PRIMA Investigator Meeting

PRIMAInvestigator Meeting Gilles Salles Vienna, June 07

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

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

PRIMA : an international collaborative effort

PRIMA RECRUITMENT

PRIMA recruitment

PRIMA RECRUITMENT Chemo regimen chosen (all pts) R-CHOP 900 74% R-CVP 272 22% R-FCM 45 4% Vienna, June 07

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

Randomization failure For the 146 patients (15.6%) that failed to be randomized: Major violation (inclusion criteria) 10 pts (3 Hbs +) pathology review 12 pts BM only 3 pts Major protocol violation (treatment) 11 pts 2nd cancer discovered during induction 7 pts 29% Toxicity and premature withdrawal 24 pts Delay during induction or at randomisation 20 pts 30% Treatment failure 32 pts Death 14 pts 33% Consent withdrawal 6 pts Investigator decision 4 pts 7% Vienna, June 07

Patients characteristics(CRF registered, medical review ongoing) Vienna, June 07

Patients characteristics(CRF registered, medical review ongoing) (only 112 patients - 10% - had those sole criteria) Vienna, June 07

Patients characteristics(CRF registered, medical review ongoing) Vienna, June 07

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

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 18th 2006 • Approval by French authorities September 2006 • Dissemination of new protocol and ICF versions to other countries: • September 18th • Accrual resumed from October 9th until January in most countries Vienna, June 07

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

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

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

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

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

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

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

Progression-free survivalafter R-CHOP 100 90 80 70 60 50 40 30 20 10 0 Median 51.9 months Progression-free survival (%) Median 23.1 months Overall log-rank test: p=0.004; HR: 0.54 0 1 2 3 4 5 Years O N Number of patients at risk : Treatment 55 98 59 31 13 4 34 91 65 48 27 8 MabThera Results of R-CHOP maintenance in the EORTC intergroup study Vienna, June 07

Time for analysis • 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 • Close tracking of events – - fax progression /death pages to gelarc “on line” • Expected first semester of 2008 ? • Will be blinded and presented to the DSMC Vienna, June 07

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

PRIMA Investigator Meeting