Relevance

Confidential and Proprietary - RV-FOL-GELARC-0683 - Relevance Synopsis v3.0 - 8 June 2012 RELEVANCE
Rituximab Lenalidomide Versus ANy ChEmotherapy
A PHASE 3 OPEN-LABEL RANDOMIZED STUDY TO COMPARE
THE EFFICACY AND SAFETY OF RITUXIMAB PLUS
LENALIDOMIDE (CC-5013) VERSUS RITUXIMAB PLUS
CHEMOTHERAPY FOLLOWED BY RITUXIMAB IN SUBJECTS
WITH PREVIOUSLY UNTREATED FOLLICULAR LYMPHOMA
The Lymphoma Academic Research Organisation
 : Centre Hospitalier Lyon Sud - Secteur Sainte Eugénie - Pavillon 6D - Study Number
Eudract N°
Title of the study
A phase 3 open label randomized study to compare the efficacy and safety of rituximab plus lenalidomide (CC-5013) versus rituximab plus chemotherapy followed by rituximab in subjects with previously untreated follicular lymphoma. Companion Study
A phase 3 study (RV-FOL_Gelarc-0683C) will be conducted as a companion to the RV-FOL-Gelarc-0683 study with a combined enrollment target of 1000 patients and will enroll up to 250 patients. The data from both studies will be collected into one database and the statistical analyses as described in Section 14 will be performed on the combined total of patients enrolled into both studies. A single data safety monitoring committee (DSMC), central pathology and central Independent Review Committee (IRC) will be utilized for these two studies. Protocol version
Investigational
Confidential and Proprietary - RV-FOL-GELARC-0683 - Relevance Synopsis v3.0 - 8 June 2012 Coordinating
investigator
Co-coordinating
investigator
This study is being conducted in collaboration with major European and Study Objectives
The primary objective of the study is to compare the efficacy of rituximab plus lenalidomide to rituximab plus chemotherapy followed by rituximab in patients with previously untreated follicular lymphoma. Efficacy determination will be based upon the co-primary endpoints of complete response (CR/CRu) rate at 120 weeks and PFS assessed by the IRC using the IWG (Cheson, 1999) criteria. The secondary objectives of the study are: o To compare the efficacy of rituximab plus lenalidomide versus rituximab plus chemotherapy followed by rituximab using other parameters of efficacy: o Event Free Survival (EFS), Time to Next Anti-Lymphoma Treatment (TTNLT), and Overall Survival (OS). To compare the safety of rituximab plus lenalidomide versus rituximab plus chemotherapy followed by rituximab Duration of the
The duration of the entire study will be approximately 12-13 years. Patients receive up to four weeks of screening, approximately 2.5 years of treatment and Number of patients. 750 (1000 with patients enrolled in companion study)
Inclusion criteria
Patients must satisfy all the following criteria to be enrolled in the study: 1. Histologically confirmed CD20+ follicular lymphoma grade 1, 2 or 3a as  a formalin fixed paraffin embedded specimen taken within 18 months before signing informed consent must be available for central review, and  a bone marrow biopsy taken within 18 months before patient signing informed consent must be available for central review. 2. Have no prior systemic treatment for lymphoma. 3. Must be in need of treatment as evidenced by at least one of the Confidential and Proprietary - RV-FOL-GELARC-0683 - Relevance Synopsis v3.0 - 8 June 2012 o a nodal or extranodal (except spleen) mass > 7cm in its o involvement of at least 3 nodal or extranodal sites (each  Presence of at least one of the following B symptoms: o fever (>38C) of unclear etiology o night sweats o weight loss greater than 10% within the prior 6 months  Compression syndrome (ureteral, orbital, gastrointestinal)  Any one of the following cytopenias due to lymphoma: o hemoglobin < 10g/dL (6.25 mmol/L) o platelets <100 x 109/L , or o absolute neutrophil count (ANC) < 1.5 x 10 /L  Pleural or peritoneal serous effusion (irrespective of cell  LDH > ULN or β2 microglobulin > ULN 4. Bi-dimensionally measurable disease with at least one mass lesion > 2 5. Stage II, III or IV disease. 6. Must be ≥ 18 years and sign an informed consent. 7. Performance status ≤ 2 on the ECOG scale. 