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)

NCT02264574 | Completed Phase 3 Results DMC FDA Drug

• 1 other identifier: PCYC-1130-CA
• Study Type: interventional
• Target: 229
• Locations: 15 countries
• Sites: 65

Brief 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). 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

Outcome Measures

Primary Outcomes (2)

• 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.

  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.

  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

  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

  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

  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

  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

  Month 30 (Median follow-up time was 31.3 months at the time of the primary analysis [data cutoff date: 26 March 2018]).

Study Arms (2)

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.

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.

Drug: Obinutuzumab; Drug: Chlorambucil

Interventions

Ibrutinib DRUG

Ibrutinib will be supplied as 140 mg hard gelatin capsules for oral (PO) administration.

IBR + OB

Obinutuzumab DRUG

Obinutuzumab will be supplied as 1000 mg/40 mL solution in a single-use vial for intravenous (IV) administration

CLB + OB; IBR + OB

Chlorambucil DRUG

Chlorambucil will be supplied as 2 mg film-coated tablets for oral (PO) administration

CLB + OB

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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:

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Pharmacyclics LLC.: lead

Study Sites (71)

Site Reference ID/Investigator# 0241

La Jolla, California, United States

Location

Site Reference ID/Investigator# 0844

Fort Myers, Florida, United States

Location

Site Reference ID/Investigator# 0763

West Palm Beach, Florida, United States

Location

Site Reference ID/Investigator# 071

Louisville, Kentucky, United States

Location

Site Reference ID/Investigator# 0712

Las Vegas, Nevada, United States

Location

Site Reference ID/Investigator# 0845

Cincinnati, Ohio, United States

Location

Site Reference ID/Investigator# 0868

Chattanooga, Tennessee, United States

Location

Site Reference ID/Investigator# 0123

Nashville, Tennessee, United States

Location

Site Reference ID/Investigator #0503

Woolloongabba, Queensland, Australia

Location

Site Reference ID/Investigator# 0650

Adelaide, South Australia, Australia

Location

Site Reference ID/Investigator# 0888

Ballarat, Victoria, Australia

Location

Site Reference ID/Investigator# 0193

Box Hill, Victoria, Australia

Location

Site Reference ID/Investigator# 0633

Fitzroy, Victoria, Australia

Location

Site Reference ID/Investigator# 0170

Heidelberg, Victoria, Australia

Location

Site Reference ID/Investigator# 0352

Linz, Austria

Location

Site Reference ID/Investigator# 0869

Salzburg, Austria

Location

Site Reference ID/Investigator# 0559

Leuven, Belgium

Location

Site Reference ID/Investigator# 0850

Turnhout, Belgium

Location

Site Reference ID/Investigator# 018

Edmonton, Alberta, Canada

Location

Site Reference ID/Investigator# 0564

Hradec Králové, Czechia

Location

Site Reference ID/Investigator# 0854

Prague, Czechia

Location

Site Reference ID/Investigator# 0769

Pessac, Gironde, France

Location

Site Reference ID/Investigator# 0520

Nantes, Loire Atlantique, France

Location

Site Reference ID/Investigator# 0775

Vandœuvre-lès-Nancy, Meurthe Et Moselle, France

Location

Site Reference ID/Investigator# 0855

Bayonne, Pyrenees Atlantiques, France

Location

Site Reference ID/Investigator# 0573

Haifa, Israel

Location

Site Reference ID/Investigator# 0577

Jerusalem, Israel

Location

Site Reference ID/Investigator# 0579

Jerusalem, Israel

Location

Site Reference ID/Investigator# 0575

Petah Tikva, Israel

Location

Site Reference ID/Investigator# 0856

Tel Aviv, Israel

Location

Site Reference ID/Investigator# 0875

Ẕerifin, Israel

Location

Site Reference ID/Investigator# 0860

