Rituximab Plus Lenalidomide for Patients With Relapsed / Refractory Indolent Non-Hodgkin's Lymphoma (Follicular Lymphoma and Marginal Zone Lymphoma)

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Lymphoma, Non-Hodgkin

Intervention / Treatment
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* Drug: Rituximab
* Drug: Lenalidomide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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 ≤ 2. Adequate bone marrow function. Willingness to follow study visit schedule, pregnancy precautions and other protocol requirements. 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. Neuropathy > Grade 1. 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. Uncontrolled intercurrent illness. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent document. Pregnant or lactating females. 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.

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rituximab and Lenalidomide<br>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. | Drug: Rituximab<br>* Rituximab 375mg/m^2 IV every week in Cycle 1 (Days 1, 8, 15 and 22) on Day 1 of every 28 day cycle from Cycles 2 to 5<br>* Other names: Rituxan;Drug: Lenalidomide<br>* Lenalidomide 20mg by mouth (PO) daily on Days 1 to 21 every 28 days up to 12 cycles<br>* Other names: CC-5013, Revlimid;|
| Active Comparator: Rituximab and Placebo<br>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. | Drug: Rituximab<br>* Rituximab 375mg/m^2 IV every week in Cycle 1 (Days 1, 8, 15 and 22) on Day 1 of every 28 day cycle from Cycles 2 to 5<br>* Other names: Rituxan;Drug: Placebo<br>* Placebo (identical matched capsule) PO daily on Days 1 to 21 every 28 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kaplan Meier Estimate of Progression Free Survival Assessed by the Independent Review Committee (IRC) According to the 2007 International Working Group Response Criteria (IWGRC) | 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. | 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). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Durable Complete Response Rate (DCCR) as Assessed by the IRC According to the 2007 IWGRC | DCCR was defined as the percentage of participants with a best response of complete response (CR) that lasted no less than one year (≥ 48 weeks) during the study prior to administration of new anti-lymphoma therapy. A CR is defined as a complete disappearance of any disease-related symptoms and normalization of biochemical abnormalities. | 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 | 
| Kaplan-Meier Estimate of Overall Survival (OS) | Overall survival was defined as the time from randomization to death from any cause. Overall survival was censored at the last date that the participant was known to be alive for participants who were alive at the time of analysis and for participants who were lost to follow-up before death was documented. | From date of randomization to death due to any cause (Average of 55.71 months and a maximum up to 95.2 months) | 
| Percentage of Participants With an Objective Response as Assessed by the IRC According to the 2007 IWGRC | Percentage of participants with an objective response is defined as having a response of at least a PR during the study without administration of new anti-lymphoma therapy. A complete response = a complete disappearance of all detectable clinical and radiographic evidence of disease, disappearance of any disease-related symptoms, and normalization of biochemical abnormalities; a partial response (PR) = 50% decrease in SPD of the 6 largest dominant nodes or nodal masses. No increase in the size of other nodes, liver, or spleen. Splenic and hepatic nodules must regress by at least 50% in the SPD. | 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 | 
| Percentage of Participants With a Best Response of Complete Response as Assessed by the IRC According to the 2007 IWGRC | Percentage of participants with a best response of at CR during the study without administration of new anti-lymphoma therapy. A CR = Complete disappearance of all detectable clinical and radiographic evidence of disease, disappearance of any disease-related symptoms, and normalization of biochemical abnormalities. | 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 Objective Response as Assessed by the IRC According to the 2007 IWGRC | Duration of response (DOR) was defined as the time from initial response (at least PR) until documented progressive disease (PD) or death. Participants who had not progressed at the time of analysis were censored at the last assessment date that the participant was known to be progression free. Participants who received a new treatment without documented progression were censored at the last assessment date that the participants was known to be progression free. | 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 Duration of Complete Response (DOCR) as Assessed by the IRC According to the 2007 IWGRC | DOCR was defined as the time from initial CR until documented PD or death. Participants who had not progressed at the time of analysis were censored at the last assessment date that the participant was known to be progression free. Participants who received a new treatment without documented progression were censored at the last assessment date that the participants was known to be progression free. | 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 | Event-free survival (EFS) was defined as the time from date of randomization to date of first documented progression, relapse, institution of new anti-lymphoma treatment (chemotherapy, radiotherapy or immunotherapy) or death from any cause. Responding participants and those who were lost to follow up were censored at their last tumor assessment date. | 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) | Time to next anti-lymphoma treatment (TTNLT) was defined as the time from date of randomization to date of first documented administration of a new anti-lymphoma treatment (including chemotherapy, radiotherapy, radioimmunotherapy or immunotherapy). The time to the next anti-lymphoma treatment was of special interest to the study. | 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) | TEAEs include AEs that started or worsened between the date of the first dose and 28 days after the date of the last dose. A serious adverse event (SAE) is any: • Death; • Life-threatening event; • Any inpatient hospitalization or prolongation of existing hospitalization; • Persistent or significant disability or incapacity; • Congenital anomaly or birth defect; • Any other important medical event. The investigator determined the relationship of an AE to study drug based on the timing of the AE relative to drug administration and whether or not other drugs, therapeutic interventions, or underlying conditions could provide a sufficient explanation for the event. The severity of an AE was evaluated by the investigator according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (Version 4.03) where Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Death | From first dose to 28 days post last dose (Average of 55.71 months and a maximum up to 95.2 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-Hodgkins Follicular lymphoma, Non-Hodgkins Marginal zone lymphoma, treatment for follicular lymphoma, treatment for Marginal zone lymphoma