A Phase 3 Study of Ibrutinib (PCI-32765) Versus Ofatumumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia (RESONATE™)

A Randomized, Multicenter, Open-label, Phase 3 Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor Ibrutinib (PCI-32765) Versus Ofatumumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

The purpose of the study is to evaluate whether treatment with ibrutinib as a monotherapy results in a clinically significant improvement in progression free survival (PFS) as compared to treatment with ofatumumab in patients with relapsed or refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

Study Overview

• Status: Completed
• Conditions: Relapsed or Refractory Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma
• Intervention / Treatment: Drug: ofatumumab; Drug: ibrutinib

Detailed Description

Study PCYC-1112-CA is a randomized, multicenter, open-label, phase 3 study of the Bruton's Tyrosine Kinase (BTK) inhibitor Ibrutinib (PCI-32765) versus Ofatumumab in patients with Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma.

Patients randomized to the ofatumumab arm may be considered to receive next subsequent therapy with ibrutinib.

• Study Type: Interventional
• Enrollment (Actual): 391
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • St. Leonards, New South Wales, Australia, 2065
      • Site # 500
  • Queensland
    • Brisbane, Queensland, Australia, 4102
      • Site # 503
  • Victoria
    • East Melbourne, Victoria, Australia, 3002
      • Site # 199
    • Fitzroy, Victoria, Australia, 3109
      • Site # 501
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Site # 502
• Austria
  • Graz, Austria, 8036
    • Site # 509
  • Linz, Austria, 4010
    • Site # 508
  • Salzburg, Austria, 5020
    • Site # 504
  • Vienna, Austria, A-1090
    • Site # 505
  • Wein, Austria, 1160
    • Site # 506
  • Wels, Austria, A-4600
    • Site # 507
• Belgium
  • Antwerpen, Belgium, 2060
    • Site # 393
• France
  • Argenteuil, France, 95107
    • Site # 519
  • Bobigny, France, 93009
    • Site # 511
  • Bordeaux, France, 33076
    • Site # 515
  • Caen, France, 14033
    • Site # 516
  • Clermont Ferrand, France, 63100
    • Site # 513
  • Marseille, France, 13273
    • Site # 510
  • Nantes, France, 44000
    • Site # 520
  • Rennes, France, 35033
    • Site # 518
  • Vandœuvre-lès-Nancy, France, 54511
    • Site # 517
• Ireland
  • Dublin, Ireland, 8
    • Site # 570
  • Dublin, Ireland, 9
    • Site # 528
  • Galway, Ireland
    • Site # 096
• Italy
  • Milano, Italy, 20089
    • Site # 522
  • Milano, Italy, 20132
    • Site # 523
  • Milano, Italy, 20162
    • Site # 526
  • Modena, Italy, 41124
    • Site # 524
  • Padova, Italy, 35128
    • Site # 527
• Poland
  • Gdansk, Poland, 80-952
    • Site # 529
  • Lodz, Poland, 93-510
    • Site # 531
• Spain
  • Barcelona, Spain, 08025
    • Site # 535
  • Barcelona, Spain, 08035
    • Site # 534
  • Barcelona, Spain, 08036
    • Site # 533
  • Coruna, Spain, 15006A
    • Site # 539
  • Madrid, Spain, 28033
    • Site # 540
  • Madrid, Spain, 28050
    • Site # 537
  • Madrid, Spain, 28222
    • Site # 536
  • Pamplona, Spain, 31008
    • Site # 538
• United Kingdom
  • Bournemouth, United Kingdom, BH7 7DW
    • Site # 551
  • Canterbury, United Kingdom, CT1 3NG
    • Site # 553
  • Cardiff, United Kingdom, CF14 4XW
    • Site # 546
  • Headington, United Kingdom, OX3 7LJ
    • Site # 554
  • Leeds, United Kingdom, LS9 7TF
    • Site # 550
  • Liverpool, United Kingdom, L7 8XP
    • Site # 552
  • London, United Kingdom, SE5 9RS
    • Site # 544
  • Nottingham, United Kingdom, NG5 1PB
    • Site # 548
  • Southampton, United Kingdom, SO16 6YD
    • Site # 545
  • Withington, United Kingdom, M20 4BX
    • Site # 541
  • Essex
    • Colchester, Essex, United Kingdom, CO4 5JL
      • Site # 549
  • Surrey
    • Sutton, Surrey, United Kingdom, SM2 5PT
      • Site # 543
• United States
  • California
    • La Jolla, California, United States, 92093-0698
      • Site #408
    • Los Angeles, California, United States, 90095
      • Site #377
    • Santa Maria, California, United States, 93454
      • Site #403
    • Stanford, California, United States, 94035
      • Site #038
  • Connecticut
    • Norwalk, Connecticut, United States, 06856
      • Site #411
  • Georgia
    • Marietta, Georgia, United States, 30060
      • Site #107
  • Indiana
    • Evansville, Indiana, United States, 47713
      • Site # 379
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Site # 390
    • Boston, Massachusetts, United States, 02115
      • Site # 391
    • Boston, Massachusetts, United States, 02215
      • Site # 349
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Site # 130
  • Minnesota
    • Rochester, Minnesota, United States, 55901
      • Site # 406
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • Site # 059
  • New York
    • New Hyde Park, New York, United States, 11042
      • Site # 350
    • New York, New York, United States, 10065
      • Site # 200
    • Rochester, New York, United States, 14642-0001
      • Site # 127
  • Ohio
    • Cincinnati, Ohio, United States, 45291
      • Site # 197
    • Columbus, Ohio, United States, 43210
      • Site # 217
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Site # 402
  • South Carolina
    • Greenville, South Carolina, United States, 29601
      • Site # 396
  • Tennessee
    • Nashville, Tennessee, United States, 37232-5505
      • Site # 410
  • Texas
    • Houston, Texas, United States, 77030
      • Site # 032
    • Laredo, Texas, United States, 78041
      • Site # 381
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • Site # 210
  • Washington
    • Seattle, Washington, United States, 98109
      • Site # 404

