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

Phase 2

Completed

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

Interventions: Drug: ABT-199 (Safety Expansion Cohort)
Drug: ABT-199 (Main Cohort)

Registration Number: NCT01889186

Lead Sponsor: AbbVie

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 158

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Safety Expansion Cohort	ABT-199 (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.
Main Cohort	ABT-199 (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.

Primary Outcome Measures

Name	Time	Method
Overall Response Rate (Main Cohort)	Up to 36 weeks	The overall response rate (ORR) is defined as the proportion of participants with an overall response (complete remission \[CR\] + complete remission with incomplete marrow recovery \[CRi\] + nodular partial remission \[nPR\] + partial remission \[PR\]) per the 2008 Modified International Workshop for Chronic Lymphocytic Leukemia (IWCLL)/National Cancer Institute-Working Group (NCI-CWG) criteria as assessed by the Independent Review Committee (IRC) in the first 70 participants treated in the Main Cohort.
Number of Participants With Adverse Events (Safety Expansion Cohort)	From the first dose of study drug until 30 days following last dose of study drug (up to 69 months)	An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. The investigator assesses the relationship of each event to the use of study drug. A serious adverse event (SAE) is an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent adverse events/treatment-emergent serious adverse events (TEAEs/TESAEs) are defined as any event that began or worsened in severity on or after the first dose of study drug.

Secondary Outcome Measures

Name	Time	Method
Duration of Overall Response	Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up	Duration of overall response (DoR) was defined as the number of days from the date of first response (CR, CRi, nPR, or PR) by either CT scan or physical exam determination to the earliest recurrence (progressive disease; PD) or death. For participants who had a PR before CR, CRi, or nPR in subsequent visits, the DoR was computed from the earliest PR. If a participant was still responding, then their data was censored at the date of their last available disease assessment. To be included in the DoR analysis, participants must have had a response per the 2008 Modified International Workshop for Chronic Lymphocytic Leukemia (IWCLL)/National Cancer Institute-Working Group (NCI-CWG) criteria (CR, CRi, confirmed nPR, or confirmed PR). For participants who never experienced response, their data was not included in the analysis.
Progression-free Survival	Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up	Duration of progression-free survival (PFS) was defined as the number of days from the date of first dose to the date of earliest disease progression or death. All disease progression was included regardless of whether the event occurred while the participant was taking ABT-199 or had previously discontinued ABT-199. If the participant does not experience disease progression or death, then the data was censored at the date of last disease assessment. Data for participants without any disease assessments performed after the baseline visit were censored at the date of first dose plus 1 day.
Event-free Survival	Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up	Event-free survival (EFS) was defined as the number of days from the date of first dose to the date of earliest disease progression, death, or start of a new anti-leukemic therapy. If the specified event (disease progression, death, start of a new anti-leukemic treatment) did not occur, participants were censored at the date of last disease assessment. Data for participants without any disease assessments performed after the baseline visit were censored at the date of first dose plus 1 day.
Time to Progression	Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up	Time to progression (TTP) was defined as the number of days from the date of first dose to the date of earliest disease progression. All disease progression was included regardless of whether the event occurred while the participant was taking ABT-199 or had previously discontinued ABT-199. If the participant did not experience disease progression, then the data was censored at the date of last available disease assessment. Data for participants without any disease assessments performed after the baseline visit were censored at the date of first dose plus 1 day.
Time to First Response	Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up	Time to first response was defined as the number of days from the date of first dose to the date of the first sign of response (CR, CRi, nPR, or PR) given the participant has had a CR, CRi, confirmed nPR, or confirmed PR per the 2008 Modified International Workshop for Chronic Lymphocytic Leukemia (IWCLL)/National Cancer Institute-Working Group (NCI-CWG) criteria. The first response could have been an assessment by physical exam as long as the results were later confirmed per the 2008 Modified IWCLL NCI-WG criteria. For participants who never experienced a response, the participant's data were not included in the analysis.
Time to 50% Reduction in Absolute Lymphocyte Count	Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up	Time to 50% reduction in absolute lymphocyte count (ALC) was defined as the number of days (hours if applicable) from the date of first dose to the date when the ALC had reduced to 50% of the baseline value. Only participants with a baseline of ALC \> 5 × 10\^9 /L were included in the analysis. For participants who never achieved a 50% reduction in ALC, the participant's data were not included in the analysis.
Overall Survival	Up to the data cutoff date of 15 December 2020, approximately 7.5 years of follow-up	Overall survival (OS) was defined as number of days from the date of first dose to the date of death. For participants who did not die, their data was censored at the date of last study visit or the last known date to be alive, whichever was later.
Percentage of Participants Who Moved on to Stem Cell Transplant	Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up	The percentage of participants who moved on to stem cell transplant was summarized.
Overall Response Rate (ORR) (Safety Expansion Cohort)	Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up	The overall response rate (ORR) is defined as the proportion of participants with an overall response (complete remission \[CR\] + complete remission with incomplete marrow recovery \[CRi\] + nodular partial remission \[nPR\] + partial remission \[PR\]) per the 2008 Modified International Workshop for Chronic Lymphocytic Leukemia (IWCLL)/National Cancer Institute-Working Group (NCI-CWG) criteria.
Complete Remission (CR) Rate	Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up	Complete remission was defined as the proportion of participants who achieved a CR or Complete Remission with Incomplete Marrow Recovery(CRi ) per the 2008 Modified International Workshop for Chronic Lymphocytic Leukemia (IWCLL)/National Cancer Institute-Working Group (NCI-CWG) criteria. Participants who did not achieve a CR or CRi were considered to be non-responders in the calculation of CR rate.
Partial Remission (PR) Rate	Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up	PR rate was defined as the proportion of participants who achieved a nodular partial remission (nPR) or PR per the 2008 Modified International Workshop for Chronic Lymphocytic Leukemia (IWCLL)/National Cancer Institute-Working Group (NCI-CWG) criteria. Participants who did not achieve a nPR or PR were considered to be non-responders in the calculation of PR rate.

