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PRIMA Investigator Meeting. Sunday, September 12, 2004 Corinthia Towers Hotel, Prague. PRIMA Investigator Meeting Agenda . Welcome and Introduction Bertrand Coiffier, Robert Marcus, Michael Herold Design of the study and Protocol Gilles Salles General organization, finances

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PRIMAInvestigator Meeting

Sunday, September 12, 2004

Corinthia Towers Hotel, Prague


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PRIMAInvestigator MeetingAgenda

  • Welcome and Introduction

    • Bertrand Coiffier, Robert Marcus, Michael Herold

  • Design of the study and Protocol

    • Gilles Salles

  • General organization, finances

    • Bertrand Coiffier, Gilles Salles, Myriam Mendila

  • Organization and regulations

    • Stephanie Baulu & Delphine Germain

  • Path Review and Biology

    • Gilles Salles

  • Discussion


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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


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PRIMA :Primary Rituximab and Maintenance

  • First contacts :

    - End of August 2003

  • Steering Committee in Paris :

    - November 6th 2003

  • Investigator Meeting in San Diego during ASH

    - December 7th 2003

  • Final draft circulation to the Steering committee :

    - June 1st 2004

  • Final draft after approval by the Steering committee : - July 30th 2004

  • Investigator Launch Meeting in Prague :

    - September 10th 2004


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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


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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


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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

Chairs : G Salles, R Marcus & M Herold


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PRIMAInvestigator Meeting

Study design and protocol

Key clinical issues

Gilles Salles : [email protected]


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PRIMAScientific 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

  • 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.


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REGISTRATION

6 x FMC

8 xRituximab

8 x CVP

8 xRituximab

6 x CHOP

8 xRituximab

6 x MCP

8 x

Rituximab

Induction

Response

Evaluation

Off Study

SD or PD

RANDOMIZATION

PR or CRu or CR

Stratification

Observation

for 24 months

12 x Rituximab

every 8 weeks

for 24 months

Maintenance

3 years

follow-up

Follow-up


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PRIMAScientific 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.


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PRIMAScientific design of the study (3)

  • 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.


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PRIMAScientific design of the study (4)

  • 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)


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PRIMAScientific design of the study (5)

  • 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 :

    • according to the FLIPI index at patient registration (study entry)

    • according to each arm of chemotherapy (CVP, CHOP, FCM and MCP)


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PRIMAScientific 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.


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PRIMAScientific design of the study (7)

Table 2- Required Number of Patients for Different Recruitment and Follow up Assumptions

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.


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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


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PRIMAInclusion criteria (1)

  • Histologically confirmed follicular lymphoma grade 1, 2 or 3a

  • Patients previously untreated.

  • 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


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PRIMAInclusion criteria (2)

  • 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

  • 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.


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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).

  • 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.

  • Major surgery (excluding lymph node biopsy) within 28 days prior to registration.


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PRIMAExclusion criteria (2)

  • 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.

  • 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.

  • 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.


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PRIMAPre-treatments assessments (1)

  • Informed consent will be obtained before any procedures are undertaken

  • 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


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PRIMAPre-treatments assessments (2)

  • 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)

  • Tumor and disease staging:

  • CT scan (thorax, abdomen, pelvis), with description of nodal locations according to the FLIPI index (appendix E3)

  • Bone marrow biopsy

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

  • B- Symptoms

  • Ann Arbor staging

  • ECOG performance status (see Appendix E1)

  • Any important additional documentation according to physician judgment (MRI for example)


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PRIMAPre-treatments assessments (3)

  • Weight, height, BSA.

  • Cardiac function evaluation by US echocardiography or left VEF according to physician decision (if patient planned to receive anthracycline).

  • 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).

  • Consideration of sperm cryo-preservation.

  • Serum and DNA storage for ancillary studies (Appendix G).

  • Quality of life questionnaires FACT-G and QLQ-C30.


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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


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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.


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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).


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PRIMAInduction treatment (3)


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PRIMAInduction treatment (4)


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PRIMAInduction treatment (5)


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PRIMAInduction treatment (6)


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PRIMAInduction 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.


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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


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PRIMAEvaluation 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.

  • Physical examination.

  • Recording of serious adverse events.

