Clinical trial NCT01722487: Open-label Phase 3 BTK Inhibitor Ibrutinib vs Chlorambucil Patients 65 Years or Older With Treatment-naive CLL or SLL
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Chronic Lymphocytic Leukemia
Small Lymphocytic Lymphoma
Keywords: CLL, SLL
Lead sponsor: Pharmacyclics LLC.
Sponsor class: INDUSTRY
Collaborators: name: Janssen Research & Development, LLC
First posted: 2012-11-06
Enrollment: 269
Sex: ALL
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: PFS (Progression Free Survival)
timeFrame: 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 outcomes:
measure: Overall Survival (OS)
timeFrame: 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.
measure: ORR (Overall Response Rate)
timeFrame: 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.
measure: Proportion of Sustained Hemoglobin Improvement
timeFrame: 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.
measure: Proportion of Sustained Hemoglobin Improvement in Subjects With Baseline Anemia
timeFrame: 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.
measure: Proportion of Sustained Platelet Improvement
timeFrame: 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.
measure: Proportion of Sustained Platelet Improvement in Subjects With Baseline Thrombocytopenia
timeFrame: 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.
Other outcomes:
Locations:
city: Duarte
country: United States
facility: Site Reference ID/Investigator #047
state: California
city: La Jolla
country: United States
facility: Site Reference ID/Investigator #408
state: California
city: Santa Rosa
country: United States
facility: Site Reference ID/Investigator #720
state: California
city: Stanford
country: United States
facility: Site Reference ID/Investigator #038
state: California
city: Atlanta
country: United States
facility: Site Reference ID/Investigator #125
state: Georgia
city: Chicago
country: United States
facility: Site Reference ID/Investigator #126
state: Illinois
city: Louisville
country: United States
facility: Site Reference ID/Investigator #071
state: Kentucky
city: Worcester
country: United States
facility: Site Reference ID/Investigator #307
state: Massachusetts
city: Ann Arbor
country: United States
facility: Site Reference ID/Investigator #387
state: Michigan
city: Saint Louis
country: United States
facility: Site Reference ID/Investigator #221
state: Missouri
city: Las Vegas
country: United States
facility: Site Reference ID/Investigator #712
state: Nevada
city: New Hyde Park
country: United States
facility: Site Reference ID/Investigator #350
state: New York
city: Rochester
country: United States
facility: Site Reference ID/Investigator #127
state: New York
city: Goldsboro
country: United States
facility: Site Reference ID/Investigator #656
state: North Carolina
city: Columbus
country: United States
facility: Site Reference ID/Investigator #734
state: Ohio
city: Portland
country: United States
facility: Site Reference ID/Investigator #677
state: Oregon
city: Pittsburgh
country: United States
facility: Site Reference ID/Investigator #050
state: Pennsylvania
city: Houston
country: United States
facility: Site Reference ID/Investigator #032
state: Texas
city: Laredo
country: United States
facility: Site Reference ID/Investigator #381
state: Texas
city: San Antonio
country: United States
facility: Site Reference ID/Investigator #653
state: Texas
city: Seattle
country: United States
facility: Site Reference ID/Investigator #404
state: Washington
city: Walla Walla
country: United States
facility: Site Reference ID/Investigator #731
state: Washington
city: Kogarah
country: Australia
facility: Site Reference ID/Investigator #654
state: New South Wales
city: Woolloongabba
country: Australia
facility: Site Reference ID/Investigator #503
state: Queensland
city: Bedford Park
country: Australia
facility: Site Reference ID/Investigator #163
state: South Australia
city: Hobart
country: Australia
facility: Site Reference ID/Investigator #555
state: Tasmania
city: Box Hill
country: Australia
facility: Site Reference ID/Investigator #193
state: Victoria
city: Clayton
country: Australia
facility: Site Reference ID/Investigator #556
state: Victoria
city: Fitzroy
country: Australia
facility: Site Reference ID/Investigator #501
state: Victoria
city: Frankston
country: Australia
facility: Site Reference ID/Investigator #715
state: Victoria
city: Geelong
country: Australia
facility: Site Reference ID/Investigator #558
state: Victoria
city: Heidelberg
country: Australia
facility: Site Reference ID/Investigator #170
state: Victoria
city: Bruxelles
country: Belgium
facility: Site Reference ID/Investigator #164
state: Brussells
city: Yvoir
country: Belgium
facility: Site Reference ID/Investigator #727
state: Namur
city: Gent
country: Belgium
facility: Site Reference ID/Investigator #560
state: Oost-Vlaanderen
city: Leuven
country: Belgium
facility: Site Reference ID/Investigator #559
state: Vlaams Brabant
city: Brugge
country: Belgium
facility: Site Reference ID/Investigator #628
state: West-Vlaanderen
city: Antwerpen
country: Belgium
facility: Site Reference ID/Investigator #561
city: Brussells
country: Belgium
facility: Site Reference ID/Investigator #184
city: Calgary
country: Canada
facility: Site Reference ID/Investigator #157
state: Alberta
city: Edmonton
country: Canada
facility: Site Reference ID/Investigator #018
state: Alberta
city: Ottawa
country: Canada
facility: Site Reference ID/Investigator #159
state: Ontario
city: Guangzhou
country: China
facility: Site Reference ID/Investigator #674
state: Guangdong
city: Nanjing
country: China
facility: Site Reference ID/Investigator #671
state: Jiangsu
city: Hangzhou
country: China
facility: Site Reference ID/Investigator #675
state: Zhejiang
city: Beijing
country: China
