1. PRIMA Investigator Meeting Wednesday, June 8, 2005 Villa Castagnola, Lugano

2. PRIMA Investigator Meeting Agenda Welcome and Introduction Welcome and Introduction Gilles Salles Gilles Salles Regulation and status of the trial Regulation and status of the trial Stephanie Baulu Stephanie Baulu Protocol and medical issues Protocol and medical issues Gilles Salles Gilles Salles Logistics of Data Logistics of Data Stephanie Baulu Stephanie Baulu Path Review Path Review Luc Xerri Luc Xerri TMA proposal : Lyndsey Goff TMA proposal : Lyndsey Goff Discussion Discussion

3. Regulation and Status Validation of country’s participation Validation of country’s participation Validation of center’s participation Validation of center’s participation Countries Status Countries Status Registration Status Registration Status

4. PRIMA ORGANIZATION PRIMA Study will be conducted in accordance with : PRIMA Study will be conducted in accordance with : ICH-GCP (Topic E6) ICH-GCP (Topic E6) Helsinki Declaration Helsinki Declaration Local laws and regulatory requirements as new European directive (2001/83 and 2002/98) Local laws and regulatory requirements as new European directive (2001/83 and 2002/98) Country regulation Center activation Patient registration Case Report Form filling SAEs declaration and AEs

5. Validation of country’s participation Define the country coordinator Define the country coordinator Define all centers that will participate to the study Define all centers that will participate to the study To be sent to the GELARC: To be sent to the GELARC: “Contract between GELA and National Representative” (National Study Group or Roche Affiliate) “Contract between GELA and National Representative” (National Study Group or Roche Affiliate) List of all centers with principal investigator’s name, address, phone number and E-mail List of all centers with principal investigator’s name, address, phone number and E-mail Curriculum Vitae (1 page) of principal investigator for each center Curriculum Vitae (1 page) of principal investigator for each center Name and address of the Pathologist in charge of local review if applicable Name and address of the Pathologist in charge of local review if applicable  GELARC send back all documents for local submission

6. Validation of country’s participation  Apply to ethics and national health authorities Send by the Local Coordinator to the GELARC: Send by the Local Coordinator to the GELARC: Ethic Committee approval Ethic Committee approval Health Authorities approval Health Authorities approval Insurance Insurance “Regulatory Documents Certification” signed by Coordinator “Regulatory Documents Certification” signed by Coordinator Informed consent and information sheet in local language Informed consent and information sheet in local language Any local amendment must be approved by GELA before local submission Any local amendment must be approved by GELA before local submission  Your country is ready to start the study

7. Validation of center’s participation GELARC will send by express-courrier to the local coordination center (National Study Group or Roche Affiliate contact) : GELARC will send by express-courrier to the local coordination center (National Study Group or Roche Affiliate contact) : Case Report Form Case Report Form Investigator’s Study File for all centers Investigator’s Study File for all centers  To be completed with all regulatory documents required by local laws.  Initiation visits could be done

8. Countries Status 29 countries participate to PRIMA study : 29 countries participate to PRIMA study : 12 in European Community (GELA official sponsor) 12 in European Community (GELA official sponsor) 17 for the rest of the world (Roche affiliates or others) 17 for the rest of the world (Roche affiliates or others) 4 countries are activated : 4 countries are activated : Belgium, Colombia, Denmark and France. Belgium, Colombia, Denmark and France. 19 countries have submitted and are waiting for the approvals : 19 countries have submitted and are waiting for the approvals : Other Latin America Countries, Turkey, Thailand, Netherlands, India, Finland, Serbia, Spain, Croatia, China, Australia/NZ and South Africa. Other Latin America Countries, Turkey, Thailand, Netherlands, India, Finland, Serbia, Spain, Croatia, China, Australia/NZ and South Africa. 6 countries are in progress for submission : 6 countries are in progress for submission : Germany, UK, Czech Republic Germany, UK, Czech Republic and Israel, Poland and Portugal and Israel, Poland and Portugal Impossible to add another new country !

