Chronic Lymphocytic LeukemiaPhase 3NCT02264574
A Multi-Center Study of Ibrutinib in Combination With Obinutuzumab Versus Chlorambucil in Combination With Obinutuzumab in Patients With Treatment naïve Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)
A Phase 3 study testing Ibrutinib, Obinutuzumab and Chlorambucil in people with Chronic Lymphocytic Leukemia and Small-Cell Lymphoma, run by Pharmacyclics LLC. at 71 sites in 16 countries.
Trial summary
The primary objective of this study is to evaluate the efficacy of ibrutinib in combination with obinutuzumab compared to chlorambucil in combination with obinutuzumab based on the Independent Review Committee (IRC) assessment of progression free survival (PFS). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Chronic Lymphocytic Leukemia, Small-Cell Lymphoma
- What is being tested?
- Ibrutinib, Obinutuzumab and Chlorambucil
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 229 participants
- Where
- 71 sitesin 16 countries
- Study dates
- 6 Oct 2014to 3 Sep 2019
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Disease Related:
- Diagnosis of CLL/SLL that meets IWCLL diagnostic criteria.
- Age 65 yrs and older OR if less than 65 years, must have at least one of the following criteria:
- Cumulative Illness Rating Score (CIRS) >6
- Creatinine clearance estimated <70 mL/min using Cockcroft-Gault equation.
- Del 17p by fluorescence in situ hybridization (FISH) or TP53 mutation by polymerase chain reaction (PCR) or Next Generation Sequencing
Show all 25Show fewer
- Active disease meeting at least 1 of the following IWCLL criteria for requiring treatment:
- Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and thrombocytopenia
- Massive, progressive, or symptomatic splenomegaly
- Massive nodes (at least 10 cm longest diameter), or progressive or symptomatic lymphadenopathy.
- Progressive lymphocytosis with an increase of more than 50 percent over a 2-month period or a lymphocyte doubling time (LDT) of <6 months. LDT may be obtained by linear regression extrapolation of absolute lymphocyte counts obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In patients with initial blood lymphocyte counts of <30,000/µL, LDT should not be used as a single parameter to define indication for treatment. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (eg, infections) should be excluded.
- Autoimmune hemolytic anemia and/or immune thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy.
- Autoimmune hemolytic anemia is defined by at least one marker of hemolysis (indirect bilirubin above the upper limit of normal (ULN) not due to liver disease, increased lactate dehydrogenase (above ULN) without alternative etiology, or increased absolute reticulocytosis (above ULN) or bone marrow erythropoiesis in the absence of bleeding AND at least one marker direct or indirect autoimmune mechanism (positive direct antiglobulin for immunoglobulin G [IgG] or C3d, cold agglutinins).
- Immune thrombocytopenia is defined by platelets ≤100,000/µL and increased megakaryocytes on the bone marrow exam.
- Constitutional symptoms, defined as one or more of the following disease-related symptoms or signs, documented in the patient's record prior to randomization:
- unintentional weight loss >10 percent within 6 months prior to screening.
- significant fatigue (inability to work or perform usual activities).
- fevers >100.5°F or 38.0°C for 2 or more weeks prior to screening without evidence of infection.
- night sweats for more than 1 month prior to screening without evidence of infection.
- Measurable nodal disease by computed tomography (CT), defined as at least 1 lymph node >1.5 cm in the longest diameter in a site that has not been previously irradiated. An irradiated lesion may be assessed for measurable disease only if there has been documented progression in that lesion since radiotherapy has ended.
- Laboratory
- Adequate hematologic function independent of transfusion and growth factor support for at least 7 days prior to screening and randomization.
- Adequate hepatic and renal function
- Men and women ≥ 18 years of age.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
Who cannot join
- Any prior treatment of CLL or SLL
- Evidence of central nervous system (CNS) involvement with primary disease of CLL/SLL
- History of other malignancies, except:
- Malignancy treated with curative intent and with no known active disease present for ≥3 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician.
- Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura
- Known or suspected history of Richter's transformation.
Show all 22Show fewer
- Concurrent administration of >20mg/day of prednisone within 7 days of randomization unless indicated for prophylaxis or management of allergic reactions (eg, contrast)
- Known hypersensitivity to one or more study drugs
- Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
- Any uncontrolled active systemic infection or an infection requiring systemic treatment that was completed ≤ 7 days before randomization.
- Known bleeding disorders or hemophilia.
- History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
- Known history of human immunodeficiency virus (HIV) or active with hepatitis B virus (HBV) or hepatitis C virus (HCV).
- Major surgery within 4 weeks of randomization.
- Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator's opinion, could compromise the subject's safety or put the study outcomes at undue risk.
- Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 3 or 4 congestive heart failure or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization.
- Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction.
- Concomitant use of warfarin or other vitamin K antagonists.
- Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor.
- Lactating or pregnant
- Unwilling or unable to participate in all required study evaluations and procedures.
- Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations).
