Open-label Phase 3 BTK Inhibitor Ibrutinib vs Chlorambucil Patients 65 Years or Older With Treatment-naive CLL or SLL

Randomized, Multicenter, Open-label, Phase 3 Study of the Bruton's Tyrosine Kinase Inhibitor Ibrutinib Versus Chlorambucil in Patients 65 Years or Older With Treatment-naive Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

A Randomized, Multicenter, Open-label, Phase 3 Study of the Bruton's Tyrosine Kinase Inhibitor PCI-32765 versus Chlorambucil in Patients 65 Years or Older with Treatment-naive Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma.

Study Overview

• Status: Completed
• Conditions: Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma
• Intervention / Treatment: Drug: Ibrutinib; Drug: Chlorambucil

Detailed Description

Study design: This is a randomized, multicenter, open-label, Phase 3 study designed to compare the safety and efficacy of Ibrutinib versus Chlorambucil in treatment-naive patients 65 years or older who have CLL or SLL.

Eligible patients will be randomized in a 1:1 ratio to Treatment Arm A or B:

• Treatment Arm A: Oral Chlorambucil 0.5 mg/kg on Days 1 and 15 of each 28-day cycle; the dose can be increased, if well tolerated, in increments of 0.1 mg/kg on Day 1 of each cycle to a maximum of 0.8 mg/kg; patients receive a minimum of 3 and a maximum of 12 cycles, in the absence of progressive disease or unacceptable toxicity.
• Treatment Arm B: Oral Ibrutinib 420 mg/day Randomization will be stratified on Eastern Cooperative Oncology Group (ECOG) performance status (0,1 versus 2); presence of advanced Rai stage (yes/no), advanced being defined as Stages 3-4; and geographic region: US versus non-US.

