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)
- Conditions
- Leukemia, Lymphocytic, Chronic, B-Cell
- Interventions
- Registration Number
- NCT03462719
- Lead Sponsor
- Janssen Research & Development, LLC
- 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
Not available
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 211
-
Adult participants 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:
- Cumulative Illness Rating Scale (CIRS) score > 6
- Creatinine clearance (CrCl) estimated less than (<) 70 milliliter per minute (mL/min) using 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]), defined as at least one lymph node > 1.5 centimeter (cm) in longest diameter
-
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Grade less than or equal to (<=) 2
-
Active CLL/SLL requiring treatment per the iwCLL criteria
- Prior anti-leukemic therapy for CLL or SLL
- Presence of deletion of the short arm of chromosome 17 (del17p) or known TP53 mutation detected at a threshold of >10 percent (%) variable allele frequency (VAF)
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Treatment Arm A: Ibrutinib and Venetoclax (I+VEN) Ibrutinib Participants will initially receive ibrutinib (420 mg \[milligrams\]/day) for 3 cycles. Venetoclax dose ramp up (from 20 to 400 mg over 5 weeks) will begin at Cycle 4 and the combination of ibrutinib and venetoclax will be given for 12 cycles (each cycle is equivalent to 28 days). Participants who subsequently develop progressive disease may enter to Subsequent Therapy Phase to receive single-agent ibrutinib until disease progression or unacceptable toxicity. Treatment Arm A: Ibrutinib and Venetoclax (I+VEN) Ibrutinib (as Subsequent Therapy) Participants will initially receive ibrutinib (420 mg \[milligrams\]/day) for 3 cycles. Venetoclax dose ramp up (from 20 to 400 mg over 5 weeks) will begin at Cycle 4 and the combination of ibrutinib and venetoclax will be given for 12 cycles (each cycle is equivalent to 28 days). Participants who subsequently develop progressive disease may enter to Subsequent Therapy Phase to receive single-agent ibrutinib until disease progression or unacceptable toxicity. Treatment Arm B: Chlorambucil and Obinutuzumab (G-Clb) Chlorambucil 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. Participants who subsequently develop progressive disease may enter to Subsequent Therapy Phase to receive single-agent ibrutinib until disease progression or unacceptable toxicity. Treatment Arm B: Chlorambucil and Obinutuzumab (G-Clb) Ibrutinib (as Subsequent Therapy) 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. Participants who subsequently develop progressive disease may enter to Subsequent Therapy Phase to receive single-agent ibrutinib until disease progression or unacceptable toxicity. Treatment Arm A: Ibrutinib and Venetoclax (I+VEN) Venetoclax Participants will initially receive ibrutinib (420 mg \[milligrams\]/day) for 3 cycles. Venetoclax dose ramp up (from 20 to 400 mg over 5 weeks) will begin at Cycle 4 and the combination of ibrutinib and venetoclax will be given for 12 cycles (each cycle is equivalent to 28 days). Participants who subsequently develop progressive disease may enter to Subsequent Therapy Phase to receive single-agent ibrutinib until disease progression or unacceptable toxicity. Treatment Arm B: Chlorambucil and Obinutuzumab (G-Clb) Obinutuzumab 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. Participants who subsequently develop progressive disease may enter to Subsequent Therapy Phase to receive single-agent ibrutinib until disease progression or unacceptable toxicity.
- Primary Outcome Measures
Name Time Method Progression Free Survival (PFS) Up to 2 years 10 months PFS: time between date of randomization and date of disease progression, as assessed by IRC, or date of death due to any cause, whichever occurs first, regardless of use of subsequent anti-cancer therapy prior to PD or death using iWCLL2008 criteria : New enlarged lymph nodes \>15 mm, new hepatomegaly or splenomegaly, or other organ infiltrates, bone lesion, ascites or pleural effusion due to CLL; \>=50% increase in longest diameter (LDi) from nadir in existing lymph node (LDi \>15 mm) or \>=50% increase from nadir in sum of diameters of multiple nodes (and at least 1 node with LDi \>15 mm); \>=50% increase from nadir in enlargement of liver/spleen; \>=50% increase from baseline in lymphocyte count (ALC; to \>=5\*10\^9/L); or \>=50% increase from nadir in ALC in \>=2 serial assessments if ALC is \>=30000\*10\^9/L and lymphocyte doubling time is rapid unless considered treatment-related lymphocytosis; new cytopenia attributable to CLL; transformation to more aggressive histology.
- Secondary Outcome Measures
Name Time Method Percentage of Participants With Sustained Platelet Improvement Up to 2 years 10 months Sustained platelet improvement is defined as the percentage of participants who achieved an increase in platelet levels from baseline by \>= 50% and lasts for at least 56 days without blood transfusion or growth factors.
