1. PRIMA Investigator Meeting Sunday, September 12, 2004 Corinthia Towers Hotel, Prague

2. PRIMA Investigator Meeting Agenda Welcome and Introduction Welcome and Introduction –Bertrand Coiffier, Robert Marcus, Michael Herold Design of the study and Protocol Design of the study and Protocol –Gilles Salles General organization, finances General organization, finances –Bertrand Coiffier, Gilles Salles, Myriam Mendila Organization and regulations Organization and regulations –Stephanie Baulu & Delphine Germain Path Review and Biology Path Review and Biology –Gilles Salles Discussion Discussion

3. 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

4. PRIMA : Primary Rituximab and Maintenance First contacts : First contacts : - End of August 2003 - End of August 2003 Steering Committee in Paris : Steering Committee in Paris : - November 6th 2003 - November 6th 2003 Investigator Meeting in San Diego during ASH Investigator Meeting in San Diego during ASH - December 7th 2003 - December 7th 2003 Final draft circulation to the Steering committee : Final draft circulation to the Steering committee : - June 1st 2004 - June 1st 2004 Final draft after approval by the Steering committee : - July 30th 2004 Final draft after approval by the Steering committee : - July 30th 2004 Investigator Launch Meeting in Prague : Investigator Launch Meeting in Prague : - September 10th 2004 - September 10th 2004

5. PRIMA : Primary Rituximab and Maintenance A multicentre, phase III, open-label, randomized study in patients with advanced follicular lymphoma evaluating the benefit of maintenance therapy with Rituximab (MabThera®) after induction of response with chemotherapy plus Rituximab in comparison with no maintenance therapy Principal Investigator : Gilles Salles Co-Investigators : Robert Marcus & Michael Herold

6. PRIMA : Primary Rituximab and Maintenance Participation of groups or center from : France, UK, Australia, Germany, Belgium, Swiss, Spain, Nordic Countries, Czech Republik, South America, Asia and others…! An international study coordinated by the GELA & GELA-RC

7. 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 stages III–IV

8. PRIMA Investigator Meeting Study design and protocol Key clinical issues Gilles Salles : gilles.salles@chu-lyon.fr

9. PRIMA Scientific design of the study (1) 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 Secondary objective: To evaluate response rates, event driven survival endpoints (EFS, PFS, OS) and quality of life of four different chemotherapy regimens combined with rituximab, with or without maintenance with rituximab, for first line treatment of advanced stage follicular lymphoma. Secondary objective: To evaluate response rates, event driven survival endpoints (EFS, PFS, OS) and quality of life of four different chemotherapy regimens combined with rituximab, with or without maintenance with rituximab, for first line treatment of advanced stage follicular lymphoma.

10. Response Evaluation Induction 6 x FMC 8 x Rituximab 6 x CHOP 8 x Rituximab 8 x CVP 8 x Rituximab PR or CRu or CR SD or PD Off Study 12 x Rituximab every 8 weeks for 24 months Stratification REGISTRATION 3 years follow-up Observation for 24 months 6 x MCP 8 x Rituximab Maintenance RANDOMIZATION Follow-up

11. PRIMA Scientific design of the study (2) 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.

12. PRIMA Scientific design of the study (3) 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. 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.

13. PRIMA Scientific design of the study (4) New anti-lymphoma treatment should be started: New anti-lymphoma treatment should be started: –if a patient does demonstrate disease progression during induction treatment; –at the discretion of the physician if a patient does not reach at least a partial response or a complete (either confirmed or unconfirmed) at the end of the induction treatment; –during the maintenance phase, for patients in both arms (rituximab maintenance or observation), at any time of documented disease progression if this progression is symptomatic and/or if the physician consider that a new treatment is necessary for patients benefit. The disease progression should be documented (see above) –during the 3 year follow-up period, at any time of documented disease progression if this progression is symptomatic and/or if the physician consider that a new treatment is necessary for patients benefit. The disease progression should be documented (see above)

