Clinical trial NCT02910583: Ibrutinib Plus Venetoclax in Subjects With Treatment-naive Chronic Lymphocytic Leukemia /Small Lymphocytic Lymphoma (CLL/SLL)
Official title: Phase 2 Study of the Combination of Ibrutinib Plus Venetoclax in Subjects With Treatment-naïve Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Leukemia
Chronic Lymphocytic Leukemia
Small Lymphocytic Lymphoma
Lead sponsor: Pharmacyclics LLC.
Sponsor class: INDUSTRY
Collaborators: name: Janssen Research & Development, LLC
First posted: 2016-09-22
Enrollment: 323
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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)

Primary outcomes:
measure: MRD Cohort: 1-Year Disease-Free Survival (DFS) Rate in Confirmed uMRD Randomized Participants
timeFrame: 1 year after randomization
measure: FD Cohort: Complete Response Rate (CRR; Complete Response/Complete Response With Incomplete Blood Count Recovery [CR/CRi]) Rate
timeFrame: From the first dose of ibrutinib to the first confirmed PD, for a median follow-up of 69.0 months.
Secondary outcomes:
measure: MRD Cohort: CRR (CR/CRi Rate)
timeFrame: From the first dose of ibrutinib to the first confirmed PD, for an overall median follow-up of 67.0 months. (Median follow up duration for the individual MRD Cohort treatment arms listed above.)
measure: MRD Cohort: Overall Response Rate (ORR)
timeFrame: From the first dose of ibrutinib to the first confirmed PD, for an overall median follow-up of 67.0 months. (Median follow up duration for the individual MRD Cohort treatment arms listed above.)
measure: MRD Cohort: Duration of Response (DOR) at 42 Months Landmark Time
timeFrame: From initial documentation of a response until PD or death from any cause, whichever occurs first, for an overall median follow-up of 67.0 months. (Median follow up duration for the individual MRD Cohort treatment arms listed above.)
measure: MRD Cohort: MRD-Negativity Rate
timeFrame: From randomization date until before any subsequent antineoplastic therapy, for an overall median follow-up of 67.0 months. (Median follow up duration for the individual MRD Cohort treatment arms listed above.)
measure: 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)
timeFrame: 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).
measure: MRD Cohort: Kaplan-Meier Estimate of Progression Free Survival (PFS) Rate at 48 Months Landmark Time
timeFrame: From the first dose of ibrutinib to the first confirmed PD or death, for an overall median follow-up of 67.0 months. (Median follow up duration for the individual MRD Cohort treatment arms listed above.)
measure: MRD Cohort: Kaplan-Meier Estimate of Overall Survival (OS) Rate at 48 Months Landmark Time
timeFrame: From the first dose of ibrutinib to time of death, for an overall median follow-up of 67.0 months. (Median follow up duration for the individual MRD Cohort treatment arms listed above.)
measure: MRD Cohort: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (SAEs), and Discontinuations Due to TEAEs
timeFrame: From first dose until 30 days following last dose of study drug. Overall median treatment duration for the MRD cohort was 45.1 months.
measure: FD Cohort: ORR
timeFrame: From the first dose of ibrutinib to the first confirmed PD, for a median follow-up of 69.0 months.
measure: FD Cohort: DOR at 60 Months Landmark Time
timeFrame: From initial documentation of a response until PD or death from any cause, whichever occurs first, for a median follow-up of 69.0 months.
measure: FD Cohort: MRD Negativity Rate
timeFrame: From randomization date until before any subsequent antineoplastic therapy, for a median follow-up of 69.0 months.
measure: FD Cohort: Kaplan-Meier Estimate of PFS Rate at 66 Months Landmark Time
timeFrame: From the first dose of ibrutinib to the first confirmed PD or death, for an median follow-up of 69.0 months.
measure: FD Cohort: Kaplan-Meier Estimate of OS Rate at 66 Months Landmark Time
timeFrame: From the first dose of ibrutinib to time of death, for a median follow-up of 69.0 months.
