Lenalidomide Plus Rituximab Followed by Lenalidomide Versus Rituximab Maintenance for Relapsed/Refractory Follicular, Marginal Zone or Mantle Cell Lymphoma.
- Registration Number
- NCT01996865
- Lead Sponsor
- Celgene
- Brief Summary
Follicular lymphoma (FL), marginal zone lymphoma (MZL), and mantle cell lymphoma (MCL) are distinct histologic types of B-cell NHL. Lenalidomide is an immunomodulatory agent with direct and immune-mediated mechanisms of action, as well as clinical activity in NHL. Recent studies in frontline and relapsed/refractory NHL show high activity for lenalidomide plus rituximab (R2), supporting further study of this combination.
- Detailed Description
MAGNIFY (NCT01996865) is a phase 3b, multicenter, open-label study of patients with grades 1-3b or transformed follicular lymphoma (FL), marginal zone lymphoma (MZL), or mantle cell lymphoma (MCL) who received ≥1 prior therapy and had stage I-IV, measurable disease. \~500 patients are planned for enrollment in 12 cycles of R2 induction, with a projected \~314 patients with ≥SD after induction randomized (1:1) to two maintenance arms. Induction includes oral lenalidomide 20 mg/day, days 1-21 per 28-day cycle (d1-21/28) plus IV rituximab 375 mg/m2, days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 3, 5, 7, 9, and 11 (28-day cycles). Patients are then randomized to maintenance lenalidomide 10 mg/day, d1-21/28, cycles 13-30, plus rituximab 375 mg/m2, day 1 of cycles 13, 15, 17, 19, 21, 23, 25, 27, and 29 (R2, Arm A), or rituximab alone (same schedule, Arm B). Patients receiving R2 maintenance after 18 cycles may continue maintenance lenalidomide monotherapy 10 mg/day, d1-21/28 (per patient and/or investigator discretion), until disease progression as tolerated. The primary endpoint is progression-free survival (per modified 1999 IWG criteria). Secondary endpoints include safety, overall survival, response rates, duration of response, and quality of life (exploratory). Patients will be followed for ≥5 years after the last patient initiated induction therapy. Enrollment in MAGNIFY began in March 2014; as of Jan 2016, 133 patients are enrolled.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 503
-- Age ≥18 years
- Histologically confirmed Follicular Lymphoma (FL, Grade 1, 2, 3a, or 3b), Transformed FL, Marginal Zone Lymphoma, or Mantle Cell Lymphoma
- Must have documented relapsed, refractory or Progressive Disease after last treatment with systemic therapy
- Bi-dimensionally measurable disease
- Eastern Cooperative Oncology Group (ECOG) Performance status < 2
- Adequate bone marrow function
- Willingness to follow pregnancy precautions
- Histology other than follicular or marginal zone lymphoma or clinical evidence of transformation or Grade 3b follicular lymphoma
- Any medical condition (other than the underlying lymphoma) that requires chronic steroid use
- Subjects taking corticosteroids during the last 1 week prior treatment, unless administered at a dose equivalent to < 20 mg/day of prednisone
- Systemic anti-lymphoma therapy within 28 days or use of antibody agents within 4 weeks use of radioimmunotherapy within 3 months
- Known seropositive for or active viral infection with hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV)
- Known sensitivity or allergy to murine products
- Presence or history of central nervous system involvement by lymphoma. Subjects who are at a risk for a thromboembolic event and are not willing to take prophylaxis for it
- Any condition that places the subject at unacceptable risk if he/she were to participate in the study or that confounds the ability to interpret data from the study
Other protocol-defined inclusion/exclusion criteria apply
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm A: Lenalidomide + rituximab followed by lenalidomide Lenalidomide Induction Period (12 cycles): Lenalidomide 20mg (10 mg if creatinine clearance ≥ 30 mL/min but \< 60mL/min) by mouth (PO) daily (QD) on Days 1 to 21 of every 28-day cycle during cycles 1 through 12 and rituximab 375mg/m\^2 intraveneously (IV) every week in Cycle 1 on Days 1, 8, 15, and 22 and on Day 1 of every 28-day cycle during cycles 3, 5, 7, 9, and 11, followed by a Maintenance Period (lasting 18 Cycles) that includes Lenalidomide 10 mg PO QD on Days 1 to 21 of every 28-day cycle during cycles 13 to 30 and rituximab 375 mg/m\^2 IV on Day 1 of every 28-day cycle during cycles 13, 15, 17, 19, 21, 23, 25, 27, and 29 followed by an optional Maintenance Period (up to Progressive Disease) receiving Lenalidomide 10mg PO QD on Days 1 through 21 of