14. PRIMA Scientific design of the study (5) Secondary efficacy parameters : Secondary efficacy parameters : – –Time To Progression (TTP) – –Time To Next Anti-Lymphoma Treatment (TTNLT) – –Time to next Chemotherapy Treatment (TTNCT) – –Overall Survival – –Overall Response Rate (Cheson criteria) – –Disease Free Survival – –Transformation rate at first progression – –Quality of Life analysis Exploratory analyses on primary and secondary endpoints : Exploratory analyses on primary and secondary endpoints : –according to the FLIPI index at patient registration (study entry) –according to each arm of chemotherapy (CVP, CHOP, FCM and MCP)

15. PRIMA Scientific design of the study (6) The primary endpoint of event-free survival was used to determine the sample size of the study. To demonstrate a 45% increase in the median event-free survival from the time of randomization (6 months after the start of induction therapy), i.e. from 30 months (Marcus et al, 2003, Hiddemann et al, 2003) to 44 months, 480 patients need to be randomised in the maintenance period. With an estimated response rate of 75% (Czuczman et al, 1999, Marcus et al, 2003, Hiddemann et al, 2003), 640 patients should be included in the induction period.

16. PRIMA Scientific design of the study (7) Table 2-Required Number of Patients for Different Recruitment and Follow up Assumptions Recruit- ment (months) Number of randomized patients per months Total number of randomiz ed patients Approx. number of patients receiving induction therapy Max. Study Duration (months from first randomized patient) Max. Study Duration (months from first patient starting induction treatment) Expected Study Duration (months from first patient randomized) 2418432576626851 2420480640556146 2422528704505642 Assumption: required number of events is 236 Based on the above considerations 480 patients will be randomized over 24 months. This implies that approximately 640 patients will receive the induction R-CHEMO.

17. 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

18. PRIMA Inclusion criteria (1) Histologically confirmed follicular lymphoma grade 1, 2 or 3a Histologically confirmed follicular lymphoma grade 1, 2 or 3a Patients previously untreated. Patients previously untreated. 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 according to the GELF criteria: nodal or extranodal mass > 7cm in its greater diameter –B symptoms –Elevated serum LDH or  2-microglobulin –involvement of at least 3 nodal sites (each with a diameter greater than 3 cm) –symptomatic splenic enlargement –compressive syndrome –pleural/peritoneal effusion

19. PRIMA Inclusion criteria (2) 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) –Absolute neutrophil count (ANC) ≥ 1.5 109/L –Platelet count ≥ 100 109/L 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). Patients regularly taking corticosteroids during the last 4 weeks, unless administered at a dose equivalent to < 20 mg/day prednisone. Patients regularly taking corticosteroids during the last 4 weeks, unless administered at a dose equivalent to < 20 mg/day prednisone. 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.

21. PRIMA Exclusion criteria (2) Poor renal function: Serum creatinine > 2.0 mg/dl (197 μmol/L), Poor renal function: Serum creatinine > 2.0 mg/dl (197 μmol/L), Poor hepatic function: total bilirubin > 2.0 mg/dl (34 μmol/L), AST (SGOT) > 3 x the upper limit of normal unless these abnormalities are related to lymphoma. Poor hepatic function: total bilirubin > 2.0 mg/dl (34 μmol/L), 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. 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.

22. PRIMA Pre-treatments assessments (1) Informed consent will be obtained before any procedures are undertaken Informed consent will be obtained before any procedures are undertaken All the following assessments should have been performed All the following assessments should have been performed –within 28 days before the first planned dose of trial medication, –excepted for histological diagnosis of FL which can be obtained within 3 months before study registration

