A Study of the Efficacy of ABT-199 in Subjects With Relapsed/Refractory or Previously Untreated Chronic Lymphocytic Leukemia With the 17p Deletion

NCT ID: NCT01889186

Last Updated: 2021-12-16

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 158 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-06-27
• Study Completion Date: 2020-12-15

Brief Summary

This was an open-label, multicenter, global study to determine the efficacy of ABT-199 (Venetoclax) monotherapy in participants with relapsed/refractory (R/R) or previously untreated chronic lymphocytic leukemia (CLL) harboring 17p deletion.

Detailed Description

This study was designed to enroll approximately 150 participants in 2 cohorts: a main cohort of approximately 100 participants, and a safety expansion (SE) cohort of approximately 50 participants. The primary objective of the main cohort was to evaluate the efficacy of ABT-199 monotherapy in participants with R/R CLL harboring the 17p deletion. The primary objective of the safety expansion cohort was to evaluate the safety of ABT-199 in approximately 50 participants with R/R CLL harboring 17p deletion treated per updated tumor lysis syndrome (TLS) prophylaxis and management measures.

Conditions

Chronic Lymphocytic Leukemia; 17p Deletion; Cancer of the Blood and Bone Marrow

Keywords

Chronic Lymphocytic Leukemia; 17p Deletion

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Main Cohort

Participants received ABT-199 tablets once daily (QD) orally for up to 79 months. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg.

Group Type: EXPERIMENTAL

ABT-199 (Main Cohort)

Intervention Type: DRUG

Participants received a test dose of ABT-199 of ≤ 20 mg on Week 1 Day 1 of the Lead-In Period. For those with significant electrolyte and/or lymphocyte changes within 24 hours of the first dose, the 20 mg dose was maintained for 7 days with escalation to 50 mg on Week 2 Day 1. If none of the electrolyte and/or lymphocyte changes occurred within 24 hours from ABT-199 20 mg dose administration, the participant was dose-escalated to 50 mg on Week 1 Day 2. After the first dose of 50 mg, if no laboratory abnormalities occurred, the participant remained on the 50 mg dose through Week 1. After receiving the 50 mg dose for approximately 1 week (6 to 7 days), the following dose escalation proceeded with weekly increases in dose: → 100 mg → 200 mg → 400 mg (or additional lead-in steps to designated 400 mg dose), as tolerated.

Safety Expansion Cohort

Participants received ABT-199 tablets once daily (QD) orally for up to 68 months. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg.

Group Type: EXPERIMENTAL

ABT-199 (Safety Expansion Cohort)

Intervention Type: DRUG

Participants received an initial dose of ABT-199 of 20 mg on Week 1 Day 1 of the Lead-In Period. If one or more electrolyte changes (from the 0 hr measurement prior to dosing) suggestive of laboratory tumor lysis syndrome (LTLS) or clinical TLS (CTLS) occurred within 24 hours of the 20 mg dose, no additional doses were administered until resolution. Upon resolution of laboratory abnormalities, the 20 mg dose was continued through Week 1. If no significant findings suggestive of clinical or laboratory TLS occurred within 24 hours, the 20 mg dose was continued through Week 1 Day 7, and escalated to a dose of 50 mg on Week 2 Day 1. Those who had drug interruptions may have been allowed to escalate to and be maintained at 50 mg for 1 week after they had been on a 20 mg dose for at least 1 week (5 - 7 days). After a week at 50 mg, weekly dose escalations were implemented as follows: 100 mg → 200 mg → 400 mg (or additional lead-in steps to designated 400 mg dose) as tolerated.

Interventions

ABT-199 (Main Cohort)

Participants received a test dose of ABT-199 of ≤ 20 mg on Week 1 Day 1 of the Lead-In Period. For those with significant electrolyte and/or lymphocyte changes within 24 hours of the first dose, the 20 mg dose was maintained for 7 days with escalation to 50 mg on Week 2 Day 1. If none of the electrolyte and/or lymphocyte changes occurred within 24 hours from ABT-199 20 mg dose administration, the participant was dose-escalated to 50 mg on Week 1 Day 2. After the first dose of 50 mg, if no laboratory abnormalities occurred, the participant remained on the 50 mg dose through Week 1. After receiving the 50 mg dose for approximately 1 week (6 to 7 days), the following dose escalation proceeded with weekly increases in dose: → 100 mg → 200 mg → 400 mg (or additional lead-in steps to designated 400 mg dose), as tolerated.

