PRIMA Investigator Meeting

PRIMAInvestigator Meeting Sunday, September 12, 2004 Corinthia Towers Hotel, Prague

PRIMAInvestigator MeetingAgenda • Welcome and Introduction • Bertrand Coiffier, Robert Marcus, Michael Herold • Design of the study and Protocol • Gilles Salles • General organization, finances • Bertrand Coiffier, Gilles Salles, Myriam Mendila • Organization and regulations • Stephanie Baulu & Delphine Germain • Path Review and Biology • Gilles Salles • Discussion

PRIMA :Primary Rituximab and Maintenance • No standard first line chemotherapy in follicular lymphoma • Rituximab when combined with chemotherapy (CVP, CHOP, CHVP+IFN, MCP, FCM…) does improve CR rate end EFS • Rituximab maintenance improves EFS in rituximab (alone) or chemo (CVP alone) treated patients • Primary objective : To evaluate in patients with advanced follicular lymphoma the benefit of maintenance therapy with rituximab after induction of response with chemotherapy plus rituximab in comparison with no maintenance therapy

PRIMA :Primary Rituximab and Maintenance • First contacts : - End of August 2003 • Steering Committee in Paris : - November 6th 2003 • Investigator Meeting in San Diego during ASH - December 7th 2003 • Final draft circulation to the Steering committee : - June 1st 2004 • Final draft after approval by the Steering committee : - July 30th 2004 • Investigator Launch Meeting in Prague : - September 10th 2004

PRIMA :Primary Rituximab and Maintenance A multicentre, phase III, open-label, randomized study in patients with advanced follicular lymphoma evaluating the benefit of maintenance therapy with Rituximab (MabThera®) after induction of response with chemotherapy plus Rituximab in comparison with no maintenance therapy Principal Investigator : Gilles Salles Co-Investigators : Robert Marcus & Michael Herold

PRIMA :Primary Rituximab and Maintenance • Participation of groups or center from : France, UK, Australia, Germany, Belgium, Swiss, Spain, Nordic Countries, Czech Republik, South America, Asia and others…! • An international study coordinated by the GELA & GELA-RC

R PRIMA Study FinalDesign MabThera Maintenance 1 dose every 8 weeks for 24 months R-CVP x 8 or R-CHOP x 6 + 2R or R-FCM x 6 + 2R or R-MCP x 6 +2R Untreated Follicular NHL stages III–IV CR/PR Observation PDs/SDs off study Chairs : G Salles, R Marcus & M Herold

PRIMAInvestigator Meeting Study design and protocol Key clinical issues Gilles Salles : gilles.salles@chu-lyon.fr

PRIMAScientific design of the study (1) • Primary objective: To evaluate in patients with advanced follicular lymphoma the benefit of maintenance therapy with rituximab after induction of response with chemotherapy plus rituximab in comparison with no maintenance therapy • Secondary objective: To evaluate response rates, event driven survival endpoints (EFS, PFS, OS) and quality of life of four different chemotherapy regimens combined with rituximab, with or without maintenance with rituximab, for first line treatment of advanced stage follicular lymphoma.

REGISTRATION 6 x FMC 8 xRituximab 8 x CVP 8 xRituximab 6 x CHOP 8 xRituximab 6 x MCP 8 x Rituximab Induction Response Evaluation Off Study SD or PD RANDOMIZATION PR or CRu or CR Stratification Observation for 24 months 12 x Rituximab every 8 weeks for 24 months Maintenance 3 years follow-up Follow-up

PRIMAScientific design of the study (2) • The primary efficacy parameter is event-free survival. Event-free survival will be measured from the day of randomization to the date of first documented disease progression, death by any cause or institution of new treatment. Responding patients and patients who are lost to follow up will be censored at their last tumor assessment date.

PRIMAScientific design of the study (3) • New anti-lymphoma treatment is defined : • as the institution of any radiation therapy (even focal) or chemotherapy or immunotherapy, alone or in any combination of them, which is instituted for lymphoma treatment. • Any new anti-lymphoma treatment not planed in the protocol will be considered as an event.

