PRIMA Investigator Meeting Saturday, December 9th, 2006 Orlando – ASH meeting

Agenda Status of the study Status of the study Study Update Study Update Protocol Amendment Protocol Amendment CT-scan review CT-scan review Monitoring / Administration / Contracts Monitoring / Administration / Contracts Questions Questions

PRIMA had became a registration trial Agreement between GELA, Roche and Genentech Agreement between GELA, Roche and Genentech - First contacts end of May, decision in July ● The results will be used for registration filing - in EU, US and rest of the world New responsabilities: New responsabilities: - For the sponsor (GELA) - For the investigators - For the coordinating centers - For monitoring the study - For the partners (Roche, Genentech) - For the DSMC - …

Status on August countries were active for recruitment. The 900 registered pts target (2 nd amendment, early 2006) - reached on August 11th pts at the time of randomization: maintenance observation - 67 failed randomization (16.5%) Argentina Australia Belgium Brazil China Colombia Croatia Czech republic Denmark Finland France India Israel Mexico Netherlands Peru Portugal Serbia / Montenegro Spain Thailand Turkey United Kingdom Uruguay Venezuela New Zealand

To become a registration trial New protocol version (version 4.0, amendment 3) needed with several changes : New protocol version (version 4.0, amendment 3) needed with several changes : Compliance with Health Authorities (EMEA, FDA) requirements (PFS, etc…) Compliance with Health Authorities (EMEA, FDA) requirements (PFS, etc…) Update statistical hypothesis taking into account the results of the EORTC and GLSG studies (patients number) Update statistical hypothesis taking into account the results of the EORTC and GLSG studies (patients number) Changes in protocol and ICF for new and already registered patients Changes in protocol and ICF for new and already registered patients Approval of the DSMC Approval of the DSMC August 4th 2006 August 4th 2006 Submission to the ethics and health authorities in the lead sponsor country : August 18th Submission to the ethics and health authorities in the lead sponsor country : August 18th Approval by french authorities september 2006 Approval by french authorities september 2006 Dissemination of new protocol and ICF versions to other countries: Dissemination of new protocol and ICF versions to other countries: september 18th september 18th Accrual resumed in France on October 9th Accrual resumed in France on October 9th

Agenda Status of the study Status of the study Study Update Study Update Protocol Amendment Protocol Amendment CT-scan review CT-scan review Monitoring / Administration / Contracts Monitoring / Administration / Contracts Questions Questions

Current STATUS 8 countries received approval to register patients again 8 countries received approval to register patients again 977 patients registered (04/12/06) 977 patients registered (04/12/06) 601 patients randomized (04/12/06) 601 patients randomized (04/12/06)  Randomization rate ± 84 % Estimated end of recruitment : March, 2007

PRIMA RECRUITMENT

Agenda Status of the study Status of the study Study Update Study Update Protocol Amendment Protocol Amendment CT-scan review CT-scan review Monitoring / Administration / Contracts Monitoring / Administration / Contracts Questions Questions

Major Changes – 3rd Amendment (1) Primary objective : PFS instead of EFS Primary objective : PFS instead of EFS Increase in the follow-up period : 3 to 5 years Increase in the follow-up period : 3 to 5 years Increase in patients number : 1200 (instead of 900) Increase in patients number : 1200 (instead of 900) Exclusion criteria : patient with any history of hepatitis B or hepatitis B virus infection Exclusion criteria : patient with any history of hepatitis B or hepatitis B virus infection Eligibility for randomization : Eligibility for randomization : Patients should have received at least : Patients should have received at least : 4 R-CHOP + 2R 4 R-CHOP + 2R or 6 R-CVP or 6 R-CVP or 4 R-FCM or 4 R-FCM Induction chemotherapy regimen : R-MCP deleted Induction chemotherapy regimen : R-MCP deleted

EORTC 20981: K-M curves for PFS Subgroup analysis according to induction median: 23.1 months median: 51.9 months H.R. 0.54

Major Changes – 3rd Amendment (2) Additional visits and CT-scan in the 2 nd year after the end of maintenance/observation Additional visits and CT-scan in the 2 nd year after the end of maintenance/observation New ICF for new patients (ICF and information letter version 2.0) New ICF for new patients (ICF and information letter version 2.0) An additional ICF to be signed by patients already registered (ICF and information letter version 2.1) An additional ICF to be signed by patients already registered (ICF and information letter version 2.1) CT-scan collection and review CT-scan collection and review Induction Chemotherapy doses required by FDA Induction Chemotherapy doses required by FDA Changes in the CRF for new patients, specific additional forms for those already registered Changes in the CRF for new patients, specific additional forms for those already registered