Trial locations and contacts
71 sites in 16 countries.
71 sites in 16 countries
Spain9 sites
Site Reference ID/Investigator# 0533
Barcelona
Site Reference ID/Investigator# 0534
Barcelona
Site Reference ID/Investigator# 0535
Barcelona
Site Reference ID/Investigator# 0604
L'Hospitalet de Llobregat, Madrid
Site Reference ID/Investigator# 0537
Madrid
Site Reference ID/Investigator# 0864
Madrid
Site Reference ID/Investigator# 0874
Madrid
Site Reference ID/Investigator# 0536
Majadahonda, Madrid
Site Reference ID/Investigator# 0790
Salamanca
United States8 sites
Site Reference ID/Investigator# 0868
Chattanooga, Tennessee
Site Reference ID/Investigator# 0845
Cincinnati, Ohio
Site Reference ID/Investigator# 0844
Fort Myers, Florida
Site Reference ID/Investigator# 0241
La Jolla, California
Site Reference ID/Investigator# 0712
Las Vegas, Nevada
Site Reference ID/Investigator# 071
Louisville, Kentucky
Site Reference ID/Investigator# 0123
Nashville, Tennessee
Site Reference ID/Investigator# 0763
West Palm Beach, Florida
Italy8 sites
Site Reference ID/Investigator# 0860
Florence
Site Reference ID/Investigator# 0523
Milan
Site Reference ID/Investigator# 0581
Milan
Site Reference ID/Investigator# 0584
Milan
Site Reference ID/Investigator# 0524
Modena
Site Reference ID/Investigator# 0582
Novara
Site Reference ID/Investigator# 0732
Roma
Site Reference ID/Investigator# 0859
Siena
Australia6 sites
Site Reference ID/Investigator# 0650
Adelaide, South Australia
Site Reference ID/Investigator# 0888
Ballarat, Victoria
Site Reference ID/Investigator# 0193
Box Hill, Victoria
Site Reference ID/Investigator# 0633
Fitzroy, Victoria
Site Reference ID/Investigator# 0170
Heidelberg, Victoria
Site Reference ID/Investigator #0503
Woolloongabba, Queensland
Israel6 sites
Site Reference ID/Investigator# 0573
Haifa
Site Reference ID/Investigator# 0577
Jerusalem
Site Reference ID/Investigator# 0579
Jerusalem
Site Reference ID/Investigator# 0575
Petah Tikva
Site Reference ID/Investigator# 0856
Tel Aviv
Site Reference ID/Investigator# 0875
Tsrifin
Turkey (Türkiye)6 sites
Site Reference ID/Investigator# 0608
Ankara
Site Reference ID/Investigator# 606
Ankara
Site Reference ID/Investigator# 0889
Denizli
Site Reference ID/Investigator# 0678
Istanbul, Nisantasi
Site Reference ID/Investigator# 0601
Izmir
Site Reference ID/Investigator# 0866
Samsun
Russia5 sites
Site Reference ID/Investigator# 0708
Nizhny Novgorod
Site Reference ID/Investigator# 0707
Ryazan
Site Reference ID/Investigator# 0881
Saint Petersburg
Site Reference ID/Investigator# 710
Saint Petersburg
Site Reference ID/Investigator# 304
Yaroslavl
France4 sites
Site Reference ID/Investigator# 0855
Bayonne, Pyrenees Atlantiques
Site Reference ID/Investigator# 0520
Nantes, Loire Atlantique
Site Reference ID/Investigator# 0769
Pessac, Gironde
Site Reference ID/Investigator# 0775
Vandœuvre-lès-Nancy, Meurthe Et Moselle
Sweden4 sites
Site Reference ID/Investigator# 0870
Borås
Site Reference ID/Investigator# 0865
Luleå
Site Reference ID/Investigator# 0631
Lund
Site Reference ID/Investigator# 0632
Stockholm
New Zealand3 sites
Site Reference ID/Investigator# 0663
Auckland
Site Reference ID/Investigator# 662
Auckland
Site Reference ID/Investigator# 0586
Hamilton
United Kingdom3 sites
Site Reference ID/Investigator# 0867
Harlow, Essex
Site Reference ID/Investigator# 0365
London
Site Reference ID/Investigator# 0543
London
Austria2 sites
Site Reference ID/Investigator# 0352
Linz
Site Reference ID/Investigator# 0869
Salzburg
Belgium2 sites
Site Reference ID/Investigator# 0559
Leuven
Site Reference ID/Investigator# 0850
Turnhout
Czechia2 sites
Site Reference ID/Investigator# 0564
Hradec Králové
Site Reference ID/Investigator# 0854
Prague
Poland2 sites
Site Reference ID/Investigator# 0592
Brzozów
Site Reference ID/Investigator# 0531
Lodz
About this study
Official title: A Randomized, Multi-center, Open-label, Phase 3 Study of the Bruton's Tyrosine Kinase Inhibitor Ibrutinib in Combination With Obinutuzumab Versus Chlorambucil in Combination With Obinutuzumab in Subjects With Treatment-naïve Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
The primary objective of this study is to evaluate the efficacy of ibrutinib in combination with obinutuzumab compared to chlorambucil in combination with obinutuzumab based on the Independent Review Committee (IRC) assessment of progression free survival (PFS). Efficacy will be evaluated according to 2008 International Workshop for Chronic Lymphocytic Leukemia (IWCLL) criteria with the modification for treatment-related lymphocytosis, in subjects with treatment-naive CLL or SLL.
