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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Relapsed or Refractory Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma

Intervention / Treatment
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* Drug: ofatumumab
* Drug: ibrutinib


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Ofatumumab (Arm A)<br>An anti-CD20 monoclonal antibody | Drug: ofatumumab<br>* 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)<br>|
| Experimental: ibrutinib (Arm B)<br>A Bruton Tyrosine Kinase Inhibitor | Drug: ibrutinib<br>* ibrutinib 420 mg (3 x 140-mg capsules) will be administered orally once daily until disease progression or unacceptable toxicity<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic, SLL, CLL, Ofatumumab, ibrutinib, RESONATE, Phase III, Leukemia, Lymphoma