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History of Changes for Study: NCT03462719
A Study of the Combination of Ibrutinib Plus Venetoclax Versus Chlorambucil Plus Obinutuzumab for the First-line Treatment of Participants With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)
Latest version (submitted August 11, 2022) on ClinicalTrials.gov
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Study Record Versions
Version A B Submitted Date Changes
1 March 6, 2018 None (earliest Version on record)
2 April 18, 2018 Study Status and Contacts/Locations
3 May 2, 2018 Recruitment Status, Study Status and Contacts/Locations
4 May 30, 2018 Contacts/Locations and Study Status
5 July 3, 2018 Contacts/Locations, Study Status, Eligibility and Outcome Measures
6 July 23, 2018 Contacts/Locations and Study Status
7 August 22, 2018 Contacts/Locations and Study Status
8 September 21, 2018 Study Status and Contacts/Locations
9 October 18, 2018 Contacts/Locations and Study Status
10 November 14, 2018 Study Status and Contacts/Locations
11 December 13, 2018 Study Status and Contacts/Locations
12 January 9, 2019 Contacts/Locations and Study Status
13 February 20, 2019 Arms and Interventions, Study Status, Eligibility and Outcome Measures
14 March 7, 2019 Contacts/Locations and Study Status
15 April 3, 2019 Contacts/Locations and Study Status
16 April 29, 2019 Contacts/Locations and Study Status
17 May 28, 2019 Study Status and Contacts/Locations
18 June 27, 2019 Recruitment Status, Study Status, Contacts/Locations and Study Design
19 July 25, 2019 Study Status
20 September 10, 2019 Arms and Interventions, Study Status, Outcome Measures and Study Description
21 November 14, 2019 Study Status and Contacts/Locations
22 January 16, 2020 Contacts/Locations, Arms and Interventions, Study Status and Study Description
23 May 28, 2020 Study Status and Contacts/Locations
24 July 23, 2020 Study Status
25 August 20, 2020 Study Status
26 February 4, 2021 Study Status
27 March 4, 2021 Study Status
28 May 27, 2021 Study Status and Contacts/Locations
29 June 24, 2021 Study Status and Contacts/Locations
30 July 22, 2021 Study Status
31 September 16, 2021 Study Status
32 October 14, 2021 Study Status
33 November 4, 2021 Study Status
34 December 2, 2021 Contacts/Locations and Study Status
35 January 27, 2022 Study Status
36 February 24, 2022 Study Status
37 February 25, 2022 Outcome Measures, Study Status, Document Section and Results
38 April 21, 2022 Study Status
39 May 19, 2022 Contacts/Locations and Study Status
40 June 23, 2022 Outcome Measures, Adverse Events, Baseline Characteristics, Study Status, Participant Flow and Contacts/Locations
41 August 11, 2022 Study Status and Contacts/Locations
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Study NCT03462719
Submitted Date:  March 6, 2018 (v1)