Regulatory Update Belgium, Croatia, Denmark, Finland, France, Thailand, Venezuela and one site of Australia received approval for 3rd amendment Belgium, Croatia, Denmark, Finland, France, Thailand, Venezuela and one site of Australia received approval for 3rd amendment Before starting recruitment, to be provided to GELARC : Before starting recruitment, to be provided to GELARC :  CV of Principal Investigator and Co-investigators in each center  PD 35 form for Inv. And Co-Inv  Page of protocol (v3.2 and 4.0) signed by PI  Approvals (Ethics Committee and Health Authorities) for amendment n°2 and n°3 + regulatory certification document  New Informed consent in local language After reception of all documents, GELARC will send to the local coordinator the new Registration form After reception of all documents, GELARC will send to the local coordinator the new Registration form

Agenda Status of the study Status of the study Study Update Study Update Protocol Amendment Protocol Amendment CT-scan review CT-scan review Administration / contract Administration / contract Questions Questions

Agenda Status of the study Status of the study Study Update Study Update Protocol Amendment Protocol Amendment CT-scan review CT-scan review Monitoring / Administration / Contracts Monitoring / Administration / Contracts Questions Questions

CRFs FLOW CHART Baseline part (p1 to 9) => sent to GELARC before randomization Baseline part (p1 to 9) => sent to GELARC before randomization Induction / randomization parts (p10 to 18) => sent as soon as possible after randomization or premature withdrawal Induction / randomization parts (p10 to 18) => sent as soon as possible after randomization or premature withdrawal Maintenance part => every 4 visits (with evaluation and toxicity pages), likely after each visit in the near future Maintenance part => every 4 visits (with evaluation and toxicity pages), likely after each visit in the near future Progression, event, death : to be faxed to GELARC and sent as soon as possible Progression, event, death : to be faxed to GELARC and sent as soon as possible AE and original forms of SAE => sent after each monitoring visit AE and original forms of SAE => sent after each monitoring visit All parts have to be monitored before being sent to the GELARC

CRFs Reception / Monitoring 638 CRF must should have been registered at the end of induction treatment as today : 638 CRF must should have been registered at the end of induction treatment as today : 97 % of complete baselines received ! 97 % of complete baselines received ! 53 % of complete induction received 53 % of complete induction received - 23 % = incomplete induction part - 24 % = missing induction part Monitoring frequency will be increased in 2007 : every 8 weeks instead of twice a year. Monitoring frequency will be increased in 2007 : every 8 weeks instead of twice a year. Many thanks for your effort to send the induction treatment before the end of this year !!!

QUERY & DATA MANAGEMENT CRFs validation CRFs validation  parametered tests + medical review CRFs are validated as follow : CRFs are validated as follow :  Baseline + induction treatment  Maintenance (every 4 visits) : increased frequency in the near future  Follow-up / progression / death / AEs (at reception) Clinical data correction Forms will be sent by GELARC after the validation of each part Clinical data correction Forms will be sent by GELARC after the validation of each part

QUERY & DATA MANAGEMENT Clinical data correction Forms will be sent by e- mail to the local coordinator (study group, Roche or other) Clinical data correction Forms will be sent by e- mail to the local coordinator (study group, Roche or other) Answers must be completed directly on the form by the investigator (do not forget to sign and date form ! ) Answers must be completed directly on the form by the investigator (do not forget to sign and date form ! ) One copy must be kept in the CRF One copy must be kept in the CRF Each completed form has to be faxed to GELARC (ASAP) and original forms have to be sent after the next monitoring visit (with CRF pages) Each completed form has to be faxed to GELARC (ASAP) and original forms have to be sent after the next monitoring visit (with CRF pages)

SAE s (1) A serious adverse event is any experience that suggests a significant hazard, contraindication, side effect or precaution. It is any adverse event that at any dose fulfils at least one of the following criteria: A serious adverse event is any experience that suggests a significant hazard, contraindication, side effect or precaution. It is any adverse event that at any dose fulfils at least one of the following criteria: is fatal (results in death) (note: death is an outcome, not an event) is fatal (results in death) (note: death is an outcome, not an event) is life-threatening (note: the term “life-threatening” refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event which could hypothetically have caused death had it been more severe) is life-threatening (note: the term “life-threatening” refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event which could hypothetically have caused death had it been more severe) required patient hospitalization or prolongation of existing hospitalization (note: “inpatient hospitalization” refers to an unplanned, overnight hospitalization) required patient hospitalization or prolongation of existing hospitalization (note: “inpatient hospitalization” refers to an unplanned, overnight hospitalization) results in persistent or significant disability/incapacity results in persistent or significant disability/incapacity is a congenital anomaly/birth defect is a congenital anomaly/birth defect is medically significant or requires intervention to prevent one or other of the outcomes listed above is medically significant or requires intervention to prevent one or other of the outcomes listed above

