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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT01722487




Registration number
NCT01722487
Ethics application status
Date submitted
29/10/2012
Date registered
6/11/2012
Date last updated
30/11/2017

Titles & IDs
Public title
Open-label Phase 3 BTK Inhibitor Ibrutinib vs Chlorambucil Patients 65 Years or Older With Treatment-naive CLL or SLL
Scientific 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
Secondary ID [1] 0 0
2012-003967-23
Secondary ID [2] 0 0
PCYC-1115-CA
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Lymphocytic Leukemia 0 0
Small Lymphocytic Lymphoma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Ibrutinib
Treatment: Drugs - Chlorambucil

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.

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.


Treatment: Drugs: 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.

Treatment: Drugs: 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.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
PFS (Progression Free Survival)
Timepoint [1] 0 0
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 [1] 0 0
Overall Survival (OS)
Timepoint [1] 0 0
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 [2] 0 0
ORR (Overall Response Rate)
Timepoint [2] 0 0
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 [3] 0 0
Proportion of Sustained Hemoglobin Improvement
Timepoint [3] 0 0
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 [4] 0 0
Proportion of Sustained Hemoglobin Improvement in Subjects With Baseline Anemia
Timepoint [4] 0 0
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 [5] 0 0
Proportion of Sustained Platelet Improvement
Timepoint [5] 0 0
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 [6] 0 0
Proportion of Sustained Platelet Improvement in Subjects With Baseline Thrombocytopenia
Timepoint [6] 0 0
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.