Open or close this module Study Identification
Unique Protocol ID: CR108428
Brief Title: A Study of the Combination of Ibrutinib Plus Venetoclax Versus Chlorambucil Plus Obinutuzumab for the First-line Treatment of Participants With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)
Official Title: A Randomized, Open-label, Phase 3 Study of the Combination of Ibrutinib Plus Venetoclax Versus Chlorambucil Plus Obinutuzumab for the First-line Treatment of Subjects With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL).
Secondary IDs: 2017-004699-77 [EudraCT Number]
54179060CLL3011 [Janssen Research & Development, LLC]
Open or close this module Study Status
Record Verification: February 2018
Overall Status: Not yet recruiting
Study Start: April 16, 2018
Primary Completion: February 2, 2021 [Anticipated]
Study Completion: April 1, 2024 [Anticipated]
First Submitted: March 6, 2018
First Submitted that
Met QC Criteria:
March 6, 2018
First Posted: March 12, 2018 [Actual]
Last Update Submitted that
Met QC Criteria:
March 6, 2018
Last Update Posted: March 12, 2018 [Actual]
Open or close this module Sponsor/Collaborators
Sponsor: Janssen Research & Development, LLC
Responsible Party: Sponsor
Collaborators: Pharmacyclics LLC.
Open or close this module Oversight
U.S. FDA-regulated Drug: Yes
U.S. FDA-regulated Device: No
Data Monitoring: Yes
Open or close this module Study Description
Brief Summary: The purpose of this study is to assess progression-free survival (PFS) from treatment with ibrutinib plus venetoclax (I+VEN) compared with obinutuzumab plus chlorambucil (G-Clb) as assessed by an Independent Review Committee (IRC).
Detailed Description: The hypothesis is treatment with combination of I+VEN will result in longer PFS compared with G-Clb in participants with previously untreated chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL) who meet International Workshop on CLL (iwCLL) treatment criteria. The study includes screening (30 days), treatment (from randomization until treatment discontinuation) and follow-up phase (from treatment discontinuation until death, lost to follow up, consent withdrawal, or study end, whichever occurs first). Participants without progression will continue disease evaluations until disease progression or death. Study duration is approximately 6 years. Safety includes review of adverse events and laboratory tests performed over time.
Open or close this module Conditions
Conditions: Leukemia, Lymphocytic, Chronic, B-Cell
Keywords:
Open or close this module Study Design
Study Type: Interventional
Primary Purpose: Treatment
Study Phase: Phase 3
Interventional Study Model: Parallel Assignment
Number of Arms: 2
Masking: None (Open Label)
Allocation: Randomized
Enrollment: 200 [Anticipated]
Open or close this module Arms and Interventions
Arms Assigned Interventions
Experimental: Treatment Arm A: Ibrutinib and Venetoclax (I+VEN)
Participants will initially receive ibrutinib (420 mg [milligrams]/day) for 3 cycles. Venetoclax dose ramp up (from 20 mg to 400 mg over 5 weeks) will begin at Cycle 4 and the combination of ibrutinib and venetoclax will be given for 12 cycles. Following the completion of I+VEN treatment, ibrutinib will be given for another 3 cycles for a total of up to 18 cycles of treatment (each cycle is equivalent to 28 days).
Drug: Ibrutinib
Participants will receive ibrutinib 420 mg orally once daily up to 18 cycles.
Drug: Venetoclax
Participants will receive venetoclax in combination with ibrutinib for a total of 12 cycles, beginning at Cycle 4. For the first 5 weeks of venetoclax treatment, the treatment dose will be ramped up from 20 mg to 400 mg.
Active Comparator: Treatment Arm B: Chlorambucil and Obinutuzumab (G-Clb)
Participants will receive chlorambucil and obinutuzumab (G-Clb) for 6 cycles. Participants will receive obinutuzumab, 1000 mg intravenously (IV) on Days 1, 8 and 15 of Cycle 1, and on Day 1 of Cycles 2 to 6 and chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight, on Days 1 and 15 of Cycles 1 to 6.
Drug: Chlorambucil
Participants will receive chlorambucil at a dose of 0.5 mg/kg body weight on Days 1 and 15 of Cycles 1 to 6.
Drug: Obinutuzumab
Participant will receive obinutuzumab 1000 mg intravenously on Days 1, 8, and 15 of Cycle 1, and Day 1 of Cycles 2 to 6.
Open or close this module Outcome Measures
Primary Outcome Measures:
1. Progression-Free Survival (PFS)
[ Time Frame: From date of randomization to date of disease progression (PD) or death, whichever occurs first (Up to approximately 6 years) ]

PFS is defined as the duration from date of randomization to date of disease progression (PD) or death, whichever occurs first. PD is defined according to the International Workshop on Chronic Lymphocytic Leukemia (iwCLL 2008 Guidelines).
Secondary Outcome Measures:
1. Percentage of Participants who are Minimal Residual Disease (MRD) Negative
[ Time Frame: Up to approximately 6 years ]

MRD negative disease status is defined as less than (<) 1 chronic lymphocytic leukemia (CLL) cell per 10,000 leukocytes or < 0.01 % in the bone marrow. MRD will be assessed by flow cytometry.
2. Overall Response Rate (ORR)
[ Time Frame: Up to approximately 6 years ]

