Clinical trial NCT02264574: 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)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Chronic Lymphocytic Leukemia
Small-Cell Lymphoma
Lead sponsor: Pharmacyclics LLC.
Sponsor class: INDUSTRY
First posted: 2014-10-15
Enrollment: 229
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

Disease Related:

1. Diagnosis of CLL/SLL that meets IWCLL diagnostic criteria.
2. 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
3. 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.
4. 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
5. Adequate hematologic function independent of transfusion and growth factor support for at least 7 days prior to screening and randomization.
6. Adequate hepatic and renal function
7. Men and women ≥ 18 years of age.
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

Exclusion Criteria:

1. Any prior treatment of CLL or SLL
2. Evidence of central nervous system (CNS) involvement with primary disease of CLL/SLL
3. 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.
4. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura
5. Known or suspected history of Richter's transformation.
6. Concurrent administration of \>20mg/day of prednisone within 7 days of randomization unless indicated for prophylaxis or management of allergic reactions (eg, contrast)
7. Known hypersensitivity to one or more study drugs
8. Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
9. Any uncontrolled active systemic infection or an infection requiring systemic treatment that was completed ≤ 7 days before randomization.
10. Known bleeding disorders or hemophilia.
11. History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
12. Known history of human immunodeficiency virus (HIV) or active with hepatitis B virus (HBV) or hepatitis C virus (HCV).
13. Major surgery within 4 weeks of randomization.
14. 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.
15. 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.
16. 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.
17. Concomitant use of warfarin or other vitamin K antagonists.
18. Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor.
19. Lactating or pregnant
20. Unwilling or unable to participate in all required study evaluations and procedures.
21. 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).