Intervention Type: DRUG

ABT-199 (Safety Expansion Cohort)

Participants received an initial dose of ABT-199 of 20 mg on Week 1 Day 1 of the Lead-In Period. If one or more electrolyte changes (from the 0 hr measurement prior to dosing) suggestive of laboratory tumor lysis syndrome (LTLS) or clinical TLS (CTLS) occurred within 24 hours of the 20 mg dose, no additional doses were administered until resolution. Upon resolution of laboratory abnormalities, the 20 mg dose was continued through Week 1. If no significant findings suggestive of clinical or laboratory TLS occurred within 24 hours, the 20 mg dose was continued through Week 1 Day 7, and escalated to a dose of 50 mg on Week 2 Day 1. Those who had drug interruptions may have been allowed to escalate to and be maintained at 50 mg for 1 week after they had been on a 20 mg dose for at least 1 week (5 - 7 days). After a week at 50 mg, weekly dose escalations were implemented as follows: 100 mg → 200 mg → 400 mg (or additional lead-in steps to designated 400 mg dose) as tolerated.

Intervention Type: DRUG

Other Intervention Names

Venetoclax; GDC-0199; Venetoclax; GDC-0199

Eligibility Criteria

Inclusion Criteria

• Participant must be greater than or equal to 18 years of age.
• Participant must have diagnosis of chronic lymphocytic leukemia (CLL) that meets published 2008 Modified IWCLL NCI-WG (International Workshop for Chronic Lymphocytic Leukemia National Cancer Institute-Working Group) Guidelines.

• Participant has an indication for treatment according to the 2008 Modified IWCLL NCI WG Guidelines;
• Participant has clinically measurable disease (lymphocytosis > 5 × 10^9/L and/or palpable and measurable nodes by physical exam and/or organomegaly assessed by physical exam);
• Participant must be refractory or have relapsed after receiving at least one prior line of therapy (participants that have progressed after 1 cycle of treatment or have completed at least 2 cycles of treatment for a given line of therapy) or previously untreated CLL (previously untreated CLL participants must have received no prior chemotherapy or immunotherapy. Participants with a history of emergency, loco-regional radiotherapy (e.g., for relief of compressive signs or symptoms) are eligible. In addition, participants must meet the CLL diagnostic criteria above and must have > 5 × 10^9/L B-Lymphocytes in the peripheral blood.);
• Participants must have 17p deletion, assessed by local laboratory (in bone marrow or peripheral blood) or assessed by central laboratory (peripheral blood).
• Participant has an Eastern Cooperative Oncology Group (ECOG) performance score of less than or equal to 2.
• Participant must have adequate bone marrow function at Screening as follows:

• Absolute Neutrophil Count (ANC) greater than or equal to 1000/µL, or
• For subjects with an ANC less than 1000/µL at Screening and bone marrow heavily infiltrated with underlying disease (unless cytopenia is clearly due to marrow involvement of CLL), growth factor support may be administered after Screening and prior to the first dose of ABT-199 to achieve the ANC eligibility criteria (greater than or equal to 1000/µL);
• Platelets greater than 30,000/mm^3 (without transfusion support within 14 days of Screening, without evidence of mucosal bleeding, without known history of bleeding episode within 3 months of Screening, and without history of bleeding disorder);
• Hemoglobin greater than or equal to 8.0 g/dL.
• Participant must have adequate coagulation, renal, and hepatic function, per laboratory reference range at Screening as follows:

• Activated partial thromboplastin time (aPTT) and prothrombin time (PT) not to exceed 1.5 × the upper limit of normal;
• Calculated creatinine clearance greater than 50 mL/min using 24-hour Creatinine Clearance or modified Cockcroft-Gault equation (using Ideal Body Mass [IBM] instead of Mass). For participants that have body mass index (BMI) of > 30 kg/m^2 or < 19 kg/m^2, 24-hour measured urine creatinine clearance is required;
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 3.0 × the upper normal limit of institution's normal range; Bilirubin less than or equal to 1.5 × upper limit of normal. Participants with Gilbert's Syndrome may have a bilirubin greater 1.5 × upper limit of normal, per correspondence between the investigator and AbbVie medical monitor.
• For participants at high risk of tumor lysis syndrome a pre-approval by the AbbVie medical monitor is required prior to enrollment.