8. Adequate hematological function (unless abnormalities are related to lymphoma infiltration of the bone marrow) within 28 days prior to signing informed consent, including:  Absolute neutrophil count (ANC) ≥ 1.5 x 10 /L 9. Must be able to adhere to the study visit schedule and other protocol 10. Females of childbearing potential (FCBP)† receiving lenalidomide must: Have two negative pregnancy tests as verified by the study doctor prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after end of study therapy. This applies even if the patient practices complete abstinence from heterosexual contact. Either commit to complete abstinence from heterosexual contact(which must be reviewed on a monthly basis) or agree to use, and be able to comply with, effective contraception without interruption, 28 days prior to starting study drug, during the study therapy (including dose interruptions), and for 28 days after Confidential and Proprietary - RV-FOL-GELARC-0683 - Relevance Synopsis v3.0 - 8 June 2012 11. Male patients receiving lenalidomide must†: Must practice complete abstinence or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 28 days following study drug discontinuation, even if he has undergone a successful vasectomy. Agree to not donate semen during study drug therapy and for 28 days after discontinuation of study drug therapy. 12. All patients receiving lenalidomide must: Have an understanding that the study drug could have a potential teratogenic risk. Agree to abstain from donating blood while taking study drug therapy and for 28 days after discontinuation of study drug therapy. Agree not to share study medication with another person. Agree to be counseled about pregnancy precautions and risk of fetal exposure Females must agree to abstain from breastfeeding during study participation and for at least 28 days after study drug discontinuation. 13. For all patients receiving Rituximab: Women must not breast feed and must use effective contraception must not be pregnant and agree not to become pregnant during participation in the trial and during the 6 months thereafter. Men must agree not to father a child during participation in the trial and during the 6 months thereafter. Exclusion criteria
The presence of any of the following will exclude a patient from enrollment: 1. Clinical evidence of transformed lymphoma by investigator assessment. 2. Grade 3b follicular lymphoma. 3. Patients taking corticosteroids during the last 4 weeks, unless administered at a dose equivalent to < 10 mg/day prednisone (over these 4 weeks). 4. Major surgery (excluding lymph node biopsy) within 28 days prior to 5. Seropositive for or active viral infection with hepatitis B virus (HBV): Confidential and Proprietary - RV-FOL-GELARC-0683 - Relevance Synopsis v3.0 - 8 June 2012  HBsAg negative, anti-HBs positive and/or anti-HBc positive and  Patients who are HBsAg negative, anti-HBs positive and/or anti- HBc positive but viral DNA negative are eligible  Patients who are seropositive due to a history of hepatitis B 6. Known seropositive for, or active infection hepatitis C virus (HCV). 7. Known seropositive for, or active viral infection with human 8. Life expectancy < 6 months. 9. Known sensitivity or allergy to murine products. 10. Prior history of malignancies, other than follicular lymphoma, unless the patient has been free of the disease for ≥ 10 years. Exceptions include a
history of previously treated:
a. Localized non-melanoma skin cancer b. Carcinoma in situ of the cervix 13. Presence or history of CNS involvement by lymphoma. 14. Patients who are at a high risk for a thromboembolic event and are not willing to take venous thromboembolic (VTE) prophylaxis. 15. Any of the following laboratory abnormalities: serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) > 3x upper limit of normal (ULN), except in patients with documented liver or pancreatic involvement by lymphoma -total bilirubin > 2.0 mg/dl (34 µmol/L) except in cases of Gilberts Syndrome and documented liver involvement by lymphoma 17. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the patient from signing the informed consent form. 19. Any condition, including the presence of laboratory abnormalities, which places the patient at unacceptable risk if he/she were to participate in the study, or which confounds the ability to interpret data from the study. Confidential and Proprietary - RV-FOL-GELARC-0683 - Relevance Synopsis v3.0 - 8 June 2012 Design of the trial
This multi-center, open-label study is designed to compare the efficacy and safety of rituximab plus lenalidomide versus rituximab plus chemotherapy followed by rituximab. The study is divided into the Screening Period, Treatment Period, and Follow-up Period. Once a patient gives written consent, the patient may enter the Screening Period, which is permitted to last up to 4 weeks. During the Screening Period, the investigator will choose one standard-of-care regimen ("investigator's choice") for the patient from a list of permitted choices of rituximab-containing chemotherapy regimens. In addition, during the Screening Period, the patient will undergo safety and other assessments to determine eligibility for the study and undergo randomization to either experimental arm (rituximab plus lenalidomide) versus