Florence, Italy

Location

Site Reference ID/Investigator# 0523

Milan, Italy

Location

Site Reference ID/Investigator# 0581

Milan, Italy

Location

Site Reference ID/Investigator# 0584

Milan, Italy

Location

Site Reference ID/Investigator# 0524

Modena, Italy

Location

Site Reference ID/Investigator# 0582

Novara, Italy

Location

Site Reference ID/Investigator# 0732

Roma, Italy

Location

Site Reference ID/Investigator# 0859

Siena, Italy

Location

Site Reference ID/Investigator# 0663

Auckland, New Zealand

Location

Site Reference ID/Investigator# 662

Auckland, New Zealand

Location

Site Reference ID/Investigator# 0586

Hamilton, New Zealand

Location

Site Reference ID/Investigator# 0592

Brzozów, Poland

Location

Site Reference ID/Investigator# 0531

Lodz, Poland

Location

Site Reference ID/Investigator# 0708

Nizhny Novgorod, Russia

Location

Site Reference ID/Investigator# 0707

Ryazan, Russia

Location

Site Reference ID/Investigator# 0881

Saint Petersburg, Russia

Location

Site Reference ID/Investigator# 710

Saint Petersburg, Russia

Location

Site Reference ID/Investigator# 304

Yaroslavl, Russia

Location

Site Reference ID/Investigator# 0604

L'Hospitalet de Llobregat, Madrid, Spain

Location

Site Reference ID/Investigator# 0536

Majadahonda, Madrid, Spain

Location

Site Reference ID/Investigator# 0533

Barcelona, Spain

Location

Site Reference ID/Investigator# 0534

Barcelona, Spain

Location

Site Reference ID/Investigator# 0535

Barcelona, Spain

Location

Site Reference ID/Investigator# 0537

Madrid, Spain

Location

Site Reference ID/Investigator# 0864

Madrid, Spain

Location

Site Reference ID/Investigator# 0874

Madrid, Spain

Location

Site Reference ID/Investigator# 0790

Salamanca, Spain

Location

Site Reference ID/Investigator# 0870

Borås, Sweden

Location

Site Reference ID/Investigator# 0865

Luleå, Sweden

Location

Site Reference ID/Investigator# 0631

Lund, Sweden

Location

Site Reference ID/Investigator# 0632

Stockholm, Sweden

Location

Site Reference ID/Investigator# 0678

Istanbul, Nisantasi, Turkey (Türkiye)

Location

Site Reference ID/Investigator# 0608

Ankara, Turkey (Türkiye)

Location

Site Reference ID/Investigator# 606

Ankara, Turkey (Türkiye)

Location

Site Reference ID/Investigator# 0889

Denizli, Turkey (Türkiye)

Location

Site Reference ID/Investigator# 0601

Izmir, Turkey (Türkiye)

Location

Site Reference ID/Investigator# 0866

Samsun, Turkey (Türkiye)

Location

Site Reference ID/Investigator# 0867

Harlow, Essex, United Kingdom

Location

Site Reference ID/Investigator# 0365

London, United Kingdom

Location

Site Reference ID/Investigator# 0543

London, United Kingdom

Location

Related Publications (6)

• 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.

  PMID: 30522969 RESULT

• Abuhelwa 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.

  PMID: 40266025 DERIVED

• Moreno 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.

  PMID: 35021599 DERIVED

• Burger 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.

  PMID: 35014928 DERIVED

• Allan 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.

  PMID: 34865212 DERIVED

• Greil 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.

  PMID: 34018029 DERIVED

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

ibrutinib; obinutuzumab; Chlorambucil

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals

Results Point of Contact

• Title: Lori Styles
• Organization: Pharmacyclics LLC, An AbbVie Company

lstyles@pcyc.com

(408) 215-3770

Study Officials

• Lori Styles

  Pharmacyclics LLC.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 1, 2014
• First Posted: October 15, 2014
• Study Start: October 6, 2014
• Primary Completion: March 26, 2018
• Study Completion: September 3, 2019
• Last Updated: September 21, 2020
• Results First Posted: April 16, 2019

Record last verified: 2020-08

Data Sharing

• IPD Sharing: Will share

Locations

RU (5); PL (2); IL (6); BE (2); US (8); ES (9); GB (3); SE (4); CZ (2); IT (8); CA (1); TU (6); AU (2); FR (4); NZ (3)