PRIMA Investigator Meeting

PRIMAInvestigator Meeting Saturday, December 9th, 2006 Orlando – ASH meeting

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

PRIMA had became a registration trial • 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: • 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 2006 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 . 25 countries were active for recruitment . The 900 registered pts target (2nd amendment, early 2006) - reached on August 11th 2006 . 406 pts at the time of randomization: - 176 maintenance - 163 observation - 67 failed randomization (16.5%)

To become a registration trial • New protocol version (version 4.0, amendment 3) needed with several changes : • 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) • Changes in protocol and ICF for new and already registered patients • Approval of the DSMC • August 4th 2006 • Submission to the ethics and health authorities in the lead sponsor country : August 18th • Approval by french authorities september 2006 • Dissemination of new protocol and ICF versions to other countries: • september 18th • Accrual resumed in France on October 9th

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

PRIMA RECRUITMENT

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

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

Major Changes – 3rd Amendment(2) • Additional visits and CT-scan in the 2nd year after the end of maintenance/observation • 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) • CT-scan collection and review • Induction Chemotherapy doses required by FDA • 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 • 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

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

CRFs FLOW CHART • 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 • 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 • 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 : • 97 % of complete baselines 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. Many thanks for your effort to send the induction treatment before the end of this year !!!

QUERY & DATA MANAGEMENT • CRFs validation • parametered tests + medical review • 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

QUERY & DATA MANAGEMENT • 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 ! ) • 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)

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: • 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) • required patient hospitalization or prolongation of existing hospitalization (note: “inpatient hospitalization” refers to an unplanned, overnight hospitalization) • results in persistent or significant disability/incapacity • is a congenital anomaly/birth defect • is medically significant or requires intervention to prevent one or other of the outcomes listed above

SAE s (2) • During the induction phase, • 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. • 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 • 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. • 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.

SAEs report and follow-up • 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 : • Ex : if pneumonia after chemo: describe blood counts at onset, any microbiology results, etc… ; • Ex : if cardiovascular, describe previous history, treatments, etc… • Please respect the delays (1 day) • Please follow-up the events • Please answer the queries

PRIMA = timelines • 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 • 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 • end of study: 5 years after the last patient has finished maintenance therapy - 11/07 - 07/08 - 05/09 - 09/14 !

Administration / Contract • All contracts will be updated : • with Cooperative Groups in EU + Australia/NZ + Brazil + Israel • with Roche Affiliates outside EU (were Roche is the sponsor) • Substantial increase in investigator fee • Paid by GELA to cooperative groups in EU, Au/NZ, Brazil, Israel • Paid by Roche affiliates in Roche sponsor countries • 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)

PRIMA : a collaborative effort for the largest follicular lymphoma trial

PRIMA Investigator Meeting