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

NCT01578707 | Completed Phase 3 Results DMC

• 2 other identifiers: PCYC-1112-CA2012-000694-23
• Study Type: interventional
• Target: 391
• Locations: 9 countries
• Sites: 71

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)

Conditions

Relapsed or Refractory Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma

Keywords

Chronic; SLL; CLL; Ofatumumab; ibrutinib; RESONATE; Phase III; Leukemia; Lymphoma

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (3)

• Overall Response Rate (ORR) by Independent Review Committee (IRC)

  About 18 months after the first subject was enrolled

• OS (Overall Survival)

  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

  From study initiation to study closure, including up to 6 years of study follow-up

Other Outcomes (2)

• Progression Free Survival (PFS) 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

• Overall Response Rate (ORR) by Investigator

  From study initiation to study closure, including up to 6 years of study follow-up

Study Arms (2)

Ofatumumab (Arm A)

ACTIVE COMPARATOR

An anti-CD20 monoclonal antibody

Drug: ofatumumab

ibrutinib (Arm B)

EXPERIMENTAL

A Bruton Tyrosine Kinase Inhibitor

Drug: ibrutinib

Interventions

ofatumumab DRUG

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)

Ofatumumab (Arm A)

ibrutinib DRUG

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

ibrutinib (Arm B)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Pharmacyclics LLC.: lead
• Janssen Research & Development, LLC: collaborator

Study Sites (76)

