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

Leukemia Clinical Trial

— Captivate  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02910583
• Other study ID #: PCYC-1142-CA
• Secondary ID: 2016-002293-12
• Status: Completed
• Phase: Phase 2
• Start date: September 28, 2016
• Est. completion date: March 27, 2024

Study information

• Verified date: March 2024
• Source: Pharmacyclics LLC.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a multicenter, 2-cohort Phase 2 study assessing both minimal residual disease (MRD)-guided discontinuation and fixed duration therapy with the combination of ibrutinib + venetoclax in subjects with treatment-naïve CLL or SLL.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 323
• Est. completion date: March 27, 2024
• Est. primary completion date: November 12, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• Diagnosis of CLL/SLL that meets 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) diagnostic criteria (Hallek et al), with active disease meeting at least 1 IWCLL criteria for requiring treatment.
• Measurable nodal disease by computed tomography (CT)
• Adequate hepatic, and renal function
• Adequate hematologic function
• absolute neutrophil count >750/µL
• platelet count >30,000 /µL
• hemoglobin >8.0 g/dL

Exclusion Criteria:

• Any prior therapy used for treatment of CLL/SLL
• Known allergy to xanthine oxidase inhibitors and/or rasburicase for subjects at risk for tumor lysis syndrome (TLS)

Related Conditions & MeSH terms

• Chronic Lymphocytic Leukemia
• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid
• Lymphoma
• Small Lymphocytic Lymphoma

Intervention

Drug:
• ibrutinib
ibrutinib administered orally once daily (three 140 mg capsules)
• 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.
• Placebo
placebo capsules to match ibrutinib administered orally once daily

Locations

Country	Name	City	State
Australia	Flinders Medical Centre /ID# 1142-0163	Bedford Park	South Australia
Australia	Monash Medical Centre /ID# 1142-0556	Clayton	Victoria
Australia	Peter MacCallum Cancer Centre-East Melbourne /ID# 1142-0633	East Melbourne	Victoria
Australia	St Vincent's Hospital Melbourne /ID# 1142-0501	Fitzroy	Victoria
Australia	Frankston Hospital /ID# 1142-0715	Frankston	Victoria
Australia	Austin Health /ID# 1142-0170	Heidelberg	Victoria
Australia	St George Hospital /ID# 1142-0654	Kogarah	New South Wales
Italy	Ospedale Policlinico San Martino /ID# 1142-0903	Genova
Italy	Ospedale San Raffaele IRCCS /ID# 1142-0523	Milan	Lombardia
Italy	ASST Grande Ospedale Metropolitano Niguarda /ID# 1142-0581	Milano
Italy	Azienda Ospedaliero-Universitaria di Modena /ID# 1142-0524	Modena
Italy	Azienda Ospedaliero Universitaria Maggiore della Carita di Novara /ID# 1142-0582	Novara
Italy	Azienda Ospedaliera di Padova /ID# 1142-1175	Padova
Italy	Azienda USL di Piacenza - Ospedale Guglielmo da Saliceto /ID# 1142-1182	Piacenza
New Zealand	North Shore Hospital /ID# 1142-0663	Auckland
New Zealand	Christchurch Hospital /ID# 1142-0589	Christchurch	Canterbury
New Zealand	Middlemore Hospital /ID# 1142-0662	Otahuhu	Auckland
New Zealand	Palmerston North Hospital /ID# 1142-0585	Palmerston North	Manawatu-Wanganui
Poland	Szpital Specjalistyczny w Brzozowie Podkarpacki Osrodek Onkologiczny im. ks. B. /ID# 1142-0592	Brzozow	Podkarpackie
Poland	Samodzielny Publiczny Szpital Klinczny Nr-1- Akademickie Cenrum Klinic /ID# 1142-0529	Gdansk	Pomorskie
Poland	Malopolskie Centrum Medyczne /ID# 1142-0364	Krakow	Malopolskie
Poland	Medical Univ. of Lodz and Copernicus Memorial Hospital /ID# 1142-0531	Lodz
Poland	Duplicate_Samodzielny Publiczny Szpital Kliniczny nr 1 w Lublinie /ID# 1142-0590	Lublin	Lubelskie
Spain	Hospital Clinic de Barcelona /ID# 1142-0533	Barcelona
Spain	Hospital Santa Creu i Sant Pau /ID# 1142-0535	Barcelona
Spain	Hospital Universitario Virgen de las Nieves /ID# 1142-1196	Granada
Spain	Hospital Duran i Reynals /ID# 1142-0604	Hospitalet de Llobregat	Barcelona
Spain	Hospital Universitario 12 de Octubre /ID# 1142-0864	Madrid
Spain	Hospital Universitario Ramon y Cajal /ID# 1142-0874	Madrid
Spain	Hospital Universitario Puerta de Hierro, Majadahonda /ID# 1142-0536	Majadahonda	Madrid
Spain	Complejo Hospitalario de Navarra /ID# 1142-1197	Pamplona	Navarra
Spain	Hospital Clinico Universitario de Salamanca /ID# 1142-0790	Salamanca
United States	Charlotte-Mecklenberg Hospital, Carolinas Healthcare System, Levine Cancer Inst /ID# 1142-0733	Charlotte	North Carolina
United States	Tennessee Oncology - Chattanooga /ID# 1142-0123	Chattanooga	Tennessee
United States	Cleveland Clinic Foundation /ID# 1142-0739	Cleveland	Ohio
United States	City of Hope /ID# 1142-0047	Duarte	California
United States	MD Anderson Cancer Center /ID# 1142-0032	Houston	Texas
United States	Moores Cancer Center at UC San Diego /ID# 1142-0241	La Jolla	California
United States	Norton Cancer Center /ID# 1142-0071	Louisville	Kentucky
United States	Rutgers Cancer Institute of New Jersey /ID# 1142-1193	New Brunswick	New Jersey
United States	Northwell Health/Long Island Jewish Hospital /ID# 1142-0350	New Hyde Park	New York
United States	New York Presbyterian Hospital/Weill Cornell Med College /ID# 1142-0200	New York	New York
United States	UC Irvine Medical Center - Chao Family Comprehensive Cancer Center /ID# 1142-0008	Orange	California
United States	University of Pennsylvania /ID# 1142-0069	Philadelphia	Pennsylvania
United States	University of Rochester Cancer Center /ID# 1142-0127	Rochester	New York
United States	Swedish Cancer Institute /ID# 1142-0114	Seattle	Washington

