A Study of ABT-263 in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia
- Registration Number
- NCT00481091
- Lead Sponsor
- AbbVie
- Brief Summary
The Phase 1 portion of the study will evaluate the pharmacokinetic profile and safety of ABT-263 under two different dosing schedules with the objective of defining the dose limiting toxicity and maximum tolerated dose. The Phase 2a portion of the study will evaluate ABT-263 at the defined recommended Phase 2 dose to obtain additional safety information and a preliminary assessment of efficacy. The Extension Study portion will allow active subjects to continue to receive ABT-263 for up to 11 years after the last subject transitions with less frequent study evaluations.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 60
- Relapsed or refractory CLL and require treatment in opinion of investigator.
- Eastern Cooperative Oncology Group (ECOG) <= 1.
- Adequate bone marrow independent of growth factor support, renal and hepatic function per defined laboratory criteria.
- History or is clinically suspicious for cancer-related Central Nervous System disease.
- Receipt of allogenic or autologous stem cell transplant.
- Recent history (within 1 year of first dose) of underlying, predisposing condition of bleeding or currently exhibits signs of bleeding.
- Active peptic ulcer disease or other potentially hemorrhagic esophagitis/gastritis.
- Active immune thrombocytopenic purpura or history of being refractory to platelet transfusions (within 1 year of first dose).
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Navitoclax 14/21 Day Cycle: 10 mg ABT-263 Navitoclax 10 mg administered for 14 consecutive days followed by 7 days off drug to complete a 21-day cycle. Navitoclax 21/21 Day Cycle: 125 mg ABT-263 Navitoclax 125 mg administered for 21 consecutive days to complete a 21-day cycle. Phase 2: Navitoclax 100 mg ABT-263 Navitoclax 100 mg in participants with CLL who had relapsed following any (but no more than 5) prior myelosuppressive/chemotherapy treatment regimen(s). Navitoclax 21/21 Day Cycle: 200 mg ABT-263 Navitoclax 200 mg administered for 21 consecutive days to complete a 21-day cycle. Navitoclax 21/21 Day Cycle: 250 mg ABT-263 Navitoclax 250 mg administered for 21 consecutive days to complete a 21-day cycle. Navitoclax 21/21 Day Cycle: 300 mg ABT-263 Navitoclax 300 mg administered for 21 consecutive days to complete a 21-day cycle. Navitoclax 14/21 Day Cycle: 110 mg ABT-263 Navitoclax 110 mg administered for 14 consecutive days followed by 7 days off drug to complete a 21-day cycle. Navitoclax 14/21 Day Cycle: 200 mg ABT-263 Navitoclax 200 mg administered for 14 consecutive days followed by 7 days off drug to complete a 21-day cycle. Navitoclax 14/21 Day Cycle: 250 mg ABT-263 Navitoclax 250 mg administered for 14 consecutive days followed by 7 days off drug to complete a 21-day cycle. Phase 2: Navitoclax 250 mg ABT-263 Navitoclax 250 mg in participants with CLL who had relapsed following any (but no more than 5) prior myelosuppressive/chemotherapy treatment regimen(s).
- Primary Outcome Measures
Name Time Method Phase 2: Dose-Normalized Plasma Concentrations After Navitoclax Once Daily Dosing Cycle 1 Day 1: 4-8 h postdose; Cycle 1 Day 15: predose; Cycle 3 Day 1: predose, 4-8 h postdose; Cycle 5 Day 1: predose, 4-8 h postdose; Cycle 7 Day 1: predose, 4-8 h postdose; Cycle 9 Day 1: predose, 4-8 h postdose Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) From first dose of study drug to 30 days post-last dose. Participants enrolled in the 14/21-day cycle received a mean of 21.7 treatment cycles; participants enrolled in the 21/21-day cycle received a mean of 19.4 treatment cycles. An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An SAE is one that: results in death, hospitalization, prolongation of hospitalization, or persistent or significant disability/incapacity; is life-threatening, a congenital anomaly, or other important medical event. Events were graded as 1=mild, 2=moderate, 3=severe, 4=life-threatening, or 5=death. The investigator assessed the relationship of each event to the use of study drug as either probably related, possibly related, probably not related or not related. A treatment-emergent adverse event is defined as any adverse event with onset or worsening reported by a subject from the time that the first dose of study drug is administered until 30 days have elapsed following discontinuation of study drug administration. Deaths category included non treatment emergent deaths.
Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Navitoclax Cycle 1 Days 1 and 14: pre-dose, 2, 4, 6, 8 hours post-dose Phase 1: Maximum Observed Plasma Concentration (Cmax) Cycle 1 Days 1 and 14: pre-dose, 2, 4, 6, 8 hours post-dose Phase 1: Terminal Phase Elimination Half-life (t1/2) of Navitoclax Cycle 1 Day 1: pre-dose, 2, 4, 6, 8 hours post-dose For t1/2, the harmonic mean and psuedo-standard deviation are used.