control arm ("investigator's choice" of rituximab-chemotherapy). The patient will enter the Treatment Period once the patient has fulfilled the required assessment in the Screening Period and has been randomized. Treatment must start as soon as possible after randomization but no later than 2 weeks after randomization. Treatment Period for each patient starts with first intake of study drug, which is defined as Study Day 1 of Cycle 1.The patients will receive protocol-specified treatments until (1) inability to achieve a 25% reduction in the sum of the products of the diameters (SPD) by 12 weeks (first CT assessment), (2) inability to achieve a response by 24 weeks (second CT assessment), (3) relapse or progression of disease, (4) withdrawal of consent or (5) unacceptable toxicity. All randomized patients will be followed for progression free survival and overall survival using the same schedule. This includes all patients who discontinue the study early for any reason without documented evidence of disease progression. Upon completion of the required treatments, the patient will enter the Follow-Up Period. In the follow-up period, the patients will be followed for disease progression and overall survival. Study Treatments
Control arm : Patients randomized to receive investigators choice will receive
ONE of the following:
Rituximab-CHOP: with six cycles of R-CHOP in 21 day cycles followed by two 21 day cycles of 375 mg/m2 rituximab; and 7 weeks later responding patients continue with 375 mg/m2 rituximab every 8 weeks for 12 cycles, Rituximab-CVP: with eight cycles of R-CVP in 21 day cycles; and 7 weeks later responding patients continue with 375 mg/m2 rituximab every 8 weeks for 12 Confidential and Proprietary - RV-FOL-GELARC-0683 - Relevance Synopsis v3.0 - 8 June 2012 Rituximab-Bendamustine: with six cycles of R-B in 28 day cycles and 8 weeks later responding patients continue with 375 mg/m2 rituximab every 8 weeks for 12 cycles. R-Bendamustine
Refer to the specific package inserts for preparation, administration, and storage guidelines. At the discretion of the investigator, the vincristine dose may be capped at 2 mg. For patient ≥70 years old, the vincristine dose may be capped at 1.5 mg. For chemotherapy, dosages may be adjusted in case of large changes in body weight compared to baseline (≥ 10%) that lead to changes in BSA. For rituximab, no dosage adjustments should be performed. Experimental arm: Patients randomized to receive rituximab-lenalidomide will
receive six cycles of lenalidomide 20 mg daily on days 2-22 every 28 days.
Patients exhibiting a CR/CRu after six cycles then receive 12 cycles of 10 mg lenalidomide daily on days 2-22 every 28 days for a total of 18 cycles. Patients exhibiting a PR after six cycles receive an additional 3 or 6 cycles of the 20 mg lenalidomide dose until they achieve a CR/CRu at which time they receive the 10 mg lenalidomide dosing for 9 or 6 cycles respectively for a total of 18 cycles. Patients who remain in PR after the additional 6 cycles will receive 10 mg lenalidomide dosing for a total of 18 cycles. All patients randomized to receive rituximab-lenalidomide receive rituximab, 375 mg/m2 on days 1, 8, 15 and 22 of cycle 1, day 1 of cycles 2 to 6; and 8 weeks later responding patients continue with 375 mg/m2 rituximab every 8 weeks for 12 cycles. Lenalidomide treatment is continued for 18 cycles or until disease progression, unacceptable toxicity, or voluntary withdrawal. The lenalidomide dose for each patient will be interrupted and modified following toxicity as described in Table 2, Table 3 and Table 4. If a dose is reduced, re-escalation is not permitted. In addition, patients who do not achieve the threshold clinical activity of 1) a 25% reduction in the sum of the products of the diameters (SPD) by 12 weeks (first CT assessment), or 2) a response by 24 weeks (second CT assessment) will be withdrawn from the study treatment and followed for survival and PFS using the same schedule of assessments as patients continuing treatment as described in Table 1. Confidential and Proprietary - RV-FOL-GELARC-0683 - Relevance Synopsis v3.0 - 8 June 2012 Screening and
Once a patient gives written consent, the patient may enter the Screening Period, which is permitted to last up to 4 weeks. During the Screening Period, Randomization
the investigator will choose one standard-of-care regimen ("investigator's choice") for the patient from the list of permitted choices of rituximab-containing chemotherapy regimens. In addition, during the Screening Period, the patient will undergo safety and other assessments to determine eligibility for the study and undergo randomization to either experimental arm (rituximab plus lenalidomide) versus control arm (Investigators Choice of R-CHOP, R-CVP, or R-B). Screening and randomization will be performed via IVRS/IWRS. Statistical analysis