23. PRIMA Pre-treatments assessments (2) Complete medical history and physical examination Complete medical history and physical examination Histological diagnosis of Follicular Lymphoma including pathologic assessment. The histological diagnosis of follicular lymphoma should have been made within the last 3 months. Material should be available for central pathology review (appendix F) Histological diagnosis of Follicular Lymphoma including pathologic assessment. The histological diagnosis of follicular lymphoma should have been made within the last 3 months. Material should be available for central pathology review (appendix F) Tumor and disease staging: Tumor and disease staging: CT scan (thorax, abdomen, pelvis), with description of nodal locations according to the FLIPI index (appendix E3) CT scan (thorax, abdomen, pelvis), with description of nodal locations according to the FLIPI index (appendix E3) Bone marrow biopsy Bone marrow biopsy 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 B- Symptoms Ann Arbor staging Ann Arbor staging ECOG performance status (see Appendix E1) ECOG performance status (see Appendix E1) Any important additional documentation according to physician judgment (MRI for example) Any important additional documentation according to physician judgment (MRI for example)

24. PRIMA Pre-treatments assessments (3) Weight, height, BSA. Weight, height, BSA. Cardiac function evaluation by US echocardiography or left VEF according to physician decision (if patient planned to receive anthracycline). Cardiac function evaluation by US echocardiography or left VEF according to physician decision (if patient planned to receive anthracycline). Laboratory assessments: Laboratory assessments: –Hemoglobin, WBC with differentials, platelets, –Sodium, potassium, calcium, –AST, ALT, total bilirubin, serum creatinine, alkaline phosphatase, total protein, albumin, –β2-microglobulin, LDH. Pregnancy test (women of childbearing potential only). Pregnancy test (women of childbearing potential only). Consideration of sperm cryo-preservation. Consideration of sperm cryo-preservation. Serum and DNA storage for ancillary studies (Appendix G). Serum and DNA storage for ancillary studies (Appendix G). Quality of life questionnaires FACT-G and QLQ-C30. Quality of life questionnaires FACT-G and QLQ-C30.

25. 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

26. 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 –or 6 cycles of CHOP in 21-day cycles –or 6 cycles of FCM in 28-day cycles –or 6 cycles of MCP in 28-day cycles.

27. 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).

28. 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 bolu s Prednisone100 mg/dayPO

29. 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

30. 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

31. 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

32. PRIMA Induction period (7) Study visits are foreseen on day 1 (first day of drug administration) and at 21 day / 28 day intervals for the treatment during the induction period. A safety blood sample will be taken on day 14 of the first treatment cycle for the assessment of hematological toxicity (weekly for R-FCM or R-MCP). Patients who progress during induction therapy should be considered for alternative treatment. Response to treatment will be assessed after 3 (R-FCM, R-MCP) or 4 cycles (R-CHOP, R-CVP) of induction treatment and within 28 days after the last treatment cycle.

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 Evaluation of response after induction After completion of the study medication a final restaging should be performed within 28 days (between 14 and 28 days) after the last immuno-chemotherapy course. After completion of the study medication a final restaging should be performed within 28 days (between 14 and 28 days) after the last immuno-chemotherapy course. Physical examination. Physical examination. Recording of serious adverse events. Recording of serious adverse events. Laboratory assessments: (see protocol) Laboratory assessments: (see protocol) Final restaging after induction therapy: CT scan of the chest, abdomen, and pelvis. Final restaging after induction therapy: CT scan of the chest, abdomen, and pelvis. 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 Bone marrow biopsy (unless initially negative). Bone marrow biopsy (unless initially negative). B-symptoms and ECOG performance status. B-symptoms and ECOG performance status. Any important additional documentation according to physician judgment (MRI for example). Any important additional documentation according to physician judgment (MRI for example). Quality of life questionnaires FACT-G and QLQ-C30. Quality of life questionnaires FACT-G and QLQ-C30.

35. 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).

36. 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

37. PRIMA Maintenance period (1) Randomization to the second phase will be stratified by chemotherapy and by response (CR/PR). All stratification factors must be verifiable at randomization. Randomization to the second phase will be stratified by chemotherapy and by response (CR/PR). All stratification factors must be verifiable at randomization. At randomization eligible patients will be randomized in a 1:1 fashion to receive either At randomization eligible patients will be randomized in a 1:1 fashion to receive either –Arm A: one injection rituximab 375 mg/m2 every 8 weeks for 24 months every 8 weeks for 24 months –Arm B: no treatment Maintenance therapy has to be started 8 weeks after the last chemotherapy or immunotherapy cycle. Maintenance therapy has to be started 8 weeks after the last chemotherapy or immunotherapy cycle.