Site #408

La Jolla, California, 92093-0698, United States

Location

Site #377

Los Angeles, California, 90095, United States

Location

Site #403

Santa Maria, California, 93454, United States

Location

Site #038

Stanford, California, 94035, United States

Location

Site #411

Norwalk, Connecticut, 06856, United States

Location

Site #107

Marietta, Georgia, 30060, United States

Location

Site # 379

Evansville, Indiana, 47713, United States

Location

Site # 390

Boston, Massachusetts, 02114, United States

Location

Site # 391

Boston, Massachusetts, 02115, United States

Location

Site # 349

Boston, Massachusetts, 02215, United States

Location

Site # 130

Detroit, Michigan, 48201, United States

Location

Site # 406

Rochester, Minnesota, 55901, United States

Location

Site # 059

New Brunswick, New Jersey, 08903, United States

Location

Site # 350

New Hyde Park, New York, 11042, United States

Location

Site # 200

New York, New York, 10065, United States

Location

Site # 127

Rochester, New York, 14642-0001, United States

Location

Site # 197

Cincinnati, Ohio, 45291, United States

Location

Site # 217

Columbus, Ohio, 43210, United States

Location

Site # 402

Philadelphia, Pennsylvania, 19104, United States

Location

Site # 396

Greenville, South Carolina, 29601, United States

Location

Site # 410

Nashville, Tennessee, 37232-5505, United States

Location

Site # 032

Houston, Texas, 77030, United States

Location

Site # 381

Laredo, Texas, 78041, United States

Location

Site # 210

Charlottesville, Virginia, 22908, United States

Location

Site # 404

Seattle, Washington, 98109, United States

Location

Site # 500

St Leonards, New South Wales, 2065, Australia

Location

Site # 503

Brisbane, Queensland, 4102, Australia

Location

Site # 199

East Melbourne, Victoria, 3002, Australia

Location

Site # 501

Fitzroy, Victoria, 3109, Australia

Location

Site # 502

Nedlands, Western Australia, 6009, Australia

Location

Site # 509

Graz, 8036, Austria

Location

Site # 508

Linz, 4010, Austria

Location

Site # 504

Salzburg, 5020, Austria

Location

Site # 505

Vienna, A-1090, Austria

Location

Site # 506

Wein, 1160, Austria

Location

Site # 507

Wels, A-4600, Austria

Location

Site # 393

Antwerp, 2060, Belgium

Location

Site # 519

Argenteuil, 95107, France

Location

Site # 511

Bobigny, 93009, France

Location

Site # 515

Bordeaux, 33076, France

Location

Site # 516

Caen, 14033, France

Location

Site # 513

Clermont-Ferrand, 63100, France

Location

Site # 510

Marseille, 13273, France

Location

Site # 520

Nantes, 44000, France

Location

Site # 518

Rennes, 35033, France

Location

Site # 517

Vandœuvre-lès-Nancy, 54511, France

Location

Site # 570

Dublin, 8, Ireland

Location

Site # 528

Dublin, 9, Ireland

Location

Site # 096

Galway, Ireland

Location

Site # 522

Milan, 20089, Italy

Location

Site # 523

Milan, 20132, Italy

Location

Site # 526

Milan, 20162, Italy

Location

Site # 524

Modena, 41124, Italy

Location

Site # 527

Padua, 35128, Italy

Location

Site # 529

Gdansk, 80-952, Poland

Location

Site # 531

Lodz, 93-510, Poland

Location

Site # 539

A Coruña, 15006A, Spain

Location

Site # 535

Barcelona, 08025, Spain

Location

Site # 534

Barcelona, 08035, Spain

Location

Site # 533

Barcelona, 08036, Spain

Location

Site # 540

Madrid, 28033, Spain

Location

Site # 537

Madrid, 28050, Spain

Location

Site # 536

Madrid, 28222, Spain

Location

Site # 538

Pamplona, 31008, Spain

Location

Site # 549

Colchester, Essex, CO4 5JL, United Kingdom

Location

Site # 543

Sutton, Surrey, SM2 5PT, United Kingdom

Location

Site # 551

Bournemouth, BH7 7DW, United Kingdom

Location

Site # 553

Canterbury, CT1 3NG, United Kingdom

Location

Site # 546

Cardiff, CF14 4XW, United Kingdom

Location

Site # 554

Headington, OX3 7LJ, United Kingdom

Location

Site # 550

Leeds, LS9 7TF, United Kingdom

Location

Site # 552

Liverpool, L7 8XP, United Kingdom

Location

Site # 544

London, SE5 9RS, United Kingdom

Location

Site # 548

Nottingham, NG5 1PB, United Kingdom

Location

Site # 545

Southampton, SO16 6YD, United Kingdom

Location

Site # 541

Withington, M20 4BX, United Kingdom

Location

Related Publications (9)

• Abuhelwa AY, Almansour SA, Brown JR, Al-Shamsi HO, Abuhelwa Z, Kharaba Z, Bustanji Y, Semreen MH, Ali S, Alhuraiji A, McKinnon RA, Sorich MJ, Alzoubi KH, Hopkins AM. Statin use and survival in CLL/SLL treated with ibrutinib: pooled analysis of 4 randomized controlled trials. Blood Adv. 2025 Jul 22;9(14):3566-3575. doi: 10.1182/bloodadvances.2024015287.

  PMID: 40266025 DERIVED

• 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.

  PMID: 31512258 DERIVED

• 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.

  PMID: 31196847 DERIVED

• 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.

  PMID: 30842083 DERIVED

• 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.

  PMID: 29470582 DERIVED

• 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.

  PMID: 28751558 DERIVED

• 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.

  PMID: 28373262 DERIVED

• 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.

  PMID: 26182309 DERIVED

• 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.

  PMID: 24881631 DERIVED

MeSH Terms

Conditions

Recurrence; Leukemia, Lymphocytic, Chronic, B-Cell; Bronchiolitis Obliterans Syndrome; Leukemia; Lymphoma

Interventions

ofatumumab; ibrutinib

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Leukemia, B-Cell; Leukemia, Lymphoid; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Organizing Pneumonia; Bronchiolitis Obliterans; Bronchiolitis; Bronchitis; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Graft vs Host Disease

Results Point of Contact

• Title: Anita Szoke
• Organization: Pharmacyclics, LLC

aszoke@pcyc.com

(669) 215-7235

Study Officials

• Anita Szoke, MD

  Pharmacyclics LLC.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 11, 2012
• First Posted: April 17, 2012
• Study Start: June 1, 2012
• Primary Completion: November 1, 2013
• Study Completion: October 25, 2018
• Last Updated: December 18, 2019
• Results First Posted: October 12, 2015

Record last verified: 2019-12

Locations

AU (6); PL (2); IT (5); GB (12); US (25); IE (3); FR (9); ES (8); BE (1)