every 28 day cycle until the disease progresses Arm A: Lenalidomide + rituximab followed by lenalidomide Rituximab Induction Period (12 cycles): Lenalidomide 20mg (10 mg if creatinine clearance ≥ 30 mL/min but \< 60mL/min) by mouth (PO) daily (QD) on Days 1 to 21 of every 28-day cycle during cycles 1 through 12 and rituximab 375mg/m\^2 intraveneously (IV) every week in Cycle 1 on Days 1, 8, 15, and 22 and on Day 1 of every 28-day cycle during cycles 3, 5, 7, 9, and 11, followed by a Maintenance Period (lasting 18 Cycles) that includes Lenalidomide 10 mg PO QD on Days 1 to 21 of every 28-day cycle during cycles 13 to 30 and rituximab 375 mg/m\^2 IV on Day 1 of every 28-day cycle during cycles 13, 15, 17, 19, 21, 23, 25, 27, and 29 followed by an optional Maintenance Period (up to Progressive Disease) receiving Lenalidomide 10mg PO QD on Days 1 through 21 of every 28 day cycle until the disease progresses Arm B: Lenalidomide + rituximab followed by rituximab Lenalidomide Induction Period (12 Cycles): Lenalidomide 20 mg PO QD (10 mg if creatinine clearance ≥ 30 mL/min but \< 60 mL/min) on Days 1 to 21 of every 28-day cycle during cycles 1 to 12 and rituximab 375 mg/m\^2 IV every week in cycle 1 on Days 1, 8, 15, and 22 and on Day 1 of every 28-day cycle during cycles 3, 5, 7, 9, and 11, followed by a Maintenance Period for 18 Cycles that includes: Rituximab 375 mg/m\^2 IV on Day 1 of every 28-day cycle during cycles 13, 15, 17, 19, 21, 23, 25, 27, and 29 Arm B: Lenalidomide + rituximab followed by rituximab Rituximab Induction Period (12 Cycles): Lenalidomide 20 mg PO QD (10 mg if creatinine clearance ≥ 30 mL/min but \< 60 mL/min) on Days 1 to 21 of every 28-day cycle during cycles 1 to 12 and rituximab 375 mg/m\^2 IV every week in cycle 1 on Days 1, 8, 15, and 22 and on Day 1 of every 28-day cycle during cycles 3, 5, 7, 9, and 11, followed by a Maintenance Period for 18 Cycles that includes: Rituximab 375 mg/m\^2 IV on Day 1 of every 28-day cycle during cycles 13, 15, 17, 19, 21, 23, 25, 27, and 29
- Primary Outcome Measures
Name Time Method Progression Free Survival (PFS) From the first dose date of maintenance therapy to objective disease progression or death from any cause, whichever occurs first (up to approximately 432 weeks) Progression free survival (PFS) is defined as the time from the date of first dose of maintenance therapy to the date of the first objective documentation of tumor progression or death due to any cause. Analysis was based on Kaplan Meier estimates. The PFS events were determined using a modification of the IWG 1999 criteria.
- Secondary Outcome Measures
Name Time Method Overall Survival (OS) From the first dose date of maintenance therapy to death from any cause (up to approximately 480 weeks) Overall Survival (OS) is defined as the time between the first dose date of maintenance therapy and death from any cause. Participants who complete the study and are still alive at the time of the clinical data cutoff date will be censored at the last visit date or the last contact date, whichever is later. Participants who were lost to follow-up prior to the clinical data cut-off date will also be censored at the time of the last contact. Analysis was based on Kaplan Meier estimates and Hazard Ratio (HR).
Improvement of Response (IOR) From the first dose date of maintenance therapy to death from any cause (up to approximately 432 weeks) Improvement of Response (IOR) is the percentage of participants with improved tumor response during the maintenance phase (converted from partial response at end of induction to complete response or complete response unconfirmed as best response) and participants who converted from stable disease at the end of induction period to partial response or better as best response during maintenance phase.
Overall Response Rate (ORR) From the first dose date of maintenance therapy up to CR, CRu, PR, or treatment change (up to approximately 432 weeks) The overall response rate (ORR) is defined as the percentage of participants with a best response of at least partial response (including complete response, complete response unconfirmed and partial response) after the first dose date of maintenance therapy and prior to any treatment change.
Complete Response Rate (CRR) From the first dose date of maintenance therapy up to CR or CRu (up to approximately 432 weeks) Best Complete Response Rate (CRR), defined as the proportion of participants with a best response of at least CRu (including CR and CRu) after the first dose date of maintenance therapy and prior to any treatment change.