Primary outcomes:
measure: Primary Analysis: Progression Free Survival (PFS) Based on Independent Review Committee (IRC) Assessment - Kaplan Meier Landmark Estimates at Month 30
timeFrame: Month 30 (Median follow-up time was 31.3 months at the time of the primary analysis [data cutoff date: 26 March 2018]).
measure: Final Analysis: PFS Based on Investigator Assessment - Kaplan Meier Landmark Estimates at Month 48
timeFrame: 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:
measure: Primary Analysis: PFS in High-Risk Sub-Population (del17p/TP53 Mutation/Del 11q) Based on IRC Assessment - Kaplan Meier Landmark Estimates at Month 30
timeFrame: Month 30 (Median follow-up time was 31.3 months at the time of the primary analysis [data cutoff date: 26 March 2018]).
measure: Primary Analysis: Rate of Sustained Hemoglobin Improvement
timeFrame: Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018).
measure: Primary Analysis: Rate of Minimal Residual Disease (MRD)-Negative Response
timeFrame: Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018).
measure: Primary Analysis: Overall Response Rate (ORR) Based on IRC Assessment
timeFrame: Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018).
measure: Primary Analysis: Overall Survival (OS) - Kaplan Meier Landmark Estimates at Month 30
timeFrame: Month 30 (Median follow-up time was 31.3 months at the time of the primary analysis [data cutoff date: 26 March 2018]).
measure: Primary Analysis: Rate of Grade ≥ 3 or Serious Infusion-Related Reaction (IRR) Adverse Events
timeFrame: Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018).
measure: Primary Analysis: Rate of Sustained Platelet Improvement
timeFrame: Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018).
measure: 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)
timeFrame: Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018).
measure: 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
timeFrame: Month 48 (Median follow-up time was 44.6 months at the time of the final analysis [data cutoff date: 17 October 2019]).
measure: Final Analysis: Rate of Sustained Hemoglobin Improvement
timeFrame: Median follow-up time was 44.6 months at the time of the final analysis (data cutoff date: 17 October 2019).
measure: Final Analysis: Rate of Minimal Residual Disease (MRD)-Negative Response
timeFrame: Median follow-up time was 44.6 months at the time of the final analysis (data cutoff date: 17 October 2019).
measure: Final Analysis: ORR Based on Investigator Assessment
timeFrame: Median follow-up time was 44.6 months at the time of the final analysis (data cutoff date: 17 October 2019).
measure: Final Analysis: Overall Survival (OS) - Kaplan Meier Landmark Estimates at Month 48
timeFrame: Month 48 (Median follow-up time was 44.6 months at the time of the final analysis [data cutoff date: 17 October 2019]).
measure: Final Analysis: Rate of Sustained Platelet Improvement
timeFrame: Median follow-up time was 44.6 months at the time of the final analysis (data cutoff date: 17 October 2019).
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: Site Reference ID/Investigator# 0241
state: California
city: Fort Myers
country: United States
facility: Site Reference ID/Investigator# 0844
state: Florida
city: West Palm Beach
country: United States
facility: Site Reference ID/Investigator# 0763
state: Florida
city: Louisville
country: United States
facility: Site Reference ID/Investigator# 071
state: Kentucky
city: Las Vegas
country: United States
facility: Site Reference ID/Investigator# 0712
state: Nevada
city: Cincinnati
country: United States
facility: Site Reference ID/Investigator# 0845
state: Ohio
city: Chattanooga
country: United States
facility: Site Reference ID/Investigator# 0868
state: Tennessee
city: Nashville
country: United States
facility: Site Reference ID/Investigator# 0123
state: Tennessee
city: Woolloongabba
country: Australia
facility: Site Reference ID/Investigator #0503
state: Queensland
city: Adelaide
country: Australia
facility: Site Reference ID/Investigator# 0650
state: South Australia
city: Ballarat
country: Australia
facility: Site Reference ID/Investigator# 0888
state: Victoria
city: Box Hill
country: Australia
facility: Site Reference ID/Investigator# 0193
state: Victoria
city: Fitzroy
country: Australia
facility: Site Reference ID/Investigator# 0633
state: Victoria
city: Heidelberg
country: Australia
facility: Site Reference ID/Investigator# 0170
state: Victoria
city: Linz
country: Austria
facility: Site Reference ID/Investigator# 0352
city: Salzburg
country: Austria
facility: Site Reference ID/Investigator# 0869
city: Leuven
country: Belgium
facility: Site Reference ID/Investigator# 0559
city: Turnhout
country: Belgium
facility: Site Reference ID/Investigator# 0850
city: Edmonton
country: Canada
facility: Site Reference ID/Investigator# 018
state: Alberta
city: Hradec Kralove
country: Czechia
facility: Site Reference ID/Investigator# 0564
city: Praha 10
country: Czechia
facility: Site Reference ID/Investigator# 0854
city: Pessac cedex
country: France
facility: Site Reference ID/Investigator# 0769
state: Gironde
city: Nantes cedex 1
country: France
facility: Site Reference ID/Investigator# 0520
state: Loire Atlantique
city: Vandoeuvre les Nancy
country: France
facility: Site Reference ID/Investigator# 0775
state: Meurthe Et Moselle
city: Bayonne
country: France
facility: Site Reference ID/Investigator# 0855
state: Pyrenees Atlantiques
city: Haifa
country: Israel
facility: Site Reference ID/Investigator# 0573
city: Jerusalem
country: Israel
facility: Site Reference ID/Investigator# 0577
city: Jerusalem
country: Israel
facility: Site Reference ID/Investigator# 0579
city: Petach Tikva
country: Israel
facility: Site Reference ID/Investigator# 0575
city: Tel Aviv
country: Israel
facility: Site Reference ID/Investigator# 0856
city: Zerifin
country: Israel
facility: Site Reference ID/Investigator# 0875
city: Firenze
country: Italy
facility: Site Reference ID/Investigator# 0860
city: Milano
country: Italy
facility: Site Reference ID/Investigator# 0523
city: Milano
country: Italy
facility: Site Reference ID/Investigator# 0581
city: Milano
country: Italy
facility: Site Reference ID/Investigator# 0584
city: Modena
country: Italy
facility: Site Reference ID/Investigator# 0524
city: Novara
country: Italy
facility: Site Reference ID/Investigator# 0582
city: Roma
country: Italy
facility: Site Reference ID/Investigator# 0732
city: Siena
country: Italy
facility: Site Reference ID/Investigator# 0859
city: Auckland
country: New Zealand
facility: Site Reference ID/Investigator# 0663
city: Auckland
country: New Zealand
facility: Site Reference ID/Investigator# 662
city: Hamilton
country: New Zealand
facility: Site Reference ID/Investigator# 0586
city: Brzozow
country: Poland
facility: Site Reference ID/Investigator# 0592
city: Lodz
country: Poland
facility: Site Reference ID/Investigator# 0531
city: Nizhniy Novgorod
country: Russian Federation
facility: Site Reference ID/Investigator# 0708
city: Ryazan
country: Russian Federation
facility: Site Reference ID/Investigator# 0707
city: Saint-Petersburg
country: Russian Federation
facility: Site Reference ID/Investigator# 0881
city: St. Petersburg
country: Russian Federation
facility: Site Reference ID/Investigator# 710
city: Yaroslavl
country: Russian Federation
facility: Site Reference ID/Investigator# 304
city: L'Hospitalet de Llobregat
country: Spain
facility: Site Reference ID/Investigator# 0604
state: Madrid
city: Majadahonda
country: Spain
facility: Site Reference ID/Investigator# 0536
state: Madrid
city: Barcelona
country: Spain
facility: Site Reference ID/Investigator# 0533
city: Barcelona
country: Spain
facility: Site Reference ID/Investigator# 0534
city: Barcelona
country: Spain
facility: Site Reference ID/Investigator# 0535
city: Madrid
country: Spain
facility: Site Reference ID/Investigator# 0537
city: Madrid
country: Spain
facility: Site Reference ID/Investigator# 0864
city: Madrid
country: Spain
facility: Site Reference ID/Investigator# 0874
city: Salamanca
country: Spain
facility: Site Reference ID/Investigator# 0790
city: Borås
country: Sweden
facility: Site Reference ID/Investigator# 0870
city: Luleå
country: Sweden
facility: Site Reference ID/Investigator# 0865
city: Lund
country: Sweden
facility: Site Reference ID/Investigator# 0631
city: Stockholm
country: Sweden
facility: Site Reference ID/Investigator# 0632
city: Istanbul
country: Turkey
facility: Site Reference ID/Investigator# 0678
state: Nisantasi
city: Ankara
country: Turkey
facility: Site Reference ID/Investigator# 0608
city: Ankara
country: Turkey
facility: Site Reference ID/Investigator# 606
city: Denizli
country: Turkey
facility: Site Reference ID/Investigator# 0889
city: Izmir
country: Turkey
facility: Site Reference ID/Investigator# 0601
city: Samsun
country: Turkey
facility: Site Reference ID/Investigator# 0866
city: Harlow
country: United Kingdom
facility: Site Reference ID/Investigator# 0867
state: Essex
city: London
country: United Kingdom
facility: Site Reference ID/Investigator# 0365
city: London
country: United Kingdom
facility: Site Reference ID/Investigator# 0543
Study officials:
affiliation: Pharmacyclics LLC.
name: Lori Styles
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.