ANZCTR - Registration

Registration number

NCT02910583

Ethics application status

Date submitted

20/09/2016

Date registered

22/09/2016

Date last updated

3/04/2024

Titles & IDs

Public title

Ibrutinib Plus Venetoclax in Subjects With Treatment-naive Chronic Lymphocytic Leukemia /Small Lymphocytic Lymphoma (CLL/SLL)

Scientific title

Phase 2 Study of the Combination of Ibrutinib Plus Venetoclax in Subjects With Treatment-naïve Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Secondary ID [1]

2016-002293-12

Secondary ID [2]

PCYC-1142-CA

Universal Trial Number (UTN)

Trial acronym

Captivate

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Leukemia

Chronic Lymphocytic Leukemia

Small Lymphocytic Lymphoma

Condition category

Condition code

Cancer

Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma

Cancer

Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma

Cancer

Leukaemia - Acute leukaemia

Cancer

Leukaemia - Chronic leukaemia

Cancer

Children's - Leukaemia & Lymphoma

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Treatment: Drugs - ibrutinib
Treatment: Drugs - venetoclax
Treatment: Drugs - Placebo

Experimental: Fixed Duration (FD) Cohort: Open Label Ibrutinib + Venetoclax - Participants receive 420 mg of single-agent ibrutinib for first 3 cycles followed by ibrutinib plus venetoclax combination treatment (ibrutinib 420 mg and venetoclax 400 mg orally once daily on a continuous schedule) for 12 cycles (a cycle is defined by 28 days) or until disease progression or unacceptable toxicity.

Experimental: MRD Cohort/Confirmed Undetectable MRD (uMRD): Randomized to Ibrutinib (Blinded) - Participants receive 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase).
Participants with confirmed uMRD are randomized to receive ibrutinib 420 mg orally once daily on a continuous schedule until MRD-positive relapse, disease progression (PD), or unacceptable toxicity.
After MRD-positive relapse or disease progression (PD) by iwCLL criteria, participants can reintroduce 400 mg venetoclax with a 5-week ramp up. If venetoclax is to be reintroduced, venetoclax treatment is to continue at the dose of 400 mg/day for up to approximately 2 years (cumulative) until PD or unacceptable toxicity.

Placebo Comparator: MRD Cohort/Confirmed uMRD: Randomized Placebo (Blinded) - Participants receive 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase).
Participants with confirmed uMRD are randomized to receive placebo orally once daily on a continuous schedule until MRD-positive relapse, PD or unacceptable toxicity.
If MRD-positive relapse or PD is confirmed after restaging per iwCLL criteria, participants can first reintroduce oral daily ibrutinib with the option of subsequently reintroducing 400 mg venetoclax with a 5-week ramp up, if subsequent disease relapse per iwCLL criteria occurs after ibrutinib reintroduction. If venetoclax is to be reintroduced, venetoclax treatment is to continue at the dose of 400 mg/day for up to approximately 2 years (cumulative) until PD or unacceptable toxicity.

Experimental: MRD Cohort/uMRD Not Confirmed: Randomized to Ibrutinib (Open-Label) - Participants receive 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre randomization phase).
Participants with uMRD not confirmed are randomized to receive open-label ibrutinib 420 mg orally once daily on a continuous schedule until PD or unacceptable toxicity.
In case of confirmed PD after restaging per iwCLL criteria, participants can continue ibrutinib and reintroduce venetoclax treatment. If venetoclax is to be reintroduced, venetoclax treatment is to continue at the dose of 400 mg/day for up to approximately 2 years (cumulative) until PD or unacceptable toxicity.

Experimental: MRD Cohort/uMRD Not Confirmed: Randomized Ibrutinib + Venetoclax (Open-Label) - Participants receive 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre randomization phase).
Participants with uMRD not confirmed are randomized to receive open-label ibrutinib 420 mg and venetoclax 400 mg orally once daily on a continuous schedule until PD or unacceptable toxicity. Venetoclax was allowed for administration up to 2 years cumulatively from first dose started in the pre-randomization phase to last dose in the randomization phase.

Treatment: Drugs: ibrutinib
ibrutinib administered orally once daily (three 140 mg capsules)

Treatment: Drugs: venetoclax
venetoclax tablets will be administered orally once daily starting with a 5 week ramp up of 20 mg, 50 mg, 100 mg, 200 mg and 400 mg. After ramp up, venetoclax will be administered at 400 mg.

Treatment: Drugs: Placebo
placebo capsules to match ibrutinib administered orally once daily

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Control group

Outcomes

Primary outcome [1]

MRD Cohort: 1-Year Disease-Free Survival (DFS) Rate in Confirmed uMRD Randomized Participants

Timepoint [1]

1 year after randomization

Primary outcome [2]

FD Cohort: Complete Response Rate (CRR; Complete Response/Complete Response With Incomplete Blood Count Recovery [CR/CRi]) Rate

Timepoint [2]

From the first dose of ibrutinib to the first confirmed PD up to primary analysis data cutoff date of 15 December 2020. Median follow-up time was 27.9 months at the time of the primary analysis.

