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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Non-Hodgkin's Lymphoma

Intervention / Treatment
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* Drug: ABT-199
* Drug: Ketoconazole


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (ABT-199 and ketoconazole)<br> | Drug: ABT-199<br>* Subjects will be dosed with ABT-199, then dosed with ABT-199 in combination with ketoconazole<br>* Other names: GDC-0199;Drug: Ketoconazole<br>* Subjects will be dosed with ABT-199, then dosed with ABT-199 in combination with ketoconazole<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of maximum observed plasma concentration (Cmax), time to Cmax (peak time, Tmax), terminal phase elimination rate constant (beta), terminal phase elimination half-life (t1/2), & area under the plasma concentration-time curve (AUC) of ABT-199 | Blood samples for pharmacokinetic (PK) analysis of ABT-199 will be collected at designated timepoints to assess the PK parameters for ABT-199 alone relative to ABT-199 with ketoconazole | Measured pre-dose and up to 96 hours post-dose ABT-199 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with adverse events | Subjects will be monitored for clinical and laboratory evidence of adverse events throughout the study | Measured up to 30 days after the last dose of study drug | 
| Percentage of subjects with adverse events | Subjects will be monitored for clinical and laboratory evidence of adverse events throughout the study | Measured up to 30 days after the last dose of study drug | 
| Change in physical exam finding, including vital signs | Body temperature, weight, blood pressure, heart rate | Measured from Day 1 up to 30 days after the last dose of study drug | 
| Change in clinical laboratory test results | Chemistry, coagulation, hematology, urinalysis | Measured from Day 1 up to 30 days after the last dose of study drug | 
| Change in cardiac assessment findings | Electrocardiogram | Measured from Day 1 up to Day 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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non-Hodgkin's lymphoma, GDC-0199, Safety, Relapsed, Refractory, ABT-199, Pharmacokinetics, Cancer