Trial Locations

Locations (48): Rutgers Cancer Institute of New Jersey /ID# 92513
🇺🇸
New Brunswick, New Jersey, United States
Hackensack Univ Med Ctr /ID# 92500
🇺🇸
Hackensack, New Jersey, United States
Peter MacCallum Cancer Ctr /ID# 91795
🇦🇺
Melbourne, Victoria, Australia
Cleveland Clinic Main Campus /ID# 92495
🇺🇸
Cleveland, Ohio, United States
Centre Henri Becquerel /ID# 98838
🇫🇷
Rouen, France
Royal North Shore Hospital /ID# 98836
🇦🇺
St Leonards, New South Wales, Australia
Uniklinik Koeln /ID# 98847
🇩🇪
Köln, Nordrhein-Westfalen, Germany
The University of Chicago Medical Center /ID# 96960
🇺🇸
Chicago, Illinois, United States
The Christie Hospital /ID# 98864
🇬🇧
Manchester, United Kingdom
Hopital Pitie Salpetriere /ID# 98842
🇫🇷
Paris, France
Samodzielny Publiczny Szpital Kliniczny Nr 1 w Lublinie /ID# 98848
🇵🇱
Lublin, Lubelskie, Poland
Columbia Univ Medical Center /ID# 94716
🇺🇸
New York, New York, United States
Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz /ID# 113236
🇩🇪
Mainz, Germany
Derriford Hospital /ID# 118335
🇬🇧
Plymouth, United Kingdom
Ingalls Memorial Hosp /ID# 92497
🇺🇸
Harvey, Illinois, United States
King's College Hospital NHS Foundation Trust /ID# 119975
🇬🇧
London, United Kingdom
Universitaetsklinikum Freiburg /ID# 113276
🇩🇪
Freiburg, Germany
Oxford Univ Hosp NHS Trust /ID# 119976
🇬🇧
Oxford, United Kingdom
Universitaetsklinikum Ulm /ID# 92533
🇩🇪
Ulm, Thueringen, Germany
The Royal Bournemouth Hospital /ID# 118975
🇬🇧
Bournemouth, United Kingdom
St Bartholomew's Hospital, Bar /ID# 98862
🇬🇧
London, United Kingdom
Duplicate_Jewish General Hospital /ID# 99476
🇨🇦
Montreal, Quebec, Canada
Columbia Univ Medical Center /ID# 103835
🇺🇸
New York, New York, United States
Addenbrookes Hospital /ID# 119977
🇬🇧
Cambridge, United Kingdom
Szpital Wojewodzki w Opolu /ID# 102855
🇵🇱
Opole, Opolskie, Poland
Universitaetsmedizin Goettingen /ID# 113258
🇩🇪
Göttingen, Germany
Royal Liverpool and Broadgreen /ID# 98860
🇬🇧
Liverpool, United Kingdom
Muenchen Klinik Schwabing /ID# 113275
🇩🇪
Muenchen, Germany
Dana-Farber Cancer Institute /ID# 92494
🇺🇸
Boston, Massachusetts, United States
University of Texas MD Anderson Cancer Center /ID# 92521
🇺🇸
Houston, Texas, United States
Stanford University School of Med /ID# 105117
🇺🇸
Stanford, California, United States
Georgetown University Hospital /ID# 96954
🇺🇸
Washington, District of Columbia, United States
University of Arizona Cancer Center - North Campus /ID# 96748
🇺🇸
Tucson, Arizona, United States
City of Hope /ID# 112875
🇺🇸
Duarte, California, United States
Northwestern University Feinberg School of Medicine /ID# 92499
🇺🇸
Chicago, Illinois, United States
Universitaetsklinikum Carl Gustav Carus an der TU Dresden /ID# 113256
🇩🇪
Dresden, Germany
John Fawkner Private Hospital /ID# 98835
🇦🇺
Coburg, Victoria, Australia
Royal Melbourne Hospital /ID# 91794
🇦🇺
Parkville, Victoria, Australia
Centre Hospitalier Lyon Sud /ID# 98839
🇫🇷
Pierre Benite CEDEX, Auvergne-Rhone-Alpes, France
Hopital Avicenne - APHP /ID# 98840
🇫🇷
Bobigny, Ile-de-France, France
Universitaetsklinikum Schleswig-Holstein Campus Kiel /ID# 113235
🇩🇪
Kiel, Schleswig-Holstein, Germany
Universitaetsklinik Heidelberg /ID# 98845
🇩🇪
Heidelberg, Baden-Wuerttemberg, Germany
St. James University Hospital /ID# 98863
🇬🇧
Leeds, United Kingdom
SP ZOZ Szpital Uniwersytecki w Krakowie /ID# 98849
🇵🇱
Krakow, Malopolskie, Poland
Royal Marsden Hospital /ID# 98861
🇬🇧
Sutton, United Kingdom
Henry Ford Health System /ID# 97795
🇺🇸
Detroit, Michigan, United States
Moore UC San Diego Cancer Center /ID# 91793
🇺🇸
La Jolla, California, United States
Leicester Royal Infirmary /ID# 98865
🇬🇧
Leicester, England, United Kingdom