A Phase 3, Double-blind, Randomized Study to Compare the Efficacy and Safety of Rituximab Plus Lenalidomide (CC-5013) Versus Rituximab Plus Placebo in Subjects With Relapsed/Refractory Indolent Lymphoma
Overview
- Phase
- Phase 3
- Status
- Completed
- Sponsor
- Celgene
- Enrollment
- 358
- Locations
- 160
- Primary Endpoint
- Kaplan Meier Estimate of Progression Free Survival Assessed by the Independent Review Committee (IRC) According to the 2007 International Working Group Response Criteria (IWGRC)
Overview
Brief Summary
This double-blind randomized, parallel group study will evaluate the efficacy and safety of lenalidomide (Revlimid, CC-5013) in combination with rituximab (MabThera/Rituxan) in patients with relapsed or refractory follicular lymphoma or marginal zone lymphoma. Patients will be randomized to receive either lenalidomide or placebo for twelve 28-day cycles in combination with rituximab. Anticipated time on study treatment is 1 year.
Detailed Description
Indolent lymphoma is a slow growing but incurable lymphoma which includes follicular lymphoma and marginal zone lymphoma. Follicular lymphoma and marginal zone lymphoma are cancers of the B lymphocyte, a type of white blood cell. Lenalidomide is an immunomodulatory drug (a drug that affects the immune system) which alters the body's immune system and it may also interfere with the development of tiny blood vessels involved in tumor growth. Therefore, lenalidomide may reduce or prevent the growth of cancer cells. Lenalidomide has also been shown to restore the immune cells' ability to attack and kill tumor cells, an ability that may be inhibited by follicular lymphoma and other lymphomas. The combination of rituximab and lenalidomide may eliminate the cancer while restoring the immune system's ability to attack tumor cells.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Age ≥18 years at the time of signing the informed consent document.
- •Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures are conducted.
- •Histologically confirmed marginal zone lymphoma or follicular lymphoma (grade 1, 2 or 3a; CD20+ by flow cytometry or histochemistry).
- •Previously treated with at least one prior systemic chemotherapy, immunotherapy or chemoimmunotherapy and have received at least 2 previous doses of rituximab.
- •Documented relapsed, refractory or progressive disease after treatment with systemic therapy and must not be rituximab-refractory.
- •Investigator considers rituximab monotherapy appropriate.
- •Bi-dimensionally measurable disease on cross sectional imaging by X-ray computed tomography (CT) or magnetic resonance imaging (MRI).
- •Need of treatment for relapsed, progressed or refractory disease as assessed by the investigator.
- •Eastern Cooperative Oncology Group (ECOG) performance status ≤
- •Adequate bone marrow function.
Exclusion Criteria
- •Histology other than follicular or marginal zone lymphoma or clinical evidence of transformation or Grade 3b follicular lymphoma.
- •Subjects taking corticosteroids during the last week prior to study treatment, unless administered at a dose equivalent to \< 20 mg/day prednisone or prednisolone.
- •Systemic anti-lymphoma therapy within 28 days or use of antibody agents within 8 weeks use of radioimmunotherapy within 6 months.
- •Known seropositive for or active viral infection with hepatitis B virus (HBV) or/and human immunodeficiency virus (HIV).
- •Known hepatitis C virus (HCV) positive with chronic HCV or active viral infection with HCV hepatitis requiring anti-viral medication (at time of randomization).
- •Life expectancy \< 6 months.
- •Known sensitivity or allergy to murine products.
- •Prior history of malignancies, other than follicular or marginal zone lymphoma, unless the subject has been free of the disease for ≥ 5 years.
- •Prior use of lenalidomide.
- •Known allergy to thalidomide.
Arms & Interventions
Rituximab and Placebo
Participants received riituximab 375 mg/m^2 IV every week in Cycle 1 (Days 1, 8, 15 and 22) and on Day 1 of every 28-day cycle from cycle 2 to 5 plus placebo (identically matched capsule) once daily on Days 1 to 21 of every 28-day cycle up, to 12 cycles.