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• ECOG performance status of 0-1.
• Diagnosis of CLL or SLL that meets IWCLL 2008 criteria.
• Active disease meeting at least 1 of the IWCLL 2008 criteria for requiring treatment.
• Must have received at least one prior therapy for CLL/SLL.
• Considered not appropriate for treatment or retreatment with purine analog based therapy.
• Measurable nodal disease by CT.
• Patients must be able to receive outpatient treatment and laboratory monitoring at the institution that administers study drug for the entire study.

Exclusion Criteria:

• Known CNS lymphoma or leukemia.
• No documentation of cytogenetic and/or FISH in patient records prior to first dose of study drug.
• Any history of Richter's transformation or prolymphocytic leukemia.
• Uncontrolled Autoimmune Hemolytic Anemia (AIHA) or idiopathic thrombocytopenia purpura (ITP).
• Prior exposure to ofatumumab or to ibrutinib.
• Prior autologous transplant within 6 months prior to first dose of study drug.
• Prior allogeneic stem cell transplant within 6 months or with any evidence of active graft versus host disease or requirement for immunosuppressants within 28 days prior to first dose of study drug.
• History of prior malignancy, with the exception of certain skin cancers and malignancies treated with curative intent and with no evidence of active disease for more than 3 years.
• Serologic status reflecting active hepatitis B or C infection.
• Unable to swallow capsules or disease significantly affecting gastrointestinal function.
• Uncontrolled active systemic fungal, bacterial, viral, or other infection.
• History of stroke or intracranial hemorrhage within 6 months prior to the first dose of study drug.
• Requires anticoagulation with warfarin.

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
Active Comparator: Ofatumumab (Arm A); An anti-CD20 monoclonal antibody	Drug: ofatumumab; The ofatumumab (IV) dosage and schedule is 12 doses administered over 24 weeks or until disease progression, unacceptable toxicity. Week 1: 300 mg initial dose Week 2 through 8: 2,000 mg (once weekly) Week 12, 16, 20 and 24: 2,000 mg (every 4 weeks)
Experimental: ibrutinib (Arm B); A Bruton Tyrosine Kinase Inhibitor	Drug: ibrutinib; ibrutinib 420 mg (3 x 140-mg capsules) will be administered orally once daily until disease progression or unacceptable toxicity

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PFS (Progression Free Survival) by Independent Review Committee (IRC), Limited to the Time of Primary Analysis 06 November 2013	The primary objective of this study was to evaluate the efficacy of ibrutinib compared to ofatumumab based on independent review committee (IRC) assessment of progression-free survival (PFS) according to 2008 IWCLL guidelines.	Analysis was conducted after observing approximately 117 PFS events, which occurred about 18 months after the first subject was enrolled.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR) by Independent Review Committee (IRC)	Overall Response Rate per the IWCLL 2008 criteria as assessed by IRC, limited to the time of primary analysis 06 November 2013	About 18 months after the first subject was enrolled
OS (Overall Survival)	OS analysis was conducted at the time of study closure, with no adjustment for crossover from the ofatumumab arm to the ibrutinib arm	OS analysis was conducted at the time of study closure, including up to 6 years of study follow-up
Rate of Sustained Hemoglobin and Platelet Improvement	Proportion of subjects with hemoglobin (HgB) increase >=20 g/L and platelet (PLT) increase >=50% over baseline continuously for >=56 days without blood transfusions or growth factors.	From study initiation to study closure, including up to 6 years of study follow-up

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS) by Investigator With up to 6 Years of Study Follow-up	Long-Term Progression Free Survival as assessed by the investigator with up to 6 years of study follow-up	From study initiation to study closure, including up to 6 years of study follow-up
Overall Response Rate (ORR) by Investigator	Overall response per the IWCLL 2008 criteria as assessed by Investigator with up to 6 years of study follow-up	From study initiation to study closure, including up to 6 years of study follow-up

Collaborators and Investigators

• Sponsor: Pharmacyclics LLC.
• Collaborators: Janssen Research & Development, LLC
• Investigators: Study Director: Anita Szoke, MD, Pharmacyclics LLC.