• Study Type: Interventional
• Enrollment (Actual): 269
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Kogarah, New South Wales, Australia, 2217
      • Site Reference ID/Investigator #654
  • Queensland
    • Woolloongabba, Queensland, Australia, 4102
      • Site Reference ID/Investigator #503
  • South Australia
    • Bedford Park, South Australia, Australia, 5042
      • Site Reference ID/Investigator #163
  • Tasmania
    • Hobart, Tasmania, Australia, 7000
      • Site Reference ID/Investigator #555
  • Victoria
    • Box Hill, Victoria, Australia, 3128
      • Site Reference ID/Investigator #193
    • Clayton, Victoria, Australia, 3168
      • Site Reference ID/Investigator #556
    • Fitzroy, Victoria, Australia, 3065
      • Site Reference ID/Investigator #501
    • Frankston, Victoria, Australia, 3199
      • Site Reference ID/Investigator #715
    • Geelong, Victoria, Australia, 3220
      • Site Reference ID/Investigator #558
    • Heidelberg, Victoria, Australia, 3084
      • Site Reference ID/Investigator #170
• Belgium
  • Antwerpen, Belgium, 2060
    • Site Reference ID/Investigator #561
  • Brussells, Belgium, 1000
    • Site Reference ID/Investigator #184
  • Brussells
    • Bruxelles, Brussells, Belgium, 1200
      • Site Reference ID/Investigator #164
  • Namur
    • Yvoir, Namur, Belgium, 5530
      • Site Reference ID/Investigator #727
  • Oost-Vlaanderen
    • Gent, Oost-Vlaanderen, Belgium, 9000
      • Site Reference ID/Investigator #560
  • Vlaams Brabant
    • Leuven, Vlaams Brabant, Belgium, 3000
      • Site Reference ID/Investigator #559
  • West-Vlaanderen
    • Brugge, West-Vlaanderen, Belgium, 8000
      • Site Reference ID/Investigator #628
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • Site Reference ID/Investigator #157
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Site Reference ID/Investigator #018
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L6
      • Site Reference ID/Investigator #159
• China
  • Beijing, China, 100142
    • Site Reference ID/Investigator #670
  • Beijing, China, 100191
    • Site Reference ID/Investigator #673
  • Guangdong
    • Guangzhou, Guangdong, China, 510060
      • Site Reference ID/Investigator #674
  • Jiangsu
    • Nanjing, Jiangsu, China, 210029
      • Site Reference ID/Investigator #671
  • Zhejiang
    • Hangzhou, Zhejiang, China, 31003
      • Site Reference ID/Investigator #675
• Czechia
  • Brno, Czechia, 625 00
    • Site Reference ID/Investigator #562
  • Plzen-Lochotin, Czechia, 304 60
    • Site Reference ID/Investigator #566
  • Kralovehradecky Kraj
    • Hradec Kralove, Kralovehradecky Kraj, Czechia, 500 05
      • Site Reference ID/Investigator #564
• Ireland
  • Dublin, Ireland, 7
    • Site Reference ID/Investigator #572
  • Dublin, Ireland, 8
    • Site Reference ID/Investigator #570
  • Galway, Ireland, ST4 6QG
    • Site Reference ID/Investigator #571
• Israel
  • Haifa, Israel, 31048
    • Site Reference ID/Investigator #573
  • Haifa, Israel, 31096
    • Site Reference ID/Investigator #576
  • Jerusalem, Israel, 91031
    • Site Reference ID/Investigator #577
  • Nahariya, Israel, 22100
    • Site Reference ID/Investigator #578
  • Petaẖ Tiqwa, Israel, 49100
    • Site Reference ID/Investigator #575
  • Ramat Gan, Israel, 52621
    • Site Reference ID/Investigator #574
• Italy
  • Bologna, Italy, 40138
    • Site Reference ID/Investigator #580
  • Milano, Italy, 20122
    • Site Reference ID/Investigator #584
  • Milano, Italy, 20132
    • Site Reference ID/Investigator #523
  • Milano, Italy, 20162
    • Site Reference ID/Investigator #581
  • Modena, Italy, 41100
    • Site Reference ID/Investigator #524
  • Lazio
    • Roma, Lazio, Italy, 00161
      • Site Reference ID/Investigator #583
  • Milano
    • Rozzano, Milano, Italy, 20089
      • Site Reference ID/Investigator #522
  • Piemonte
    • Novara, Piemonte, Italy, 28100
      • Site Reference ID/Investigator #582
  • Veneto
    • Padova, Veneto, Italy, 35128
      • Site Reference ID/Investigator #527
• New Zealand
  • Auckland, New Zealand, 0622
    • Site Reference ID/Investigator #663
  • Auckland, New Zealand, 1023
    • Site Reference ID/Investigator #588
  • Wellington, New Zealand, 6021
    • Site Reference ID/Investigator #587
  • Canterbury
    • Christchurch, Canterbury, New Zealand, 8011
      • Site Reference ID/Investigator #589
  • Waikato
    • Hamilton, Waikato, New Zealand, 3240
      • Site Reference ID/Investigator #586
• Poland
  • Chorzow, Poland, 40
    • Site Reference ID/Investigator #591
  • Gdansk, Poland, 80-952
    • Site Reference ID/Investigator #529
  • Lodz, Poland, 93-510
    • Site Reference ID/Investigator #531
  • Lubelskie
    • Lublin, Lubelskie, Poland, 20-081
      • Site Reference ID/Investigator #590
  • Podkarpackie
    • Brzozowie, Podkarpackie, Poland, 36.200
      • Site Reference ID/Investigator #592
• Russian Federation
