Relapsed or Refractory Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma
Conditions
Keywords
Chronic, SLL, CLL, Ofatumumab, ibrutinib, RESONATE, Phase III, Leukemia, 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.
Interventions
DRUGofatumumab
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)
DRUGibrutinib
ibrutinib 420 mg (3 x 140-mg capsules) will be administered orally once daily until disease progression or unacceptable toxicity
Sponsors
Janssen Research & Development, LLC
Pharmacyclics LLC.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PFS (Progression Free Survival) by Independent Review Committee (IRC), Limited to the Time of Primary Analysis 06 November 2013 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) by Independent Review Committee (IRC) | 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) | 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 | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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 | 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 |
Countries
Australia, Austria, Belgium, France, Ireland, Italy, Poland, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ofatumumab (Arm A) An anti-CD20 monoclonal antibody
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) | 196 |
| Ibrutinib (Arm B) A Bruton Tyrosine Kinase Inhibitor
ibrutinib: ibrutinib 420 mg (3 x 140-mg capsules) will be administered orally once daily until disease progression or unacceptable toxicity | 195 |
| Total | 391 |
Baseline characteristics
| Characteristic | Ofatumumab (Arm A) | Ibrutinib (Arm B) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 121 Participants | 118 Participants | 239 Participants |
| Age, Categorical Between 18 and 65 years | 75 Participants | 77 Participants | 152 Participants |
| Age, Continuous | 66.8 years STANDARD_DEVIATION 8.88 | 66.1 years STANDARD_DEVIATION 10.15 | 66.5 years STANDARD_DEVIATION 9.53 |
| Sex: Female, Male Female | 59 Participants | 66 Participants | 125 Participants |
| Sex: Female, Male Male | 137 Participants | 129 Participants | 266 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 16 / 191 | 24 / 195 |
| other Total, other adverse events | 185 / 191 | 194 / 195 |
| serious Total, serious adverse events | 59 / 191 | 141 / 195 |
Outcome results
Primary
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.
Time frame: Analysis was conducted after observing approximately 117 PFS events, which occurred about 18 months after the first subject was enrolled.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ofatumumab (Arm A) | PFS (Progression Free Survival) by Independent Review Committee (IRC), Limited to the Time of Primary Analysis 06 November 2013 | 8.1 months |
| Ibrutinib (Arm B) | PFS (Progression Free Survival) by Independent Review Committee (IRC), Limited to the Time of Primary Analysis 06 November 2013 | NA months |
p-value: <0.0001Log Rank
Secondary
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
Time frame: OS analysis was conducted at the time of study closure, including up to 6 years of study follow-up
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ofatumumab (Arm A) | OS (Overall Survival) | 65.1 months |
| Ibrutinib (Arm B) | OS (Overall Survival) | 67.7 months |
p-value: 0.1653Log Rank
Secondary
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
Time frame: About 18 months after the first subject was enrolled
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ofatumumab (Arm A) | Overall Response Rate (ORR) by Independent Review Committee (IRC) | 4.1 percentage of participants |
| Ibrutinib (Arm B) | Overall Response Rate (ORR) by Independent Review Committee (IRC) | 42.6 percentage of participants |
p-value: <0.0001Fisher Exact
Secondary
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.
Time frame: From study initiation to study closure, including up to 6 years of study follow-up
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ofatumumab (Arm A) | Rate of Sustained Hemoglobin and Platelet Improvement | Hgb Improvement in patient with baseline anemia | 32.6 percentage of participants |
| Ofatumumab (Arm A) | Rate of Sustained Hemoglobin and Platelet Improvement | Platelet improvement in baseline thrombocytopenia | 9.4 percentage of participants |
| Ibrutinib (Arm B) | Rate of Sustained Hemoglobin and Platelet Improvement | Hgb Improvement in patient with baseline anemia | 69.7 percentage of participants |
| Ibrutinib (Arm B) | Rate of Sustained Hemoglobin and Platelet Improvement | Platelet improvement in baseline thrombocytopenia | 78.4 percentage of participants |
Other Pre-specified
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
Time frame: From study initiation to study closure, including up to 6 years of study follow-up
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ofatumumab (Arm A) | Overall Response Rate (ORR) by Investigator | 22.4 percentage of participants |
| Ibrutinib (Arm B) | Overall Response Rate (ORR) by Investigator | 87.7 percentage of participants |
Other Pre-specified
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
Time frame: From study initiation to study closure, including up to 6 years of study follow-up
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ofatumumab (Arm A) | Progression Free Survival (PFS) by Investigator With up to 6 Years of Study Follow-up | 8.1 months |
| Ibrutinib (Arm B) | Progression Free Survival (PFS) by Investigator With up to 6 Years of Study Follow-up | 44.1 months |