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

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

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.

Study Overview

• Status: Completed
• Conditions: Chronic Lymphocytic Leukemia
• Intervention / Treatment: Drug: ABT-263

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • Peter MacCallum Cancer Ctr /ID# 6583
    • Parkville, Victoria, Australia, 3050
      • The Royal Melbourne Hospital /ID# 5576
• Germany
  • Nordrhein-Westfalen
    • Köln, Nordrhein-Westfalen, Germany, 50937
      • Universitaetsklinikum Koeln /ID# 5924
• United Kingdom
  • England
    • Leicester, England, United Kingdom, LE1 5WW
      • Leicester Royal Infirmary /ID# 15081
• United States
  • California
    • La Jolla, California, United States, 92093
      • Moores Cancer Center at UC San Diego /ID# 5566
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute /ID# 5547
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center /ID# 12261
  • New York
    • New Hyde Park, New York, United States, 11040
      • North Shore University Hospital /ID# 12267
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas MD Anderson Cancer Center /ID# 5575
  • Washington
    • Tacoma, Washington, United States, 98405
      • Northwest Medical Specialties - Tacoma /ID# 26428

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

10

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Navitoclax 14/21 Day Cycle: 10 mg; Navitoclax 10 mg administered for 14 consecutive days followed by 7 days off drug to complete a 21-day cycle.	Drug: ABT-263; Tablet; Oral; Other Names: Navitoclax
Experimental: Navitoclax 14/21 Day Cycle: 110 mg; Navitoclax 110 mg administered for 14 consecutive days followed by 7 days off drug to complete a 21-day cycle.	Drug: ABT-263; Tablet; Oral; Other Names: Navitoclax
Experimental: Navitoclax 14/21 Day Cycle: 200 mg; Navitoclax 200 mg administered for 14 consecutive days followed by 7 days off drug to complete a 21-day cycle.	Drug: ABT-263; Tablet; Oral; Other Names: Navitoclax
Experimental: Navitoclax 14/21 Day Cycle: 250 mg; Navitoclax 250 mg administered for 14 consecutive days followed by 7 days off drug to complete a 21-day cycle.	Drug: ABT-263; Tablet; Oral; Other Names: Navitoclax
Experimental: Navitoclax 21/21 Day Cycle: 125 mg; Navitoclax 125 mg administered for 21 consecutive days to complete a 21-day cycle.	Drug: ABT-263; Tablet; Oral; Other Names: Navitoclax
Experimental: Navitoclax 21/21 Day Cycle: 200 mg; Navitoclax 200 mg administered for 21 consecutive days to complete a 21-day cycle.	Drug: ABT-263; Tablet; Oral; Other Names: Navitoclax
Experimental: Navitoclax 21/21 Day Cycle: 250 mg; Navitoclax 250 mg administered for 21 consecutive days to complete a 21-day cycle.	Drug: ABT-263; Tablet; Oral; Other Names: Navitoclax
Experimental: Navitoclax 21/21 Day Cycle: 300 mg; Navitoclax 300 mg administered for 21 consecutive days to complete a 21-day cycle.	Drug: ABT-263; Tablet; Oral; Other Names: Navitoclax
Experimental: Phase 2: Navitoclax 100 mg; 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; Tablet; Oral; Other Names: Navitoclax
Experimental: Phase 2: Navitoclax 250 mg; 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; Tablet; Oral; Other Names: Navitoclax

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: AbbVie
• Collaborators: Genentech, Inc.
• Investigators: Study Director: ABBVIE INC., AbbVie

Publications and helpful links

General Publications

• 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: results of a phase I study of navitoclax in patients with relapsed or refractory disease. J Clin Oncol. 2012 Feb 10;30(5):488-96. doi: 10.1200/JCO.2011.34.7898. Epub 2011 Dec 19.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): July 25, 2007
• Primary Completion (Actual): May 12, 2022
• Study Completion (Actual): May 12, 2022

Study Registration Dates

• First Submitted: May 30, 2007
• First Submitted That Met QC Criteria: May 30, 2007
• First Posted (Estimated): June 1, 2007

Study Record Updates

• Last Update Posted (Estimated): June 13, 2023
• Last Update Submitted That Met QC Criteria: June 12, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Cancer; Chronic Lymphocytic Leukemia (CLL); Navitoclax; ABT-263
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Leukemia, B-Cell; Chronic Disease; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Antineoplastic Agents; Navitoclax
• Other Study ID Numbers: M06-873; 2007-002143-25 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual and trial-level data (analysis data sets), as well as other information (e.g., protocols, analyses plans, clinical study reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications.
• IPD Sharing Time Frame: For details on when studies are available for sharing visit https://vivli.org/ourmember/abbvie/
• IPD Sharing Access Criteria: Access to this clinical trial data can be requested by any qualified researchers who engage in rigorous independent scientific research, and will be provided following review and approval of a research proposal and statistical analysis plan and execution of a data sharing statement. Data requests can be submitted at any time after approval in the US and/or EU and a primary manuscript is accepted for publication. For more information on the process, or to submit a request, visit the following link https://www.abbvieclinicaltrials.com/hcp/data-sharing/
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No