  • Ryazan, Russian Federation, 390039
    • Site Reference ID/Investigator #707
  • Yaroslavl, Russian Federation, 150062
    • Site Reference ID/Investigator #304
• Spain
  • Barcelona, Spain, 08035
    • Site Reference ID/Investigator #534
  • Barcelona, Spain, 08036
    • Site Reference ID/Investigator #533
  • Barcelona, Spain, 08041
    • Site Reference ID/Investigator #535
  • Barcelona, Spain, 08908
    • Site Reference ID/Investigator #604
  • Madrid, Spain, 28050
    • Site Reference ID/Investigator #537
  • Madrid
    • Majadahonda, Madrid, Spain, 28222
      • Site Reference ID/Investigator #536
• Turkey
  • Ankara, Turkey, 06500
    • Site Reference ID/Investigator #608
  • Ankara, Turkey, 06590
    • Site Reference ID/Investigator #606
  • Istanbul, Turkey, 34390
    • Site Reference ID/Investigator #599
  • Izmir, Turkey, 35040
    • Site Reference ID/Investigator #714
  • Izmir, Turkey, 35340
    • Site Reference ID/Investigator #601
  • Kayseri, Turkey, 38039
    • Site Reference ID/Investigator #602
• Ukraine
  • Cherkas'ka Oblast
    • Cherkasy, Cherkas'ka Oblast, Ukraine, 18009
      • Site Reference ID/Investigator #597
  • Dnipropetrovs'ka Oblast'
    • Dnipropetrovsk, Dnipropetrovs'ka Oblast', Ukraine, 49102
      • Site Reference ID/Investigator #594
  • Kharkivs'ka Oblast
    • Kharkiv, Kharkivs'ka Oblast, Ukraine, 61070
      • Site Reference ID/Investigator #725
  • L'vivs'ka Oblast
    • Lviv, L'vivs'ka Oblast, Ukraine, 79044
      • Site Reference ID/Investigator #596
  • Respublika Krym
    • Simferopol, Respublika Krym, Ukraine, 95023
      • Site Reference ID/Investigator #598
  • Vinnyts'ka Oblast
    • Vinnytsia, Vinnyts'ka Oblast, Ukraine, 21018
      • Site Reference ID/Investigator #595
  • Zhytomyrs'ka Oblast'
    • Zhytomyr, Zhytomyrs'ka Oblast', Ukraine, 10022
      • Site Reference ID/Investigator #724
• United Kingdom
  • Birmingham, United Kingdom, B9 5SS
    • Site Reference ID/Investigator #721
  • Nottingham, United Kingdom, NG5 1PB
    • Site Reference ID/Investigator #548
  • Southampton, United Kingdom, SO16 6YD
    • Site Reference ID/Investigator #367
  • Dorset
    • Bournemouth, Dorset, United Kingdom, BH7 7DW
      • Site Reference ID/Investigator #551
  • England
    • London, England, United Kingdom, SE5 9RS
      • Site Reference ID/Investigator #544
    • Oxford, England, United Kingdom, OX3 7LE
      • Site Reference ID/Investigator #668
  • Essex
    • Colchester, Essex, United Kingdom, CO4 5JL
      • Site Reference ID/Investigator #549
  • South Glamergon
    • Cardiff, South Glamergon, United Kingdom, CF14 4XW
      • Site Reference ID/Investigator #607
  • Yorkshire
    • Leeds, Yorkshire, United Kingdom, LS9 7TF
      • Site Reference ID/Investigator #550
• United States
  • California
    • Duarte, California, United States, 91010
      • Site Reference ID/Investigator #047
    • La Jolla, California, United States, 92093
      • Site Reference ID/Investigator #408
    • Santa Rosa, California, United States, 95403
      • Site Reference ID/Investigator #720
    • Stanford, California, United States, 94305
      • Site Reference ID/Investigator #038
  • Georgia
    • Atlanta, Georgia, United States, 30318
      • Site Reference ID/Investigator #125
  • Illinois
    • Chicago, Illinois, United States, 60637
      • Site Reference ID/Investigator #126
  • Kentucky
    • Louisville, Kentucky, United States, 40207
      • Site Reference ID/Investigator #071
  • Massachusetts
    • Worcester, Massachusetts, United States, 01655
      • Site Reference ID/Investigator #307
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Site Reference ID/Investigator #387
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Site Reference ID/Investigator #221
  • Nevada
    • Las Vegas, Nevada, United States, 89169
      • Site Reference ID/Investigator #712
  • New York
    • New Hyde Park, New York, United States, 11042
      • Site Reference ID/Investigator #350
    • Rochester, New York, United States, 14642
      • Site Reference ID/Investigator #127
  • North Carolina
    • Goldsboro, North Carolina, United States, 27534
      • Site Reference ID/Investigator #656
  • Ohio
    • Columbus, Ohio, United States, 43219
      • Site Reference ID/Investigator #734
  • Oregon
    • Portland, Oregon, United States, 97227
      • Site Reference ID/Investigator #677
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • Site Reference ID/Investigator #050
  • Texas
    • Houston, Texas, United States, 77030
      • Site Reference ID/Investigator #032
    • Laredo, Texas, United States, 78041
      • Site Reference ID/Investigator #381
    • San Antonio, Texas, United States, 78229
      • Site Reference ID/Investigator #653
  • Washington
    • Seattle, Washington, United States, 98109
      • Site Reference ID/Investigator #404
    • Walla Walla, Washington, United States, 99362
      • Site Reference ID/Investigator #731