Sponsors (2)

Lead Sponsor	Collaborator
Pharmacyclics LLC.	Janssen Research & Development, LLC

Countries where clinical trial is conducted

United States,  Australia,  Italy,  New Zealand,  Poland,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	MRD Cohort: 1-Year Disease-Free Survival (DFS) Rate in Confirmed uMRD Randomized Participants	DFS is defined as time from randomization date to MRD-positive relapse, or disease progression per investigator assessment (per 2008 International Workshop for Chronic Lymphocytic Leukemia [IWCLL] criteria [Halleck et al]) or death from any cause, whichever occurred first. 1-year DFS estimated using Kaplan-Meier method at 12 months landmark time.	1 year after randomization
Primary	FD Cohort: Complete Response Rate (CRR; Complete Response/Complete Response With Incomplete Blood Count Recovery [CR/CRi]) Rate	CR/CRi rate is defined as the percentage of participants achieving a best overall response of complete response (CR), CR with incomplete blood count recovery (CRi) per 2008 IWCLL criteria (halleck et al.) on or prior to initiation of subsequent antineoplastic therapy or, if applicable, reintroduction of study treatment, whichever occurred earlier.	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	MRD Cohort: CRR (CR/CRi Rate)	CR/CRi rate is defined as the percentage of participants achieving a best overall response of CR or CRi per 2008 IWCLL criteria (Halleck et al.) on or prior to initiation of subsequent antineoplastic therapy or, if applicable, reintroduction of study treatment, whichever occurred earlier.	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	MRD Cohort: Overall Response Rate (ORR)	ORR, defined as the percentage of participants achieving a best overall response of protocol-specified complete response (CR), CR with incomplete blood count recovery (CRi), nodular partial response (nPR), partial response (PR), or PR with lymphocytosis (PRL) evaluated in accordance with the 2008 IWCLL criteria (Halleck et al). Participants who did not have any postbaseline response assessment were considered as non-responders. This table is based on response assessments performed on or prior to initiation of subsequent antineoplastic therapy or, if applicable, reintroduction of study treatment, whichever occurs earlier. Kaplan-Meier estimate.	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	MRD Cohort: Duration of Response (DOR)	Duration of response was calculated for participants achieving a response (CR, CRi, nPR, PR) based on 2008 IWCLL response criteria (Halleck et al.) and defined as the interval between the date of initial documentation of a response including PR with lymphocytosis, until disease progression (PD) or death from any cause, whichever occurred first. As the median DOR was not reached as of the median 38.2 months study follow-up, the Kaplan-Meier estimate of DOR at 36 months landmark time was presented.	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	MRD Cohort: MRD-Negativity Rate (MRR)	MRR is defined as the percentage of participants who achieve MRD-negativity in either peripheral blood (PB) or bone marrow (BM) and achieve confirmed clinical response PR or better per 2008 IWCLL criteria (Halleck et al.). MRD-negativity is defined as <1 CLL cell per 10,000 leukocytes (<1 x 10^4), as assessed by flow cytometry of a PB or BM aspirate sample. Confirmed MRD-negative response for randomization purposes requires MRD-negativity serially over at least 3 cycles, with negativity in both BM and PB.; This rate is calculated in the uMRD Not Confirmed randomized population during the period from randomization date and before any reintroduced treatment.	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	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)	TLS risk reduction was summarized by the percentage of participants with TLS risk reduced from high at baseline to medium or low after ibrutinib lead-in. A reduction in TLS risk from high risk to medium or low risk is clinically meaningful because there is a reduction in the extent of TLS monitoring and risk of hospitalization. TLS risk category is defined as the tumor burden category, where: Low=All lymph nodes (LN) < 5 cm AND absolute lymphocyte count (ALC) < 25 x 10^9/L; Medium=Any LN 5 cm to < 10 cm OR ALC = 25 x 10^9/L; High=Any LN = 10 cm OR ALC = 25 x10^9/L AND any LN = 5 cm.	