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

Chronic Lymphocytic Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00481091
• Other study ID #: M06-873
• Secondary ID: 2007-002143-25
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: July 25, 2007
• Est. completion date: May 12, 2022

Study information

• Verified date: June 2023
• Source: AbbVie
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 60
• Est. completion date: May 12, 2022
• Est. primary completion date: May 12, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• Chronic Lymphocytic Leukemia
• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid

Intervention

Drug:
• ABT-263
Tablet; Oral

Locations

Country	Name	City	State
Australia	Peter MacCallum Cancer Ctr /ID# 6583	Melbourne	Victoria
Australia	The Royal Melbourne Hospital /ID# 5576	Parkville	Victoria
Germany	Universitaetsklinikum Koeln /ID# 5924	Köln	Nordrhein-Westfalen
United Kingdom	Leicester Royal Infirmary /ID# 15081	Leicester	England
United States	Dana-Farber Cancer Institute /ID# 5547	Boston	Massachusetts
United States	University of Texas MD Anderson Cancer Center /ID# 5575	Houston	Texas
United States	Moores Cancer Center at UC San Diego /ID# 5566	La Jolla	California
United States	North Shore University Hospital /ID# 12267	New Hyde Park	New York
United States	University of Nebraska Medical Center /ID# 12261	Omaha	Nebraska
United States	Northwest Medical Specialties - Tacoma /ID# 26428	Tacoma	Washington

Sponsors (2)

Lead Sponsor	Collaborator
AbbVie	Genentech, Inc.

Countries where clinical trial is conducted

United States,  Australia,  Germany,  United Kingdom, 

References & Publications (1)

Roberts AW, Seymour JF, Brown JR, Wierda WG, Kipps TJ, Khaw SL, Carney DA, He SZ, Huang DC, Xiong H, Cui Y, Busman TA, McKeegan EM, Krivoshik AP, Enschede SH, Humerickhouse R. Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.
Primary	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
Primary	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
Primary	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
Primary	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
Primary	Phase 1: Maximum Observed Plasma Concentration (Cmax)		Cycle 1 Days 1 and 14: pre-dose, 2, 4, 6, 8 hours post-dose
Primary	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
Primary	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
Primary	Phase 1: Cmax/Dose		Cycle 1 Days 1 and 14: pre-dose, 2, 4, 6, 8 hours post-dose
Primary	Phase 1: AUC8/Dose		Cycle 1 Days 1 and 14: pre-dose, 2, 4, 6, 8 hours post-dose
Primary	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
Primary	Phase 1: Terminal Phase Elimination Rate Constant (ß) for Navitoclax		Cycle 1 Day 1: pre-dose, 2, 4, 6, 8 hours post-dose
Primary	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
Primary	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.
Primary	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

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