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

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 1/2a Study Evaluating the Safety, Pharmacokinetics, and Efficacy of ABT-263 in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia

Conditions
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Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Drug: ABT-263


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion 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).

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Navitoclax 14/21 Day Cycle: 10 mg<br>Navitoclax 10 mg administered for 14 consecutive days followed by 7 days off drug to complete a 21-day cycle. | Drug: ABT-263<br>* Tablet; Oral<br>* Other names: Navitoclax;|
| Experimental: Navitoclax 14/21 Day Cycle: 110 mg<br>Navitoclax 110 mg administered for 14 consecutive days followed by 7 days off drug to complete a 21-day cycle. | Drug: ABT-263<br>* Tablet; Oral<br>* Other names: Navitoclax;|
| Experimental: Navitoclax 14/21 Day Cycle: 200 mg<br>Navitoclax 200 mg administered for 14 consecutive days followed by 7 days off drug to complete a 21-day cycle. | Drug: ABT-263<br>* Tablet; Oral<br>* Other names: Navitoclax;|
| Experimental: Navitoclax 14/21 Day Cycle: 250 mg<br>Navitoclax 250 mg administered for 14 consecutive days followed by 7 days off drug to complete a 21-day cycle. | Drug: ABT-263<br>* Tablet; Oral<br>* Other names: Navitoclax;|
| Experimental: Navitoclax 21/21 Day Cycle: 125 mg<br>Navitoclax 125 mg administered for 21 consecutive days to complete a 21-day cycle. | Drug: ABT-263<br>* Tablet; Oral<br>* Other names: Navitoclax;|
| Experimental: Navitoclax 21/21 Day Cycle: 200 mg<br>Navitoclax 200 mg administered for 21 consecutive days to complete a 21-day cycle. | Drug: ABT-263<br>* Tablet; Oral<br>* Other names: Navitoclax;|
| Experimental: Navitoclax 21/21 Day Cycle: 250 mg<br>Navitoclax 250 mg administered for 21 consecutive days to complete a 21-day cycle. | Drug: ABT-263<br>* Tablet; Oral<br>* Other names: Navitoclax;|
| Experimental: Navitoclax 21/21 Day Cycle: 300 mg<br>Navitoclax 300 mg administered for 21 consecutive days to complete a 21-day cycle. | Drug: ABT-263<br>* Tablet; Oral<br>* Other names: Navitoclax;|
| Experimental: Phase 2: Navitoclax 100 mg<br>Navitoclax 100 mg in participants with CLL who had relapsed following any (but no more than 5) prior myelosuppressive/chemotherapy treatment regimen(s). | Drug: ABT-263<br>* Tablet; Oral<br>* Other names: Navitoclax;|
| Experimental: Phase 2: Navitoclax 250 mg<br>Navitoclax 250 mg in participants with CLL who had relapsed following any (but no more than 5) prior myelosuppressive/chemotherapy treatment regimen(s). | Drug: ABT-263<br>* Tablet; Oral<br>* Other names: Navitoclax;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | 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. | 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. | 
| Phase 1: Number of Participants With DLTs in the Dose Escalation Phase | 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. | Cycle 1 (Up to 21 days) plus 7 days | 
| Phase 1: Maximum Tolerated Dose (MTD) in the Dose Escalation Phase | 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. | Cycle 1 (Up to 21 days) plus 7 days | 
| Phase 1: Recommended Phase 2 Dose (RPTD) Determined in the Dose Escalation Phase | 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.) | Cycle 1 (Up to 21 days) plus 7 days | 
| 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: 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: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 24 (AUC24) | 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. | 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 | 
| Phase 1: Cmax/Dose |  | 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 | 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. | 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 | 
| 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: Terminal Phase Elimination Half-life (t1/2) of Navitoclax | For t1/2, the harmonic mean and psuedo-standard deviation are used. | Cycle 1 Day 1: pre-dose, 2, 4, 6, 8 hours post-dose | 
| Phase 2: Number of Participants With TEAEs, SAEs, and Discontinuations Due to AEs | 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. | 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. | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Lymphocytic Leukemia (CLL), Navitoclax, ABT-263, Cancer