Clinical trial NCT01578707: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Relapsed or Refractory Chronic Lymphocytic Leukemia
Small Lymphocytic Lymphoma
Keywords: Chronic
SLL
CLL
Ofatumumab
ibrutinib
RESONATE
Phase III
Leukemia
Lymphoma
Lead sponsor: Pharmacyclics LLC.
Sponsor class: INDUSTRY
Collaborators: name: Janssen Research & Development, LLC
First posted: 2012-04-17
Enrollment: 391
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: PFS (Progression Free Survival) by Independent Review Committee (IRC), Limited to the Time of Primary Analysis 06 November 2013
timeFrame: Analysis was conducted after observing approximately 117 PFS events, which occurred about 18 months after the first subject was enrolled.
Secondary outcomes:
measure: Overall Response Rate (ORR) by Independent Review Committee (IRC)
timeFrame: About 18 months after the first subject was enrolled
measure: OS (Overall Survival)
timeFrame: OS analysis was conducted at the time of study closure, including up to 6 years of study follow-up
measure: Rate of Sustained Hemoglobin and Platelet Improvement
timeFrame: From study initiation to study closure, including up to 6 years of study follow-up
Other outcomes:
measure: Progression Free Survival (PFS) by Investigator With up to 6 Years of Study Follow-up
timeFrame: From study initiation to study closure, including up to 6 years of study follow-up
measure: Overall Response Rate (ORR) by Investigator
timeFrame: From study initiation to study closure, including up to 6 years of study follow-up
Locations:
city: La Jolla
country: United States
facility: Site #408
state: California
city: Los Angeles
country: United States
facility: Site #377
state: California
city: Santa Maria
country: United States
facility: Site #403
state: California
city: Stanford
country: United States
facility: Site #038
state: California
city: Norwalk
country: United States
facility: Site #411
state: Connecticut
city: Marietta
country: United States
facility: Site #107
state: Georgia
city: Evansville
country: United States
facility: Site # 379
state: Indiana
city: Boston
country: United States
facility: Site # 390
state: Massachusetts
city: Boston
country: United States
facility: Site # 391
state: Massachusetts
city: Boston
country: United States
facility: Site # 349
state: Massachusetts
city: Detroit
country: United States
facility: Site # 130
state: Michigan
city: Rochester
country: United States
facility: Site # 406
state: Minnesota
city: New Brunswick
country: United States
facility: Site # 059
state: New Jersey
city: New Hyde Park
country: United States
facility: Site # 350
state: New York
city: New York
country: United States
facility: Site # 200
state: New York
city: Rochester
country: United States
facility: Site # 127
state: New York
city: Cincinnati
country: United States
facility: Site # 197
state: Ohio
city: Columbus
country: United States
facility: Site # 217
state: Ohio
city: Philadelphia
country: United States
facility: Site # 402
state: Pennsylvania
city: Greenville
country: United States
facility: Site # 396
state: South Carolina
city: Nashville
country: United States
facility: Site # 410
state: Tennessee
city: Houston
country: United States
facility: Site # 032
state: Texas
city: Laredo
country: United States
facility: Site # 381
state: Texas
city: Charlottesville
country: United States
facility: Site # 210
state: Virginia
city: Seattle
country: United States
facility: Site # 404
state: Washington
city: St. Leonards
country: Australia
facility: Site # 500
state: New South Wales
city: Brisbane
country: Australia
facility: Site # 503
state: Queensland
city: East Melbourne
country: Australia
facility: Site # 199
state: Victoria
city: Fitzroy
country: Australia
facility: Site # 501
state: Victoria
city: Nedlands
country: Australia
facility: Site # 502
state: Western Australia
city: Graz
country: Austria
facility: Site # 509
city: Linz
country: Austria
facility: Site # 508
city: Salzburg
country: Austria
facility: Site # 504
city: Vienna
country: Austria
facility: Site # 505
city: Wein
country: Austria
facility: Site # 506
city: Wels
country: Austria
facility: Site # 507
city: Antwerpen
country: Belgium
facility: Site # 393
city: Argenteuil
country: France
facility: Site # 519
city: Bobigny
country: France
facility: Site # 511
city: Bordeaux
country: France
facility: Site # 515
city: Caen
country: France
facility: Site # 516
city: Clermont Ferrand
country: France
facility: Site # 513
city: Marseille
country: France
facility: Site # 510
city: Nantes
country: France
facility: Site # 520
city: Rennes
country: France
facility: Site # 518
city: Vandœuvre-lès-Nancy
country: France
facility: Site # 517
city: Dublin
country: Ireland
facility: Site # 570
city: Dublin
country: Ireland
facility: Site # 528
city: Galway
country: Ireland
facility: Site # 096
city: Milano
country: Italy
facility: Site # 522
city: Milano
country: Italy
facility: Site # 523
city: Milano
country: Italy
facility: Site # 526
city: Modena
country: Italy
facility: Site # 524
city: Padova
country: Italy
facility: Site # 527
city: Gdansk
country: Poland
facility: Site # 529
city: Lodz
country: Poland
facility: Site # 531
city: Barcelona
country: Spain
facility: Site # 535
city: Barcelona
country: Spain
facility: Site # 534
city: Barcelona
country: Spain
facility: Site # 533
city: Coruna
country: Spain
facility: Site # 539
city: Madrid
country: Spain
facility: Site # 540
city: Madrid
country: Spain
facility: Site # 537
city: Madrid
country: Spain
facility: Site # 536
city: Pamplona
country: Spain
facility: Site # 538
city: Colchester
country: United Kingdom
facility: Site # 549
state: Essex
city: Sutton
country: United Kingdom
facility: Site # 543
state: Surrey
city: Bournemouth
country: United Kingdom
facility: Site # 551
city: Canterbury
country: United Kingdom
facility: Site # 553
city: Cardiff
country: United Kingdom
facility: Site # 546
city: Headington
country: United Kingdom
facility: Site # 554
city: Leeds
country: United Kingdom
facility: Site # 550
city: Liverpool
country: United Kingdom
facility: Site # 552
city: London
country: United Kingdom
facility: Site # 544
city: Nottingham
country: United Kingdom
facility: Site # 548
city: Southampton
country: United Kingdom
facility: Site # 545
city: Withington
country: United Kingdom
facility: Site # 541
Study officials:
affiliation: Pharmacyclics LLC.
name: Anita Szoke, MD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.