38. PRIMA Maintenance period (2) Study visits are foreseen every 8 weeks for all patients (with or without rituximab) in the maintenance period. Study visits are foreseen every 8 weeks for all patients (with or without rituximab) in the maintenance period. Patients randomized to maintenance therapy should start treatment with rituximab 8 weeks (56 +/- 7 days) after the day 1 of the last treatment cycle (chemo-immunotherapy or rituximab, which ever last). Patients randomized to maintenance therapy should start treatment with rituximab 8 weeks (56 +/- 7 days) after the day 1 of the last treatment cycle (chemo-immunotherapy or rituximab, which ever last). Rituximab should be given every 8 weeks (56 +/- 7 days) until progression, relapse, institution of a new treatment, death, or toxicity for a maximum period of 2 years. Rituximab should be given every 8 weeks (56 +/- 7 days) until progression, relapse, institution of a new treatment, death, or toxicity for a maximum period of 2 years. Any new treatment initiation unplanned in the protocol is considered as an event. Any new treatment initiation unplanned in the protocol is considered as an event.

39. PRIMA Maintenance period (3) Rituximab 375 mg/m2 : Rituximab 375 mg/m2 : –administered by IV infusion every 8 weeks –starting 8 weeks after the last chemotherapy cycle –dosage calculations for rituximab will be based on the patient’s body surface area (BSA), using actual weight for calculations –premedication consisting of an analgesic/antipyretic (e.g. paracetamol) and an antihistaminic agent (e.g. diphenhydramine) should always be administered before each infusion of rituximab. No dose adjustement (except BSA) No dose adjustement (except BSA)

40. PRIMA Maintenance period (4) At each visit, every 2 months, for all patients: At each visit, every 2 months, for all patients: –Physical examination. –Recording of infusion-related toxicity within the first 24 hours after the start of study treatment. –Recording of adverse events and serious adverse events. –Laboratory assessments: Hemoglobin, WBC with differential, platelets, Sodium, potassium, Serum creatinine. In addition, every 6 months, for all patients: In addition, every 6 months, for all patients: –β2-microglobulin, LDH –Tumor lesion assessment: two dimensional diameters of all lymph nodes, spleen and liver enlargement –CT scan of the chest, abdomen, and pelvis –(Note: Use the same method of assessment for each lesion at every evaluation throughout the study. Patients with symptoms suggestive of PD may have tumor assessments performed at times other than those described in the protocol at the investigator’s discretion). In addition, every 12 months, for all patients: In addition, every 12 months, for all patients: –Quality of life questionnaires FACT-G and QLQ-C30.

41. PRIMA Response assessment after maintenance (or no !) After completion of the maintenance period, for all patients (with or without rituximab) a final restaging should be performed within 28 days of the last rituximab course. After completion of the maintenance period, for all patients (with or without rituximab) a final restaging should be performed within 28 days of the last rituximab course. Physical examination. Physical examination. Recording of adverse events and serious adverse events. Recording of adverse events and serious adverse events. Laboratory assessments: Laboratory assessments: 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 Bone marrow biopsy (unless initially negative). Bone marrow biopsy (unless initially negative). B-symptoms and ECOG performance status. B-symptoms and ECOG performance status. CT scan of the chest, abdomen, and pelvis. CT scan of the chest, abdomen, and pelvis. Any important additional documentation according to physician judgment (MRI for example). Any important additional documentation according to physician judgment (MRI for example). Quality of life questionnaires FACT-G and QLQ-C30. Quality of life questionnaires FACT-G and QLQ-C30.

42. 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

43. 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 –Tumor lesion assessment: two dimensional diameters of all lymph nodes, spleen and liver enlargement –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.