Eligibility
Key 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
Minimum age
65 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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 design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
1/03/2013
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
1/05/2015
Sample size
Target
Accrual to date
Final
269
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,TAS,VIC
Recruitment hospital [1] 0 0
Site Reference ID/Investigator #654 - Kogarah
Recruitment hospital [2] 0 0
Site Reference ID/Investigator #503 - Woolloongabba
Recruitment hospital [3] 0 0
Site Reference ID/Investigator #163 - Bedford Park
Recruitment hospital [4] 0 0
Site Reference ID/Investigator #555 - Hobart
Recruitment hospital [5] 0 0
Site Reference ID/Investigator #193 - Box Hill
Recruitment hospital [6] 0 0
Site Reference ID/Investigator #556 - Clayton
Recruitment hospital [7] 0 0
Site Reference ID/Investigator #501 - Fitzroy
Recruitment hospital [8] 0 0
Site Reference ID/Investigator #715 - Frankston
Recruitment hospital [9] 0 0
Site Reference ID/Investigator #558 - Geelong
Recruitment hospital [10] 0 0
Site Reference ID/Investigator #170 - Heidelberg
Recruitment postcode(s) [1] 0 0
2217 - Kogarah
Recruitment postcode(s) [2] 0 0
4102 - Woolloongabba
Recruitment postcode(s) [3] 0 0
5042 - Bedford Park
Recruitment postcode(s) [4] 0 0
7000 - Hobart
Recruitment postcode(s) [5] 0 0
3128 - Box Hill
Recruitment postcode(s) [6] 0 0
3168 - Clayton
Recruitment postcode(s) [7] 0 0
3065 - Fitzroy
Recruitment postcode(s) [8] 0 0
3199 - Frankston
Recruitment postcode(s) [9] 0 0
3220 - Geelong
Recruitment postcode(s) [10] 0 0
3084 - Heidelberg
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Georgia
Country [3] 0 0
United States of America
State/province [3] 0 0
Illinois
Country [4] 0 0
United States of America
State/province [4] 0 0
Kentucky
Country [5] 0 0
United States of America
State/province [5] 0 0
Massachusetts
Country [6] 0 0
United States of America
State/province [6] 0 0
Michigan
Country [7] 0 0
United States of America
State/province [7] 0 0
Missouri
Country [8] 0 0
United States of America
State/province [8] 0 0
Nevada
Country [9] 0 0
United States of America
State/province [9] 0 0
New York
Country [10] 0 0
United States of America
State/province [10] 0 0
North Carolina
Country [11] 0 0
United States of America
State/province [11] 0 0
Ohio
Country [12] 0 0
United States of America
State/province [12] 0 0
Oregon
Country [13] 0 0
United States of America
State/province [13] 0 0
Pennsylvania
Country [14] 0 0
United States of America
State/province [14] 0 0
Texas
Country [15] 0 0
United States of America
State/province [15] 0 0
Washington
Country [16] 0 0
Belgium
State/province [16] 0 0
Brussells
Country [17] 0 0
Belgium
State/province [17] 0 0
Namur
Country [18] 0 0
Belgium
State/province [18] 0 0
Oost-Vlaanderen
Country [19] 0 0
Belgium
State/province [19] 0 0
Vlaams Brabant
Country [20] 0 0
Belgium
State/province [20] 0 0
West-Vlaanderen
Country [21] 0 0
Belgium
State/province [21] 0 0
Antwerpen
Country [22] 0 0
Canada
State/province [22] 0 0
Alberta
Country [23] 0 0
Canada
State/province [23] 0 0
Ontario
Country [24] 0 0
China
State/province [24] 0 0
Guangdong
Country [25] 0 0
China
State/province [25] 0 0
Jiangsu
Country [26] 0 0
China
State/province [26] 0 0
Zhejiang
Country [27] 0 0
China
State/province [27] 0 0
Beijing
Country [28] 0 0
Czechia
State/province [28] 0 0
Kralovehradecky Kraj
Country [29] 0 0
Czechia
State/province [29] 0 0
Brno
Country [30] 0 0
Czechia
State/province [30] 0 0
Plzen-Lochotin
Country [31] 0 0
Ireland
State/province [31] 0 0
Dublin
Country [32] 0 0
Ireland
State/province [32] 0 0
Galway
Country [33] 0 0
Israel
State/province [33] 0 0
Haifa
Country [34] 0 0
Israel
State/province [34] 0 0
Jerusalem
Country [35] 0 0
Israel
State/province [35] 0 0
Nahariya
Country [36] 0 0
Israel
State/province [36] 0 0
Peta? Tiqwa
Country [37] 0 0
Israel
State/province [37] 0 0
Ramat Gan
Country [38] 0 0
Italy
State/province [38] 0 0
Lazio
Country [39] 0 0
Italy
State/province [39] 0 0
Milano
Country [40] 0 0
Italy
State/province [40] 0 0
Piemonte
Country [41] 0 0
Italy
State/province [41] 0 0
Veneto
Country [42] 0 0
Italy
State/province [42] 0 0
Bologna
Country [43] 0 0
Italy
State/province [43] 0 0
Modena
Country [44] 0 0
New Zealand
State/province [44] 0 0
Canterbury
Country [45] 0 0
New Zealand
State/province [45] 0 0
Waikato
Country [46] 0 0
New Zealand
State/province [46] 0 0
Auckland
Country [47] 0 0
New Zealand
State/province [47] 0 0
Wellington
Country [48] 0 0
Poland
State/province [48] 0 0
Lubelskie
Country [49] 0 0
Poland
State/province [49] 0 0
Podkarpackie
Country [50] 0 0
Poland
State/province [50] 0 0
Chorzow
Country [51] 0 0
Poland
State/province [51] 0 0
Gdansk
Country [52] 0 0
Poland
State/province [52] 0 0
Lodz
Country [53] 0 0
Russian Federation
State/province [53] 0 0
Ryazan
Country [54] 0 0
Russian Federation
State/province [54] 0 0
Yaroslavl
Country [55] 0 0
Spain
State/province [55] 0 0
Madrid
Country [56] 0 0
Spain
State/province [56] 0 0
Barcelona
Country [57] 0 0
Turkey
State/province [57] 0 0
Ankara
Country [58] 0 0
Turkey
State/province [58] 0 0
Istanbul
Country [59] 0 0
Turkey
State/province [59] 0 0
Izmir
Country [60] 0 0
Turkey
State/province [60] 0 0
Kayseri
Country [61] 0 0
Ukraine
State/province [61] 0 0
Cherkas'ka Oblast
Country [62] 0 0
Ukraine
State/province [62] 0 0
Dnipropetrovs'ka Oblast'
Country [63] 0 0
Ukraine
State/province [63] 0 0
Kharkivs'ka Oblast
Country [64] 0 0
Ukraine
State/province [64] 0 0
L'vivs'ka Oblast
Country [65] 0 0
Ukraine
State/province [65] 0 0
Respublika Krym
Country [66] 0 0
Ukraine
State/province [66] 0 0
Vinnyts'ka Oblast
Country [67] 0 0
Ukraine
State/province [67] 0 0
Zhytomyrs'ka Oblast'
Country [68] 0 0
United Kingdom
State/province [68] 0 0
Dorset
Country [69] 0 0
United Kingdom
State/province [69] 0 0
England
Country [70] 0 0
United Kingdom
State/province [70] 0 0
Essex
Country [71] 0 0
United Kingdom
State/province [71] 0 0
South Glamergon
Country [72] 0 0
United Kingdom
State/province [72] 0 0
Yorkshire
Country [73] 0 0
United Kingdom
State/province [73] 0 0
Birmingham
Country [74] 0 0
United Kingdom
State/province [74] 0 0
Nottingham
Country [75] 0 0
United Kingdom
State/province [75] 0 0
Southampton

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Pharmacyclics LLC.
Address
Country
Other collaborator category [1] 0 0
Commercial sector/industry
Name [1] 0 0
Janssen Research & Development, LLC
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/study/NCT01722487
Trial related presentations / publications
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.
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.
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.
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.
Public notes

Contacts
Principal investigator
Name 0 0
Lori Styles, MD
Address 0 0
Pharmacyclics LLC.
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT01722487