M13-982

AbbVie

AbbVie House, Vanwall Business Park, Vanwall Road, Maidenhead, Berkshire, United Kingdom, SL6-4UB

Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.com

Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.com

No

No

No

Final

28 Oct 2020

No

Yes

28 Oct 2020

No

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. 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.

Subjects must have voluntarily signed and dated an informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study specific procedures.

27 Jun 2013

No

Yes

Australia: 19

Canada: 5

France: 4

Germany: 56

Poland: 12

United Kingdom: 27

United States: 35

158

72

0

0

0

0

0

0

66

91

1

Overall Study (overall period)

Non-randomised - controlled

Yes

ABT-199 (Main Cohort)

Venetoclax, GDC-0199

Film-coated tablet

Oral use

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.

ABT-199 (Safety Expansion Cohort)

Venetoclax, GDC-0199

Film-coated tablet

Oral use

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.

Main Cohort

Safety Expansion Cohort

Main Cohort

Safety Expansion Cohort

All Treated Participants

Participants in the Main Cohort received ABT-199 tablets once daily (QD) orally for up to 79 months,and those in the Safety Expansion Cohort received ABT-199 tablets once daily (QD) orally for up to 68 months. For both groups, the starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg.

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.

Primary

Up to 36 weeks

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.

Primary

From the first dose of study drug until 30 days following last dose of study drug (up to 69 months)

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.

Secondary

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.

Secondary

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.

Secondary

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 (NCICWG) criteria (CR, CRi, confirmed nPR, or confirmed PR). For participants who never experienced response, their data was not included in the analysis. 999 and 99999 in the table below = not calculable/estimable due to insufficient number of events

Secondary

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. 99999 in the table below = not calculable/estimable due to insufficient number of events

Secondary

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. 99999 in the table below = not calculable/estimable due to insufficient number of events

Secondary

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. 99999 in the table below = not calculable/estimable due to insufficient number of events

Secondary

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.

Secondary

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.

Secondary

Up to the data cutoff date of 15 June 2017, approximately 4 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. 99999 in the table below = not calculable/estimable due to insufficient number of events

Secondary

Up to the data cutoff date of 15 December 2020, approximately 7.5 years of follow-up

The percentage of participants who moved on to stem cell transplant was summarized.

Secondary

Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up

Treatment-emergent adverse events (TEAEs) and serious adverse events (TESAEs) were collected from first dose of study drug until 30 days after last study drug administration, up to 80 months for Main Cohort and up to 69 months for Safety Expansion Cohort.

TEAEs and SAEs are defined as any AE or SAE with onset or worsening reported by a participant from the time that the first dose of study drug is administered until 30 days have elapsed following discontinuation of study drug. TEAEs were collected whether elicited or spontaneously reported by the participant.

23.1

Main Cohort

Safety Expansion Cohort