Now Available: Final Rule for FDAAA 801 and NIH Policy on Clinical Trial Reporting

A 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 (RESONATE™-2)

This study has been completed.
Sponsor:
Collaborator:
Janssen Research & Development, LLC
Information provided by (Responsible Party):
Pharmacyclics LLC.
ClinicalTrials.gov Identifier:
NCT01722487
First received: October 29, 2012
Last updated: May 4, 2016
Last verified: May 2016
  Purpose
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.

Condition Intervention Phase
Chronic Lymphocytic Leukemia
Small Lymphocytic Lymphoma
Drug: Ibrutinib
Drug: Chlorambucil
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A 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 (RESONATE™-2)

Resource links provided by NLM:


Further study details as provided by Pharmacyclics LLC.:

Primary Outcome Measures:
  • PFS (Progression Free Survival) [ Time Frame: 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. ] [ Designated as safety issue: No ]

    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 A

      • Lymphadenopathy, increase ≥50%
      • Hepatomegaly, increase ≥50%
      • Splenomegaly, increase ≥50%
      • Blood lymphocytes, increase ≥ 50% over baseline
    • Group B

      • Platelets counts, decrease of ≥ 50% from baseline secondary to CLL
      • Hemoglobin, decrease of > 2 g/dL from baseline secondary to CLL


Secondary Outcome Measures:
  • Overall Survival (OS) [ Time Frame: 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. ] [ Designated as safety issue: No ]
    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.

  • ORR (Overall Response Rate) [ Time Frame: 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. ] [ Designated as safety issue: No ]
    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.

  • Proportion of Sustained Hemoglobin Improvement [ Time Frame: 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. ] [ Designated as safety issue: No ]
    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.

  • Proportion of Sustained Hemoglobin Improvement in Subjects With Baseline Anemia [ Time Frame: 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. ] [ Designated as safety issue: No ]
    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.

  • Proportion of Sustained Platelet Improvement [ Time Frame: 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. ] [ Designated as safety issue: No ]
    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.

  • Proportion of Sustained Platelet Improvement in Subjects With Baseline Thrombocytopenia [ Time Frame: 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. ] [ Designated as safety issue: No ]
    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.


Enrollment: 269
Study Start Date: March 2013
Study Completion Date: May 2015
Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

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

Ages Eligible for Study:   65 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01722487

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

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Pharmacyclics LLC.
ClinicalTrials.gov Identifier: NCT01722487     History of Changes
Other Study ID Numbers: PCYC-1115-CA  2012-003967-23 
Study First Received: October 29, 2012
Results First Received: March 31, 2016
Last Updated: May 4, 2016
Health Authority: United States: Food and Drug Administration
Australia: Department of Health and Ageing Therapeutic Goods Administration
Belgium: Federal Agency for Medicinal Products and Health Products
Canada: Health Canada
China: Food and Drug Administration
Czech Republic: State Institute for Drug Control
Ireland: Irish Medicines Board
Israel: Israeli Health Ministry Pharmaceutical Administration
Italy: The Italian Medicines Agency
New Zealand: Food Safety Authority
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Russia: Ministry of Health of the Russian Federation
Spain: Agencia Española de Medicamentos y Productos Sanitarios
Turkey: Ministry of Health
Ukraine: State Pharmacological Center - Ministry of Health
United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Pharmacyclics LLC.:
CLL, SLL

Additional relevant MeSH terms:
Lymphoma
Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Chlorambucil
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents

ClinicalTrials.gov processed this record on December 05, 2016