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years and older (Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Males or females of 65 years of age or greater. Patients between the ages of 65 and 70 years of age must have 1 or more of the following comorbidities that may preclude the use of frontline chemo-immunotherapy with fludarabine, cyclophosphamide, or rituximab:

   • creatinine clearance < 70 mL/min using the Cockcroft-Gault equation
   • platelet count < 100,000/μL or hemoglobin < 10 g/dL
   • clinically apparent autoimmune cytopenia (autoimmune hemolytic anemia or immune thrombocytopenia)
   • ECOG performance score = 1 or 2
2. Diagnosis of CLL/SLL that meets IWCLL diagnostic criteria (Hallek 2008)

3. Active disease meeting at least 1 of the following IWCLL criteria (Hallek 2008) for requiring treatment:

   • Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia Massive, progressive, or symptomatic splenomegaly
   • Massive nodes or progressive or symptomatic lymphadenopathy
   • Progressive lymphocytosis
   • Autoimmune hemolytic anemia and/or immune thrombocytopenia that is poorly responsive to corticosteroids or standard therapy
   • Constitutional symptoms
4. Measurable nodal disease by computed tomography (CT)
5. ECOG performance status of 0-2
6. Life expectancy > 4 months from randomization
7. Adequate hematologic function, defined as absolute neutrophil count (ANC) ≥ 1,000/μL (independent of growth factor support for at least 7 days prior to screening) and platelet count ≥ 50,000/μL (independent of transfusion and growth factor support for at least 7 days prior to screening)
8. Adequate hepatic function, defined as serum aspartate transaminase (AST) and alanine transaminase (ALT) < 2.5 x upper limit of normal (ULN), and total bilirubin ≤ 1.5 x ULN
9. Adequate renal function, defined as estimated creatinine clearance ≥ 30 mL/min using the Cockcroft-Gault equation
10. Willingness to receive all outpatient treatment, all laboratory monitoring, and all radiological evaluations at the institution that administers study drug for the entire study
11. Willingness of male patients, if sexually active with a female of childbearing potential, to use an effective barrier method of contraception during the study and for 3 months following the last dose of study drug
12. Ability to provide written informed consent and to understand and comply with the requirements of the study

Exclusion Criteria:

1. Known involvement of the central nervous system by lymphoma or leukemia
2. History or current evidence of Richter's transformation or prolymphocytic leukemia
3. Documentation of deletion of the short arm of chromosome 17: del(17p13.1) in more than 20% of cells examined on any pretreatment fluorescence in situ hybridization (FISH) or cytogenetic evaluation
4. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura
5. Any previous treatment (chemotherapy, radiotherapy, and/or monoclonal antibodies) intended specifically to treat CLL/SLL
6. Received any immunotherapy, vaccine, or investigational drug within 4 weeks prior to randomization
7. Corticosteroid use within 1 week prior to first dose of study drug, with the exception of inhaled, topical, or other local administrations. Patients requiring systemic steroids at daily doses > 20 mg prednisone (or corticosteroid equivalent, see Appendix N), or those who are administered steroids for leukemia control or white blood cell (WBC)-count-lowering are excluded.
8. Major surgery within 4 weeks prior to randomization

9. History of prior malignancy, with the exception of the following:

   • malignancy treated with curative intent and with no evidence of active disease present for more than 3 years prior to screening and felt to be at low risk for recurrence by treating physician
   • adequately treated nonmelanomatous skin cancer or lentigo maligna melanoma without current evidence of disease
   • adequately treated cervical carcinoma in situ without current evidence of disease
10. Currently active, clinically significant cardiovascular disease or a history of myocardial infarction within 6 months prior to randomization
11. Inability to swallow capsules or tablets, or disease significantly affecting gastrointestinal function
12. Uncontrolled active systemic fungal, bacterial, viral, or other infection or requirement for intravenous (IV) antibiotics
13. Known history of infection with human immunodeficiency virus (HIV)
14. Serologic status reflecting active hepatitis B or C infection
15. History of stroke or intracranial hemorrhage within 6 months prior to enrollment
16. Current life-threatening illness, medical condition, or organ-system dysfunction that could compromise patient safety or put the study at risk
17. Requirement for anticoagulation with warfarin
18. Requirement for treatment with a strong CYP3A4/5 and/or CYP2D6 inhibitor