- Conditions
- Chronic Lymphocytic Leukemia, Small-Cell Lymphoma
- Being tested
- Ibrutinib, Obinutuzumab, Chlorambucil
- Medical subject headings
- Leukemia, Lymphocytic, Chronic, B-Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
IbrutinibDrug
Ibrutinib will be supplied as 140 mg hard gelatin capsules for oral (PO) administration.
ObinutuzumabDrug
Obinutuzumab will be supplied as 1000 mg/40 mL solution in a single-use vial for intravenous (IV) administration
ChlorambucilDrug
Chlorambucil will be supplied as 2 mg film-coated tablets for oral (PO) administration
| Study group | Role | What they receive |
|---|---|---|
| IBR + OB | Experimental | Ibrutinib (IBR) given orally at a dose of 420 mg/day until progressive disease or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until progressive disease or unacceptable toxicity. Receives: Drug: Ibrutinib; Drug: Obinutuzumab |
| CLB + OB | Experimental | Chlorambucil (CLB) given orally at a dose of 0.5 mg/kg body weight up to a total of 6 cycles on Days 1 and 15 of each cycle or until disease progression or unacceptable toxicity.
Intravenous obinutuzumab given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until disease progression or unacceptable toxicity. Receives: Drug: Obinutuzumab; Drug: Chlorambucil |
What is being measured
The primary outcome is the main question the study is designed to answer.
Primary Analysis: Progression Free Survival (PFS) Based on Independent Review Committee (IRC) Assessment - Kaplan Meier Landmark Estimates at Month 30
PFS was defined as time from the date randomization to the date of first IRC-confirmed disease progression (PD) or date of death due to any cause, whichever occurred first, regardless of the use of subsequent antineoplastic therapy prior to documented PD or death. Assessment of PD was conducted in accordance with the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria (Halleck et al) with the modification that treatment-related lymphocytosis in the absence of other signs or symptoms of disease progression was not considered progressive disease.
The primary analysis was performed after observing 94 PFS events as pre-specified in the study protocol. As the median PFS was not reached in the experimental (IBR+OB) arm at the time of the analysis, Kaplan Meier landmark estimates of the PFS rate at 30 months (that is, the estimated percentage of participants with progression-free survival at Month 30) are presented.
Measured: Month 30 (Median follow-up time was 31.3 months at the time of the primary analysis [data cutoff date: 26 March 2018]).
Final Analysis: PFS Based on Investigator Assessment - Kaplan Meier Landmark Estimates at Month 48
PFS was defined as time from the date randomization to the date of first investigator-confirmed PD or date of death due to any cause, whichever occurred first, regardless of the use of subsequent antineoplastic therapy prior to documented PD or death. Assessment of PD was conducted in accordance with the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria (Halleck et al) with the modification that treatment-related lymphocytosis in the absence of other signs or symptoms of disease progression was not considered progressive disease.
As the median PFS was not reached in the experimental (IBR+OB) arm at the time of the analysis, Kaplan Meier landmark estimates of the PFS rate at 48 months (that is, the estimated percentage of participants with progression-free survival at Month 48) are presented.
Measured: Month 48 (Median follow-up time was 44.6 months at the time of the final analysis [data cutoff date: 17 October 2019]).
Secondary outcomes (14)
Primary Analysis: PFS in High-Risk Sub-Population (del17p/TP53 Mutation/Del 11q) Based on IRC Assessment - Kaplan Meier Landmark Estimates at Month 30
PFS was analyzed within the high-risk sub-population of participants with del17p or TP53 mutation or del 11q at baseline per central lab results. PFS was defined as time from the date randomization to the date of first IRC-confirmed PD or date of death due to any cause, whichever occurred first, regardless of the use of subsequent antineoplastic therapy prior to documented PD or death. Assessment of PD was conducted in accordance with the IWCLL 2008 criteria (Halleck et al) with the modification that treatment-related lymphocytosis in the absence of other signs or symptoms of PD was not considered progressive disease.
As the median PFS was not reached in the experimental (IBR+OB) arm at the time of the analysis, Kaplan Meier landmark estimates of the PFS rate at 30 months (that is, the estimated percentage of participants with progression-free survival at Month 30) are presented.
Measured: Month 30 (Median follow-up time was 31.3 months at the time of the primary analysis [data cutoff date: 26 March 2018]).