Duration of Response (DOR) From the initial response (at least PR) after the first dose date of maintenance therapy and prior to treatment change to documented disease progression or death, whichever occurs first (up to approximately 432 weeks) DOR is from initial response (at least CRu) after the first dose date of maintenance therapy and prior to treatment change to documented disease progression or death. Participants who have not progressed or died at the time of the clinical data cutoff date will be censored at the last assessment showing no progression. Participants who change treatment without evidence of disease progression will be censored at the last assessment showing no progression prior to treatment change. Analysis was based on Kaplan Meier estimates.
Time to Next Anti-lymphoma Treatment From the first dose date of maintenance therapy to the time of first documented administration of new anti-lymphoma therapy (up to approximately 300 weeks) Time to next anti-lymphoma treatment is defined as the time from the first dose date of maintenance therapy to the time of first documented administration of new anti-lymphoma therapy. Participants without new treatment therapy will be censored at the last visit. Analysis was based on Kaplan Meier estimates.
Time to Histological Transformation From the first dose date of maintenance therapy to the time of histological transformation (up to approximately 432 weeks) Time to histological transformation is defined as from the first dose date of maintenance therapy to the time of histological transformation as measured based on documentation of histological transformation (as assessed by the investigator). Analysis was based on Kaplan Meier estimates.
In case of clinical suspicion of transformation, including rapid disease progression, unexpected changes in "B" symptoms or rapidly increasing LDH, a biopsy should be performed. In this clinical trial, histological transformation will be considered disease progression. This endpoint will not be calculated for participants randomized with transformed Follicular Lymphoma (tFL).Duration of Complete Response (DOCR) From the initial CR/CRu after the first dose date of maintenance therapy and prior to treatment change to documented disease progression or death, whichever occurs first (up to approximately 432 weeks) Duration of complete response (DOCR) is calculated as the time from the initial response (CR or CRu) after the first dose date of maintenance therapy and prior to treatment change to documented disease progression or death. Analysis was based on Kaplan Meier estimates. Participants who have not progressed or died at the time of the clinical data cutoff date will be censored at the last assessment showing no progression. Participants who change treatment without evidence of disease progression will be censored at the last assessment showing no progression prior to treatment change.
Participants Experiencing Treatment Emergent Adverse Events (TEAEs) From first dose up to 30 days after last dose (up to approximately 64 weeks for induction period and 427 weeks for maintenance period) Number of participants experiencing AEs, SAEs, AEs leading to study discontinuation, and AEs of interest (AEIs). An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. SAEs is any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires inpatient hospitalization; results significant disability; or is a congenital anomaly/birth defect. TEAEs are defined as AEs with an onset date on or after the first dose of study treatment up to 30 days after the last dose of study treatment in the study, or if a pre-existing condition worsens in severity or becomes serious after receiving the first dose of study treatment.
Participants Experiencing Adverse Events Related to Vital Signs From first dose up to 30 days after last dose (up to approximately 64 weeks for induction period and 427 weeks for maintenance period) The number of participants who experienced adverse events related to vital sign measurements
Participants With Grade 3 or Grade 4 Hematology Parameters From first dose up to 30 days after last dose (up to approximately 64 weeks for induction period and 427 weeks for maintenance period) Clinical laboratory values in induction period include any laboratory values that are taken after the first dose date of induction therapy through 28 days after the last dose date of induction therapy or before the first dose date of maintenance therapy, whichever is earlier. Graded according to the NCI CTCAE version 4.03, except for tumor flare reaction, which is accessed using NCI CTCAE version 3.0. Participants with zero maximum grade are excluded.
Participants With Grade 3 or Grade 4 Serum Chemistry Parameters From first dose up to 30 days after last dose (up to approximately 64 weeks for induction period and 427 weeks for maintenance period) Clinical laboratory values in induction period include any laboratory values that are taken after the first dose date of induction therapy through 28 days after the last dose date of therapy. Graded according to the NCI CTCAE version 4.03, except for tumor flare reaction, which is accessed using NCI CTCAE version 3.0. Participants with zero maximum grade are excluded.
Trial Locations
- Locations (126)
Local Institution - 055
🇺🇸Tucson, Arizona, United States
Local Institution - 077
🇺🇸Little Rock, Arkansas, United States
Local Institution - 079
🇺🇸Berkeley, California, United States
Local Institution - 142
🇺🇸Concord, California, United States
Bay Area Cancer Research Group, LLC
🇺🇸Pleasant Hill, California, United States
Sutter Hematology and Oncology
🇺🇸Sacramento, California, United States
Local Institution - 032
🇺🇸San Diego, California, United States
Local Institution - 130
🇺🇸Santa Barbara, California, United States
Local Institution - 052
🇺🇸Boulder, Colorado, United States
Local Institution - 106
🇺🇸Denver, Colorado, United States
Scroll for more (116 remaining)Local Institution - 055🇺🇸Tucson, Arizona, United States