1. PRIMA Investigator Meeting Gilles Salles Vienna, June 07

2. PRIMA investigator meeting Introduction and Welcome Introduction and Welcome Study & Patients Study & Patients Prima is a Registration trial = changes & regulatory aspects Prima is a Registration trial = changes & regulatory aspects Next steps Next steps Vienna, June 07

3. STATUS From 24/12/2004 until 11/04/07 From 24/12/2004 until 11/04/07 1217 patients registered 1217 patients registered 25 active countries (with at least 1 patient) 25 active countries (with at least 1 patient)

4. PRIMA : an international collaborative effort

5. PRIMA RECRUITMENT

6. PRIMA recruitment

7. PRIMA RECRUITMENT Chemo regimen chosen (all pts) R-CHOP90074% R-CVP27222% R-FCM 45 4% Vienna, June 07

8. STATUS On June 5 th, 821 patients (84% or those that reached the time of randomization) were effectively randomized: Maintenance 417 pts Observation 404 pts

9. Randomization failure For the 146 patients (15.6%) that failed to be randomized: Major violation (inclusion criteria)10 pts (3 Hbs +) pathology review12 pts BM only 3 pts Major protocol violation (treatment)11 pts 2 nd cancer discovered during induction 7 pts29% Toxicity and premature withdrawal24 pts Delay during induction or at randomisation20 pts 30% Treatment failure32 pts Death14 pts33% Consent withdrawal 6 pts Investigator decision 4 pts 7% Vienna, June 07

10. Patients characteristics Patients characteristics (CRF registered, medical review ongoing) Total 1071 pts Nb Patients Nb Patients% Male55953 Female50847 PS ECOG 0-1 100594 PS ECOG 2-3 476 AA Stage I-II 13014 AA Stage III-IV 92086 Vienna, June 07

11. Total 1071 patients Nb Patients Nb Patients% Nodal or ex-nodal > 7 cm 46543 B symptoms presence 31529 Elevated LDH or β2-micro 60356 * Involvement 3 nodal sites > 3 cm 33331 Splenic enlargement 22621 Compressive syndrome 18017 Pleural / peritoneal effusion 12412 (only 112 patients - 10% - had those sole criteria) Patients characteristics Patients characteristics (CRF registered, medical review ongoing) Vienna, June 07

12. Total 1048 pts Nb Patients Nb Patients% FLIPI 0-1 22622 FLIPI 2 37636 FLIPI 3-5 44643 Patients characteristics Patients characteristics (CRF registered, medical review ongoing) Vienna, June 07

13. PRIMA had became a registration trial Agreement between GELA, Roche and Genentech Agreement between GELA, Roche and Genentech The results will be used for registration filing The results will be used for registration filing - in EU, US and rest of the world New responsibilities New responsibilities - For the sponsor (GELA) - For the investigators - For the coordinating centers - For the partners (Roche, Genentech) - For the DSMB - … Vienna, June 07

14. To become a registration trial New protocol version (version 4.0, amendment 3) needed some changes: Compliance with Health Authorities (EMEA, FDA) requirements (PFS, etc…) Update statistical hypothesis taking into account the results of the EORTC and GLSG studies (sample size) 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 18 th 2006 Approval by French authorities September 2006 Dissemination of new protocol and ICF versions to other countries: September 18th Accrual resumed from October 9 th until January in most countries Vienna, June 07

15. Regulatory aspects 3rd amendment approval needed even if no additional patient was included (regulatory, follow-up, etc…) No CT scan collection without this approval Additional ICF to be signed by patients registered before the 3rd amendment New contract between GELA – cooperative group/Roche affiliate Vienna, June 07

16. Monitoring and follow-up Close monitoring of centers (every 2 months) to complete and clean the data base - 89% of baseline received (2% incomplete) - 72% of induction / response received (11% incomplete) - 65% of first follow-up received (40% incomplete) Assure timely follow-up of patients and events Answer queries CT-scan review process with Bio-Imaging (only for randomized patients) Vienna, June 07

17. Some clinical aspects “maintenance or observation” 1) Please follow the protocol recommendations for - visits every 8 weeks during the 2 years arm A & B then - clinical visits every 3 months (2 y) and 6 months (3 y) - CT scans every 6 months (3 y) and 12 months (2 y) 2) For women in age of being pregnant: - please recommend contraceptives in the maintenance arm Vienna, June 07

18. PRIMA safety No obvious safety issues reported during induction No obvious safety issues reported during induction - next DSMB meeting in 2007 - next DSMB meeting in 2007 Follow carefully AE and SAE during maintenance Follow carefully AE and SAE during maintenance Document well what happens Document well what happens Follow-up of patients with side effects Follow-up of patients with side effects EORTC intergroup study data EORTC intergroup study data Any clinical study has to weight the risk/benefit ratio Any clinical study has to weight the risk/benefit ratio Vienna, June 07

19. PRIMA efficacy Progression: Progression: 1) Fast track declaration of progressions after randomization by FAX 2) Document well : Tumor measurements (CT scans) Tumor measurements (CT scans) Biopsy Biopsy Treatment (can be delayed) Treatment (can be delayed) 3) Follow subsequent events : Death Adequate follow-up for all patients Adequate follow-up for all patients Respect planed visits and evaluation Respect planed visits and evaluation Vienna, June 07

20. Financial agreements Patient fees were changed Patient fees were changed After randomization After randomization Time of final analysis Time of final analysis End of study End of study + CT-scan review + CT-scan review First payments to the country coordinating group in GELA-sponsored country will be done in timely manner First payments to the country coordinating group in GELA-sponsored country will be done in timely manner June 07 (if the amended contract signed) June 07 (if the amended contract signed) Then once a year Then once a year Final analysis Final analysis End of study End of study Vienna, June 07

21. Next steps for PRIMA - With 1217 pts recruited, PRIMA is the largest trial ever performed in first line follicular lymphoma patients - An opportunity for answering a very important question with a high standard quality trial : - Rituximab maintenance benefit after R-chemo Vienna, June 07

22. Results of R-CHOP maintenance in the EORTC intergroup study Overall log-rank test: p=0.004; HR: 0.54 Progression-free survival after R-CHOP ONNumber of patients at risk : 55985931134 34916548278MabThera Treatment 100 90 80 70 60 50 40 30 20 10 0 Years 0 1 2 3 45 Median 23.1 months Median 51.9 months Progression-free survival (%) Vienna, June 07

23. Time for analysis Estimated number of event to confirm the hypothesis (45% increase of PFS) : 344 events Estimated number of event to confirm the hypothesis (45% increase of PFS) : 344 events First interim analysis to be performed when 172 events will have occurred First interim analysis to be performed when 172 events will have occurred Close tracking of events – Close tracking of events – - fax progression /death pages to gelarc “on line” Expected first semester of 2008 ? Expected first semester of 2008 ? Will be blinded and presented to the DSMC Will be blinded and presented to the DSMC Vienna, June 07

24. Thanks to all of you for your cooperation for your cooperation Vienna, June 07