Intervention: Rituximab (Drug)
Rituximab and Lenalidomide
Participants received rituximab 375 mg/m^2 intravenously (IV) every week in Cycle 1 (Days 1, 8, 15 and 22) and on Day 1 of every 28-day cycle from Cycles 2 to 5 plus lenalidomide 20 mg by mouth (PO) once daily on Days 1 to 21 every 28 days, up to 12 cycles (21-day treatment and 7-day rest period); if creatinine clearance (CrCl) was ≥ 30 mL/min but < 60 mL/min, participants received lenalidomide 10 mg capsules on days 1 to 21 every 28 days.
Intervention: Rituximab (Drug)
Rituximab and Lenalidomide
Participants received rituximab 375 mg/m^2 intravenously (IV) every week in Cycle 1 (Days 1, 8, 15 and 22) and on Day 1 of every 28-day cycle from Cycles 2 to 5 plus lenalidomide 20 mg by mouth (PO) once daily on Days 1 to 21 every 28 days, up to 12 cycles (21-day treatment and 7-day rest period); if creatinine clearance (CrCl) was ≥ 30 mL/min but < 60 mL/min, participants received lenalidomide 10 mg capsules on days 1 to 21 every 28 days.
Intervention: Lenalidomide (Drug)
Rituximab and Placebo
Participants received riituximab 375 mg/m^2 IV every week in Cycle 1 (Days 1, 8, 15 and 22) and on Day 1 of every 28-day cycle from cycle 2 to 5 plus placebo (identically matched capsule) once daily on Days 1 to 21 of every 28-day cycle up, to 12 cycles.
Intervention: Placebo (Drug)
Outcomes
Primary Outcomes
Kaplan Meier Estimate of Progression Free Survival Assessed by the Independent Review Committee (IRC) According to the 2007 International Working Group Response Criteria (IWGRC)
Time Frame: From randomization of study drug up to disease progression or death, which occurred first; up to the data cut-off date of 22 June 2018; overall median follow-up time for all participants was 28.30 months (range: 0.1 to 51.3 months).
Progression-free survival (PFS) was defined as the time from date of randomization into the study to the first observation of documented disease progression or death due to any cause, whichever occurred first. PFS was based on the data from the IRC review using the modified 2007 International Working Group Response Criteria (IWGRC) using FDA censoring rules.
Secondary Outcomes
- Percentage of Participants With an Objective Response as Assessed by the IRC According to the 2007 IWGRC(From date of first dose to data cut-off date of 22 June 2018; the median treatment duration was 11.19 months in the rituximab/lenalidomide arm and 11.04 months in the rituximab/placebo arm)
- Durable Complete Response Rate (DCCR) as Assessed by the IRC According to the 2007 IWGRC(From first dose of investigational product (IP) to data cut-off date of 22 June 2018; the median treatment duration was 11.19 months in the rituximab/lenalidomiade arm and 11.04 months in the rituximab/placebo arm)
- Percentage of Participants With a Best Response of Complete Response as Assessed by the IRC According to the 2007 IWGRC(From date of first dose up to data cut-off date of 22 June 2018; the median treatment duration was 11.19 months in the rituximab/lenalidomide arm and 11.04 months in the rituximab/placebo arm)
- Kaplan-Meier Estimate of Duration of Complete Response (DOCR) as Assessed by the IRC According to the 2007 IWGRC(From randomization up to data cut-off date of 22 June 2018; overall median follow-up time for all participants was 28.30 months (range: 0.1 to 51.3 months).)
- Kaplan-Meier Estimate of Overall Survival (OS)(From date of randomization to death due to any cause (Average of 55.71 months and a maximum up to 95.2 months))
- Kaplan-Meier Estimate of Duration of Objective Response as Assessed by the IRC According to the 2007 IWGRC(From randomization up to data cut-off date of 22 June 2018; overall median follow-up time for all participants was 28.30 months (range: 0.1 to 51.3 months).)
- Kaplan Meier Estimate of Event Free Survival as Assessed by the IRC According to the 2007 IWGRC(From date of randomization to data cut-off date of 22 June 2018; overall median follow-up time for all participants was 28.30 months (range: 0.1 to 51.3 months).)
- Kaplan Meier Estimate of Time to Next Anti-Lymphoma Treatment (TTNLT)(From date of randomization to date of first documented administration of a new anti-lymphoma treatment (Average of 55.71 months and a maximum up to 95.2 months))
- Number of Participants With Treatment Emergent Adverse Events (TEAEs)(From first dose to 28 days post last dose (Average of 55.71 months and a maximum up to 95.2 months))