A Study to Assess the Effect of Ketoconazole on the Metabolism of ABT-199

A Phase 1 Study to Assess the Effect of Ketoconazole on the Pharmacokinetics of ABT-199

This is an open-label multicenter, study to assess the pharmacokinetic interaction of ketoconazole with ABT-199 in up to 12 subjects with relapsed or refractory non-Hodgkin's lymphoma.

This is a Phase 1 study designed to assess how the body processes the study drug ABT-199 when taken alone and in combination with ketoconazole and to assess the safety of ABT-199 in combination with ketoconazole. Subjects may enroll in a separate extension study to continue receiving ABT-199 after completion of this study.

Inclusion Criteria:

• Subject must have relapsed or refractory non-Hodgkin's lymphoma.

• Subject must have histologically documented diagnosis of non-Hodgkin's lymphoma as defined by a B-cell neoplasm in the World Health Organization (WHO) classification scheme except as noted in the exclusion criteria.

• Subject has an Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 2.

• Subject must have adequate bone marrow (independent of growth factor support per local laboratory reference range), coagulation, renal and hepatic function:

  • Absolute Neutrophil Count (ANC) greater than or equal to 1000/µL (without growth factor support unless neutropenia is clearly due to underlying disease);
  • Platelets greater than or equal to 75,000/mm3 (unless thrombocytopenia is clearly due to disease-related immune thrombocytopenia or to underlying disease; entry platelet count must be independent of transfusion within 14 days of Screening);
  • Hemoglobin greater than or equal to 9.0 g/dL (unless anemia is clearly due to underlying disease; entry hemoglobin must be independent of transfusion within 14 days of Screening);
  • If cytopenias are present, no evidence of myelodysplastic syndrome or hypoplastic bone marrow;
  • Subject must have activated partial thromboplastin time (aPTT) and prothrombin time (PT) not to exceed 1.5 × the upper normal limit (ULN);
  • Calculated creatinine clearance greater than or equal to 50 mL/min using a 24-hour urine collection for creatinine clearance or per the Cockcroft-Gault equation;
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to 3.0 × ULN of institution's normal range;
  • Bilirubin less than or equal to 1.5 × ULN. Subjects with Gilbert's Syndrome may have a bilirubin greater than 1.5 × ULN per discussion with the AbbVie medical monitor.

Exclusion Criteria:

• Subject has been diagnosed with Post-Transplant Lymphoproliferative Disease (PTLD), Burkitt's lymphoma, Burkitt-like lymphoma, lymphoblastic lymphoma/leukemia, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or mantle cell lymphoma (MCL).
• Subject is receiving combination anti-retroviral therapy for HIV (due to potential drug-drug interactions between anti-retroviral medications and ABT-199, as well as anticipated ABT-199 mechanism based lymphopenia that may potentially increase the risk of opportunistic infections).
• Subject has hypersensitivity to ketoconazole.
• Subject has a cardiovascular disability status of New York Heart Association Class greater than or equal to 2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea or anginal pain.
• Subject has a significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, cardiovascular, or hepatic disease within the past 6 months that in the opinion of the investigator would adversely affect his/her participating in this study.
• Subject has malabsorption syndrome or other condition which precludes enteral route of administration (e.g., prior surgical resection).
• Subject has undergone an allogeneic stem cell transplant.