44. PRIMA Investigator Meeting General Organization and Finances

45. PRIMA General organization The GELA-RC will organize and coordinate all administrative and financials items that relate to the PRIMA study The GELA-RC will organize and coordinate all administrative and financials items that relate to the PRIMA study The randomization, CRF, data-base, trial files, etc… will be collected by the GELA-RC The randomization, CRF, data-base, trial files, etc… will be collected by the GELA-RC

46. PRIMA General organization In each country, a collaborative group or a center will coordinate the efforts for trial implementation and organization : In each country, a collaborative group or a center will coordinate the efforts for trial implementation and organization : –Contacts with Roche affiliates regarding Mabthera supply for maintenance and regulatory issues –Regulatory issues, ethics, insurance –Choice and coordination of centers –Monitoring organization –Contact with the GELA-RC

47. PRIMA General organization The national collaborative group or the coordinating center will sign a contract with the GELA-RC The national collaborative group or the coordinating center will sign a contract with the GELA-RC –Agreement with GCP, ICH, … –The GELA will support investigator and national work by providing 500€ per observation (complete !) –Insurance fees to be covered –Intellectual properties of data

48. PRIMA General organization Drug supply during induction Drug supply during induction – –Rituximab has been approved in EU for first line treatment of follicular patients on August 3rd – –According to the new EU CTD, it is not considered as an investigational medicinal product in induction However, in some countries, free drug for induction may be needed and this issue should be discussed with the Roche affiliates Drug supply during maintenance Drug supply during maintenance – –In each country, Rituximab will be supplied free of charge for patients allocated to the maintenance arm – –Drug distribution will be organized at a national level through Roche affiliates

49. PRIMA General organization Monitoring Monitoring – –Monitoring is mandatory according to EU CTD and for the study performance ! – –Two visits per site per year during treatment phase and then one visit per year latter on – –Monitoring on key parameters – –Monitoring will be conducted by the local study group or a CRO

50. PRIMA General organization Publication Publication It is the responsibility of the investigators to publish the clinical study results as soon as possible after the completion of the study. In a multicentre study, the principal investigator must ensure that the data from one center is not published before the publication of the whole study. All active centers will be co-authors of the publication or acknowledged in the manuscript according to their participation to the study.

51. PRIMA Investigator Meeting Sunday, September 12, 2004 Corinthia Towers Hotel, Prague Stéphanie Baulu & Delphine Germain

52. REGULATORY ASPECT PRIMA Study will be conducted in accordance with : PRIMA Study will be conducted in accordance with : –ICH-GCP (Topic E6) –Helsinki Declaration –Local laws and regulatory requirements as new European directive (2001/83 and 2002/98)

53. PRIMA ORGANISATION How to validate your country’s participation? How to validate your country’s participation? How to validate the center’s participation? How to validate the center’s participation? How to register and randomize a patient ? How to register and randomize a patient ? How to complete a CRF ? How to complete a CRF ? How to follow safety process? How to follow safety process? Country regulation Center activation Patient registration Case Report Form filing SAEs declaration and AEs

54. How to validate your 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 by Coordinator to the GELARC: To be sent by Coordinator to the GELARC: –“Study agreement” (signed by coordinator) –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 –Name of the Pathologist in charge of local review if applicable

55. How to validate your country’s participation ? (2) Send by GELARC to Coordinator (by email): Send by GELARC to Coordinator (by email): –Last version of protocol –English version of synopsis –English model of informed consent –Quality of life questionnaire in local language –Quotation proposal for insurance (eventually) –Case Report Form  Apply to ethics and national health authorities

56. How to validate your country’s participation ? (3) Send by Coordinator to GELARC: Send by Coordinator to GELARC: –Ethic Committee approval –Health Authorities approval –Insurance –“Regulatory Documents Certification” signed by Coordinator Any local amendment must be approved by GELARC before local submission Any local amendment must be approved by GELARC before local submission  Your country is ready to start the study

57. PRIMA ORGANISATION How to validate your country’s participation ? How to validate your country’s participation ? How to validate the center’s participation ? How to validate the center’s participation ? How to register and randomize a patient ? How to register and randomize a patient ? How to complete a CRF ? How to complete a CRF ? How to follow safety process? How to follow safety process?

