Clinical trial NCT01969669: A Study to Assess the Effect of Ketoconazole on the Metabolism of ABT-199
Official title: A Phase 1 Study to Assess the Effect of Ketoconazole on the Pharmacokinetics of ABT-199
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Non-Hodgkin's Lymphoma
Keywords: non-Hodgkin's lymphoma
GDC-0199
Safety
Relapsed
Refractory
ABT-199
Pharmacokinetics
Cancer
Lead sponsor: AbbVie
Sponsor class: INDUSTRY
Collaborators: name: Genentech, Inc.
First posted: 2013-10-25
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: 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
timeFrame: Measured pre-dose and up to 96 hours post-dose ABT-199
Secondary outcomes:
measure: Number of subjects with adverse events
timeFrame: Measured up to 30 days after the last dose of study drug
measure: Percentage of subjects with adverse events
timeFrame: Measured up to 30 days after the last dose of study drug
measure: Change in physical exam finding, including vital signs
timeFrame: Measured from Day 1 up to 30 days after the last dose of study drug
measure: Change in clinical laboratory test results
timeFrame: Measured from Day 1 up to 30 days after the last dose of study drug
measure: Change in cardiac assessment findings
timeFrame: Measured from Day 1 up to Day 12
Other outcomes:
Locations:
city: Tucson
country: United States
facility: Site Reference ID/Investigator# 97498
state: Arizona
city: Lebanon
country: United States
facility: Site Reference ID/Investigator# 92593
state: New Hampshire
city: Hackensack
country: United States
facility: Site Reference ID/Investigator# 101415
state: New Jersey
Study officials:
affiliation: AbbVie
name: David Chien, MD
role: STUDY_DIRECTOR
References:
citation: Agarwal SK, Salem AH, Danilov AV, Hu B, Puvvada S, Gutierrez M, Chien D, Lewis LD, Wong SL. Effect of ketoconazole, a strong CYP3A inhibitor, on the pharmacokinetics of venetoclax, a BCL-2 inhibitor, in patients with non-Hodgkin lymphoma. Br J Clin Pharmacol. 2017 Apr;83(4):846-854. doi: 10.1111/bcp.13175. Epub 2017 Jan 18.