Exclusion Criteria

• Participant has undergone an allogeneic stem cell transplant.
• Participant has developed Richter's transformation confirmed by biopsy.
• Participant has prolymphocytic leukemia.
• Participant has active and uncontrolled autoimmune cytopenias (for 2 weeks prior to Screening), including autoimmune hemolytic anemia and idiopathic thrombocytopenic purpura despite low dose corticosteroids.
• Participant has previously received ABT-199.
• Participant has received a biologic agent for anti-neoplastic intent within 30 days prior to the first dose of study drug.
• Participant has received any of the following within 14 days or 5 half-lives as applicable prior to the first dose of study drug, or has not recovered to less than Common Toxicity Criteria (CTC) grade 2 clinically significant adverse effect(s)/toxicity(s) of the previous therapy:

• Any anti-cancer therapy including chemotherapy, or radiotherapy;
• Investigational therapy, including targeted small molecule agents.
• Participant has known allergy to both xanthine oxidase inhibitors and rasburicase.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 99 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Genentech, Inc.

INDUSTRY

Sponsor Role: collaborator

AbbVie

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

ABBVIE INC.

Role: STUDY_DIRECTOR

AbbVie

Locations

University of Arizona Cancer Center - North Campus /ID# 96748

Tucson, Arizona, United States

City of Hope /ID# 112875

Duarte, California, United States

Moore UC San Diego Cancer Center /ID# 91793

La Jolla, California, United States

Stanford University School of Med /ID# 105117

Stanford, California, United States

Georgetown University Hospital /ID# 96954

Washington D.C., District of Columbia, United States

Northwestern University Feinberg School of Medicine /ID# 92499

Chicago, Illinois, United States

The University of Chicago Medical Center /ID# 96960

Chicago, Illinois, United States

Ingalls Memorial Hosp /ID# 92497

Harvey, Illinois, United States

Dana-Farber Cancer Institute /ID# 92494

Boston, Massachusetts, United States

Henry Ford Health System /ID# 97795

Detroit, Michigan, United States

Hackensack Univ Med Ctr /ID# 92500

Hackensack, New Jersey, United States

Rutgers Cancer Institute of New Jersey /ID# 92513

New Brunswick, New Jersey, United States

Columbia Univ Medical Center /ID# 103835

New York, New York, United States

Columbia Univ Medical Center /ID# 94716

New York, New York, United States

Cleveland Clinic Main Campus /ID# 92495

Cleveland, Ohio, United States

University of Texas MD Anderson Cancer Center /ID# 92521

Houston, Texas, United States

Royal North Shore Hospital /ID# 98836

St Leonards, New South Wales, Australia

John Fawkner Private Hospital /ID# 98835

Coburg, Victoria, Australia

Peter MacCallum Cancer Ctr /ID# 91795

Melbourne, Victoria, Australia

Royal Melbourne Hospital /ID# 91794

Parkville, Victoria, Australia

Duplicate_Jewish General Hospital /ID# 99476

Montreal, Quebec, Canada

Centre Hospitalier Lyon Sud /ID# 98839

Pierre-Bénite, Auvergne-Rhône-Alpes, France

Hopital Pitie Salpetriere /ID# 98842

Paris, , France

Centre Henri Becquerel /ID# 98838

Rouen, , France

Hopital Avicenne - APHP /ID# 98840

Bobigny, Île-de-France Region, France

Universitaetsklinik Heidelberg /ID# 98845

Heidelberg, Baden-Wurttemberg, Germany

Uniklinik Koeln /ID# 98847

Cologne, North Rhine-Westphalia, Germany

Universitaetsklinikum Schleswig-Holstein Campus Kiel /ID# 113235

Kiel, Schleswig-Holstein, Germany

Universitaetsklinikum Ulm /ID# 92533

Ulm, Thuringia, Germany