ORR is defined as percentage of participants with complete response [CR], complete response with an incomplete marrow recovery (CRi), partial response (PR), and nodular PR (nPR), for at least 2 months. CR: lymph nodes none greater than (>) 1.5 centimeter (cm), no hepatomegaly and splenomegaly, bone marrow normocellular with less than (<) 30% lymphocytes and no lymphoid nodules, blood lymphocytes < 4,000 per microliter (mcL), platelet count >100,000/mcL, hemoglobin >11 gram per deciliter (g/dL), neutrophils >1500/mcL. PR is at least 50% reduction in at least 2 Group A (lymphadenopathy, hepatomegaly, splenomegaly, blood lymphocytes and marrow infiltrates) and improvement in at least 1 Group B (platelet count, hemoglobin and neutrophils). CRi: complete response with an incomplete recovery of the participant's bone marrow. nPR: response that meets criteria for CR, but bone marrow biopsy shows lymphoid nodules.
3. Complete Response (CR) Rate
[ Time Frame: Up to approximately 6 years ]

CR is lymph nodes none > 1.5 cm, no hepatomegaly and splenomegaly, < 30% lymphocytes, bone marrow normocellular and no lymphoid nodules.
4. Duration of Response (DOR)
[ Time Frame: From the date of initial documentation of a response to the date of first documented evidence of progressive disease or death (up to approximately 6 years) ]

DOR is defined as duration in days from the date of initial documentation of a response to the date of first documented evidence of progressive disease or death. Response and PD are defined according to iwCLL 2008 Guidelines.
5. Overall Survival (OS)
[ Time Frame: From the date of randomization to the date of death from any cause (up to approximately 6 years) ]

OS is defined as the time from the date of randomization to the date of the participant's death from any cause.
6. Time-to-Next Treatment
[ Time Frame: From date of randomization to the start date of any anti-leukemic therapy subsequent to the study treatment (up to approximately 6 years) ]

The time from date of randomization to the start date of any anti-leukemic therapy subsequent to the study treatment.
7. Time to Worsening as Measured by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)
[ Time Frame: From the date of randomization to the start date of worsening (up to approximately 6 years) ]

Worsening in functional and global QoL scales is defined by clinically important negative change. Differences >= 10 points on EORTC scales are considered clinically important.
8. Time to Worsening as Measured by Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Total Score
[ Time Frame: From the date of randomization to the start date of worsening (up to approximately 6 years) ]

Worsening is defined by clinically important negative change. A difference of >= 3 points in FACIT-Fatigue score is considered clinically important.
9. Time to Worsening as Measured by Using EuroQol 5 Dimension 5 Level questionnaire (EQ-5D 5L)
[ Time Frame: From the date of randomization to the start date of worsening (up to approximately 6 years) ]

Worsening is defined by clinically important negative change. A minimum difference of >= 0.07 points change in utility score is considered clinically important; for the VAS health rating, a minimum important difference is >= 7 points change.
10. Number of Participants with Adverse Events (AEs) as a Measure of Safety and Tolerability
[ Time Frame: Up to approximately 18 months ]

An AE is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product.
11. Number of Participants with Abnormal Clinical Laboratory Findings
[ Time Frame: Up to approximately 18 months ]

The number of participants with abnormal clinical laboratory findings will be reported.
12. Percentage of Participants with Sustained Hemoglobin Improvement
[ Time Frame: Up to approximately 6 years ]

The percentage of study participants with sustained hemoglobin improvement from baseline will be reported
13. Percentage of Participants with Sustained Platelet Improvement
[ Time Frame: Up to approximately 6 years ]

Sustained platelet improvement rate is defined as the percentage of participants who achieve a sustained increase of platelet levels from baseline.
14. Concentration at End of Dosing Interval (24h) at Steady-state (Ctrough, ss)
[ Time Frame: Day 1 of Cycles 2, 3, 5 and 6 (each cycle is defined as 28 days) (up to approximately 6 years) ]

Ctrough,ss is defined as concentration at the end of dosing interval (24h) at steady-state. The ibrutinib Ctrough, ss data in the absence and presence of venetoclax will be evaluated.
Open or close this module Eligibility
Minimum Age: 18 Years
Maximum Age:
Sex: All
Gender Based:
Accepts Healthy Volunteers: No
Criteria:

Inclusion Criteria:

  • Adult subjects who are: (a) greater than or equal to (>=) 65 years old or, (b) 18 to 64 years old and have at least 1 of the following:
    1. Cumulative Illness Rating Scale (CIRS) score greater than (>) 6
    2. Creatinine clearance (CrCl) estimated less than (<) 70 milliliter per minute (mL/min) using the Cockcroft-Gault equation
  • Diagnosis of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) that meets International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria
  • Measurable nodal disease (by computed tomography [CT]) is defined as at least one lymph node > 1.5 centimeter (cm) in longest diameter
  • Eastern Cooperative Oncology Group (ECOG) Performance Status Grade less than or equal to (<=) 2
  • Active CLL/SLL requiring treatment per the iwCLL criteria