9. Registration Status

10. The first patient will be randomized for maintenance on July 2005 in France The first patient will be randomized for maintenance on July 2005 in France

11. PRIMA Investigator Meeting Agenda Welcome and Introduction Welcome and Introduction Gilles Salles Gilles Salles Regulation and status of the trial Regulation and status of the trial Stephanie Baulu Stephanie Baulu Protocol and medical issues Protocol and medical issues Gilles Salles Gilles Salles Logistics of Data Logistics of Data Stephanie Baulu Stephanie Baulu Path Review Path Review Luc Xerri Luc Xerri TMA proposal : Lyndsey Goff TMA proposal : Lyndsey Goff Discussion Discussion

12. PRIMA : Primary Rituximab and Maintenance No standard first line chemotherapy in follicular lymphoma 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 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 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 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

13. PRIMA Study Final Design PDs/SDs off study MabThera Maintenance 1 dose every 8 weeks for 24 months Observation R CR/PR Chairs : G Salles, R Marcus & M Herold 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 High tumor burden

14. PRIMA Scientific design of the study 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. 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.

15. PRIMA Scientific design of the study New anti-lymphoma treatment is defined : 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. 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. Any new anti-lymphoma treatment not planed in the protocol will be considered as an event.

16. PRIMA Inclusion criteria (1) Patients previously untreated Patients previously untreated Histologically confirmed follicular lymphoma grade 1, 2 or 3a Histologically confirmed follicular lymphoma grade 1, 2 or 3a With a path report of less than 3 months With a path report of less than 3 months

17. PRIMA Inclusion criteria (2) Patients with at least one of the following symptoms requiring initiation of treatment: Patients with at least one of the following symptoms requiring initiation of treatment: Bulky disease at study entry Bulky disease at study entry nodal or extranodal mass > 7cm in its greater diameter nodal or extranodal mass > 7cm in its greater diameter B symptoms B symptoms Elevated serum LDH (above N) or  2-microglobulin (> 3mg/L) Elevated serum LDH (above N) or  2-microglobulin (> 3mg/L) involvement of at least 3 nodal sites (each with a diameter greater than 3 cm) involvement of at least 3 nodal sites (each with a diameter greater than 3 cm) symptomatic splenic enlargement symptomatic splenic enlargement compressive syndrome compressive syndrome pleural/peritoneal effusion pleural/peritoneal effusion Of note, stage I or II if present these criteria can be included Of note, stage I or II if present these criteria can be included

18. PRIMA Inclusion criteria (3) Age must be > 18 years. Age must be > 18 years. Performance status < 2 on the ECOG scale (see appendix E). 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: 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) Hemoglobin ≥ 8.0 g/dl (5.0 mmol/L) Absolute neutrophil count (ANC) ≥ 1.5 109/L Absolute neutrophil count (ANC) ≥ 1.5 109/L Platelet count ≥ 100 109/L Platelet count ≥ 100 109/L

19. PRIMA Inclusion criteria (4) 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. 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. Having previously signed a written informed consent form.

20. PRIMA Exclusion criteria (1) Transformation to high-grade lymphoma (secondary to “low-grade” follicular lymphoma). Transformation to high-grade lymphoma (secondary to “low-grade” follicular lymphoma). Grade 3b follicular lymphoma. Grade 3b follicular lymphoma. Presence or history of CNS disease (either CNS lymphoma or lymphomatous meningitis). Presence or history of CNS disease (either CNS lymphoma or lymphomatous meningitis).

21. PRIMA Exclusion criteria (2) Patients regularly taking corticosteroids during the last 4 weeks, unless administered at a dose equivalent to < 20 mg/day prednisone (over the last 4 weeks). Patients regularly taking corticosteroids during the last 4 weeks, unless administered at a dose equivalent to < 20 mg/day prednisone (over the last 4 weeks). Patients with prior or concomitant malignancies except non- melanoma skin cancer or adequately treated in situ cervical cancer. 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. Major surgery (excluding lymph node biopsy) within 28 days prior to registration.

22. PRIMA Exclusion criteria (3) Poor renal function: Poor renal function: Serum creatinine > 2.0 mg/dl (197 μmol/L), Serum creatinine > 2.0 mg/dl (197 μmol/L), Poor hepatic function: Poor hepatic function: total bilirubin > 2.0 mg/dl (34 μmol/L) or AST (SGOT) > 3 x the upper limit of normal unless these abnormalities are related to lymphoma total bilirubin > 2.0 mg/dl (34 μmol/L) or 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 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 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

23. PRIMA Exclusion criteria (4) Life expectancy < 6 months Life expectancy < 6 months Known sensitivity or allergy to murine products Known sensitivity or allergy to murine products Treatment within a clinical trial within 30 days prior to trial entry Treatment within a clinical trial within 30 days prior to trial entry Adult patient under tutelage Adult patient under tutelage

24. PRIMA Study Final Design PDs/SDs off study MabThera Maintenance 1 dose every 8 weeks for 24 months Observation R CR/PR 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

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

26. PRIMA Induction treatment (2) After registration induction therapy has to be started within 7 days from registration 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) 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). 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).