PRIMAScientific design of the study (4) • New anti-lymphoma treatment should be started: • if a patient does demonstrate disease progression during induction treatment; • at the discretion of the physician if a patient does not reach at least a partial response or a complete (either confirmed or unconfirmed) at the end of the induction treatment; • during the maintenance phase, for patients in both arms (rituximab maintenance or observation), at any time of documented disease progression if this progression is symptomatic and/or if the physician consider that a new treatment is necessary for patients benefit. The disease progression should be documented (see above) • during the 3 year follow-up period, at any time of documented disease progression if this progression is symptomatic and/or if the physician consider that a new treatment is necessary for patients benefit. The disease progression should be documented (see above)

PRIMAScientific design of the study (5) • Secondary efficacy parameters : • Time To Progression (TTP) • Time To Next Anti-Lymphoma Treatment (TTNLT) • Time to next Chemotherapy Treatment (TTNCT) • Overall Survival • Overall Response Rate (Cheson criteria) • Disease Free Survival • Transformation rate at first progression • Quality of Life analysis • Exploratory analyses on primary and secondary endpoints : • according to the FLIPI index at patient registration (study entry) • according to each arm of chemotherapy (CVP, CHOP, FCM and MCP)

PRIMAScientific design of the study (6) The primary endpoint of event-free survival was used to determine the sample size of the study. To demonstrate a 45% increase in the median event-free survival from the time of randomization (6 months after the start of induction therapy), i.e. from 30 months (Marcus et al, 2003, Hiddemann et al, 2003) to 44 months, 480 patients need to be randomised in the maintenance period. With an estimated response rate of 75% (Czuczman et al, 1999, Marcus et al, 2003, Hiddemann et al, 2003), 640 patients should be included in the induction period.

PRIMAScientific design of the study (7) Table 2- Required Number of Patients for Different Recruitment and Follow up Assumptions Assumption: required number of events is 236 Based on the above considerations 480 patients will be randomized over 24 months. This implies that approximately 640 patients will receive the induction R-CHEMO.

R PRIMA Study FinalDesign MabThera Maintenance 1 dose every 8 weeks for 24 months R-CVP x 8 or R-CHOP x 6 + 2R or R-FCM x 6 + 2R or R-MCP x 6 +2R Untreated Follicular NHL stages III–IV CR/PR Observation PDs/SDs off study

PRIMAInclusion criteria (1) • Histologically confirmed follicular lymphoma grade 1, 2 or 3a • Patients previously untreated. • Patients with at least one of the following symptoms requiring initiation of treatment: • Bulky disease at study entry according to the GELF criteria: nodal or extranodal mass > 7cm in its greater diameter • B symptoms • Elevated serum LDH or 2-microglobulin • involvement of at least 3 nodal sites (each with a diameter greater than 3 cm) • symptomatic splenic enlargement • compressive syndrome • pleural/peritoneal effusion

PRIMAInclusion criteria (2) • Age must be > 18 years. • Performance status < 2 on the ECOG scale (see appendix E). • Adequate hematological function within 28 days prior to registration (unless those abnormalities are related to lymphoma extension), this includes: • Hemoglobin ≥ 8.0 g/dl (5.0 mmol/L) • Absolute neutrophil count (ANC) ≥ 1.5 109/L • Platelet count ≥ 100 109/L • Women are not breast feeding, are using effective contraception, are not pregnant and agree not to become pregnant during participation in the trial and during the 12 months thereafter. Men agree not to father a child during participation in the trial and during the 12 months thereafter. • Having previously signed a written informed consent form.

PRIMAExclusion criteria (1) • Transformation to high-grade lymphoma (secondary to “low-grade” follicular lymphoma). • Grade 3b follicular lymphoma. • Presence or history of CNS disease (either CNS lymphoma or lymphomatous meningitis). • Patients regularly taking corticosteroids during the last 4 weeks, unless administered at a dose equivalent to < 20 mg/day prednisone. • Patients with prior or concomitant malignancies except non-melanoma skin cancer or adequately treated in situ cervical cancer. • Major surgery (excluding lymph node biopsy) within 28 days prior to registration.

PRIMAExclusion criteria (2) • Poor renal function: Serum creatinine > 2.0 mg/dl (197 μmol/L), • Poor hepatic function: total bilirubin > 2.0 mg/dl (34 μmol/L), AST (SGOT) > 3 x the upper limit of normal unless these abnormalities are related to lymphoma. • Known HIV infection or active HBV or HCV infection. • Serious underlying medical conditions, which could impair the ability of the patient to participate in the trial (e.g. ongoing infection, uncontrolled diabetes mellitus, gastric ulcers, active autoimmune disease). Judgment is up to the investigator. • Life expectancy < 6 months • Known sensitivity or allergy to murine products • Treatment within a clinical trial within 30 days prior to trial entry • Adult patient under tutelage.