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ibrutinib; Ibrutinib will be supplied as hard gelatin 140-mg capsules for oral (PO) administration. Ibrutinib 420 mg (3 x 140-mg capsules) is administered orally once daily. The first dose will be delivered in the clinic on Day 1, after which subsequent dosing is typically on an outpatient basis. Ibrutinib will be dispensed to patients in bottles at each visit.	Drug: Ibrutinib; Ibrutinib will be supplied as hard gelatin 140-mg capsules for oral (PO) administration. Ibrutinib 420 mg (3 x 140-mg capsules) is administered orally once daily. The first dose will be delivered in the clinic on Day 1, after which subsequent dosing is typically on an outpatient basis. Ibrutinib will be dispensed to patients in bottles at each visit.
Active Comparator: Chlorambucil; Chlorambucil will be supplied as 2-mg tablets for PO administration. Chlorambucil is administered orally on Days 1 and 15 of each 28-day cycle.The starting dosage (Cycle 1) is 0.5 mg/kg. If well tolerated, the Chlorambucil dose can be increased starting at Cycle 2, with increments of 0.1 mg/kg on Day 1 of each cycle to a maximum of 0.8 mg/kg.	Drug: Chlorambucil; Chlorambucil will be supplied as 2-mg tablets for PO administration. Chlorambucil is administered orally on Days 1 and 15 of each 28-day cycle. The starting dosage (Cycle 1) is 0.5 mg/kg. If well tolerated, the Chlorambucil dose can be increased starting at Cycle 2, with increments of 0.1 mg/kg on Day 1 of each cycle to a maximum of 0.8 mg/kg.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PFS (Progression Free Survival)	The primary objective of this study was to evaluate the efficacy of Ibrutinib compared with Chlorambucil based on the independent review committee (IRC) assessment of PFS Progressive disease according to 2008 IWCLL guidelines was defined as: Group ALymphadenopathy, increase ≥50%Hepatomegaly, increase ≥50%Splenomegaly, increase ≥50%Blood lymphocytes, increase ≥ 50% over baseline; Group BPlatelets counts, decrease of ≥ 50% from baseline secondary to CLLHemoglobin, decrease of > 2 g/dL from baseline secondary to CLL	Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	OS is calculated for all randomized subjects as the duration of time from the date of randomization to the date of death due to any cause or the date last known alive for subjects who were not known to have died at study closure.	Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.
ORR (Overall Response Rate)	ORR is defined as the proportion of subjects who achieved complete response (CR), complete response with incomplete marrow recovery (CRi), nodule partial response (nPR) or PR per IRC assessment. Response criteria are as outlined in the International Workshop on CLL (iwCLL) 2008 criteria with the 2012 iwCLL modification stating that treatment-related lymphocytosis in the setting of improvement in other parameters was not considered as PD and the 2013 iwCLL clarification of criteria for a partial response to therapy.	Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.
Proportion of Sustained Hemoglobin Improvement	The proportion of subjects who achieved Hemoglobin >11 g/dL or increase ≥ 2 g/dL over baseline and persisted continuously for ≥56 days (8 weeks) without blood transfusion or growth factors.	Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.
Proportion of Sustained Hemoglobin Improvement in Subjects With Baseline Anemia	In randomized subjects with baseline hemoglobin ≤ 11 g/dL, the proportion of subjects who achieved Hemoglobin >11 g/dL or increase ≥ 2 g/dL over baseline persisted continuously for ≥56 days (8 weeks) without blood transfusion or growth factors.	Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.
Proportion of Sustained Platelet Improvement	The proportion of subjects who achieved platelet >100 x 10^9/L or increase ≥50% over baseline and persisted continuously for ≥56 days (8 weeks) without blood transfusion or growth factors.	Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.
Proportion of Sustained Platelet Improvement in Subjects With Baseline Thrombocytopenia	In randomized subjects with baseline platelet ≤ 100 x 10^9/L, the proportion of subjects who achieved platelet >100 x 10^9/L or increase ≥50% over baseline persisted continuously for ≥56 days (8 wee without blood transfusion or growth factors.	Analysis was conducted when 15 months had elapsed after the last subject was randomized with cutoff date of 4 May 2015. The median follow-up time is 18 month.