27. PRIMA Induction treatment (3) 8 R-CVP / 21-day CYCLES (cycles 1 to 8) Chemotheray regimenDoseModeD1D2D3D4D5 Rituximab375 mg/m 2 IV Cyclophosphamide750 mg/m 2 IV push Vincristine1.4 mg/m 2 (2 mg max.) IV bolus Prednisone40 mg/m 2 day PO

28. PRIMA Induction treatment (4) 6 R-CHOP / 21-day CYCLES (cycles 1 to 6) Chemotheray regimenDoseModeD1D2D3D4D5 Rituximab375 mg/m 2 IV Cyclophosphamide750 mg/m 2 IV Doxorubicin50 mg/m 2 IV push Vincristine1.4 mg/m 2 (2 mg max.) IV push Prednisone100 mg/dayPO 2 Rituximab / 21-day CYCLES (cycles 7 and 8) Rituximab375 mg/m 2 IV1 injection 21 days (3 weeks) after cycle 6 of R-CHOP 1 injection 42 days (6 weeks) after cycle 6 of R-CHOP

29. PRIMA Induction treatment (5) 6 R-FCM / 28- day cycles (cycles 1 to 6) C1 to C6 Chemotherapy regimen DoseModeD1D2D3 Rituximab375 mg/m 2 IV Cyclophosphamide200 mg/m 2 IV – 4 hours infusion Fludarabine25 mg/m 2 IV - 30 min. infusion Mitoxantrone6 mg/m 2 IV – 30 min. infusion 2 RituximabD15 of C1D15 of C4 Rituximab375 mg/m 2 IV

30. PRIMA Induction treatment (6) 6 R-MCP / 28-day cycles (cycles 1 to 6) C1 to C6 Chemotherapy regimenDoseModeD1D2D3D4D4 D5 Rituximab375 mg/m 2 IV Mitoxantrone8 mg/m 2 IV – 30 min. infusion Chlorambucil3 x 3 mg/m 2 PO Prednisolone25 mg/m 2 PO 2 RituximabD15 of C1D15 of C4 Rituximab375 mg/m 2 IV

31. PRIMA Requirements for Randomization Being registered in the trial before treatment and having filled / send the CRF for baseline period 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. 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 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. 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). Exclusion : Patient with delayed chemotherapy courses for more than 2 weeks (> 14 days).

32. PRIMA Study Final Design PDs/SDs off study MabThera Maintenance 1 dose every 8 weeks for 24 months Observation R CR/PR 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

33. PRIMA Study Final Design PDs/SDs off study MabThera Maintenance 1 dose every 8 weeks for 24 months Observation R CR/PR 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

34. PRIMA 3 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: 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 Physical examination Tumor lesion assessment: two dimensional diameters of all lymph nodes, spleen and liver enlargement Tumor lesion assessment: two dimensional diameters of all lymph nodes, spleen and liver enlargement B-symptoms and ECOG performance status B-symptoms and ECOG performance status Every 6 months: CT scan of the chest, abdomen, and pelvis Every 6 months: CT scan of the chest, abdomen, and pelvis Every 12 months: Quality of life questionnaires FACT-G and QLQ-C30. Every 12 months: Quality of life questionnaires FACT-G and QLQ-C30.

35. PRIMA Investigator Meeting Agenda Welcome and Introduction Welcome and Introduction Gilles Salles Gilles Salles Regulation and status of the trial Regulation and status of the trial Stephanie Baulu Stephanie Baulu Protocol and medical issues Protocol and medical issues Gilles Salles Gilles Salles Logistics of Data Logistics of Data Stephanie Baulu Stephanie Baulu Path Review Path Review Luc Xerri Luc Xerri TMA proposal : Lyndsey Goff TMA proposal : Lyndsey Goff Discussion Discussion

36. Logistical Aspects Registration Registration CRFs and Monitoring CRFs and Monitoring Serious Adverse Events Serious Adverse Events