Universitaetsklinikum Carl Gustav Carus an der TU Dresden /ID# 113256

Dresden, , Germany

Universitaetsklinikum Freiburg /ID# 113276

Freiburg im Breisgau, , Germany

Universitaetsmedizin Goettingen /ID# 113258

Göttingen, , Germany

Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz /ID# 113236

Mainz, , Germany

Muenchen Klinik Schwabing /ID# 113275

München, , Germany

SP ZOZ Szpital Uniwersytecki w Krakowie /ID# 98849

Krakow, Lesser Poland Voivodeship, Poland

Samodzielny Publiczny Szpital Kliniczny Nr 1 w Lublinie /ID# 98848

Lublin, Lublin Voivodeship, Poland

Szpital Wojewodzki w Opolu /ID# 102855

Opole, Opole Voivodeship, Poland

Leicester Royal Infirmary /ID# 98865

Leicester, England, United Kingdom

The Royal Bournemouth Hospital /ID# 118975

Bournemouth, , United Kingdom

Addenbrookes Hospital /ID# 119977

Cambridge, , United Kingdom

St. James University Hospital /ID# 98863

Leeds, , United Kingdom

Royal Liverpool and Broadgreen /ID# 98860

Liverpool, , United Kingdom

St Bartholomew's Hospital, Bar /ID# 98862

London, , United Kingdom

King's College Hospital NHS Foundation Trust /ID# 119975

London, , United Kingdom

The Christie Hospital /ID# 98864

Manchester, , United Kingdom

Oxford Univ Hosp NHS Trust /ID# 119976

Oxford, , United Kingdom

Derriford Hospital /ID# 118335

Plymouth, , United Kingdom

Royal Marsden Hospital /ID# 98861

Sutton, , United Kingdom

Countries

United States; Australia; Canada; France; Germany; Poland; United Kingdom

References

Stilgenbauer S, Eichhorst B, Schetelig J, Coutre S, Seymour JF, Munir T, Puvvada SD, Wendtner CM, Roberts AW, Jurczak W, Mulligan SP, Bottcher S, Mobasher M, Zhu M, Desai M, Chyla B, Verdugo M, Enschede SH, Cerri E, Humerickhouse R, Gordon G, Hallek M, Wierda WG. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 2016 Jun;17(6):768-778. doi: 10.1016/S1470-2045(16)30019-5. Epub 2016 May 10.

Reference Type: BACKGROUND

PMID: 27178240 (View on PubMed)

Stilgenbauer S, Tausch E, Roberts AW, Davids MS, Eichhorst B, Hallek M, Hillmen P, Schneider C, Schetelig J, Bottcher S, Kater AP, Jiang Y, Boyer M, Popovic R, Ghanim MT, Moran M, Sinai WJ, Wang X, Mukherjee N, Chyla B, Wierda WG, Seymour JF. Six-year follow-up and subgroup analyses of a phase 2 trial of venetoclax for del(17p) chronic lymphocytic leukemia. Blood Adv. 2024 Apr 23;8(8):1992-2004. doi: 10.1182/bloodadvances.2023011741.

Reference Type: DERIVED

PMID: 38290108 (View on PubMed)

Roberts AW, Ma S, Kipps TJ, Coutre SE, Davids MS, Eichhorst B, Hallek M, Byrd JC, Humphrey K, Zhou L, Chyla B, Nielsen J, Potluri J, Kim SY, Verdugo M, Stilgenbauer S, Wierda WG, Seymour JF. Efficacy of venetoclax in relapsed chronic lymphocytic leukemia is influenced by disease and response variables. Blood. 2019 Jul 11;134(2):111-122. doi: 10.1182/blood.2018882555. Epub 2019 Apr 25.

Reference Type: DERIVED

PMID: 31023700 (View on PubMed)

Stilgenbauer S, Eichhorst B, Schetelig J, Hillmen P, Seymour JF, Coutre S, Jurczak W, Mulligan SP, Schuh A, Assouline S, Wendtner CM, Roberts AW, Davids MS, Bloehdorn J, Munir T, Bottcher S, Zhou L, Salem AH, Desai M, Chyla B, Arzt J, Kim SY, Verdugo M, Gordon G, Hallek M, Wierda WG. Venetoclax for Patients With Chronic Lymphocytic Leukemia With 17p Deletion: Results From the Full Population of a Phase II Pivotal Trial. J Clin Oncol. 2018 Jul 1;36(19):1973-1980. doi: 10.1200/JCO.2017.76.6840. Epub 2018 May 1.

Reference Type: DERIVED

PMID: 29715056 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2012-004027-20

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

M13-982

Identifier Type: -

Identifier Source: org_study_id