A Study of ABT-263 in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia

Primary outcomes

1. Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs)

   Time frame: 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.

2. Phase 1: Number of Participants With DLTs in the Dose Escalation Phase

   Time frame: 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.

3. Phase 1: Maximum Tolerated Dose (MTD) in the Dose Escalation Phase

   Time frame: 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.

4. Phase 1: Recommended Phase 2 Dose (RPTD) Determined in the Dose Escalation Phase

   Time frame: 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.)

5. Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Navitoclax

   Time frame: Cycle 1 Days 1 and 14: pre-dose, 2, 4, 6, 8 hours post-dose

6. Phase 1: Maximum Observed Plasma Concentration (Cmax)

   Time frame: Cycle 1 Days 1 and 14: pre-dose, 2, 4, 6, 8 hours post-dose

7. Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 8 (AUC8)

   Time frame: Cycle 1 Days 1 and 14: pre-dose, 2, 4, 6, 8 hours post-dose

8. Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 24 (AUC24)

   Time frame: 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.

9. Phase 1: Cmax/Dose

   Time frame: Cycle 1 Days 1 and 14: pre-dose, 2, 4, 6, 8 hours post-dose

10. Phase 1: AUC8/Dose

    Time frame: Cycle 1 Days 1 and 14: pre-dose, 2, 4, 6, 8 hours post-dose

11. Phase 1: AUC24/Dose

    Time frame: 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.

12. Phase 1: Terminal Phase Elimination Rate Constant (β) for Navitoclax

    Time frame: Cycle 1 Day 1: pre-dose, 2, 4, 6, 8 hours post-dose

13. Phase 1: Terminal Phase Elimination Half-life (t1/2) of Navitoclax

    Time frame: 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.

14. Phase 2: Number of Participants With TEAEs, SAEs, and Discontinuations Due to AEs

    Time frame: 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.

15. Phase 2: Dose-Normalized Plasma Concentrations After Navitoclax Once Daily Dosing

    Time frame: 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