Primary Analysis: Rate of Sustained Hemoglobin Improvement
Percentage of participants with sustained hemoglobin improvement, defined as hemoglobin increase ≥ 2 g/dL over baseline continuously for ≥ 56 days without blood transfusions or growth factors.
Measured: Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018).
Primary Analysis: Rate of Minimal Residual Disease (MRD)-Negative Response
Percentage of participants who achieved MRD-negative response, defined as < 1 CLL cell per 10,000 leukocytes as assessed by flow cytometry of a bone marrow aspirate per central laboratory. MRD samples were collected before initiation of subsequent antineoplastic treatment and MRD status was reported by central lab within 5 days after collection date. Participants with missing MRD data were considered non-responders.
Measured: Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018).
Primary Analysis: Overall Response Rate (ORR) Based on IRC Assessment
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), or partial response (PR) per IRC assessment at or prior to initiation of subsequent antineoplastic therapy. Assessment of response included physical examination, radiographic imaging, and evaluation of blood and marrow (if applicable), evaluated in accordance with the IWCLL 2008 criteria (Halleck et al). CR, CRi, nPR, and PR required confirmation with 2 consecutive assessments that were at least 56 days apart and no use of blood supportive product and/or growth factor during this period. Kaplan-Meier estimate.
Measured: Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018).
Primary Analysis: Overall Survival (OS) - Kaplan Meier Landmark Estimates at Month 30
OS, defined as the time from the date of randomization to the date of death from any cause. All deaths observed as the time of the analysis were considered as events. For participants who were not known to have died at the time of the analysis, OS data were censored at the date last known alive.
As the median OS was not reached in either treatment arm at the time of the analysis, Kaplan Meier landmark estimates of the OS rate (that is, the estimated percentage of participants still surviving at Month 30 [primary analysis]) are presented.
Measured: Month 30 (Median follow-up time was 31.3 months at the time of the primary analysis [data cutoff date: 26 March 2018]).
Primary Analysis: Rate of Grade ≥ 3 or Serious Infusion-Related Reaction (IRR) Adverse Events
Percentage of participants experiencing grade ≥ 3 (severe or life threatening) or serious IRR adverse events that started on the day of an obinutuzumab infusion and were assessed as related or possibly related to obinutuzumab. Categories included those events with the Medical Dictionary for Regulatory Activities (MedDRA) dictionary preferred term of IRR and those events which are among the customized standardized MedDRA query (SMQ) for IRR.
Measured: Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018).
Primary Analysis: Rate of Sustained Platelet Improvement
Percentage of participants with platelet counts increase ≥ 50% over baseline continuously for ≥ 56 days without blood transfusion or growth factors.
Measured: Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018).
Primary Analysis: Rate of Clinically Meaningful Improvement in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire EuroQol Five-Dimension (EQ-5D-5L)
Percentage of participants with EQ-5D-5L utility score increase ≥ 0.08 points over baseline at or prior to initiation of subsequent antineoplastic therapy. The EQ-5D-5L is a standardized non-disease specific instrument for describing and valuing health-related quality of life, comprising 5 dimensions of health (mobility, self -care, usual activities, pain/discomfort, and anxiety/depression) to describe the participant's current health state. Each dimension comprises 5 levels with corresponding numeric scores, where 1 indicates no problems, and 5 indicates extreme problems. A unique EQ-5D-5L health state is defined by combining the numeric level scores for each of the 5 dimensions and the total score is normalized from -0.594 to 1.000, with higher scores representing a better health state. An increase in the EQ-5D-5L total score indicates improvement. Participants with missing EQ-5D-5L data were considered not achieving clinically meaningful improvement.
Measured: Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018).
Final Analysis: PFS in High-Risk Population (del17p/TP53 Mutation/Del 11q/Unmutated Immunoglobulin Heavy Chain Variable Region [IGHV]) Based on Investigator Assessment - Kaplan Meier Landmark Estimates at Month 48
PFS was analyzed within the high-risk population of participants with del17p or TP53 mutation or del 11q or IGHV unmutated at baseline per central lab results. PFS was defined as time from the date randomization to the date of first investigator-confirmed PD or date of death due to any cause, whichever occurred first, regardless of the use of subsequent antineoplastic therapy prior to documented PD or death. Assessment of PD was conducted in accordance with the IWCLL 2008 criteria (Halleck et al) with the modification that treatment-related lymphocytosis in the absence of other signs or symptoms of PD was not considered progressive disease.
As the median PFS was not reached in the experimental (IBR+OB) arm at the time of the analysis, Kaplan Meier landmark estimates of the PFS rate at 48 months (that is, the estimated percentage of participants with progression-free survival at Month 48) are presented.
Measured: Month 48 (Median follow-up time was 44.6 months at the time of the final analysis [data cutoff date: 17 October 2019]).
Final Analysis: Rate of Sustained Hemoglobin Improvement
Percentage of participants with sustained hemoglobin improvement, defined as hemoglobin increase ≥ 2 g/dL over baseline continuously for ≥ 56 days without blood transfusions or growth factors.