Plasma Concentration of Ibrutinib and Venetoclax Ibrutinib: Pre-dose-Day 1 of Cycles 2, 3, 5 and 6 (each cycle is defined as 28 days), Venetoclax: Pre-dose-Day 1 of Cycles 5 and 6 Plasma concentrations of ibrutinib and venetoclax were determined by validated liquid chromatography-tandem mass spectrometry.
Minimal Residual Disease (MRD) Negative Rate Up to 2 years 10 months MRD-negative rate is defined as the percentage of participants who achieved MRD-negative status (that is, less than \[\<\] 1 chronic lymphocytic leukemia (CLL) cell per 10,000 leukocytes or \<0.01 percentage \[%\]) in the bone marrow as assessed by next-generation sequencing (NGS). Participants with missing MRD data were considered MRD positive.
Percentage of Participants With Sustained Hemoglobin Improvement Up to 2 years 10 months Sustained hemoglobin improvement is defined as the percentage of participants who achieved an increase in hemoglobin levels from baseline by \>= 2 grams per deciliter (g/dL) and lasts for at least 56 days without blood transfusion or growth factors.
Complete Response Rate (CRR) Up to 2 years 10 months Complete response rate is defined as the percentage of participants who achieved complete response or complete response with an incomplete marrow recovery (CRi) on or prior to initiation of subsequent anti-leukemic therapy per the IRC assessment. International Workshop on Chronic Lymphocytic Leukemia (iWCLL) 2008 criteria: CR- No lymphadenopathy and hepatosplenomegaly, no constitutional symptoms, neutrophils \>1.5\*10\^9/liter (L), platelets \>100\*10\^9/L, Hgb \>11 gram per deciliter (g/dL), absolute lymphocyte count \<4000/microliter (mcL) and normocellular bone marrow with \<30% lymphocytes and no B lymphoid nodules; CRi- CR with incomplete recovery of bone marrow.
Overall Response Rate (ORR) Up to 2 years 10 months ORR: percentage of participants who achieved best overall response of either CR, CRi, nodular PR (nPR) and partial response (PR). iWCLL 2008 criteria: CR- No lymphadenopathy and hepatosplenomegaly, no constitutional symptoms, neutrophils \>1.5\*10\^9/liter (L), platelets \>100\*10\^9/L, Hgb \>11 g/dL and ALC \<4000/mcL, normocellular bone marrow with \<30% lymphocytes and no B lymphoid nodules; CRi- CR with incomplete recovery of bone marrow; nPR- participants meet criteria for CR, but bone marrow biopsy shows B-lymphoid nodules (reflecting residual disease); PR-2 of following when abnormal at baseline: \>=50% decrease in ALC, \>=50% decrease in sum of products of multiple nodes, \>=50% decrease in enlargement of spleen or liver; and 1 of following: neutrophils \>1.5\*10\^9/L, Platelets \>100\*10\^9/L and Hgb\>11 g/dL or \>=50% improvement over baseline in any of these; 50% reduction in bone marrow infiltrates or B lymphoid nodules; no new enlarged nodes or new hepatosplenomegaly.
Overall Survival (OS) Up to 4 years 10 months OS is defined as the time from date of randomization to date of death from any cause.
Duration of Response (DOR) Up to 2 years 10 months DOR is defined as the interval between the date of initial documentation of a response including partial response with lymphocytosis (PRL) and the date of first documented evidence of PD or death or date of censoring per the IRC assessment. iWCLL 2008 criteria for PD: New enlarged nodes \>1.5 cm, new hepatomegaly or splenomegaly, or other organ infiltrates; \>= 50% increase from nadir in existing lymph node or \>=50% increase from nadir in sum of product of diameters of multiple nodes; \>=50% increase from nadir in enlargement of liver or spleen; \>=50% increase from baseline in lymphocyte count (and to \>=5\*10\^9/L) unless considered treatment-related lymphocytosis; new cytopenia (Hemoglobin b or platelets) attributable to CLL; transformation to a more aggressive histology.
Time-to-Next Treatment Up to 2 years 10 months Time-to-next treatment was measured from the date of randomization to the start date of any subsequent anti-leukemic therapy.
Time to Worsening as Measured by Using EuroQol 5 Dimension 5 Level Questionnaire (EQ-5D-5L) Up to 2 years 10 months Time to worsening= time interval (months) from randomization to first observation of deterioration. EQ-5D-5L consists of a 5-item descriptive system and the EuroQol visual analog scale (EQ-5D VAS). EQ-5D-VAS self-rating records respondent's own assessment of his/her overall health status at time of completion, on scale of 0 (worst health you can imagine) to 100 (best health you can imagine). Worsening is defined as a decrease of \>= 7 points (on a 0-100 scale).