measure: FD Cohort: TLS Risk Reduction Rate With 3-Cycle Ibrutinib Lead-In (Percentage of Participants No Longer High Risk After 3-cycle Lead-in)
timeFrame: 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).
measure: FD Cohort: Percentage of Participants With TEAEs, Treatment-Emergent SAEs, and Discontinuations Due to TEAEs
timeFrame: From first dose until 30 days following last dose of study drug. Overall median treatment duration for the FD cohort was 13.8 months.
measure: MRD Cohort: Pharmacokinetics (PK) of Ibrutinib When Dosed in Combination With Venetoclax: Observed Maximum Concentration (Cmax)
timeFrame: 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)
measure: 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)
timeFrame: 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)
measure: 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)
timeFrame: 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)
measure: MRD Cohort: PK of Ibrutinib When Dosed in Combination With Venetoclax: Terminal Elimination Rate Constant (λz)
timeFrame: 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)
measure: MRD Cohort: PK of Ibrutinib When Dosed in Combination With Venetoclax: Apparent Total Clearance at Steady-State (CLss/F)
timeFrame: 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)
measure: MRD Cohort: PK of Venetoclax When Dosed in Combination With Ibrutinib: Cmax
timeFrame: 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)
measure: MRD Cohort: PK of Venetoclax When Dosed in Combination With Ibrutinib: Tmax
timeFrame: 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)
measure: MRD Cohort: PK of Venetoclax When Dosed in Combination With Ibrutinib: AUC0-24h
timeFrame: 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)
measure: MRD Cohort: PK of Venetoclax When Dosed in Combination With Ibrutinib: CLss/F
timeFrame: 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)
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope /ID# 1142-0047
state: California
city: La Jolla
country: United States
facility: Moores Cancer Center at UC San Diego /ID# 1142-0241
state: California
city: Orange
country: United States
facility: UC Irvine Medical Center - Chao Family Comprehensive Cancer Center /ID# 1142-0008
state: California
city: Louisville
country: United States
facility: Norton Cancer Center /ID# 1142-0071
state: Kentucky
city: New Brunswick
country: United States
facility: Rutgers Cancer Institute of New Jersey /ID# 1142-1193
state: New Jersey
city: New Hyde Park
country: United States
facility: Northwell Health/Long Island Jewish Hospital /ID# 1142-0350
state: New York
city: New York
country: United States
facility: New York Presbyterian Hospital/Weill Cornell Med College /ID# 1142-0200
state: New York
city: Rochester
country: United States
facility: University of Rochester Cancer Center /ID# 1142-0127
state: New York
city: Charlotte
country: United States
facility: Charlotte-Mecklenberg Hospital, Carolinas Healthcare System, Levine Cancer Inst /ID# 1142-0733
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation /ID# 1142-0739
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania /ID# 1142-0069
state: Pennsylvania
city: Chattanooga
country: United States
facility: Tennessee Oncology - Chattanooga /ID# 1142-0123
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center /ID# 1142-0032
state: Texas
city: Seattle
country: United States
facility: Swedish Cancer Institute /ID# 1142-0114
state: Washington
city: Kogarah
country: Australia
facility: St George Hospital /ID# 1142-0654
state: New South Wales
city: Bedford Park
country: Australia
facility: Flinders Medical Centre /ID# 1142-0163
