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

• ClinicalTrials.gov Identifier: NCT01578707
• Recruitment Status: Completed
• First Posted: April 17, 2012
• Results First Posted: October 12, 2015
• Last Update Posted: December 18, 2019
• Sponsor: Pharmacyclics LLC.
• Collaborator: Janssen Research & Development, LLC
• Information provided by (Responsible Party): Pharmacyclics LLC.

Tracking Information

• First Submitted Date: April 11, 2012
• First Posted Date: April 17, 2012
• Results First Submitted Date: June 23, 2015
• Results First Posted Date: October 12, 2015
• Last Update Posted Date: December 18, 2019
• Actual Study Start Date: June 2012
• Actual Primary Completion Date: November 2013 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 3, 2019)

PFS (Progression Free Survival) by Independent Review Committee (IRC), Limited to the Time of Primary Analysis 06 November 2013 [ Time Frame: Analysis was conducted after observing approximately 117 PFS events, which occurred about 18 months after the first subject was enrolled. ]

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.

• Original Primary Outcome Measures (submitted: April 13, 2012): PFS (Progression Free Survival) [ Time Frame: 2 years ]

Current Secondary Outcome Measures (submitted: December 3, 2019)

• Overall Response Rate (ORR) by Independent Review Committee (IRC) [ Time Frame: About 18 months after the first subject was enrolled ]
  Overall Response Rate per the IWCLL 2008 criteria as assessed by IRC, limited to the time of primary analysis 06 November 2013
• OS (Overall Survival) [ Time Frame: OS analysis was conducted at the time of study closure, including up to 6 years of study follow-up ]
  OS analysis was conducted at the time of study closure, with no adjustment for crossover from the ofatumumab arm to the ibrutinib arm
• Rate of Sustained Hemoglobin and Platelet Improvement [ Time Frame: From study initiation to study closure, including up to 6 years of study follow-up ]
  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.

Original Secondary Outcome Measures (submitted: April 13, 2012)

• ORR (Overall Response Rate) [ Time Frame: 2 years ]
• OS (Overall Survival) [ Time Frame: 3 years ]
• Hematological Improvements [ Time Frame: 2 years ]
• Investigator-assessed PFS [ Time Frame: Time from randomization until disease progression ]
• Investigator-assessed ORR [ Time Frame: 2 years ]
• Improvement of disease-related symptoms (fatigue, night sweats, and splenomegaly). [ Time Frame: 2 years ]

Current Other Pre-specified Outcome Measures (submitted: December 3, 2019)

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

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Phase 3 Study of Ibrutinib (PCI-32765) Versus Ofatumumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia
• Official Title: 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
• Brief Summary: 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)

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
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Relapsed or Refractory Chronic Lymphocytic Leukemia
• Small Lymphocytic Lymphoma

Intervention

• 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)

• Drug: ibrutinib
  ibrutinib 420 mg (3 x 140-mg capsules) will be administered orally once daily until disease progression or unacceptable toxicity

Study Arms

• Active Comparator: Ofatumumab (Arm A)
  An anti-CD20 monoclonal antibody
  Intervention: Drug: ofatumumab
• Experimental: ibrutinib (Arm B)
  A Bruton Tyrosine Kinase Inhibitor
  Intervention: Drug: ibrutinib

Publications *

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 16, 2013): 391
• Original Estimated Enrollment (submitted: April 13, 2012): 350
• Actual Study Completion Date: October 25, 2018
• Actual Primary Completion Date: November 2013 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Austria, Belgium, France, Ireland, Italy, Poland, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT01578707
• Other Study ID Numbers: PCYC-1112-CA; 2012-000694-23 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Pharmacyclics LLC.
• Original Responsible Party: Same as current
• Current Study Sponsor: Pharmacyclics LLC.
• Original Study Sponsor: Same as current
• Collaborators: Janssen Research & Development, LLC

Investigators

• Study Director: Anita Szoke, MD; Pharmacyclics LLC.

• PRS Account: Pharmacyclics LLC.
• Verification Date: December 2019