Exclusion Criteria:

  • Prior anti-leukemic therapy for CLL or SLL
  • Presence of deletion of the short arm of chromosome 17 (del17p) or known TP53 mutation
  • Major surgery within 4 weeks of first dose of study treatment
  • Known bleeding disorders (example, von Willebrand's disease or hemophilia)
  • Central nervous system (CNS) involvement or suspected Richter's syndrome
Open or close this module Contacts/Locations
Central Contact Person: Study Contact
Telephone: 844-434-4210
Email: JNJ.CT@sylogent.com
Study Officials: Janssen Research & Development, LLC Clinical Trial
Study Director
Janssen Research & Development, LLC
Locations: Belgium
ZNA Stuivenberg
Antwerpen, Belgium, 2060
Institut - Jules Bordet
Brussel, Belgium, 1000
UZ Gent
Gent, Belgium, 9000
Virga Jessa Ziekenhuis
Hasselt, Belgium, 3500
UZ Leuven Gasthuisberg
Leuven, Belgium, 3000
Canada, Alberta
Tom Baker Cancer Centre
Calgary, Alberta, Canada, T2N 4N2
Cross Cancer Institute
Edmonton, Alberta, Canada, T6G 1Z2
Canada, Ontario
Juravinski Cancer Centre
Hamilton, Ontario, Canada, L8V 5C2
The Ottawa Hospital - General Campus
Ottawa, Ontario, Canada
Canada, Quebec
CIUSSS de l'Est-de-l'Île-de-Montréal Installation Hôpital Maisonneuve-Rosemont
Montreal, Quebec, Canada, H1T 2M4
Jewish General Hospital
Montreal, Quebec, Canada, H3T 1E2
Czechia
Fakultni nemocnice Brno, Interni hematologicka a onkologicka klinika
Brno, Czechia, 625 00
Fakultni nemocnice Hradec Kralove
Hradec Kralove, Czechia, 500 05
Fakultni nemocnice Ostrava
Ostrava, Czechia, 708 52
Fakultni nemocnice Plzen, Hemato-onkologicke oddeleni
Plzen, Czechia, 304 60
Vseobecna fakultni nemocnice v Praze - I. interni klinika - klinika hematologie
Praha 2, Czechia, 128 08
Denmark
Aalborg University Hospital
Aalborg, Denmark, 9000
Aarhus Universitetshospital
Aarhus, Denmark, 8200
Rigshospitalet Copenhagen University Hospital
Copenhagen, Denmark, 2100
Herlev Hospital
Herlev, Denmark, 2730
Odense Universitetshospital
Odense C, Denmark, 5000
Roskilde Sygehus
Roskilde, Denmark
France
CHU de Clermont-Ferrand
Clermont Ferrand, France, 63000
CHU Montpellier
Montpellier, France, 34295
Hopital Haut Leveque Service Maladie Du Sang
Pessac, France, 33604
Centre Hospitalier Universitaire de Reims, Hôpital Robert Debré
Reims, France, 51100
Institut Universitaire du Cancer Toulouse Oncopole
Toulouse Cedex 9, France, 31059
CHU Bretonneau
Tours Cedex 9, France, 37044
CHU-Nancy
Vandoeuvre Les Nancy, France, 54511
Institut Gustave Roussy
Villejuif, France, 94805
Israel
Bnai Zion Medical Center
Haifa, Israel, 31048
Carmel Medical Center
Haifa, Israel, 34362
Hadassah Medical Center
Jerusalem, Israel, 9112001
Western Galilee Medical Center
Nahariya, Israel, 22100
Sheba Medical Center
Ramat Gan, Israel, 52621
Tel Aviv Sourasky Medical Center
Tel Aviv, Israel, 64239
Netherlands
Flevoziekenhuis
Almere, Netherlands, 1315RA
Academic Medical Center
Amsterdam, Netherlands, 1105 AZ
OLVG
Amsterdam, Netherlands
Reinier de Graaf Gasthuis
Delft, Netherlands, 2625 AD
MC Haaglanden
Den Haag, Netherlands, 2512 VA
Albert Schweitzer Ziekenhuis
Dordrecht, Netherlands, 3318 AT
Catharinaziekenhuis