37. REGISTRATION Obtain consent of patient : the patient must sign 3 copies of the informed consent form (1 for himself, 1 for the investigator and 1 for the GELA) Obtain consent of patient : the patient must sign 3 copies of the informed consent form (1 for himself, 1 for the investigator and 1 for the GELA) Complete and fax the registration form to the GELA randomization center with the pathological report Complete and fax the registration form to the GELA randomization center with the pathological report GELA send it back in 1 day (Monday to Friday) with patient registration number GELA send it back in 1 day (Monday to Friday) with patient registration number Local coordination center and Principal Investigator of each country will be informed of country inclusions by email Local coordination center and Principal Investigator of each country will be informed of country inclusions by email Case Report Form (CRF) sent by local monitor after each inclusion Case Report Form (CRF) sent by local monitor after each inclusion  Only patient initials (3 first of the surname + 2 first of the firstname) should be recorded on the forms

38. GELA Randomization Center Registration and Randomization Forms have to be faxed to GELA randomization center : Registration and Randomization Forms have to be faxed to GELA randomization center : St Louis Hospital – Centre Hayem Fax : +33 1 42 49 99 72 Monday to Friday - 09:00 am to 05:00 pm (French time)

39. CRF and Monitoring CRFs have to be completed in English. Only patient initials should be recorded on the CRF pages. CRFs have to be completed in English. Only patient initials should be recorded on the CRF pages. Monitoring of data reported on CRF is planned on key parameters (underlined), twice a year for all patients, following an organization at your convenience. Monitoring of data reported on CRF is planned on key parameters (underlined), twice a year for all patients, following an organization at your convenience. Baseline period has to be monitored before randomization Baseline period has to be monitored before randomization Pages of CRF are Triplicate Forms Pages of CRF are Triplicate Forms After monitoring, please send as soon as possible to GELARC 2 forms (original and 1 copy) of complete parts After monitoring, please send as soon as possible to GELARC 2 forms (original and 1 copy) of complete parts

40. Flow Chart of Queries After Double data entry, Data management may edit queries about datas After Double data entry, Data management may edit queries about datas Queries/data corrections will be sent by email to the local coordinator for all centers Queries/data corrections will be sent by email to the local coordinator for all centers Each Investigator has to answer on the Query Form, sign and date it (print name) and keep a copy in the CRF Each Investigator has to answer on the Query Form, sign and date it (print name) and keep a copy in the CRF Original forms must be : Original forms must be : 1/ faxed to GELARC 2/ sent with CRF pages after monitoring

41. Serious Adverse Event Complete in English the 3 pages Complete in English the 3 pages Attach documents if necessary Attach documents if necessary Signed by a physician (authorized person) Signed by a physician (authorized person) Fax it to your local coordination center Fax it to your local coordination center Local coordination center will send it to GELARC Local coordination center will send it to GELARC SAE Form must be monitored with the CRF and original + 1 copy must be sent with CRF pages SAE Form must be monitored with the CRF and original + 1 copy must be sent with CRF pages GELARC will send back (by fax) SAE registration number/ query about SAE to local coordination center which transmit to center GELARC will send back (by fax) SAE registration number/ query about SAE to local coordination center which transmit to center

42. SAE Form Flow Chart Complementary information SAE Number / Summary CIOMS (e-mail) Investigator GELARC Genentech - Hoffman La Roche PV - Basel French Health Authorities + Ethic Committee Local EC + Local Authorities SUSAR All Local Investigators CIOMS – DIL (e-mail) Complementary Information SAEs / SUSARs According to local law Roche Affiliate / National Study Group All SAEs (fax) All SAEs

43. Pr Gilles SALLES : gilles.salles@chu-lyon.fr gilles.salles@chu-lyon.fr Delphine GERMAIN : delphine.germain@chu-lyon.fr delphine.germain@chu-lyon.fr Stéphanie BAULU : steph.baulu@chu-lyon.fr steph.baulu@chu-lyon.fr http://prima.gela.org Contacts

44. Pathology Study PRIMA TRIAL Luc Xerri For the french GELA reviewing panel : N. Brousse, F. Charlotte, B. Fabiani

45. Aims of the Pathology Review Process Aims of the Pathology Review Process 1) to confirm the diagnosis of follicular lymphoma 1) to confirm the diagnosis of follicular lymphoma appropriate panel of antbodies (CD20, CD5, Bcl-6, Bcl2) appropriate panel of antbodies (CD20, CD5, Bcl-6, Bcl2) To classify it according to the WHO grading (2001), To classify it according to the WHO grading (2001), 2) store a block of the tumoral sample 2) store a block of the tumoral sample Tissue-Micro-Array of follicular lymphoma specimens Tissue-Micro-Array of follicular lymphoma specimens To evaluate the relevance of the expression of prognostic markers in the response to therapy and outcome. To evaluate the relevance of the expression of prognostic markers in the response to therapy and outcome.