Clinical trial NCT01889186: A Study of the Efficacy of ABT-199 in Subjects With Relapsed/Refractory or Previously Untreated Chronic Lymphocytic Leukemia With the 17p Deletion
Official title: A Phase 2 Open-Label Study of the Efficacy of ABT-199 (GDC-0199) in Subjects With Relapsed/Refractory or Previously Untreated Chronic Lymphocytic Leukemia Harboring the 17p Deletion
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Lymphocytic Leukemia
17p Deletion
Cancer of the Blood and Bone Marrow
Keywords: Chronic Lymphocytic Leukemia
17p Deletion
Lead sponsor: AbbVie
Sponsor class: INDUSTRY
Collaborators: name: Genentech, Inc.
First posted: 2013-06-28
Enrollment: 158
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Overall Response Rate (Main Cohort)
timeFrame: Up to 36 weeks
measure: Number of Participants With Adverse Events (Safety Expansion Cohort)
timeFrame: From the first dose of study drug until 30 days following last dose of study drug (up to 69 months)
Secondary outcomes:
measure: Overall Response Rate (ORR) (Safety Expansion Cohort)
timeFrame: Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up
measure: Complete Remission (CR) Rate
timeFrame: Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up
measure: Partial Remission (PR) Rate
timeFrame: Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up
measure: Duration of Overall Response
timeFrame: Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up
measure: Progression-free Survival
timeFrame: Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up
measure: Event-free Survival
timeFrame: Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up
measure: Time to Progression
timeFrame: Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up
measure: Time to First Response
timeFrame: Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up
measure: Time to 50% Reduction in Absolute Lymphocyte Count
timeFrame: Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up
measure: Overall Survival
timeFrame: Up to the data cutoff date of 15 December 2020, approximately 7.5 years of follow-up
measure: Percentage of Participants Who Moved on to Stem Cell Transplant
timeFrame: Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up
Other outcomes:
Locations:
city: Tucson
country: United States
facility: University of Arizona Cancer Center - North Campus /ID# 96748
state: Arizona
city: Duarte
country: United States
facility: City of Hope /ID# 112875
state: California
city: La Jolla
country: United States
facility: Moore UC San Diego Cancer Center /ID# 91793
state: California
city: Stanford
country: United States
facility: Stanford University School of Med /ID# 105117
state: California
city: Washington
country: United States
facility: Georgetown University Hospital /ID# 96954
state: District of Columbia
city: Chicago
country: United States
facility: Northwestern University Feinberg School of Medicine /ID# 92499
state: Illinois
city: Chicago
country: United States
facility: The University of Chicago Medical Center /ID# 96960
state: Illinois
city: Harvey
country: United States
facility: Ingalls Memorial Hosp /ID# 92497
state: Illinois
city: Boston
country: United States
facility: Dana-Farber Cancer Institute /ID# 92494
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Health System /ID# 97795
state: Michigan
city: Hackensack
country: United States
facility: Hackensack Univ Med Ctr /ID# 92500
state: New Jersey
city: New Brunswick
country: United States
facility: Rutgers Cancer Institute of New Jersey /ID# 92513
state: New Jersey
city: New York
country: United States
facility: Columbia Univ Medical Center /ID# 103835
state: New York
city: New York
country: United States
facility: Columbia Univ Medical Center /ID# 94716
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic Main Campus /ID# 92495
state: Ohio
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center /ID# 92521
state: Texas
city: St Leonards
country: Australia
facility: Royal North Shore Hospital /ID# 98836
state: New South Wales
city: Coburg
country: Australia
facility: John Fawkner Private Hospital /ID# 98835
state: Victoria
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Ctr /ID# 91795
state: Victoria
city: Parkville
country: Australia
facility: Royal Melbourne Hospital /ID# 91794
state: Victoria
city: Montreal
country: Canada
facility: Duplicate_Jewish General Hospital /ID# 99476
state: Quebec
city: Pierre Benite CEDEX
country: France
facility: Centre Hospitalier Lyon Sud /ID# 98839
state: Auvergne-Rhone-Alpes
city: Bobigny
country: France
facility: Hopital Avicenne - APHP /ID# 98840
state: Ile-de-France
city: Paris
country: France
facility: Hopital Pitie Salpetriere /ID# 98842
city: Rouen
country: France
facility: Centre Henri Becquerel /ID# 98838
city: Heidelberg
country: Germany
facility: Universitaetsklinik Heidelberg /ID# 98845
state: Baden-Wuerttemberg
city: Köln
country: Germany
facility: Uniklinik Koeln /ID# 98847
state: Nordrhein-Westfalen
city: Kiel
country: Germany
facility: Universitaetsklinikum Schleswig-Holstein Campus Kiel /ID# 113235
state: Schleswig-Holstein
city: Ulm
country: Germany
facility: Universitaetsklinikum Ulm /ID# 92533
state: Thueringen
city: Dresden
country: Germany
facility: Universitaetsklinikum Carl Gustav Carus an der TU Dresden /ID# 113256
city: Freiburg
country: Germany
facility: Universitaetsklinikum Freiburg /ID# 113276
city: Göttingen
country: Germany
facility: Universitaetsmedizin Goettingen /ID# 113258
city: Mainz
country: Germany
facility: Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz /ID# 113236
city: Muenchen
country: Germany
facility: Muenchen Klinik Schwabing /ID# 113275
city: Lublin
country: Poland
facility: Samodzielny Publiczny Szpital Kliniczny Nr 1 w Lublinie /ID# 98848
state: Lubelskie
city: Krakow
country: Poland
facility: SP ZOZ Szpital Uniwersytecki w Krakowie /ID# 98849
state: Malopolskie
city: Opole
country: Poland
facility: Szpital Wojewodzki w Opolu /ID# 102855
state: Opolskie
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary /ID# 98865
state: England
city: Bournemouth
country: United Kingdom
facility: The Royal Bournemouth Hospital /ID# 118975
city: Cambridge
country: United Kingdom
facility: Addenbrookes Hospital /ID# 119977
city: Leeds
country: United Kingdom
facility: St. James University Hospital /ID# 98863
city: Liverpool
country: United Kingdom
facility: Royal Liverpool and Broadgreen /ID# 98860
city: London
country: United Kingdom
facility: St Bartholomew's Hospital, Bar /ID# 98862
city: London
country: United Kingdom
facility: King's College Hospital NHS Foundation Trust /ID# 119975
city: Manchester
country: United Kingdom
facility: The Christie Hospital /ID# 98864
city: Oxford
country: United Kingdom
facility: Oxford Univ Hosp NHS Trust /ID# 119976
city: Plymouth
country: United Kingdom
facility: Derriford Hospital /ID# 118335
city: Sutton
country: United Kingdom
facility: Royal Marsden Hospital /ID# 98861
Study officials:
affiliation: AbbVie
name: ABBVIE INC.
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.