Phase 2: Number of Participants With TEAEs, SAEs, and Discontinuations Due to AEs From first dose of study drug to 30 days post-last dose. Participants enrolled in Phase 2 received a mean of 15.6 treatment cycles. An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An SAE is one that: results in death, hospitalization, prolongation of hospitalization, or persistent or significant disability/incapacity; is life-threatening, a congenital anomaly, or other important medical event. Events were graded as 1=mild, 2=moderate, 3=severe, 4=life-threatening, or 5=death. The investigator assessed the relationship of each event to the use of study drug as either probably related, possibly related, probably not related or not related. A treatment-emergent adverse event is defined as any adverse event with onset or worsening reported by a subject from the time that the first dose of study drug is administered until 30 days have elapsed following discontinuation of study drug administration. Deaths category included non treatment emergent deaths.
Phase 1: Maximum Tolerated Dose (MTD) in the Dose Escalation Phase Cycle 1 (Up to 21 days) plus 7 days The MTD was defined as the dose at which 30% of participants experienced a DLT during the first cycle. DLTs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0 (grade 1=mild; grade 2=moderate; grade 3=severe; grade 4=life threatening; grade 5=death). Any of the following events, considered possibly or probably related to the administration of navitoclax, were considered a DLT: Grade 4 thrombocytopenia (\< 25,000/mm\^3); platelet counts \< 25,000/mm\^3, Grade 2 or higher bleeding associated with thrombocytopenia; all other Grade 3, 4 or 5 adverse events were considered a DLT. Exceptions included: Grade 3, 4 febrile neutropenia less than 7 days; Grade 3, 4 leukopenia; Grade 3, 4 lymphopenia; Grade 3 nausea, vomiting and/or diarrhea unless unresponsive to treatment; Grade 2 toxicity that requires dose modification or delay of \> 1 week.
Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 24 (AUC24) Cycle 1 Day 1: pre-dose, 2, 4, 6, 8, and 24 hours post-dose; Cycle 1 Days 14: pre-dose, 2, 4, 6, 8 The AUC24 was derived and reported from Cycle 1 Day 1 values and Cycle 1 Day 14 values; the pre-dose value taken on Day 14 was utilized as 24-hour timepoint on Day 14 to generate AUC24 for Day 14.
Phase 1: Cmax/Dose Cycle 1 Days 1 and 14: pre-dose, 2, 4, 6, 8 hours post-dose Phase 1: Terminal Phase Elimination Rate Constant (β) for Navitoclax Cycle 1 Day 1: pre-dose, 2, 4, 6, 8 hours post-dose Phase 1: Number of Participants With DLTs in the Dose Escalation Phase Cycle 1 (Up to 21 days) plus 7 days DLTs were graded according to NCI CTCAE version 3.0 (grade 1=mild; grade 2=moderate; grade 3=severe; grade 4=life threatening; grade 5=death). Any of the following events, considered possibly or probably related to the administration of navitoclax, were considered a DLT: Grade 4 thrombocytopenia (\< 25,000/mm\^3); platelet counts \< 25,000/mm\^3, Grade 2 or higher bleeding associated with thrombocytopenia; all other Grade 3, 4 or 5 adverse events were considered a DLT. Exceptions included: Grade 3, 4 febrile neutropenia less than 7 days; Grade 3, 4 leukopenia; Grade 3, 4 lymphopenia; Grade 3 nausea, vomiting and/or diarrhea unless unresponsive to treatment; Grade 2 toxicity that requires dose modification or delay of \> 1 week.
Phase 1: Recommended Phase 2 Dose (RPTD) Determined in the Dose Escalation Phase Cycle 1 (Up to 21 days) plus 7 days The RPTD was determined based on observed DLTs and/or determination of the MTD in phase 1. (See Outcome Measures 2 and 3 above for definition of DLT and MTD.)
Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 8 (AUC8) Cycle 1 Days 1 and 14: pre-dose, 2, 4, 6, 8 hours post-dose Phase 1: AUC8/Dose Cycle 1 Days 1 and 14: pre-dose, 2, 4, 6, 8 hours post-dose Phase 1: AUC24/Dose Cycle 1 Day 1: pre-dose, 2, 4, 6, 8, and 24 hours post-dose; Cycle 1 Days 14: pre-dose, 2, 4, 6, 8 The AUC24 was derived and reported from Cycle 1 Day 1 values and Cycle 1 Day 14 values; the pre-dose value taken on Day 14 was utilized as 24-hour timepoint on Day 14 to generate AUC24 for Day 14.
- Secondary Outcome Measures
Name Time Method
Trial Locations
- Locations (10)
Dana-Farber Cancer Institute /ID# 5547
🇺🇸Boston, Massachusetts, United States
Leicester Royal Infirmary /ID# 15081
🇬🇧Leicester, England, United Kingdom
Moores Cancer Center at UC San Diego /ID# 5566
🇺🇸La Jolla, California, United States
University of Nebraska Medical Center /ID# 12261
🇺🇸Omaha, Nebraska, United States
North Shore University Hospital /ID# 12267
🇺🇸New Hyde Park, New York, United States
Northwest Medical Specialties - Tacoma /ID# 26428
🇺🇸Tacoma, Washington, United States
Peter MacCallum Cancer Ctr /ID# 6583
🇦🇺Melbourne, Victoria, Australia
University of Texas MD Anderson Cancer Center /ID# 5575
🇺🇸Houston, Texas, United States
The Royal Melbourne Hospital /ID# 5576
🇦🇺Parkville, Victoria, Australia
Universitaetsklinikum Koeln /ID# 5924
🇩🇪Köln, Nordrhein-Westfalen, Germany