Secondary outcome [1]

MRD Cohort: CRR (CR/CRi Rate)

Timepoint [1]

From the first dose of ibrutinib to the first confirmed PD (up to primary analysis data cutoff date of 15 December 2020). Overall median follow-up time was 38.2 months at the time of the primary analysis (data cutoff date: 15 December 2020).

Secondary outcome [2]

MRD Cohort: Overall Response Rate (ORR)

Timepoint [2]

From the first dose of ibrutinib to the first confirmed PD (up to primary analysis data cutoff date of 15 December 2020). Overall median follow-up time was 38.2 months at the time of the primary analysis (data cutoff date: 15 December 2020).

Secondary outcome [3]

MRD Cohort: Duration of Response (DOR)

Timepoint [3]

From initial documentation of a response, until PD or death from any cause, whichever occurs first. Overall median follow-up time was 38.2 months at the time of the primary analysis (data cutoff date: 15 December 2020).

Secondary outcome [4]

MRD Cohort: MRD-Negativity Rate (MRR)

Timepoint [4]

From randomization date until before any reintroduced treatment. Overall median follow-up time was 38.2 months at the time of the primary analysis (data cutoff date: 15 December 2020).

Secondary outcome [5]

MRD Cohort: Tumor Lysis Syndrome (TLS) Risk Reduction Rate With 3-Cycle Ibrutinib Lead-In (Percentage of Participants No Longer High Risk After 3-cycle Lead-in)

Timepoint [5]

Baseline, and last post-baseline value on or prior to venetoclax first dose date (cycle 4 day 1) or, for participants who never received venetoclax, the post-baseline value closest to cycle 4 day 1 (i.e. 84 days after the first dose date of ibrutinib).

Secondary outcome [6]

MRD Cohort: Kaplan-Meier Estimate of Progression Free Survival (PFS) Rate at 36 Months Landmark Time

Timepoint [6]

From the first dose of ibrutinib to the first confirmed PD or death. Overall median follow-up time was 38.2 months at the time of the primary analysis (data cutoff date: 15 December 2020).

Secondary outcome [7]

MRD Cohort: Kaplan-Meier Estimate of Overall Survival (OS) Rate at 36 Months Landmark Time

Timepoint [7]

From the first dose of ibrutinib to the first confirmed PD or death (up to primary analysis data cutoff date of 15 December 2020). Overall median follow-up time was 38.2 months at the time of the primary analysis (data cutoff date: 15 December 2020).

Secondary outcome [8]

MRD Cohort: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (SAEs), and Discontinuations Due to TEAEs

Timepoint [8]

From first dose until 30 days following last dose of study drug (up to data cutoff date of 15 Dec 2020). Treatment duration for the MRD cohort was 28.7 months for ibrutinib and 15.4 for venetoclax.

Secondary outcome [9]

FD Cohort: ORR

Timepoint [9]

From the first dose of ibrutinib to the first confirmed PD up to primary analysis data cutoff date of 15 December 2020. Median follow-up time was 27.9 months at the time of the primary analysis.

Secondary outcome [10]

FD Cohort: DOR

Timepoint [10]

From initial documentation of a response, until PD or death from any cause, whichever occurs first. Overall median follow-up time was 27.9 months at the time of the primary analysis (data cutoff date: 15 December 2020).

Secondary outcome [11]

FD Cohort: MRR

Timepoint [11]

From randomization date until before any reintroduced treatment. Overall median follow-up time was 27.9 months at the time of the primary analysis (data cutoff date: 15 December 2020).

Secondary outcome [12]

FD Cohort: Kaplan-Meier Estimate of PFS Rate at 24 Months Landmark Time

Timepoint [12]

From the first dose of ibrutinib to the first confirmed PD or death. Overall median follow-up time was 27.9 months at the time of the primary analysis (data cutoff date: 15 December 2020).

Secondary outcome [13]

FD Cohort: Kaplan-Meier Estimate of OS Rate at 24 Months Landmark Time

Timepoint [13]

From the first dose of ibrutinib to time of death. Overall median follow-up time was 27.9 months at the time of the primary analysis (data cutoff date: 15 December 2020).

Secondary outcome [14]

FD Cohort: TLS Risk Reduction Rate With 3-Cycle Ibrutinib Lead-In (Percentage of Participants No Longer High Risk After 3-cycle Lead-in)

Timepoint [14]

Baseline, and last post-baseline value on or prior to venetoclax first dose date (cycle 4 day 1) or, for participants who never received venetoclax, the post-baseline value closest to cycle 4 day 1 (i.e. 84 days after the first dose date of ibrutinib).

Secondary outcome [15]

FD Cohort: Percentage of Participants With TEAEs, Treatment-Emergent SAEs, and Discontinuations Due to TEAEs

Timepoint [15]

From first dose until 30 days following last dose of study drug (up to data cutoff date of 15 Dec 2020). Treatment duration for the FD cohort was 13.3 months for ibrutinib and 11.1 for venetoclax.

Secondary outcome [16]

MRD Cohort: Pharmacokinetics (PK) of Ibrutinib When Dosed in Combination With Venetoclax: Observed Maximum Concentration (Cmax)

Timepoint [16]