SAE s (2) During the induction phase, During the induction phase, all SAEs have to be recorded up to 30 days after the last dose of induction therapy all SAEs have to be recorded up to 30 days after the last dose of induction therapy treatment related SAEs have to be reported at any time beyond 30 days after the last dose of induction therapy. treatment related SAEs have to be reported at any time beyond 30 days after the last dose of induction therapy. During the maintenance phase, During the maintenance phase, all serious adverse events encountered up to 6 months after the last dose of rituximab or last observation visit have to be reported all serious adverse events encountered up to 6 months after the last dose of rituximab or last observation visit have to be reported treatment related SAEs have to be reported at any time beyond 6 months after the last dose of maintenance therapy/last observation visit. treatment related SAEs have to be reported at any time beyond 6 months after the last dose of maintenance therapy/last observation visit.

SAE s (3) All Serious Adverse Events (SAE) must be reported to the respective Group Principal Investigator or Data Manager by fax within 24 hours of the initial observation of the event. All Serious Adverse Events (SAE) must be reported to the respective Group Principal Investigator or Data Manager by fax within 24 hours of the initial observation of the event. Any adverse event that is considered SERIOUS must be reported within one working day (IMMEDIATELY) by the investigator to the GELARC Safety Desk. Any adverse event that is considered SERIOUS must be reported within one working day (IMMEDIATELY) by the investigator to the GELARC Safety Desk. It is a legal requirement to report serious adverse events. It is a legal requirement to report serious adverse events.

SAEs report and follow-up o Please be precise in the description of the medical event : provide one event, but detail the presence of absence of relevant conditions, specially when the outcome is fatal : o Ex : if pneumonia after chemo: describe blood counts at onset, any microbiology results, etc… ; o Ex : if cardiovascular, describe previous history, treatments, etc… o Please respect the delays (1 day) o Please follow-up the events o Please answer the queries

PRIMA = timelines according to the assumptions in the protocol the analyses are planned at the following timepoints: according to the assumptions in the protocol the analyses are planned at the following timepoints: 1st interim analysis (172 events) - 29 months after the first patient has been randomized to maintenance 1st interim analysis (172 events) - 29 months after the first patient has been randomized to maintenance 2nd interim analysis (258 events) - 37 months after the first patient has been randomized to maintenance 2nd interim analysis (258 events) - 37 months after the first patient has been randomized to maintenance final analysis (344 events) - 46 months after the first patient has been randomized to maintenance final analysis (344 events) - 46 months after the first patient has been randomized to maintenance end of study: 5 years after the last patient has finished maintenance therapy end of study: 5 years after the last patient has finished maintenance therapy - 11/ / / /14 !

Administration / Contract All contracts will be updated : All contracts will be updated : with Cooperative Groups in EU + Australia/NZ + Brazil + Israel with Cooperative Groups in EU + Australia/NZ + Brazil + Israel with Roche Affiliates outside EU (were Roche is the sponsor) with Roche Affiliates outside EU (were Roche is the sponsor) Substantial increase in investigator fee Substantial increase in investigator fee Paid by GELA to cooperative groups in EU, Au/NZ, Brazil, Israel Paid by GELA to cooperative groups in EU, Au/NZ, Brazil, Israel Paid by Roche affiliates in Roche sponsor countries Paid by Roche affiliates in Roche sponsor countries Monitoring Plan + SDV Plan will be attached to the new contract Monitoring Plan + SDV Plan will be attached to the new contract 1st batch of Investigator’s fees will be paid at the beginning of 2007 (if contract is signed) 1st batch of Investigator’s fees will be paid at the beginning of 2007 (if contract is signed)

PRIMA : a collaborative effort for the largest follicular lymphoma trial

Agenda Status of the study Status of the study Study Update Study Update Protocol Amendment Protocol Amendment CT-scan review CT-scan review Monitoring / Administration / Contracts Monitoring / Administration / Contracts Questions Questions