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	MRD Cohort: Kaplan-Meier Estimate of Progression Free Survival (PFS) Rate at 36 Months Landmark Time	PFS was defined as time from the first dose date of study treatment until disease progression (PD) or death from any cause, whichever occurs first. Assessment of PD was conducted in accordance with the 2008 IWCLL criteria (Halleck et al). As the median PFS was not reached as of the median 38.2 months study follow-up, the Kaplan-Meier estimate of PFS rate at 36 months landmark time was presented.	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	MRD Cohort: Kaplan-Meier Estimate of Overall Survival (OS) Rate at 36 Months Landmark Time	OS is defined as the time from the first dose date of study treatment until date of death due to any cause. As the median OS was not reached as of the median 38.2 months study follow-up, the Kaplan-Meier estimate of OS rate at 36 months landmark time was presented.	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	MRD Cohort: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (SAEs), and Discontinuations Due to TEAEs	An adverse event (AE) is any untoward medical occurrence, which does not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) is any untoward medical occurrence that at any dose: results in death; is life-threatening; requires unplanned in-patient hospitalization >24 hours or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is an important medical event. Severity of events were graded according to the Common Terminology Criteria for Adverse Events version 4.03: mild=grade1, moderate=grade 2, severe=grade 3, life-threatening=grade 4, death=grade 5. Causal relation of study drug and event was assessed as not related, unlikely, possibly or probably related to the study drug.	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	FD Cohort: ORR	ORR is defined as the percentage of participants who achieve a best overall response CR, CRi, nPR, PR, or PRL as evaluated by investigator using 2008 IWCLL criteria (Halleck et al.). Participants who did not have any postbaseline response assessment were considered as non-responders. This table is based on response assessments performed on or prior to initiation of subsequent antineoplastic therapy or, if applicable, reintroduction of study treatment, whichever occurs earlier. Kaplan-Meier estimate.	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	FD Cohort: DOR	Duration of response was calculated for participants achieving a response (CR, CRi, nPR, PR) based on 2008 IWCLL response criteria (Halleck et al.) and defined as the interval between the date of initial documentation of a response including PR with lymphocytosis, until disease progression (PD) or death from any cause, whichever occurred first. As the median DOR was not reached as of the median 27.9 months study follow-up, the Kaplan-Meier estimate of DOR at 24 months landmark time was presented.	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	FD Cohort: MRR	MRR is defined as the percentage of participants who achieve MRD-negativity in either peripheral blood (PB) or bone marrow (BM) and achieve confirmed clinical response PR or better per 2008 IWCLL criteria (Halleck et al.). MRD-negativity is defined as <1 CLL cell per 10,000 leukocytes (<1 x 10^4), as assessed by flow cytometry of a PB or BM aspirate sample. Confirmed MRD-negative response for randomization purposes requires MRD-negativity serially over at least 3 cycles, with negativity in both BM and PB.	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	FD Cohort: Kaplan-Meier Estimate of PFS Rate at 24 Months Landmark Time	PFS was defined as time from the first dose date of study treatment until disease progression (PD) or death from any cause, whichever occurs first. Assessment of PD was conducted in accordance with the 2008 IWCLL criteria (Halleck et al). As the median PFS was not reached as of the median 27.9 months study follow-up, the Kaplan-Meier estimate of PFS rate at 24 months landmark time was presented.	