Eindhoven, Netherlands, 5623 EJ
Spaarne Gasthuis
Hoofddorp, Netherlands, 2134 TM
Zuyderland Medical Center
Sittard-Geleen, Netherlands, 6162 BG
Antonius hospital
Sneek, Netherlands, 8601 ZK
Elisabeth zkh
Tilburg, Netherlands, 5022 GC
Poland
Samodzielny Publiczny Zaklad Opieki Zdrowotnej Zespol Szpitali Miejskich
Chorzów, Poland, 41-500
Wojewodzki Szpital Specjalistyczny im. M. Kopernika w Lodzi
Lodz, Poland, 93-510
Samodzielny Publiczny Szpital Kliniczny Nr 1
Lublin, Poland, 20-081
Wojewodzki Szpital Specjalistyczny im. Janusza Korczaka,
Slupsk, Poland, 76-200
Instytut Hematologii i Transfuzjologii
Warszawa, Poland, 02-776
Klinika Hematologii, Nowotworow Krwi i Transplantacji Szpiku SPSK nr 1
Wroclaw, Poland, 50-367
Russian Federation
Clinical Oncology Center of Tatarstan
Kazan, Russian Federation, 420029
S.P. Botkin Moscow City Clinical Hospital
Moscow, Russian Federation, 125101
S.P. Botkin Moscow City Clinical Hospital
Moscow, Russian Federation, 345300
Nizhniy Novgorod Region Clinical Hospital
Nizhny Novgorod, Russian Federation, 603126
Ryazan Regional Clinical Hospital
Ryazan, Russian Federation, 390039
FSBIFederal Centre of Heart, Blood and Endocrinology named after V.A.Almazov MoH of the RF
Saint Petersburg, Russian Federation
St.-Petersburg Clinical Research Institute of Hematology and Transfusiology
St. Petersburg, Russian Federation, 193024
Spain
Hosp. Univ. Vall D Hebron
Barcelona, Spain, 08035
Hosp. Clinic I Provincial de Barcelona
Barcelona, Spain, 08036
Hosp. Univ. de La Princesa
Madrid, Spain, 28006
Hosp. Univ. Infanta Leonor
Madrid, Spain, 28031
Hospital Ramon y Cajal
Madrid, Spain, 28034
Hosp. Univ. Fund. Jimenez Diaz
Madrid, Spain, 28040
Clinica Univ. de Navarra
Pamplona, Spain, 31008
Hospital Clinico Universitario Salamanca
Salamanca, Spain, 37007
Hosp. Virgen Del Rocio
Sevilla, Spain, 41013
Sweden
Sunderby Sjukhus Medicinkliniken
Luelå, Sweden, 97180
Skånes universitetssjukhus
Lund, Sweden, 22185
Karolinska Universitetssjukhuset Solna, Centrum för Hematologi, Stockholm
Stockholm, Sweden, 171 76
Turkey
Gazi Universitesi Tip FalKultesi
Ankara, Turkey, 06500
Ankara Universitesi Tip Fakültesi İbn-i Sina Hastanesi
Ankara, Turkey, 06590
Ondokuz Mayis Universitesi Tip Fakultesi
Atakum, Turkey, 55270
V.K.V. Amerikan Hastanesi
Istanbul, Turkey, 34365
Dokuz Eylul Universitesi Tip Fakultesi
Izmir, Turkey, 35340
United Kingdom
Birmingham Heartlands Hospital
Birmingham, United Kingdom, B9 5ST
Royal Bournemouth Hospital
Bournemouth, United Kingdom, BH7 7DW
Addenbrookes Hospital
Cambridge, United Kingdom, CB2 0QQ
Queen Mary University of London
Charterhouse Square, United Kingdom, EC1M 6BQ
New Victoria Hospital
Glasgow, United Kingdom, G42 9LF
St James's Hospital
Leeds, United Kingdom, LS9 7T
Derriford Hospital
Plymouth, United Kingdom, PL6 8DH
Barking Havering and Redbridge University Hospitals NHS Trust
Romford, United Kingdom, RM7 0AG
Royal Hallamshire Hospital
Sheffield, United Kingdom, S10 2JF
Open or close this module IPDSharing
Plan to Share IPD:
Open or close this module References
Links:
Available IPD/Information:

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