Measured: Median follow-up time was 44.6 months at the time of the final analysis (data cutoff date: 17 October 2019).
Final Analysis: Rate of Minimal Residual Disease (MRD)-Negative Response
Percentage of participants who achieved MRD-negative response, defined as < 1 CLL cell per 10,000 leukocytes as assessed by flow cytometry of a bone marrow aspirate per central laboratory. MRD samples were collected before initiation of subsequent antineoplastic treatment and MRD status was reported by central lab within 5 days after collection date. Participants with missing MRD data were considered non-responders.
Measured: Median follow-up time was 44.6 months at the time of the final analysis (data cutoff date: 17 October 2019).
Final Analysis: ORR Based on Investigator Assessment
ORR, defined as the percentage of participants achieving a best overall response of protocol-specified CR, CRi, nPR or PR per investigator assessment at or prior to initiation of subsequent antineoplastic therapy. Assessment of response included physical examination, radiographic imaging, and evaluation of blood and marrow (if applicable), evaluated in accordance with the IWCLL 2008 criteria (Halleck et al). CR, CRi, nPR, and PR required confirmation with 2 consecutive assessments that were at least 56 days apart and no use of blood supportive product and/or growth factor during this period. Kaplan-Meier estimate.
Measured: Median follow-up time was 44.6 months at the time of the final analysis (data cutoff date: 17 October 2019).
Final Analysis: Overall Survival (OS) - Kaplan Meier Landmark Estimates at Month 48
OS, defined as the time from the date of randomization to the date of death from any cause. All deaths observed as the time of the analysis were considered as events. For participants who were not known to have died at the time of the analysis, OS data were censored at the date last known alive.
As the median OS was not reached in either treatment arm at the time of the analysis, Kaplan Meier point estimates of the OS rate (that is, the estimated percentage of participants still surviving at Month 48 [final analysis]) are presented.
Measured: Month 48 (Median follow-up time was 44.6 months at the time of the final analysis [data cutoff date: 17 October 2019]).
Final Analysis: Rate of Sustained Platelet Improvement
Percentage of participants with platelet counts increase ≥ 50% over baseline continuously for ≥ 56 days without blood transfusion or growth factors.
Measured: Median follow-up time was 44.6 months at the time of the final analysis (data cutoff date: 17 October 2019).
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Oct 2014 (estimated)
- Study start6 Oct 2014
- Primary completion26 Mar 2018
- Study completion3 Sep 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (6)Papers the sponsor has linked to this study.
- Other trials for Chronic Lymphocytic LeukemiaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 229 participants (actual)
Sponsor and investigators
- Lead sponsor
- Pharmacyclics LLC.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Lori Styles, Study director, Pharmacyclics LLC.
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02264574
- Sponsor's protocol ID
- PCYC-1130-CA
- Status last verified
- Aug 2020
- First submitted
- 1 Oct 2014
- Last updated
- 21 Sep 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- Individual data sharing
- Yes: Requests for access to individual participant data from clinical studies conducted by Pharmacyclics LLC, an AbbVie Company, can be submitted through Yale Open Data Access (YODA) Project site at the following link.
Publications
Moreno C, Greil R, Demirkan F, Tedeschi A, Anz B, Larratt L, Simkovic M, Samoilova O, Novak J, Ben-Yehuda D, Strugov V, Gill D, Gribben JG, Hsu E, Lih CJ, Zhou C, Clow F, James DF, Styles L, Flinn IW. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019 Jan;20(1):43-56. doi: 10.1016/S1470-2045(18)30788-5. Epub 2018 Dec 3.
PubMed 30522969Abuhelwa AY, Almansour SA, Brown JR, Al-Shamsi HO, Abuhelwa Z, Kharaba Z, Bustanji Y, Semreen MH, Ali S, Alhuraiji A, McKinnon RA, Sorich MJ, Alzoubi KH, Hopkins AM. Statin use and survival in CLL/SLL treated with ibrutinib: pooled analysis of 4 randomized controlled trials. Blood Adv. 2025 Jul 22;9(14):3566-3575. doi: 10.1182/bloodadvances.2024015287.
PubMed 40266025Moreno C, Greil R, Demirkan F, Tedeschi A, Anz B, Larratt L, Simkovic M, Novak J, Strugov V, Gill D, Gribben JG, Kwei K, Dai S, Hsu E, Dean JP, Flinn IW. First-line treatment of chronic lymphocytic leukemia with ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab: final analysis of the randomized, phase III iLLUMINATE trial. Haematologica. 2022 Sep 1;107(9):2108-2120. doi: 10.3324/haematol.2021.279012.