Publications and helpful links

General Publications

• Maddocks KJ, Ruppert AS, Lozanski G, Heerema NA, Zhao W, Abruzzo L, Lozanski A, Davis M, Gordon A, Smith LL, Mantel R, Jones JA, Flynn JM, Jaglowski SM, Andritsos LA, Awan F, Blum KA, Grever MR, Johnson AJ, Byrd JC, Woyach JA. Etiology of Ibrutinib Therapy Discontinuation and Outcomes in Patients With Chronic Lymphocytic Leukemia. JAMA Oncol. 2015 Apr;1(1):80-7. doi: 10.1001/jamaoncol.2014.218.
• 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.
• 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.
• O'Brien SM, Jaglowski S, Byrd JC, Bannerji R, Blum KA, Fox CP, Furman RR, Hillmen P, Kipps TJ, Montillo M, Sharman J, Suzuki S, James DF, Chu AD, Coutre SE. Prognostic Factors for Complete Response to Ibrutinib in Patients With Chronic Lymphocytic Leukemia: A Pooled Analysis of 2 Clinical Trials. JAMA Oncol. 2018 May 1;4(5):712-716. doi: 10.1001/jamaoncol.2017.5604.
• Munir T, Brown JR, O'Brien S, Barrientos JC, Barr PM, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Kipps TJ, Moreno C, Montillo M, Burger JA, Byrd JC, Hillmen P, Dai S, Szoke A, Dean JP, Woyach JA. Final analysis from RESONATE: Up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma. Am J Hematol. 2019 Dec;94(12):1353-1363. doi: 10.1002/ajh.25638. Epub 2019 Oct 13.
• Byrd JC, Hillmen P, O'Brien S, Barrientos JC, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Barr PM, Furman RR, Kipps TJ, Thornton P, Moreno C, Montillo M, Pagel JM, Burger JA, Woyach JA, Dai S, Vezan R, James DF, Brown JR. Long-term follow-up of the RESONATE phase 3 trial of ibrutinib vs ofatumumab. Blood. 2019 May 9;133(19):2031-2042. doi: 10.1182/blood-2018-08-870238. Epub 2019 Mar 6.
• Barr PM, Brown JR, Hillmen P, O'Brien S, Barrientos JC, Reddy NM, Coutre S, Mulligan SP, Jaeger U, Furman RR, Cymbalista F, Montillo M, Dearden C, Robak T, Moreno C, Pagel JM, Burger JA, Suzuki S, Sukbuntherng J, Cole G, James DF, Byrd JC. Impact of ibrutinib dose adherence on therapeutic efficacy in patients with previously treated CLL/SLL. Blood. 2017 May 11;129(19):2612-2615. doi: 10.1182/blood-2016-12-737346. Epub 2017 Apr 3.
• Byrd JC, Brown JR, O'Brien S, Barrientos JC, Kay NE, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Devereux S, Barr PM, Furman RR, Kipps TJ, Cymbalista F, Pocock C, Thornton P, Caligaris-Cappio F, Robak T, Delgado J, Schuster SJ, Montillo M, Schuh A, de Vos S, Gill D, Bloor A, Dearden C, Moreno C, Jones JJ, Chu AD, Fardis M, McGreivy J, Clow F, James DF, Hillmen P; RESONATE Investigators. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014 Jul 17;371(3):213-23. doi: 10.1056/NEJMoa1400376. Epub 2014 May 31.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2012
• Primary Completion (Actual): November 1, 2013
• Study Completion (Actual): October 25, 2018

Study Registration Dates

• First Submitted: April 11, 2012
• First Submitted That Met QC Criteria: April 13, 2012
• First Posted (Estimate): April 17, 2012

Study Record Updates

• Last Update Posted (Actual): December 18, 2019
• Last Update Submitted That Met QC Criteria: December 3, 2019
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Keywords: Ofatumumab; Lymphoma; Phase III; Leukemia; CLL; Chronic; ibrutinib; SLL; RESONATE
• 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; Antineoplastic Agents; Ofatumumab
• Other Study ID Numbers: PCYC-1112-CA; 2012-000694-23 (EudraCT Number)