facility: Site Reference ID/Investigator #670
city: Beijing
country: China
facility: Site Reference ID/Investigator #673
city: Hradec Kralove
country: Czechia
facility: Site Reference ID/Investigator #564
state: Kralovehradecky Kraj
city: Brno
country: Czechia
facility: Site Reference ID/Investigator #562
city: Plzen-Lochotin
country: Czechia
facility: Site Reference ID/Investigator #566
city: Dublin
country: Ireland
facility: Site Reference ID/Investigator #572
city: Dublin
country: Ireland
facility: Site Reference ID/Investigator #570
city: Galway
country: Ireland
facility: Site Reference ID/Investigator #571
city: Haifa
country: Israel
facility: Site Reference ID/Investigator #573
city: Haifa
country: Israel
facility: Site Reference ID/Investigator #576
city: Jerusalem
country: Israel
facility: Site Reference ID/Investigator #577
city: Nahariya
country: Israel
facility: Site Reference ID/Investigator #578
city: Petaẖ Tiqwa
country: Israel
facility: Site Reference ID/Investigator #575
city: Ramat Gan
country: Israel
facility: Site Reference ID/Investigator #574
city: Roma
country: Italy
facility: Site Reference ID/Investigator #583
state: Lazio
city: Rozzano
country: Italy
facility: Site Reference ID/Investigator #522
state: Milano
city: Novara
country: Italy
facility: Site Reference ID/Investigator #582
state: Piemonte
city: Padova
country: Italy
facility: Site Reference ID/Investigator #527
state: Veneto
city: Bologna
country: Italy
facility: Site Reference ID/Investigator #580
city: Milano
country: Italy
facility: Site Reference ID/Investigator #584
city: Milano
country: Italy
facility: Site Reference ID/Investigator #523
city: Milano
country: Italy
facility: Site Reference ID/Investigator #581
city: Modena
country: Italy
facility: Site Reference ID/Investigator #524
city: Christchurch
country: New Zealand
facility: Site Reference ID/Investigator #589
state: Canterbury
city: Hamilton
country: New Zealand
facility: Site Reference ID/Investigator #586
state: Waikato
city: Auckland
country: New Zealand
facility: Site Reference ID/Investigator #663
city: Auckland
country: New Zealand
facility: Site Reference ID/Investigator #588
city: Wellington
country: New Zealand
facility: Site Reference ID/Investigator #587
city: Lublin
country: Poland
facility: Site Reference ID/Investigator #590
state: Lubelskie
city: Brzozowie
country: Poland
facility: Site Reference ID/Investigator #592
state: Podkarpackie
city: Chorzow
country: Poland
facility: Site Reference ID/Investigator #591
city: Gdansk
country: Poland
facility: Site Reference ID/Investigator #529
city: Lodz
country: Poland
facility: Site Reference ID/Investigator #531
city: Ryazan
country: Russian Federation
facility: Site Reference ID/Investigator #707
city: Yaroslavl
country: Russian Federation
facility: Site Reference ID/Investigator #304
city: Majadahonda
country: Spain
facility: Site Reference ID/Investigator #536
state: Madrid
city: Barcelona
country: Spain
facility: Site Reference ID/Investigator #534
city: Barcelona
country: Spain
facility: Site Reference ID/Investigator #533
city: Barcelona
country: Spain
facility: Site Reference ID/Investigator #535
city: Barcelona
country: Spain
facility: Site Reference ID/Investigator #604
city: Madrid
country: Spain
facility: Site Reference ID/Investigator #537
city: Ankara
country: Turkey
facility: Site Reference ID/Investigator #608
city: Ankara
country: Turkey
facility: Site Reference ID/Investigator #606
city: Istanbul
country: Turkey
facility: Site Reference ID/Investigator #599
city: Izmir
country: Turkey
facility: Site Reference ID/Investigator #714
city: Izmir
country: Turkey
facility: Site Reference ID/Investigator #601
city: Kayseri
country: Turkey
facility: Site Reference ID/Investigator #602
city: Cherkasy
country: Ukraine
facility: Site Reference ID/Investigator #597
state: Cherkas'ka Oblast
city: Dnipropetrovsk
country: Ukraine
facility: Site Reference ID/Investigator #594
state: Dnipropetrovs'ka Oblast'
city: Kharkiv
country: Ukraine
facility: Site Reference ID/Investigator #725
state: Kharkivs'ka Oblast
city: Lviv
country: Ukraine
facility: Site Reference ID/Investigator #596
state: L'vivs'ka Oblast
city: Simferopol
country: Ukraine
facility: Site Reference ID/Investigator #598
state: Respublika Krym
city: Vinnytsia
country: Ukraine
facility: Site Reference ID/Investigator #595
state: Vinnyts'ka Oblast
city: Zhytomyr
country: Ukraine
facility: Site Reference ID/Investigator #724
state: Zhytomyrs'ka Oblast'
city: Bournemouth
country: United Kingdom
facility: Site Reference ID/Investigator #551
state: Dorset
city: London
country: United Kingdom
facility: Site Reference ID/Investigator #544
state: England
city: Oxford
country: United Kingdom
facility: Site Reference ID/Investigator #668
state: England
city: Colchester
country: United Kingdom
facility: Site Reference ID/Investigator #549
state: Essex
city: Cardiff
country: United Kingdom
facility: Site Reference ID/Investigator #607
state: South Glamergon
city: Leeds
country: United Kingdom
facility: Site Reference ID/Investigator #550
state: Yorkshire
city: Birmingham
country: United Kingdom
facility: Site Reference ID/Investigator #721
city: Nottingham
country: United Kingdom
facility: Site Reference ID/Investigator #548
city: Southampton
country: United Kingdom
facility: Site Reference ID/Investigator #367
Study officials:
affiliation: Pharmacyclics LLC.
name: Lori Styles, MD
role: STUDY_DIRECTOR
References:
citation: 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.
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.
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citation: 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.
citation: 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.
citation: 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.