58. How to validate the center’s participation ? GELARC will send by mail to each center an Investigator’s Study File containing: GELARC will send by mail to each center an Investigator’s Study File containing: –2 copies of the protocol –1 copy of ICH –1 copy of CTCAE (v3) –5 kits (paper forms) for inclusion –4 Serious Adverse Event Report Forms –2 copies of “Study Protocol Agreement” –An electronic version of the IB

59. How to validate the center’s participation ? (2) The country coordinator will send all local regulatory documents and informed consent in local language to each center The country coordinator will send all local regulatory documents and informed consent in local language to each center The PI of each center must sign 2 copies of “Study Protocol Agreement” (1 for him, 1 for the GELA-RC) and send one back to the GELA- RC The PI of each center must sign 2 copies of “Study Protocol Agreement” (1 for him, 1 for the GELA-RC) and send one back to the GELA- RC  Each center is ready to start the study

60. PRIMA ORGANISATION How to validate your country’s participation? How to validate your country’s participation? How to validate the center’s participation? How to validate the center’s participation? How to register and randomize a patient ? How to register and randomize a patient ? How to complete a CRF ? How to complete a CRF ? How to follow safety process? How to follow safety process?

61. How to register a patient ? Obtain consent of patient : the patient must sign 3 copies of the informed consent form (1 for him, 1 for investigator and 1 for GELARC) Obtain consent of patient : the patient must sign 3 copies of the informed consent form (1 for him, 1 for investigator and 1 for GELARC) Complete and fax the registration form to the GELA randomization center with informed consent Complete and fax the registration form to the GELA randomization center with informed consent GELARC will send it back in 24 hours (Monday to Friday) with patient trial number GELARC will send it back in 24 hours (Monday to Friday) with patient trial number Country Coordinator informed of country inclusions by email Country Coordinator informed of country inclusions by email Case Report Form (CRF) sent by mail for each included patient Case Report Form (CRF) sent by mail for each included patient

62. Registration Form Center’s and Patient’s Informations Inclusion and Exclusion Criteria For Registration Investigator’s signature GELA’s validation and patient’s registration number

63. How to randomize a patient ? Your patient has received all the induction treatment and has reached a PR, CRu or CR Your patient has received all the induction treatment and has reached a PR, CRu or CR Baseline period (from CRF) has been monitored and sent to GELARC Baseline period (from CRF) has been monitored and sent to GELARC Complete and fax randomization form to GELA randomization center Complete and fax randomization form to GELA randomization center GELARC will send it back in 24 hours GELARC will send it back in 24 hours –Arm for maintenance treatment assigned Coordinator informed of country randomizations by email Coordinator informed of country randomizations by email

64. Randomization Form Center’s Informations Patient’s Informations : -Identification -Treatment (regimen and last administration) -Response Inclusion and Exclusion Criteria For Randomization Investigator’s signature GELA’s validation and Arm for Maintenance Treatment

65. GELA Randomization Center Registration and Randomization Forms have to be faxed to : Registration and Randomization Forms have to be faxed to : GELA randomization center 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 (local time)

66. PRIMA ORGANISATION How to validate your country’s participation? How to validate your country’s participation? How to validate the center’s participation? How to validate the center’s participation? How to include and randomize a patient ? How to include and randomize a patient ? How to complete the CRF ? How to complete the CRF ? How to follow safety process? How to follow safety process?

