PRIMA Investigator Meeting

PRIMAInvestigator Meeting Wednesday, June 8, 2005 Villa Castagnola, Lugano

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

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

Country regulation Center activation Patient registration Case Report Form filling SAEs declaration and AEs PRIMA ORGANIZATION • 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)

Validation of country’s participation • Define the country coordinator • Define all centers that will participate to the study • To be sent to the GELARC: • “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 • Curriculum Vitae (1 page) of principal investigator for each center • Name and address of the Pathologist in charge of local review if applicable  GELARC send back all documents for local submission

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

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

Countries Status • 29 countries participate to PRIMA study : • 12 in European Community (GELA official sponsor) • 17 for the rest of the world (Roche affiliates or others) • 4 countries are activated : • Belgium, Colombia, Denmark and France. • 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. • 6 countries are in progress for submission : • Germany, UK, Czech Republic • and Israel, Poland and Portugal Impossible to add another new country !

Registration Status

Registration Status • The first patient will be randomized for maintenance on July 2005 in France

PRIMA :Primary Rituximab and Maintenance • 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 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

R PRIMA Study FinalDesign MabThera Maintenance 1 dose every 8 weeks for 24 months 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 CR/PR Observation PDs/SDs off study Chairs : G Salles, R Marcus & M Herold

PRIMAScientific 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.

PRIMAScientific design of the study • 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.

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

PRIMAInclusion criteria (2) • Patients with at least one of the following symptoms requiring initiation of treatment: • Bulky disease at study entry • nodal or extranodal mass > 7cm in its greater diameter • B symptoms • 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) • symptomatic splenic enlargement • compressive syndrome • pleural/peritoneal effusion • Of note, stage I or II if present these criteria can be included

PRIMAInclusion criteria (3) • Age must be > 18 years. • 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: • Hemoglobin ≥ 8.0 g/dl (5.0 mmol/L) • Absolute neutrophil count (ANC) ≥ 1.5 109/L • Platelet count ≥ 100 109/L

PRIMAInclusion 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. • Having previously signed a written informed consent form.

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

PRIMAExclusion 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 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.

PRIMAExclusion criteria (3) • Poor renal function: • Serum creatinine > 2.0 mg/dl (197 μmol/L), • 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 • 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

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

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

PRIMAInduction treatment (1) • Induction of response with 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.

PRIMAInduction treatment (2) • 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) • 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).

PRIMAInduction treatment (3)

PRIMARequirements for Randomization • 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. • 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. • Exclusion : Patient with delayed chemotherapy courses for more than 2 weeks (> 14 days).

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

PRIMA3 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: • 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 12 months: Quality of life questionnaires FACT-G and QLQ-C30.

Logistical Aspects • Registration • CRFs and Monitoring • Serious Adverse Events

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) • Complete and fax the registration form to the GELA randomization center withthe pathological report • 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 • 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

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)

CRF and Monitoring • 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. • Baseline period has to be monitored before randomization • 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

Flow Chart of Queries • 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 • 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 : 1/ faxed to GELARC 2/ sent with CRF pages after monitoring

Serious Adverse Event • Complete in English the 3 pages • Attach documents if necessary • Signed by a physician (authorized person) • Fax it to your local coordination center • 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 • GELARC will send back (by fax) SAE registration number/ query about SAE to local coordination center which transmit to center

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

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

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

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

PRIMA Investigator Meeting