PubMed 35021599Burger JA, Robak T, Demirkan F, Bairey O, Moreno C, Simpson D, Munir T, Stevens DA, Dai S, Cheung LWK, Kwei K, Lal I, Hsu E, Kipps TJ, Tedeschi A. Up to 6.5 years (median 4 years) of follow-up of first-line ibrutinib in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma and high-risk genomic features: integrated analysis of two phase 3 studies. Leuk Lymphoma. 2022 Jun;63(6):1375-1386. doi: 10.1080/10428194.2021.2020779. Epub 2022 Jan 11.
PubMed 35014928Allan JN, Shanafelt T, Wiestner A, Moreno C, O'Brien SM, Li J, Krigsfeld G, Dean JP, Ahn IE. Long-term efficacy of first-line ibrutinib treatment for chronic lymphocytic leukaemia in patients with TP53 aberrations: a pooled analysis from four clinical trials. Br J Haematol. 2022 Feb;196(4):947-953. doi: 10.1111/bjh.17984. Epub 2021 Dec 5.
PubMed 34865212Greil R, Tedeschi A, Moreno C, Anz B, Larratt L, Simkovic M, Gill D, Gribben JG, Flinn IW, Wang Z, Cheung LWK, Nguyen AN, Zhou C, Styles L, Demirkan F. Pretreatment with ibrutinib reduces cytokine secretion and limits the risk of obinutuzumab-induced infusion-related reactions in patients with CLL: analysis from the iLLUMINATE study. Ann Hematol. 2021 Jul;100(7):1733-1742. doi: 10.1007/s00277-021-04536-6. Epub 2021 May 20.
PubMed 34018029
Study at a glance
From the registry record, last updated by the sponsor on 21 Sep 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomized, Multi-center, Open-label, Phase 3 Study of the Bruton's Tyrosine Kinase Inhibitor Ibrutinib in Combination With Obinutuzumab Versus Chlorambucil in Combination With Obinutuzumab in Subjects With Treatment-naïve Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
- ClinicalTrials.gov ID
- NCT02264574
- Acronym / sponsor ID
- PCYC-1130-CA
- Conditions
- Chronic Lymphocytic Leukemia, Small-Cell Lymphoma
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 229 participants (actual)
- Lead sponsor
- Pharmacyclics LLC.Industry (pharma, biotech, devices)
- Study start
- 6 Oct 2014 (actual)
- Primary completion
- 26 Mar 2018 (actual)
- Study completion
- 3 Sep 2019 (actual)
- First posted
- 15 Oct 2014 (estimated)
- Results
- Posted 16 Apr 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The primary objective of this study is to evaluate the efficacy of ibrutinib in combination with obinutuzumab compared to chlorambucil in combination with obinutuzumab based on the Independent Review Committee (IRC) assessment of progression free survival (PFS). Efficacy will be evaluated according to 2008 International Workshop for Chronic Lymphocytic Leukemia (IWCLL) criteria with the modification for treatment-related lymphocytosis, in subjects with treatment-naive CLL or SLL.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| IBR + OB | Experimental | Drug: Ibrutinib, Drug: ObinutuzumabIbrutinib (IBR) given orally at a dose of 420 mg/day until progressive disease or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until progressive disease or unacceptable toxicity. |
| CLB + OB | Experimental | Drug: Obinutuzumab, Drug: ChlorambucilChlorambucil (CLB) given orally at a dose of 0.5 mg/kg body weight up to a total of 6 cycles on Days 1 and 15 of each cycle or until disease progression or unacceptable toxicity. Intravenous obinutuzumab given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until disease progression or unacceptable toxicity. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (25 listed)
- Diagnosis of CLL/SLL that meets IWCLL diagnostic criteria.
- Age 65 yrs and older OR if less than 65 years, must have at least one of the following criteria:
- Active disease meeting at least 1 of the following IWCLL criteria for requiring treatment:
- Measurable nodal disease by computed tomography (CT), defined as at least 1 lymph node >1.5 cm in the longest diameter in a site that has not been previously irradiated. An irradiated lesion may be assessed for measurable disease only if there has been documented progression in that lesion since radiotherapy has ended.
- Laboratory
Key exclusion criteria (22 listed)
- Any prior treatment of CLL or SLL
- Evidence of central nervous system (CNS) involvement with primary disease of CLL/SLL
- History of other malignancies, except:
- Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura
- Known or suspected history of Richter's transformation.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| IbrutinibIbrutinib will be supplied as 140 mg hard gelatin capsules for oral (PO) administration. | Drug | IBR + OB |
| ObinutuzumabObinutuzumab will be supplied as 1000 mg/40 mL solution in a single-use vial for intravenous (IV) administration | Drug | CLB + OB, IBR + OB |
| ChlorambucilChlorambucil will be supplied as 2 mg film-coated tablets for oral (PO) administration | Drug | CLB + OB |
Primary outcome
Primary Analysis: Progression Free Survival (PFS) Based on Independent Review Committee (IRC) Assessment - Kaplan Meier Landmark Estimates at Month 30
Time frame: Month 30 (Median follow-up time was 31.3 months at the time of the primary analysis [data cutoff date: 26 March 2018]).