67. How to complete a Case Report Form ? CRF will be send after each inclusion to the investigator of each center CRF will be send after each inclusion to the investigator of each center CRF must be completed in English, using a black ball point pen CRF must be completed in English, using a black ball point pen Pages of CRF are Triplicate Forms Pages of CRF are Triplicate Forms Toxicities will be graded according to CTCAE v3 (present in Investigator’s Study File) Toxicities will be graded according to CTCAE v3 (present in Investigator’s Study File)

68. Case Report Form (1) CRF contains 8 parts: CRF contains 8 parts: –Baseline period –Induction Treatment (with response) –Maintenance Treatment (with randomization) –End of Treatment Evaluation / Withdrawal –Follow-up visits –Progression / relapse form - Death form –Adverse Events forms –Follow-up of Adverse Events forms

69. Case Report Form (2) Monitoring of data reported on CRF is planned on key parameters, twice a year Monitoring of data reported on CRF is planned on key parameters, twice a year Each country may organize monitoring as its convenience Each country may organize monitoring as its convenience After monitoring, please send to GELARC 2 forms of complete parts After monitoring, please send to GELARC 2 forms of complete parts Queries/data corrections could be sent by GELARC Data Management Queries/data corrections could be sent by GELARC Data Management

70. PRIMA ORGANISATION How to validate your country’s participation ? How to validate your country’s participation ? How to validate the center’s participation ? How to validate the center’s participation ? How to register and randomize a patient ? How to register and randomize a patient ? How to complete a CRF ? How to complete a CRF ? How to follow safety process ? How to follow safety process ?

71. SAFETY OPERATIONS Distinction between simple toxicity, toxicity reported as AE and toxicity reported as SAE Distinction between simple toxicity, toxicity reported as AE and toxicity reported as SAE – –All toxicities are graded according to CTCAE v3 and reported on CRF toxicity pages (induction and maintenance) – –Only toxicities grade 3, 4 or 5 (and 2 for infections) are recorded as adverse event (AE) – –All toxicity (all grades) corresponding to a SAE definition (see infra) are recorded as AE and SAE

72. SAFETY OPERATIONS Adverse events are recorded only during the maintenance treatment and up to 6 months after the last study drug administration Adverse events are recorded only during the maintenance treatment and up to 6 months after the last study drug administration All Adverse events are reported on specific pages in CRF (initial and follow-up) All Adverse events are reported on specific pages in CRF (initial and follow-up)

73. Serious Adverse Event (SAE) Definition An Adverse Event is Serious if it: An Adverse Event is Serious if it: –Results in death –Is life-threatening –Require patient hospitalization or prolongation of existing hospitalization –Results in persistent or significant disability/incapacity –Is a congenital anomaly/birth defect –Is medically significant

74. Serious Adverse Event (SAE) Reporting Timeframe SAEs should be reported from registration until 6 months after the last drug administration (chemotherapy or rituximab) SAEs should be reported from registration until 6 months after the last drug administration (chemotherapy or rituximab) Fatal/Life-threatening SAEs should be reported as soon as possible and no later than 7 calendar days from first knowledge by investigator Fatal/Life-threatening SAEs should be reported as soon as possible and no later than 7 calendar days from first knowledge by investigator Other SAEs should be reported as soon as possible and no later than 15 days from first knowledge by investigator Other SAEs should be reported as soon as possible and no later than 15 days from first knowledge by investigator

75. SAE Reporting (1) Complete SAE report form with as many informations as possible SAE report form included : diagnosis and intensity of adverse event, relationship with study drug, action taken, outcome … SAE report form included : diagnosis and intensity of adverse event, relationship with study drug, action taken, outcome … Fax the form to GELARC Safety Desk – –on +33 4 72 66 93 71 within 24 hours AND to the local Roche affiliates and local authorities

76. SAE Reporting (2) GELARC send back SAE number and eventually requests further information Information not available at the time of the initial report must be documented as a follow-up report Follow-up reports are handled in exactly the same manner as initial reports Coordinator is responsible for informing the IRC/Ethics Committee in his area

77. Let’s start the study ! We expect a lot of inclusions !!! We expect an excellent tracking of data !!!

78. PRIMA Investigator Meeting QoL Pathology Review Ancillary studies

79. PRIMA QoL study Questionnaires with FACT-G and QLQ-C30 will be distributed Questionnaires with FACT-G and QLQ-C30 will be distributed –by the clinician to the patient –at diagnosis, at the end of induction therapy and then every year in both arms and for all follow-up period (7 questionnaires per patient). –The patient will be encouraged to fill in the questionnaire within one week after the physician visit. An anonymous envelope will be provided to send back the questionnaire directly to the GELA-RC data center. –(GELARC will provide both questionnaires in every language !)