PRIMAPre-treatments assessments (1) • Informed consent will be obtained before any procedures are undertaken • All the following assessments should have been performed • within 28 days before the first planned dose of trial medication, • excepted for histological diagnosis of FL which can be obtained within 3 months before study registration

PRIMAPre-treatments assessments (2) • Complete medical history and physical examination • Histological diagnosis of Follicular Lymphoma including pathologic assessment. The histological diagnosis of follicular lymphoma should have been made within the last 3 months. Material should be available for central pathology review (appendix F) • Tumor and disease staging: • CT scan (thorax, abdomen, pelvis), with description of nodal locations according to the FLIPI index (appendix E3) • Bone marrow biopsy • Tumor lesion assessment: two dimensional diameters of all lymph nodes, spleen and liver enlargement • B- Symptoms • Ann Arbor staging • ECOG performance status (see Appendix E1) • Any important additional documentation according to physician judgment (MRI for example)

PRIMAPre-treatments assessments (3) • Weight, height, BSA. • Cardiac function evaluation by US echocardiography or left VEF according to physician decision (if patient planned to receive anthracycline). • Laboratory assessments: • Hemoglobin, WBC with differentials, platelets, • Sodium, potassium, calcium, • AST, ALT, total bilirubin, serum creatinine, alkaline phosphatase, total protein, albumin, • β2-microglobulin, LDH. • Pregnancy test (women of childbearing potential only). • Consideration of sperm cryo-preservation. • Serum and DNA storage for ancillary studies (Appendix G). • Quality of life questionnaires FACT-G and QLQ-C30.

PRIMAInduction treatment (1) • Induction of response with 8 x rituximab combined • with 8 cycles of CVP every 21 days • or 6 cycles of CHOP in 21-day cycles • or 6 cycles of FCM in 28-day cycles • or 6 cycles of MCP in 28-day cycles.

PRIMAInduction treatment (2) • After registration induction therapy has to be started within 7 days from registration • The assignment to one of the four chemotherapy groups (R-CVP, R-CHOP, R-FCM and R-MCP) is on a per centre decision. Every centre has to decide upfront (before initiation of the study) which chemotherapy schedule is standard of care for follicular lymphoma patients in that center and therefore will be given to all patients of that center throughout the study (information will be reported on registration form) • In France, only R-CVP and R-CHOP will be considered as standard. In Germany, the regimen will be allocated to each patient through randomization (OSHO/GLSG procedure).

PRIMAInduction treatment (3)

PRIMAInduction period (7) • Study visits are foreseen on day 1 (first day of drug administration) and at 21 day / 28 day intervals for the treatment during the induction period. • A safety blood sample will be taken on day 14 of the first treatment cycle for the assessment of hematological toxicity (weekly for R-FCM or R-MCP). • Patients who progress during induction therapy should be considered for alternative treatment. • Response to treatment will be assessed after 3 (R-FCM, R-MCP) or 4 cycles (R-CHOP, R-CVP) of induction treatment and within 28 days after the last treatment cycle.

PRIMAEvaluation of response after induction • After completion of the study medication a final restaging should be performed within 28 days (between 14 and 28 days) after the last immuno-chemotherapy course. • Physical examination. • Recording of serious adverse events. • Laboratory assessments: (see protocol) • Final restaging after induction therapy: CT scan of the chest, abdomen, and pelvis. • Tumor lesion assessment : two dimensional diameters of all lymph nodes, spleen and liver enlargement • Bone marrow biopsy (unless initially negative). • B-symptoms and ECOG performance status. • Any important additional documentation according to physician judgment (MRI for example). • Quality of life questionnaires FACT-G and QLQ-C30.

PRIMARequirements for Randomization • Being registered in the trial before treatment and having filled / send the CRF for baseline period • All lesions reported in the on-study form have been re-evaluated. • Patient must have reached a PR, CRu or CR. (According to appendix C). • Patient should have received all full doses of induction treatment, excepted planned modifications. • Exclusion : Patient with delayed chemotherapy courses for more than 2 weeks (> 14 days).

PRIMAMaintenance period (1) • Randomization to the second phase will be stratified by chemotherapy and by response (CR/PR). All stratification factors must be verifiable at randomization. • At randomization eligible patients will be randomized in a 1:1 fashion to receive either • Arm A: one injection rituximab 375 mg/m2 every 8 weeks for 24 months • Arm B: no treatment • Maintenance therapy has to be started 8 weeks after the last chemotherapy or immunotherapy cycle.

PRIMAMaintenance period (2) • Study visits are foreseen every 8 weeks for all patients (with or without rituximab) in the maintenance period. • Patients randomized to maintenance therapy should start treatment with rituximab 8 weeks (56 +/- 7 days) after the day 1 of the last treatment cycle (chemo-immunotherapy or rituximab, which ever last). • Rituximab should be given every 8 weeks (56 +/- 7 days) until progression, relapse, institution of a new treatment, death, or toxicity for a maximum period of 2 years. • Any new treatment initiation unplanned in the protocol is considered as an event.

