metastatic setting
- 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 treatment-naive patients in the dose-expansion part) (Appendix 1)
- Karnofsky Performance Status (KPS) ≥ 80% (Appendix 2)
- Tumor tissue (archival or recent acquisition) must be available (block or 10 - 15 unstained slides of FFPE tissue) for correlative studies
- In Arm I-1 and I-3, subjects may be treatment naive or may have received prior systemic therapy.
- Subjects enrolled in the I-1, I-3 expansion arms and IN-3 addition arms must not have received any prior systemic therapy for RCC with the following exceptions: a) One prior adjuvant or neoadjuvant therapy for localized or locally advanced RCC is allowed provided recurrence occurred ≥ 6 months after the last dose of the adjuvant or neoadjuvant therapy. b) Only prior cytokine based treatment for metastatic RCC (eg, interferon-alpha (IFN-alpha) or interleukin 2 (IL-2) as prior therapy is allowed.
- Age and Reproductive Status (See Section 3.3.3 for the definition of WOCBP)
- Women of childbearing potential (WOCBP) must use method(s) of contraception based on the tables in Appendix 9. For a teratogenic study drug and/or when there is insufficient information to assess teratogenicity (preclinical studies have not been done), a highly effective method(s) of contraception (failure rate of less than 1% per year) is required. The individual methods of contraception should be determined in consultation with the investigator. WOCBP must follow instructions for birth control when the half life of the investigational drug is greater than 24 hours, contraception should be continued for a period of 30 days plus the time required for the investigational drug to undergo five half lives.
- WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of investigational product.
- Women must not be breastfeeding
- Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men that are sexually active with WOCBP must follow instructions for birth control when the half life of the investigational drug is greater than 24 hours, contraception should be continued for a period of 90 days plus the time required for the investigational drug to undergo five half lives.
- Target Disease Exceptions
- 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 treatment assignment
- Medical History and Concurrent Diseases
- 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
- Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
- Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV RNA) indicating acute or chronic infection
- Ongoing symptomatic cardiac dysrhythmias, uncontrolled atrial fibrillation, or prolongation of the Fridericia corrected QT (QTcF) interval defined as > 450 msec for males and > 470 msec for females
- 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
- History of cerebrovascular accident including transient ischemic attack within the past 12 months
- History of pulmonary embolism or deep venous thrombosis (DVT) within the past 6 months
- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months
- Serious, non-healing wound, ulcer, or bone fracture
- 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
- Any requirement for anti-coagulation except short-term dosing for prevention of DVT in high-risk patients immobilized for short durations during required procedures.
- 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
- 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 (> 10 mg/day prednisone equivalents) or any other immunosuppressive agents less than 14 days prior to administration of study drug
- Presence of toxicities attributed to prior anti-cancer therapy other than alopecia that have not resolved to grade 1 (NCI CTCAE version 4) or baseline before administration of study drug
- 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
- For Arm S and Arm P only
- For dose escalation cohorts - 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
- For dose escalation cohorts - subjects who received both prior sunitinib and pazopanib
- Poorly controlled hypertension (SBP ≥ 140 mmHg or DBP ≥ 90 mmHg), despite antihypertensive therapy
- Evidence of active bleeding or bleeding susceptibility; or medically significant hemorrhage within prior 30 days
- Receiving concomitant strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, nefazodone, telithromycin, voriconazole) and/or inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort)
- 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)
- Physical and Laboratory Test Findings
- WBC < 2,000/mm3
- Neutrophils < 1,500/mm3
- Platelets < 100,000/mm3
- AST or ALT > 3 x ULN
- Total Bilirubin > 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)
- Cardiac ejection fraction < LLN
- Serum creatinine > 1.5 X upper limit of normal (ULN) or creatinine clearance < 40 mL/min (measured or calculated by Cockroft-Gault formula) (Appendix 3)
- Allergies and Adverse Drug Reaction
- Known allergic/hypersensitivity reaction to any of the components of study treatments
- History of severe hypersensitivity reaction to any monoclonal antibody
- Sex and Reproductive Status
- Sexually active fertile men not using effective birth control if their partners are WOCBP (Note: refer to Section 3.3.1 criterion #3 for females)
- Other Exclusion Criteria
- Prisoners or subjects who are involuntarily incarcerated
- Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness
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