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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT01889186
Registration number
NCT01889186
Ethics application status
Date submitted
26/06/2013
Date registered
28/06/2013
Date last updated
16/12/2021
Titles & IDs
Public title
A Study of the Efficacy of ABT-199 in Subjects With Relapsed/Refractory or Previously Untreated Chronic Lymphocytic Leukemia With the 17p Deletion
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Scientific 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
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Secondary ID [1]
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2012-004027-20
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Secondary ID [2]
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M13-982
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Chronic Lymphocytic Leukemia
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17p Deletion
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Cancer of the Blood and Bone Marrow
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Condition category
Condition code
Cancer
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Leukaemia - Acute leukaemia
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Cancer
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Leukaemia - Chronic leukaemia
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Cancer
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Children's - Leukaemia & Lymphoma
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Intervention/exposure
Study type
Interventional(has expanded access)
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Description of intervention(s) / exposure
Treatment: Drugs - ABT-199 (Main Cohort)
Treatment: Drugs - ABT-199 (Safety Expansion Cohort)
Experimental: 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.
Experimental: 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.
Treatment: Drugs: 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.
Treatment: Drugs: 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.
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Overall Response Rate (Main Cohort)
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Assessment method [1]
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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.
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Timepoint [1]
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Up to 36 weeks
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Primary outcome [2]
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Number of Participants With Adverse Events (Safety Expansion Cohort)
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Assessment method [2]
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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.
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Timepoint [2]
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From the first dose of study drug until 30 days following last dose of study drug (up to 69 months)
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Secondary outcome [1]
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Overall Response Rate (ORR) (Safety Expansion Cohort)
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Assessment method [1]
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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.
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Timepoint [1]
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Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up
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Secondary outcome [2]
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Complete Remission (CR) Rate
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Assessment method [2]
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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.
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Timepoint [2]
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Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up
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Secondary outcome [3]
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Partial Remission (PR) Rate
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Assessment method [3]
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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.
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Timepoint [3]
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Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up
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Secondary outcome [4]
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Duration of Overall Response
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Assessment method [4]
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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.
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Timepoint [4]
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Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up
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Secondary outcome [5]
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Progression-free Survival
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Assessment method [5]
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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.
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Timepoint [5]
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Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up
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Secondary outcome [6]
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Event-free Survival
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Assessment method [6]
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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.
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Timepoint [6]
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Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up
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Secondary outcome [7]
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Time to Progression
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Assessment method [7]
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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.
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Timepoint [7]
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Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up
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Secondary outcome [8]
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Time to First Response
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Assessment method [8]
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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.
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Timepoint [8]
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Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up
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Secondary outcome [9]
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Time to 50% Reduction in Absolute Lymphocyte Count
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Assessment method [9]
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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.
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Timepoint [9]
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Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up
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Secondary outcome [10]
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Overall Survival
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Assessment method [10]
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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.
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Timepoint [10]
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Up to the data cutoff date of 15 December 2020, approximately 7.5 years of follow-up
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Secondary outcome [11]
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Percentage of Participants Who Moved on to Stem Cell Transplant
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Assessment method [11]
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The percentage of participants who moved on to stem cell transplant was summarized.
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Timepoint [11]
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Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up
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Eligibility
Key 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.
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Minimum age
18
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Maximum age
99
Years
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key 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.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Non-randomised trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Single group
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Other design features
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Phase
Phase 2
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
27/06/2013
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
15/12/2020
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Sample size
Target
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Accrual to date
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Final
158
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Recruitment in Australia
Recruitment state(s)
NSW,VIC
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Recruitment hospital [1]
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Royal North Shore Hospital /ID# 98836 - St Leonards
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Recruitment hospital [2]
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John Fawkner Private Hospital /ID# 98835 - Coburg
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Recruitment hospital [3]
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Peter MacCallum Cancer Ctr /ID# 91795 - Melbourne
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Recruitment hospital [4]
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Royal Melbourne Hospital /ID# 91794 - Parkville
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Recruitment postcode(s) [1]
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2065 - St Leonards
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Recruitment postcode(s) [2]
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3058 - Coburg
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Recruitment postcode(s) [3]
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3000 - Melbourne
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Recruitment postcode(s) [4]
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3050 - Parkville
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Recruitment outside Australia
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United States of America
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Arizona
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United States of America
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California
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United States of America
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District of Columbia
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Illinois
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Massachusetts
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United States of America
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Michigan
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New Jersey
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New York
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Ohio
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Texas
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Canada
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Quebec
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France
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Auvergne-Rhone-Alpes
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France
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Ile-de-France
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France
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Paris
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France
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Rouen
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Germany
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Baden-Wuerttemberg
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Germany
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Nordrhein-Westfalen
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Germany
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Schleswig-Holstein
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Germany
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Thueringen
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Germany
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Dresden
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Germany
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Freiburg
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Germany
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Göttingen
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Germany
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Mainz
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Germany
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Muenchen
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Poland
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Lubelskie
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Poland
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Malopolskie
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Poland
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Opolskie
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England
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Bournemouth
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Cambridge
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Leeds
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Liverpool
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London
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Manchester
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Oxford
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Plymouth
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United Kingdom
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Sutton
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
AbbVie
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Address
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Other collaborator category [1]
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Commercial sector/Industry
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Name [1]
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Genentech, Inc.
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Ethics approval
Ethics application status
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Summary
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.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT01889186
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Trial related presentations / publications
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.
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Public notes
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Contacts
Principal investigator
Name
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ABBVIE INC.
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AbbVie
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Contact person for public queries
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT01889186
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