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	FD Cohort: Kaplan-Meier Estimate of OS Rate at 24 Months Landmark Time	OS is defined as the time from the first dose date of study treatment until date of death due to any cause. As the median OS was not reached as of the median 38.2 months study follow-up, the Kaplan-Meier estimate of OS rate at 24 months landmark time was presented.	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	FD Cohort: TLS Risk Reduction Rate With 3-Cycle Ibrutinib Lead-In (Percentage of Participants No Longer High Risk After 3-cycle Lead-in)	TLS risk reduction was summarized by the percentage of participants with TLS risk reduced from high at baseline to medium or low after ibrutinib lead-in. A reduction in TLS risk from high risk to medium or low risk is clinically meaningful because there is a reduction in the extent of TLS monitoring and risk of hospitalization. TLS risk category is defined as the tumor burden category, where: Low=All lymph nodes (LN) < 5 cm AND absolute lymphocyte count (ALC) < 25 x 10^9/L; Medium=Any LN 5 cm to < 10 cm OR ALC = 25 x 10^9/L; High=Any LN = 10 cm OR ALC = 25 x10^9/L AND any LN = 5 cm.	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	FD Cohort: Percentage of Participants With TEAEs, Treatment-Emergent SAEs, and Discontinuations Due to TEAEs	An AE is any untoward medical occurrence, which does not necessarily have a causal relationship with this treatment. An SAE is any untoward medical occurrence that at any dose: results in death; is life-threatening; requires unplanned in-patient hospitalization >24 hours or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is an important medical event. Severity of events were graded according to the Common Terminology Criteria for Adverse Events version 4.03: mild=grade1, moderate=grade 2, severe=grade 3, life-threatening=grade 4, death=grade 5. Causal relation of study drug and event was assessed as not related, unlikely, possibly or probably related to the study drug.	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	MRD Cohort: Pharmacokinetics (PK) of Ibrutinib When Dosed in Combination With Venetoclax: Observed Maximum Concentration (Cmax)		Cycle 6 Day 1: predose, at dose, 1 h (±15 min), 2 h (±15 min), 4 h (±15 min), 6 h (±15 min), 8 h (±15 min)
Secondary	MRD Cohort: PK of Ibrutinib When Dosed in Combination With Venetoclax: Time to Cmax (Tmax); Time of Last Measurable Concentration (Tlast); Terminal Elimination Half-Life (t1/2,Term)		Cycle 6 Day 1: predose, at dose, 1 h (±15 min), 2 h (±15 min), 4 h (±15 min), 6 h (±15 min), 8 h (±15 min)
Secondary	MRD Cohort: PK of Ibrutinib When Dosed in Combination With Venetoclax: Area Under the Plasma Concentration-Time Curve (AUC) Over the Last 24-hour Dosing Interval (AUC0-24h); AUC From Time Zero to the Time of Last Quantifiable Concentration (AUClast)		Cycle 6 Day 1: predose, at dose, 1 h (±15 min), 2 h (±15 min), 4 h (±15 min), 6 h (±15 min), 8 h (±15 min)
Secondary	MRD Cohort: PK of Ibrutinib When Dosed in Combination With Venetoclax: Terminal Elimination Rate Constant (?z)		Cycle 6 Day 1: predose, at dose, 1 h (±15 min), 2 h (±15 min), 4 h (±15 min), 6 h (±15 min), 8 h (±15 min)
Secondary	MRD Cohort: PK of Ibrutinib When Dosed in Combination With Venetoclax: Apparent Total Clearance at Steady-State (CLss/F)		Cycle 6 Day 1: predose, at dose, 1 h (±15 min), 2 h (±15 min), 4 h (±15 min), 6 h (±15 min), 8 h (±15 min)
Secondary	MRD Cohort: PK of Venetoclax When Dosed in Combination With Ibrutinib: Cmax		Cycle 6 Day 1: predose, at dose, 1 h (±15 min), 2 h (±15 min), 4 h (±15 min), 6 h (±15 min), 8 h (±15 min)
Secondary	MRD Cohort: PK of Venetoclax When Dosed in Combination With Ibrutinib: Tmax		Cycle 6 Day 1: predose, at dose, 1 h (±15 min), 2 h (±15 min), 4 h (±15 min), 6 h (±15 min), 8 h (±15 min)
Secondary	MRD Cohort: PK of Venetoclax When Dosed in Combination With Ibrutinib: AUC0-24h		Cycle 6 Day 1: predose, at dose, 1 h (±15 min), 2 h (±15 min), 4 h (±15 min), 6 h (±15 min), 8 h (±15 min)
Secondary	MRD Cohort: PK of Venetoclax When Dosed in Combination With Ibrutinib: CLss/F		Cycle 6 Day 1: predose, at dose, 1 h (±15 min), 2 h (±15 min), 4 h (±15 min), 6 h (±15 min), 8 h (±15 min)