Collaborators and Investigators

• Sponsor: Pharmacyclics LLC.
• Collaborators: Janssen Research & Development, LLC

Publications and helpful links

General Publications

• 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.
• 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.
• Barr PM, Owen C, Robak T, Tedeschi A, Bairey O, Burger JA, Hillmen P, Coutre SE, Dearden C, Grosicki S, McCarthy H, Li JY, Offner F, Moreno C, Zhou C, Hsu E, Szoke A, Kipps TJ, Ghia P. Up to 8-year follow-up from RESONATE-2: first-line ibrutinib treatment for patients with chronic lymphocytic leukemia. Blood Adv. 2022 Jun 14;6(11):3440-3450. doi: 10.1182/bloodadvances.2021006434.
• Coutre SE, Byrd JC, Hillmen P, Barrientos JC, Barr PM, Devereux S, Robak T, Kipps TJ, Schuh A, Moreno C, Furman RR, Burger JA, O'Dwyer M, Ghia P, Valentino R, Chang S, Dean JP, James DF, O'Brien SM. Long-term safety of single-agent ibrutinib in patients with chronic lymphocytic leukemia in 3 pivotal studies. Blood Adv. 2019 Jun 25;3(12):1799-1807. doi: 10.1182/bloodadvances.2018028761.
• Barr PM, Robak T, Owen C, Tedeschi A, Bairey O, Bartlett NL, Burger JA, Hillmen P, Coutre S, Devereux S, Grosicki S, McCarthy H, Li J, Simpson D, Offner F, Moreno C, Zhou C, Styles L, James D, Kipps TJ, Ghia P. Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: extended phase 3 results from RESONATE-2. Haematologica. 2018 Sep;103(9):1502-1510. doi: 10.3324/haematol.2018.192328. Epub 2018 Jun 7.
• Brown JR, Moslehi J, O'Brien S, Ghia P, Hillmen P, Cymbalista F, Shanafelt TD, Fraser G, Rule S, Kipps TJ, Coutre S, Dilhuydy MS, Cramer P, Tedeschi A, Jaeger U, Dreyling M, Byrd JC, Howes A, Todd M, Vermeulen J, James DF, Clow F, Styles L, Valentino R, Wildgust M, Mahler M, Burger JA. Characterization of atrial fibrillation adverse events reported in ibrutinib randomized controlled registration trials. Haematologica. 2017 Oct;102(10):1796-1805. doi: 10.3324/haematol.2017.171041. Epub 2017 Jul 27.
• Burger JA, Tedeschi A, Barr PM, Robak T, Owen C, Ghia P, Bairey O, Hillmen P, Bartlett NL, Li J, Simpson D, Grosicki S, Devereux S, McCarthy H, Coutre S, Quach H, Gaidano G, Maslyak Z, Stevens DA, Janssens A, Offner F, Mayer J, O'Dwyer M, Hellmann A, Schuh A, Siddiqi T, Polliack A, Tam CS, Suri D, Cheng M, Clow F, Styles L, James DF, Kipps TJ; RESONATE-2 Investigators. Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. N Engl J Med. 2015 Dec 17;373(25):2425-37. doi: 10.1056/NEJMoa1509388. Epub 2015 Dec 6.

Helpful Links

• www.pharmacyclics.com

Study record dates

Study Major Dates

• Study Start: March 1, 2013
• Primary Completion (Actual): May 1, 2015
• Study Completion (Actual): May 1, 2015

Study Registration Dates

• First Submitted: October 29, 2012
• First Submitted That Met QC Criteria: November 2, 2012
• First Posted (Estimate): November 6, 2012

Study Record Updates

• Last Update Posted (Actual): November 30, 2017
• Last Update Submitted That Met QC Criteria: November 27, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: CLL, SLL
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia, B-Cell; Lymphoma; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Chlorambucil
• Other Study ID Numbers: PCYC-1115-CA; 2012-003967-23 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: We share this information with FDA and other authorities for the purposes of analyzing the study but not with other researchers