Ensayos clínicos

Inclusion Criteria:

• Adults at least 18 years of age.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.
• Subjects with histopathologically or cytologically confirmed diagnosis of non-uveal melanoma, RCC or NSCLC, for whom the use of nivolumab is indicated. NSCLC subjects with EGFR or ALK genomic aberrations in tumor should have disease progression on FDA-approved therapy for these aberrations prior to receiving nivolumab. (Phase 1b).
• Subjects with histopathologically or cytologically confirmed diagnosis of non-uveal melanoma, or NSCLC, for whom the use of nivolumab is indicated (Phase 2 expansion). With Protocol Amendment 5, subjects with NSCLC are not eligible for enrollment.
• Non-uveal melanoma and NSCLC patients whose disease has progressed after achieving stable disease (SD) for at least 3 months, with partial response (PR) or complete response) CR as the best response that has been documented by imaging studies on previous treatment with a PD-L1 inhibitor with proven efficacy (Phase 2 expansion). With Protocol Amendment 5, subjects with NSCLC are not eligible for enrollment.
• Subject must have at least one measurable target lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1.  Melanoma subjects participating in the optional serial tumor biopsy sub-study must have tumor tissue available from a metastatic or unresectable site for PD-L1 and correlative biomarker analysis.
• All prior systemic therapy (chemotherapy, mutation targeting therapy, immune checkpoint therapy), surgical or radiation treatment must have been completed at least 4 weeks before study drug administration (2 weeks for palliative radiotherapy, 1 week for minor surgery) pending full recovery from therapy.
• The following laboratory results within 7 days prior to study drug administration: Adequate hematopoietic, electrolyte, hepatic, and renal laboratory findings as defined below: white blood cells (WBC) ≥ 3000/μL, neutrophils ≥ 1500/μL, platelets ≥ 100x103/μL, hemoglobin ≥ 9.0 g/dL independent of transfusion, creatinine ≤ 1.5 mg/dL, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x upper limit of normal (ULN), alkaline phosphatase ≤ 2.5 x ULN unless bone metastases present, bilirubin ≤ 1.5 x ULN (unless known Gilbert’s disease where it must be ≤ 3 x ULN) and serum albumin ≥ 3.0 g/dL.
• Life expectancy ≥ 12 weeks.
• A negative serum pregnancy test at baseline for women of childbearing potential.
• Are willing to abstain from heterosexual activity or practice physical barrier contraception prior to time of study entry to at least 5 months after the last day of treatment.
• Have the ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• History of Grade 3 or above hypersensitivity reactions to other monoclonal antibodies.
• Subjects with a history of a cardiovascular illness including:
  • Congestive heart failure (New York Heart Association Grade III or IV);
  • Unstable angina or myocardial infarction within the previous 6 months; or
  • Symptomatic cardiac arrhythmia despite medical management. In addition, for Phase 1b only: QTc (Fridericia’s correction) (QTcF) > 450 ms in male, and > 470 ms in female, congenital long QT syndrome.
• Uncontrolled hypertension, systolic blood pressure (SBP) > 160 mmHg or diastolic blood pressure (DBP) >100 mmHg.
• Subjects with active brain metastasis; previously treated brain metastasis is allowed if it has been stable for 4 weeks or more and not requiring steroids.
• Presence of leptomeningeal disease.  History of hemorrhagic diarrhea, inflammatory bowel disease, active uncontrolled peptic ulcer disease or recurrent pleural effusion requiring repetitive palliative thoracentesis within 3 months prior to study entry, except for subjects with a pleurex port; and immune-mediated toxicity leading to treatment discontinuation.
• Active, known, or suspected serious autoimmune disease, except for type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia).
• Active uncontrolled bacterial, viral, or fungal infection requiring systemic therapy.
• Known history of testing positive for human immunodeficiency virus (HIV), known acquired immunodeficiency syndrome (AIDS).
• Active hepatitis B (serum hepatitis B surface antigen [HBV sAg] positive), or hepatitis C (hepatitis C virus [HCV] antibody test or serum hepatitis C ribonucleic acid [RNA] positive) indicating acute or chronic infection.
• Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids are permitted.
• Use of other investigational agent (drug not marketed for any indication) within 28 days or at least 5 half-lives (whichever is shorter) before study drug administration.
• Pregnant or breast-feeding women.
• Second malignancy unless in remission for 2 years, except for non-melanomatous skin cancer, carcinoma in situ of the cervix treated with curative intent, curatively treated prostate cancer with prostate-specific antigen (PSA) < 0.1 ng/mL.
• Underlying medical conditions that, in the Investigator’s opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity determination or adverse events.
• Unwilling or unable to comply with procedures required in this protocol.