A Phase 2 Multicenter Study to Assess the Activity and the Safety of Front-line Ibrutinib Plus Rituximab (IR) in Unfit Patients With Chronic Lymphocytic Leukemia (CLL).
Overview
- Phase
- Phase 2
- Intervention
- Ibrutinib
- Conditions
- Chronic Lymphocyte Leukemia
- Sponsor
- Gruppo Italiano Malattie EMatologiche dell'Adulto
- Enrollment
- 156
- Locations
- 36
- Primary Endpoint
- Number of patients on progression-free survival
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
The present study aims at evaluating whether treatment with two different drugs, Ibrutinib and Rituximab is both efficient and safe for newly diagnosed patients with chronic lymphocytic leukemia.
Detailed Description
Given that: * Ibrutinib as single agent has been associated with a high response rate and PFS in previously treated patients, and in patients with poor prognosis clinical and biologic features. * Ibrutinib as single agent has proven activity and is associated with a good safety profile in elderly patients with CLL. * The Ibrutinib plus Rituximab combination has been associated with a high response rate and PFS in previously treated patients, and in patients with poor prognosis clinical and biologic features. * The combined administration of Ibrutinib and Rituximab could be an effective and safe front-line treatment schedule for unfit patients with CLL. * The current study is designed to evaluate whether first line treatment with Ibrutinib and Rituximab results in a significant improvement in PFS at 12 months as compared with chlorambucil plus rituximab in patients unfit for fludarabine- or bendamustine-based treatments.
Investigators
Eligibility Criteria
Inclusion Criteria
- •18 years of age or older.
- •Diagnosis of CLL meeting IWCLL criteria.
- •The diagnosis of CLL requires a history of lymphocytosis with a B-lymphocyte count ≥5,000/μL. Prolymphocytes may comprise no more than 55% of blood lymphocytes.
- •Active disease meeting at least 1 of the following IWCLL 2008 criteria for requiring treatment:
- •Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia or thrombocytopenia.
- •Massive (ie, at least 6 cm below the left costal margin), progressive, or symptomatic splenomegaly.
- •Massive nodes (ie, at least 10 cm in longest diameter), progressive, or symptomatic lymphadenopathy.
- •Progressive lymphocytosis with an increase of more than 50% over a 2-month period or a lymphocyte doubling time (LDT) of less than 6 months (which may be extrapolated). Lymphocyte doubling time can be obtained by linear regression extrapolation of ALCs obtained at intervals of 2 weeks over an observation period of 2 to 3 months. For patients with initial blood lymphocyte counts of less than 30 x 109/L (30,000/μL), LDT should not be used as a single parameter to define indication for treatment. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (eg, infections) should be excluded.
- •Constitutional symptoms, defined as 1 or more of the following disease-related symptoms or signs:
- •Unintentional weight loss \>10% within the previous 6 months prior to screening
Exclusion Criteria
- •Any significant concurrent, uncontrolled medical condition or organ system dysfunction and/or laboratory abnormality or psychiatric disease which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk or prevent the subject from signing the informed consent form.
- •Pregnant or lactating females
- •Known presence of alcohol and/or drug abuse.
- •Any potential subject who meets any of the following criteria will be excluded from participating in the study.
- •Major surgery within 4weeks of randomization.
- •Uncontrolled autoimmune hemolytic anemia or thrombocytopenia.
- •Known central nervous system lymphoma.
- •History of stroke or intracranial hemorrhage within 6 months prior to randomization, or of a significant cerebrovascular disease in the past 6 months or ongoing event with active symptoms or sequelae.
- •Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) in any moment of the study.
- •Requires treatment with strong CYP3A inhibitors.
Arms & Interventions
Treatment
Ibrutinib (PCI-32765) 420 mg (3 x 140 mg capsules) will be administered orally once daily. The first dose will be delivered in the clinic on Day 1, after which subsequent dosing is typically on an outpatient basis. Treatment duration with Ibrutinib will be based on what comes first of the following three options: * Treatment until progression or toxicity * Treatment until MRD negativity for 6 months * Treatment for 6 years. Rituximab 375 mg/m2 iv. Month 1: day 1 of weeks 1, 2, 3, 4; months 2-6: day 1of week 1.
Intervention: Ibrutinib
Treatment
Ibrutinib (PCI-32765) 420 mg (3 x 140 mg capsules) will be administered orally once daily. The first dose will be delivered in the clinic on Day 1, after which subsequent dosing is typically on an outpatient basis. Treatment duration with Ibrutinib will be based on what comes first of the following three options: * Treatment until progression or toxicity * Treatment until MRD negativity for 6 months * Treatment for 6 years. Rituximab 375 mg/m2 iv. Month 1: day 1 of weeks 1, 2, 3, 4; months 2-6: day 1of week 1.
Intervention: Rituximab
Outcomes
Primary Outcomes
Number of patients on progression-free survival
Time Frame: At 12 months from treatment start
To estimate Progression-Free Survival (PFS) at 12 months in patients treated with Ibrutinib plus Rituximab combination in unfit patients with CLL.
Secondary Outcomes
- Number of patients in complete response (CR) or partial response (OR)(At the end of induction therapy, that is, 7 months from treatment start)
- Number of patients in CR(At the end of induction therapy, that is, at 7 months from treatment start)
- Number of patients in event-free survival(At 36 months from treatment start)
- Number of patients in overall survival (OS)(At 36 months from treatment start)
- Number of patients in which there is a hematological improvement(At the end of the study, that is, at 90 months from treatment start)
- Number of patients with improvement in the immunoglobulin levels(At 90 months from treatment start)
- Number of negative minimal residual disease CRs(At the end of induction therapy, that is, at 7 months from treatment start)
- Number of days from treatment discontinuation to new treatment restart.(At the end of the study, that is, 90 months from treatment start)
- Number of adverse events and serious adverse events(At 90 months from study start)
- Number of patients requiring hospitalization(At 90 months from study entry)
- Number of patients in which clinical and biological features can be linked(At 90 months from study entry)
- Number of leukemic subpopulations(At 90 months from start)
- Number of patients with RS identified by FDG-PET/CT(At 90 months from study start)