80. PRIMA Pathological review (1) The PRIMA study requires a histological review of all cases included in the trial at diagnosis and progression, requiring both morphology and immuno- histochemistry. The review process will be organized in collaboration with the GELA either per country or on an international basis. The review panel of pathologists will be co-ordinated by Prof. Luc Xerri.

81. PRIMA Pathological review (2) In each country participating to PRIMA, the choice can be made between: – –a review of the cases through a national panel in collaboration with the GELA panel review. This national panel will design one person that will be the correspondent of the GELA pathologist (Prof. Luc Xerri) in charge of the study. A meeting of pathologists from the different countries will be organized for central review of cases. – –a review of the cases through the review process organized by the GELA itself. In this case, each center should send the material (slides and/or paraffin blocks) of their cases directly to the Institut de Pathologie du GELA in Paris (Hotel-Dieu).

82. PRIMA Pathological review (3) Practical aspects of the GELA review: – –As soon as the inclusion of the patient is effective, the primary pathologist will receive from the Institut de Pathologie du GELA: – –a copy of the inclusion/randomization form – –an explanatory letter underlying tissue micro-arrays projects – –a request: 1. for sending the paraffin embedded block of the tumor. In case where the block does not contain tumor material anymore, stained slides could be sent to the Institute and will be returned as soon as the review is completed. 2. for a copy of histological report if it was not obtained before 3. for one H&E and 5 unstained slides of the bone marrow biopsy with pathological report.

83. PRIMA Pathological review (4) All these requirements (excluding frozen tissue) will be sent in a prepaid envelope (for France and Belgium, to be further defined elsewhere) to the following address: Institut de Pathologie du GELA, GELA-PRIMA study Service d'Anatomie et de Cytologie Pathologique Hôpital Hôtel-Dieu - 75181 Paris Cedex 04 – France Tél: + 33 1 42 34 86 99 – Fax: +33 1 42 34 86 41 Email: pathology-institut@gela.orgpathology-institut@gela.org The review panel of PRIMA will send to the pathologist and to each pathology center that submitted the case its review conclusion, based on consensus diagnosis from three pathologists. The block will be returned to the pathologist with the answer.

84. PRIMA Ancillary studies (1) Rationale The PRIMA study represent a unique opportunity to collect biological samples from patients with follicular lymphoma at diagnosis that can be used to improve the comprehension of the disease, to better define the prognostic criteria in follicular lymphoma and to identify new factors that influence treatments results and outcome. These scientific studies will be performed as ancillary studies based on the PRIMA protocol.

85. PRIMA Ancillary studies (2) Tumor Biopsy On paraffin embedded tissue, a tissue micro-array collection will be performed, to assess the expression of markers identified to influence the prognosis of follicular lymphoma. Serum Sample Proteomic serum analysis appears as a powerful tool to identify new markers of disease and new markers indentifying response to therapy. Serum samples will be collected at individual centers under a standardized procedure and collected at the end of the trial. Genomic DNA Host genetic appears to be able to influence the activity of monoclonal antibodies such as rituximab. A specific informed consent form will be set to allow the collection of blood samples for genomic DNA preparation and storage to analyze markers known to influence disease outcome and response to therapy.

86. PRIMA Ancillary studies (3) In France, we will perform all three analysis (tumor, serum, genomic DNA) We encourage you to see what are the aspects you can realistically concentrate on : – –Tumor tissues micro-arrays on paraffin blocks – –Serum conservation – –Genomic DNA And let us know what you will be able to organize with us !

87. PRIMA Primary Rituximab and Maintenance A unique challenge A unique challenge – an important clinical issue for patients – an international clinical trial – an opportunity for further clinical and scientific collaborations The success of our project depends on the commitment and the quality of the work of everybody ! The success of our project depends on the commitment and the quality of the work of everybody !