EQ-5D-5L descriptive system comprises 5 dimensions of health (mobility, self -care, usual activities, pain/discomfort, and anxiety/depression) to describe participant's current health state. Responses for 5 dimensions are combined into a 5-digit number describing respondents health state that can be converted into a single index value or utility score (using the United Kingdom weights), ranging from -1 to 1, where lower scores indicate a worse health status. Worsening is defined as a decrease of \>=0.08 points (on a 0-1 scale).Time to Worsening Measured by European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire (EORTC QLQ)-C30) Up to 2 years 10 months Time to worsening= time interval from randomization to first observation of deterioration. EORTC QLQ-C30 includes 30 separate items: 5 functional scales (physical, role, emotional, cognitive, and social Functioning), 1 global health status (GHS) and QoL scale, 3 symptom scales (fatigue, nausea/vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Each item, except GHS, is answered on 4-point scale (1=not at all to 4=very much) and GHS is measured on 1-7 scale: 1=very poor and 7=excellent. Scores derived using validated scoring algorithms as per EORTC QLQ-C30 Manual and linearly transformed in a range from 0-100. For functional and global QoL scales, higher scores=better level of functioning/QoL. For symptom-oriented scales, higher score=more severe symptoms. Worsening in functional and global health scores=decrease of \>=10 points (on 0-100 scale) and in symptom scores=increase of \>=10 points (on 0-100 scale).
Time to Worsening and Time to Improvement as Measured by Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Total Score Up to 2 years 10 months Responses to the 13-item FACIT Fatigue Scale are reported on a 5-point categorical response scale ranging from 0 (not at all) to 4 (very much). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worst score) to 52 (best score). Time to Worsening is defined as time interval (months) from randomization to first observation of deterioration. Worsening is defined as a decrease \>= 3 points (on a 0-52 scale). Time to improvement is defined as the time interval (months) from randomization to the first observation of improvement. Improvement is defined as an increase \>=3 points (on a 0-52 scale).
Number of Participants With Adverse Events (AEs) as a Measure of Safety and Tolerability Up to 4 years 10 months An adverse event (AE) is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study.
Number of Participants With Abnormal Clinical Laboratory Findings Up to 4 years 10 months Number of participants with abnormal clinical laboratory findings (hematology and serum chemistry) were reported.
Trial Locations
- Locations (87)
Wojewodzki Szpital Specjalistyczny im Janusza Korczaka
🇵🇱Slupsk, Poland
Norton Cancer Institute
🇺🇸Louisville, Kentucky, United States
John Theurer Cancer Center
🇺🇸Hackensack, New Jersey, United States
Novant Health
🇺🇸Charlotte, North Carolina, United States
Institut - Jules Bordet
🇧🇪Anderlecht, Belgium
ZNA Stuivenberg
🇧🇪Antwerpen, Belgium
Universitair Ziekenhuis Gent
🇧🇪Gent, Belgium
Virga Jessa Ziekenhuis
🇧🇪Hasselt, Belgium
UZ Leuven Gasthuisberg
🇧🇪Leuven, Belgium
Arthur J E Child Comprehensive Cancer Centre
🇨🇦Calgary, Alberta, Canada
Cross Cancer Institute
🇨🇦Edmonton, Alberta, Canada
Juravinski Cancer Centre
🇨🇦Hamilton, Ontario, Canada
The Ottawa Hospital - General Campus
🇨🇦Ottawa, Ontario, Canada
CIUSSS de l Est de l Ile de Montreal Installation Hopital Maisonneuve Rosemont
🇨🇦Montreal, Quebec, Canada
Jewish General Hospital
🇨🇦Montreal, Quebec, Canada
Fakultni nemocnice Brno, Interni hematologicka a onkologicka klinika
🇨🇿Brno, Czechia
Fakultni nemocnice Hradec Kralove