PFS was defined as time from the date randomization to the date of first IRC-confirmed disease progression (PD) or date of death due to any cause, whichever occurred first, regardless of the use of subsequent antineoplastic therapy prior to documented PD or death. Assessment of PD was conducted in accordance with the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria (Halleck et al) with the modification that treatment-related lymphocytosis in the absence of other signs or symptoms of disease progression was not considered progressive disease. The primary analysis was performed after observing 94 PFS events as pre-specified in the study protocol. As the median PFS was not reached in the experimental (IBR+OB) arm at the time of the analysis, Kaplan Meier landmark estimates of the PFS rate at 30 months (that is, the estimated percentage of participants with progression-free survival at Month 30) are presented.
Final Analysis: PFS Based on Investigator Assessment - Kaplan Meier Landmark Estimates at Month 48
Time frame: Month 48 (Median follow-up time was 44.6 months at the time of the final analysis [data cutoff date: 17 October 2019]).
PFS was defined as time from the date randomization to the date of first investigator-confirmed PD or date of death due to any cause, whichever occurred first, regardless of the use of subsequent antineoplastic therapy prior to documented PD or death. Assessment of PD was conducted in accordance with the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria (Halleck et al) with the modification that treatment-related lymphocytosis in the absence of other signs or symptoms of disease progression was not considered progressive disease. As the median PFS was not reached in the experimental (IBR+OB) arm at the time of the analysis, Kaplan Meier landmark estimates of the PFS rate at 48 months (that is, the estimated percentage of participants with progression-free survival at Month 48) are presented.
14 secondary outcomes
Primary Analysis: PFS in High-Risk Sub-Population (del17p/TP53 Mutation/Del 11q) Based on IRC Assessment - Kaplan Meier Landmark Estimates at Month 30
Time frame: Month 30 (Median follow-up time was 31.3 months at the time of the primary analysis [data cutoff date: 26 March 2018]).
Primary Analysis: Rate of Sustained Hemoglobin Improvement
Time frame: Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018).
Primary Analysis: Rate of Minimal Residual Disease (MRD)-Negative Response
Time frame: Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018).
Primary Analysis: Overall Response Rate (ORR) Based on IRC Assessment
Time frame: Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018).
Primary Analysis: Overall Survival (OS) - Kaplan Meier Landmark Estimates at Month 30
Time frame: Month 30 (Median follow-up time was 31.3 months at the time of the primary analysis [data cutoff date: 26 March 2018]).
Primary Analysis: Rate of Grade ≥ 3 or Serious Infusion-Related Reaction (IRR) Adverse Events
Time frame: Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018).
Primary Analysis: Rate of Sustained Platelet Improvement
Time frame: Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018).
Primary Analysis: Rate of Clinically Meaningful Improvement in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire EuroQol Five-Dimension (EQ-5D-5L)
Time frame: Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018).
Final Analysis: PFS in High-Risk Population (del17p/TP53 Mutation/Del 11q/Unmutated Immunoglobulin Heavy Chain Variable Region [IGHV]) Based on Investigator Assessment - Kaplan Meier Landmark Estimates at Month 48
Time frame: Month 48 (Median follow-up time was 44.6 months at the time of the final analysis [data cutoff date: 17 October 2019]).
Final Analysis: Rate of Sustained Hemoglobin Improvement
Time frame: Median follow-up time was 44.6 months at the time of the final analysis (data cutoff date: 17 October 2019).
Final Analysis: Rate of Minimal Residual Disease (MRD)-Negative Response
Time frame: Median follow-up time was 44.6 months at the time of the final analysis (data cutoff date: 17 October 2019).
Final Analysis: ORR Based on Investigator Assessment
Time frame: Median follow-up time was 44.6 months at the time of the final analysis (data cutoff date: 17 October 2019).
Final Analysis: Overall Survival (OS) - Kaplan Meier Landmark Estimates at Month 48
Time frame: Month 48 (Median follow-up time was 44.6 months at the time of the final analysis [data cutoff date: 17 October 2019]).
Final Analysis: Rate of Sustained Platelet Improvement
Time frame: Median follow-up time was 44.6 months at the time of the final analysis (data cutoff date: 17 October 2019).
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Sep 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 30522969Moreno C, Greil R, Demirkan F, Tedeschi A, Anz B, Larratt L, Simkovic M, Samoilova O, Novak J, Ben-Yehuda D, Strugov V, Gill D, Gribben JG, Hsu E, Lih CJ, Zhou C, Clow F, James DF, Styles L, Flinn IW. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019 Jan;20(1):43-56. doi: 10.1016/S1470-2045(18)30788-5. Epub 2018 Dec 3.
- Derived from this study: PubMed 40266025Abuhelwa AY, Almansour SA, Brown JR, Al-Shamsi HO, Abuhelwa Z, Kharaba Z, Bustanji Y, Semreen MH, Ali S, Alhuraiji A, McKinnon RA, Sorich MJ, Alzoubi KH, Hopkins AM. Statin use and survival in CLL/SLL treated with ibrutinib: pooled analysis of 4 randomized controlled trials. Blood Adv. 2025 Jul 22;9(14):3566-3575. doi: 10.1182/bloodadvances.2024015287.