state: South Australia
city: Clayton
country: Australia
facility: Monash Medical Centre /ID# 1142-0556
state: Victoria
city: East Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre-East Melbourne /ID# 1142-0633
state: Victoria
city: Fitzroy
country: Australia
facility: St Vincent's Hospital Melbourne /ID# 1142-0501
state: Victoria
city: Frankston
country: Australia
facility: Frankston Hospital /ID# 1142-0715
state: Victoria
city: Heidelberg
country: Australia
facility: Austin Health /ID# 1142-0170
state: Victoria
city: Milan
country: Italy
facility: Ospedale San Raffaele IRCCS /ID# 1142-0523
state: Lombardia
city: Genova
country: Italy
facility: Ospedale Policlinico San Martino /ID# 1142-0903
city: Milano
country: Italy
facility: ASST Grande Ospedale Metropolitano Niguarda /ID# 1142-0581
city: Modena
country: Italy
facility: Azienda Ospedaliero-Universitaria di Modena /ID# 1142-0524
city: Novara
country: Italy
facility: Azienda Ospedaliero Universitaria Maggiore della Carita di Novara /ID# 1142-0582
city: Padova
country: Italy
facility: Azienda Ospedaliera di Padova /ID# 1142-1175
city: Piacenza
country: Italy
facility: Azienda USL di Piacenza - Ospedale Guglielmo da Saliceto /ID# 1142-1182
city: Otahuhu
country: New Zealand
facility: Middlemore Hospital /ID# 1142-0662
state: Auckland
city: Christchurch
country: New Zealand
facility: Christchurch Hospital /ID# 1142-0589
state: Canterbury
city: Palmerston North
country: New Zealand
facility: Palmerston North Hospital /ID# 1142-0585
state: Manawatu-Wanganui
city: Auckland
country: New Zealand
facility: North Shore Hospital /ID# 1142-0663
city: Lublin
country: Poland
facility: Duplicate_Samodzielny Publiczny Szpital Kliniczny nr 1 w Lublinie /ID# 1142-0590
state: Lubelskie
city: Krakow
country: Poland
facility: Malopolskie Centrum Medyczne /ID# 1142-0364
state: Malopolskie
city: Brzozow
country: Poland
facility: Szpital Specjalistyczny w Brzozowie Podkarpacki Osrodek Onkologiczny im. ks. B. /ID# 1142-0592
state: Podkarpackie
city: Gdańsk
country: Poland
facility: Samodzielny Publiczny Szpital Klinczny Nr-1- Akademickie Cenrum Klinic /ID# 1142-0529
state: Pomorskie
city: Lodz
country: Poland
facility: Medical Univ. of Lodz and Copernicus Memorial Hospital /ID# 1142-0531
city: Hospitalet de Llobregat
country: Spain
facility: Hospital Duran i Reynals /ID# 1142-0604
state: Barcelona
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta de Hierro, Majadahonda /ID# 1142-0536
state: Madrid
city: Pamplona
country: Spain
facility: Complejo Hospitalario de Navarra /ID# 1142-1197
state: Navarra
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona /ID# 1142-0533
city: Barcelona
country: Spain
facility: Hospital Santa Creu i Sant Pau /ID# 1142-0535
city: Granada
country: Spain
facility: Hospital Universitario Virgen de las Nieves /ID# 1142-1196
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal /ID# 1142-0874
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre /ID# 1142-0864
city: Salamanca
country: Spain
facility: Hospital Clinico Universitario de Salamanca /ID# 1142-0790
Study officials:
affiliation: AbbVie
name: ABBVIE INC.
role: STUDY_DIRECTOR
References:
citation: Wierda WG, Allan JN, Siddiqi T, Kipps TJ, Opat S, Tedeschi A, Badoux XC, Kuss BJ, Jackson S, Moreno C, Jacobs R, Pagel JM, Flinn I, Pak Y, Zhou C, Szafer-Glusman E, Ninomoto J, Dean JP, James DF, Ghia P, Tam CS. Ibrutinib Plus Venetoclax for First-Line Treatment of Chronic Lymphocytic Leukemia: Primary Analysis Results From the Minimal Residual Disease Cohort of the Randomized Phase II CAPTIVATE Study. J Clin Oncol. 2021 Dec 1;39(34):3853-3865. doi: 10.1200/JCO.21.00807. Epub 2021 Oct 7.