PRIMAMaintenance period (3) • Rituximab 375 mg/m2 : • administered by IV infusion every 8 weeks • starting 8 weeks after the last chemotherapy cycle • dosage calculations for rituximab will be based on the patient’s body surface area (BSA), using actual weight for calculations • premedication consisting of an analgesic/antipyretic (e.g. paracetamol) and an antihistaminic agent (e.g. diphenhydramine) should always be administered before each infusion of rituximab. • No dose adjustement (except BSA)

PRIMAMaintenance period (4) • At each visit, every 2 months, for all patients: • Physical examination. • Recording of infusion-related toxicity within the first 24 hours after the start of study treatment. • Recording of adverse events and serious adverse events. • Laboratory assessments: Hemoglobin, WBC with differential, platelets, Sodium, potassium, Serum creatinine. • In addition,every 6 months, for all patients: • β2-microglobulin, LDH • Tumor lesion assessment: two dimensional diameters of all lymph nodes, spleen and liver enlargement • CT scan of the chest, abdomen, and pelvis • (Note: Use the same method of assessment for each lesion at every evaluation throughout the study. Patients with symptoms suggestive of PD may have tumor assessments performed at times other than those described in the protocol at the investigator’s discretion). • In addition, every 12 months, for all patients: • Quality of life questionnaires FACT-G and QLQ-C30.

PRIMAResponse assessment after maintenance (or no !) • After completion of the maintenance period, for all patients (with or without rituximab) a final restaging should be performed within 28 days of the last rituximab course. • Physical examination. • Recording of adverse events and serious adverse events. • Laboratory assessments: • Tumor lesion assessment : two dimensional diameters of all lymph nodes, spleen and liver enlargement • Bone marrow biopsy (unless initially negative). • B-symptoms and ECOG performance status. • CT scan of the chest, abdomen, and pelvis. • Any important additional documentation according to physician judgment (MRI for example). • Quality of life questionnaires FACT-G and QLQ-C30.

PRIMA3 years follow-up period ! • Following assessments for response evaluation should be performed, every three months during the first year then every 6 months during two additional years: • Physical examination • Tumor lesion assessment: two dimensional diameters of all lymph nodes, spleen and liver enlargement • B-symptoms and ECOG performance status • Every 6 months: CT scan of the chest, abdomen, and pelvis • Every 12 months: Quality of life questionnaires FACT-G and QLQ-C30.

PRIMAInvestigator Meeting General Organization and Finances

PRIMAGeneral organization • The GELA-RC will organize and coordinate all administrative and financials items that relate to the PRIMA study • The randomization, CRF, data-base, trial files, etc… will be collected by the GELA-RC

PRIMAGeneral organization • In each country, a collaborative group or a center will coordinate the efforts for trial implementation and organization : • Contacts with Roche affiliates regarding Mabthera supply for maintenance and regulatory issues • Regulatory issues, ethics, insurance • Choice and coordination of centers • Monitoring organization • Contact with the GELA-RC

PRIMAGeneral organization • The national collaborative group or the coordinating center will sign a contract with the GELA-RC • Agreement with GCP, ICH, … • The GELA will support investigator and national work by providing 500€ per observation (complete !) • Insurance fees to be covered • Intellectual properties of data

PRIMAGeneral organization • Drug supply during induction • Rituximab has been approved in EU for first line treatment of follicular patients on August 3rd • According to the new EU CTD, it is not considered as an investigational medicinal product in induction • However, in some countries, free drug for induction may be needed and this issue should be discussed with the Roche affiliates • Drug supply during maintenance • In each country, Rituximab will be supplied free of charge for patients allocated to the maintenance arm • Drug distribution will be organized at a national level through Roche affiliates

PRIMAGeneral organization • Monitoring • Monitoring is mandatory according to EU CTD and for the study performance ! • Two visits per site per year during treatment phase and then one visit per year latter on • Monitoring on key parameters • Monitoring will be conducted by the local study group or a CRO

PRIMAGeneral organization • Publication It is the responsibility of the investigators to publish the clinical study results as soon as possible after the completion of the study. In a multicentre study, the principal investigator must ensure that the data from one center is not published before the publication of the whole study. All active centers will be co-authors of the publication or acknowledged in the manuscript according to their participation to the study.

PRIMA Investigator Meeting