- Derived from this study: PubMed 35021599Moreno C, Greil R, Demirkan F, Tedeschi A, Anz B, Larratt L, Simkovic M, Novak J, Strugov V, Gill D, Gribben JG, Kwei K, Dai S, Hsu E, Dean JP, Flinn IW. First-line treatment of chronic lymphocytic leukemia with ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab: final analysis of the randomized, phase III iLLUMINATE trial. Haematologica. 2022 Sep 1;107(9):2108-2120. doi: 10.3324/haematol.2021.279012.
- Derived from this study: PubMed 35014928Burger JA, Robak T, Demirkan F, Bairey O, Moreno C, Simpson D, Munir T, Stevens DA, Dai S, Cheung LWK, Kwei K, Lal I, Hsu E, Kipps TJ, Tedeschi A. Up to 6.5 years (median 4 years) of follow-up of first-line ibrutinib in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma and high-risk genomic features: integrated analysis of two phase 3 studies. Leuk Lymphoma. 2022 Jun;63(6):1375-1386. doi: 10.1080/10428194.2021.2020779. Epub 2022 Jan 11.
- Derived from this study: PubMed 34865212Allan JN, Shanafelt T, Wiestner A, Moreno C, O'Brien SM, Li J, Krigsfeld G, Dean JP, Ahn IE. Long-term efficacy of first-line ibrutinib treatment for chronic lymphocytic leukaemia in patients with TP53 aberrations: a pooled analysis from four clinical trials. Br J Haematol. 2022 Feb;196(4):947-953. doi: 10.1111/bjh.17984. Epub 2021 Dec 5.
- Derived from this study: PubMed 34018029Greil R, Tedeschi A, Moreno C, Anz B, Larratt L, Simkovic M, Gill D, Gribben JG, Flinn IW, Wang Z, Cheung LWK, Nguyen AN, Zhou C, Styles L, Demirkan F. Pretreatment with ibrutinib reduces cytokine secretion and limits the risk of obinutuzumab-induced infusion-related reactions in patients with CLL: analysis from the iLLUMINATE study. Ann Hematol. 2021 Jul;100(7):1733-1742. doi: 10.1007/s00277-021-04536-6. Epub 2021 May 20.
- Individual participant dataSharing planned: Yes. Requests for access to individual participant data from clinical studies conducted by Pharmacyclics LLC, an AbbVie Company, can be submitted through Yale Open Data Access (YODA) Project site at the following link.
Related trials for Chronic Lymphocytic Leukemia
RecruitingPhase 2
Tafasitamab With Acalabrutinib and Venetoclax for the Treatment of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Chronic Lymphocytic Leukemia, Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Active, not recruitingPhase 2
Clofarabine and Melphalan Before Donor Stem Cell Transplant in Treating Patients With Myelodysplasia, Acute Leukemia in Remission, or Chronic Myelomonocytic Leukemia
Adult Acute Lymphoblastic Leukemia in Remission, Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
Not yet recruitingPhase 2
Nemtabrutinib for Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Leukemia (SLL) Refractory to Covalent Bruton Tyrosine Kinase Inhibitor or Pirtobrutinib and Previously Treated With a BCL2 Inhibitor
Chronic Lymphocytic Leukemia, Small Lymphocytic Leukemia
RecruitingObservational study
Natural History Study of Monoclonal B Cell Lymphocytosis (MBL), Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL), Lymphoplasmacytic Lymphoma (LPL)/Waldenstrom Macroglobulinemia (WM), and Splenic Marginal Zone Lymphoma (SMZL)
Waldenstrom Macroglobulinemia, Lymphoplasmacytic Lymphoma
RecruitingPhase 3
A Study of Nemtabrutinib Plus Venetoclax vs Venetoclax + Rituximab (VR) in Second-line (2L) + Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) (MK-1026-010/BELLWAVE-010).
Leukemia, Lymphocytic, Chronic, B-Cell, Leukemia, Chronic Lymphocytic
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Lori Styles study director
Pharmacyclics LLC.
71 sites in 16 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Ibrutinib, Obinutuzumab and Chlorambucil in people with Chronic Lymphocytic Leukemia and Small-Cell Lymphoma, run by Pharmacyclics LLC. at 71 sites in 16 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 25 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 21 Sep 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 71 sites in Spain, United States, Italy, Australia, Israel and 11 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 16 Apr 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Primary Analysis: Progression Free Survival (PFS) Based on Independent Review Committee (IRC) Assessment - Kaplan Meier Landmark Estimates at Month 30 (time frame: Month 30 (Median follow-up time was 31.3 months at the time of the primary analysis [data cutoff date: 26 March 2018]).). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02264574, which also lists 6 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Sep 2020.