🇨🇿Hradec Kralove, Czechia
Fakultni Nemocnice Ostrava
🇨🇿Ostrava, Czechia
Fakultni nemocnice Plzen, Hemato-onkologicke oddeleni
🇨🇿Plzen, Czechia
Vseobecna fakultni nemocnice v Praze - I. interni klinika - klinika hematologie
🇨🇿Praha 2, Czechia
Aalborg University Hospital
🇩🇰Aalborg, Denmark
Aarhus Universitetshospital
🇩🇰Aarhus, Denmark
Rigshospitalet
🇩🇰Copenhagen, Denmark
Odense Universitetshospital
🇩🇰Odense C, Denmark
Roskilde Sygehus
🇩🇰Roskilde, Denmark
CHU de Clermont Ferrand
🇫🇷Clermont Ferrand, France
Hopital Claude Huriez
🇫🇷Lille, France
CHU Montpellier
🇫🇷Montpellier, France
Hopital Haut Leveque Service Maladie Du Sang
🇫🇷Pessac, France
Centre Hospitalier Universitaire de Reims, Hôpital Robert Debré
🇫🇷Reims, France
Institut Universitaire du Cancer Toulouse Oncopole
🇫🇷Toulouse Cedex 9, France
CHU Bretonneau
🇫🇷Tours Cedex 9, France
CHU-Nancy
🇫🇷Vandoeuvre les Nancy, France
Institut Gustave Roussy
🇫🇷Villejuif, France
Bnai Zion Medical Center
🇮🇱Haifa, Israel
Carmel Medical Center
🇮🇱Haifa, Israel
Hadassah Medical Center
🇮🇱Jerusalem, Israel
Western Galilee Medical Center
🇮🇱Nahariya, Israel
Sheba Medical Center
🇮🇱Ramat Gan, Israel
Tel Aviv Sourasky Medical Center
🇮🇱Tel Aviv, Israel
Flevoziekenhuis
🇳🇱Almere, Netherlands
OLVG
🇳🇱Amsterdam, Netherlands
Academic Medical Center
🇳🇱Amsterdam, Netherlands
Reinier de Graaf Gasthuis
🇳🇱Delft, Netherlands
MC Haaglanden
🇳🇱Den Haag, Netherlands
Albert Schweitzer Ziekenhuis
🇳🇱Dordrecht, Netherlands
Catharinaziekenhuis
🇳🇱Eindhoven, Netherlands
Spaarne Gasthuis
🇳🇱Hoofddorp, Netherlands
Zuyderland Medical Center
🇳🇱Sittard-Geleen, Netherlands
Antonius hospital
🇳🇱Sneek, Netherlands
Elisabeth zkh
🇳🇱Tilburg, Netherlands
Samodzielny Publiczny Zaklad Opieki Zdrowotnej Zespol Szpitali Miejskich
🇵🇱Chorzow, Poland
Wojewodzkie Wielospecjalistyczne Centrum Onkologii i Traumatologii im M Kopernika w Lodzi
🇵🇱Lodz, Poland
Uniwersytecki Szpital Kliniczny Nr 1 w Lublinie
🇵🇱Lublin, Poland
Instytut Hematologii i Transfuzjologii
🇵🇱Warszawa, Poland
Moscow Multidisciplinary Scientific and Clinical Center named after S P Botkin
🇷🇺Moscow, Russian Federation
S.P. Botkin Moscow City Clinical Hospital
🇷🇺Moscow, Russian Federation
Nizhniy Novgorod Region Clinical Hospital
🇷🇺Nizhny Novgorod, Russian Federation
Ryazan Regional Clinical Hospital
🇷🇺Ryazan, Russian Federation
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
Hosp Univ Vall D Hebron
🇪🇸Barcelona, Spain
Hosp Clinic de Barcelona
🇪🇸Barcelona, Spain
Hosp. de La Santa Creu I Sant Pau
🇪🇸Barcelona, Spain
Hosp. Univ. de La Princesa
🇪🇸Madrid, Spain
Hosp. Gral. Univ. Gregorio Maranon
🇪🇸Madrid, Spain
Hosp. Univ. Infanta Leonor
🇪🇸Madrid, Spain
Hospital Ramon y Cajal
🇪🇸Madrid, Spain
Hosp Univ Fund Jimenez Diaz
🇪🇸Madrid, Spain
Clinica Univ. de Navarra
🇪🇸Pamplona, Spain
Hospital Clinico Universitario Salamanca
🇪🇸Salamanca, Spain
Hosp. Virgen Del Rocio
🇪🇸Sevilla, Spain
Sunderby Sjukhus Medicinkliniken
🇸🇪Luelå, Sweden
Karolinska Universitetssjukhuset Solna, Centrum för Hematologi, Stockholm
🇸🇪Stockholm, Sweden
Gazi Universitesi Tip FalKultesi
🇹🇷Ankara, Turkey
Ankara Universitesi Tip Fakültesi Ibn-i Sina Hastanesi
🇹🇷Ankara, Turkey
Ondokuz Mayis University
🇹🇷Atakum, Turkey
V K V Amerikan Hastanesi
🇹🇷Istanbul, Turkey
Dokuz Eylul Universitesi Tip Fakultesi
🇹🇷Izmir, Turkey
Birmingham Heartlands Hospital
🇬🇧Birmingham, United Kingdom
Addenbrookes Hospital
🇬🇧Cambridge, United Kingdom
Queen Mary University of London
🇬🇧Charterhouse Square, United Kingdom
New Victoria Hospital
🇬🇧Glasgow, United Kingdom
St James's Hospital
🇬🇧Leeds, United Kingdom
Derriford Hospital
🇬🇧Plymouth, United Kingdom
Barking Havering and Redbridge University Hospitals NHS Trust
🇬🇧Romford, United Kingdom
Royal Hallamshire Hospital
🇬🇧Sheffield, United Kingdom