Sample size:
Sample size calculation is based on providing adequate power to evaluate treatment effect on the co-primary efficacy endpoints. The co-primary efficacy endpoints are complete response (CR/CRu) rate at 120 weeks and PFS. To fulfill the primary objective of the study, it must be shown that the experimental arm is superior to the control arm on both co-primary endpoints at  = 0.05 level (Shih 2003). It is hypothesized that the complete response (CR/CRu) rate at 120 weeks is 60% in the control arm and 72% in the experimental arm. For 90% power to detect this difference with two-sided  = 0.05, a total of 644 patients (322 in each arm) will be required. It is hypothesized that the median PFS is 83 months in the control arm, and there is a 30% increase in the median PFS in the experimental arm (corresponding hazard ratio of 0.7692). For 80% power to detect this difference with two-sided  = 0.05, a total of 456 progression/relapse/death events will be required. It is planned to randomize a total of 1000 patients in 1:1 ratio to the two treatment arms (500 in each arm). Analysis Plan:
The co-primary efficacy endpoints are the complete response (CR/CRu) rate at 120 weeks and the PFS. The primary efficacy analysis will be based on the ITT population. Analysis based on the mITT population is supportive. The number and percent of patients with complete response (CR/CRu) at 120 weeks assessment will be tabulated by treatment arm. The experimental arm will be declared superior if the two-sided p-value from a chi-square test is ≤ 0.05 in favor of the experimental arm. If the experimental arm is declared superior than the control arm on this endpoint, the study will still continue to collect data for the PFS analysis. The primary analysis will be performed using a stratified Cochran-Mantel-Haenszel (CMH) test to adjust for possible confounding effects of the stratification factors: FLIPI score (0-1 vs 2 vs 3-5), Age (>60 vs ≤ 60), longest diameter of the largest node (> 6 v < 6 cm). The un-stratified test will be a supportive analysis. PFS will be compared between the two treatment arms when the required 456 progress/relapse/death events are observed. The Kaplan-Meier estimates of PFS function will be provided. If a patient has a missing or incomplete CT scan, all other available CT scans or MRIs of the patient will still be used for the Confidential and Proprietary - RV-FOL-GELARC-0683 - Relevance Synopsis v3.0 - 8 June 2012 analysis. The experimental arm will be declared superior if the two-sided p-value from a stratified log-rank test is ≤ 0.05 in favor of the experimental arm. Conventionally, hazard ratio with two-sided 95% confidence interval (CI) will be estimated using the Cox proportional hazards model. But the treatment effect will be determined by the p-value, not by this 95% CI. The un-stratified log-rank test will be a supportive analysis. Subgroup analysis for PFS will be performed as appropriate. The secondary efficacy endpoints are EFS, TTNLT, and OS. In order to control an overall two-sided 0.05 study-wise Type I error rate, a fixed-sequence gate-keeping procedure will be employed to interpret the analysis results of these three secondary efficacy endpoints in the order of EFS, TTNLT, and OS. The analysis of secondary endpoints will be performed at the end of study when the PFS analysis is performed.
Interim Analysis:
For the co-primary endpoint of the complete response (CR/CRu) rate at 120 weeks, two interim analyses for futility are pre-planned. The first interim analysis will be performed when the first 200 patients have their response assessments done at 6 months of treatment or have had disease progression prior to this timepoint. The second interim analysis will be performed when the first 200 patients have their response assessments done at 120 weeks or have had disease progression prior to this timepoint. The intention of these two interim futility analyses is to assess risk-benefit and ensure patient safety. The proposed futility boundaries are non-binding. The results of these two futility analyses will be reviewed by the independent DMC to make recommendation of go/no go. There is no plan to claim efficacy superiority based on these interim results, therefore, no Type I error rate adjustment is needed. Planned start/end of December, 2011 - March, 2015
recruitment

Source: http://www.cancertrials.be/sites/default/files/mocol-130/trials/schemeoftrial/RV_FOL_Synopsisv3.0_Lysarc_En_08June2012.pdf