  • Laboratory assessments: (see protocol)

  • 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

  • Bone marrow biopsy (unless initially negative).

  • B-symptoms and ECOG performance status.

  • Any important additional documentation according to physician judgment (MRI for example).

  • Quality of life questionnaires FACT-G and QLQ-C30.


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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).


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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


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PRIMAMaintenance 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.

  • 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

    • Arm B: no treatment

  • Maintenance therapy has to be started 8 weeks after the last chemotherapy or immunotherapy cycle.


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PRIMAMaintenance period (2)

  • 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).

  • 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.


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PRIMAMaintenance period (3)

  • 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)


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PRIMAMaintenance period (4)

  • 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:

    • 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:

    • Quality of life questionnaires FACT-G and QLQ-C30.


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PRIMAResponse 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.

  • Physical examination.

  • Recording of adverse events and serious adverse events.

  • Laboratory assessments:

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

  • Bone marrow biopsy (unless initially negative).

  • B-symptoms and ECOG performance status.

  • CT scan of the chest, abdomen, and pelvis.

  • Any important additional documentation according to physician judgment (MRI for example).

  • Quality of life questionnaires FACT-G and QLQ-C30.


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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


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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.


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PRIMAInvestigator Meeting

General Organization and Finances


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PRIMAGeneral organization

  • 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


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PRIMAGeneral 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


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PRIMAGeneral organization

  • 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


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PRIMAGeneral organization

  • 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

    • 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


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PRIMAGeneral organization

  • 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


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PRIMAGeneral organization

  • 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.


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PRIMAInvestigator Meeting

Sunday, September 12, 2004

Corinthia Towers Hotel, Prague

Stéphanie Baulu & Delphine Germain


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REGULATORY ASPECT

  • 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)


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PRIMA ORGANISATION

  • How to validate your country’s participation?

  • How to validate the center’s participation?

  • How to register and randomize a patient ?

  • How to complete a CRF ?

  • How to follow safety process?

Country

regulation

Center

activation

Patient registration

Case Report

Form filing

SAEs declaration

and AEs


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How to validate your country’s participation ?

  • Define the country coordinator

  • Define all centers that will participate to the study

  • 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


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How to validate your country’s participation ? (2)

  • 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


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How to validate your country’s participation ? (3)

  • 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

     Your country is ready to start the study


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PRIMA ORGANISATION

  • How to validate your country’s participation ?

  • How to validate the center’s participation ?

  • How to register and randomize a patient ?

  • How to complete a CRF ?

  • How to follow safety process?


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How to validate the center’s participation ?

  • 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


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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 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


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PRIMA ORGANISATION

  • How to validate your country’s participation?

  • How to validate the center’s participation?

  • How to register and randomize a patient ?

  • How to complete a CRF ?

  • How to follow safety process?


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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)

  • 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

  • Country Coordinator informed of country inclusions by email

  • Case Report Form (CRF) sent by mail for each included patient


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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


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How to randomize a patient ?

  • 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

  • Complete and fax randomization form to GELA randomization center

  • GELARC will send it back in 24 hours

    • Arm for maintenance treatment assigned

  • Coordinator informed of country randomizations by email


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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


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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

    (local time)


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PRIMA ORGANISATION

  • How to validate your country’s participation?

  • How to validate the center’s participation?

  • How to include and randomize a patient ?

  • How to complete the CRF ?

  • How to follow safety process?


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How to complete a Case Report Form ?

  • 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

  • Pages of CRF are Triplicate Forms

  • Toxicities will be graded according to CTCAE v3 (present in Investigator’s Study File)


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Case Report Form (1)

  • 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


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Case Report Form (2)

  • Monitoring of data reported on CRF is planned on key parameters, twice a year

  • Each country may organize monitoring as its convenience

  • After monitoring, please send to GELARC 2 forms of complete parts

  • Queries/data corrections could be sent by GELARC Data Management


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PRIMA ORGANISATION

  • How to validate your country’s participation ?

  • How to validate the center’s participation ?

  • How to register and randomize a patient ?

  • How to complete a CRF ?

  • How to follow safety process ?


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SAFETY OPERATIONS

  • 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


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SAFETY OPERATIONS

  • 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)


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Serious Adverse Event (SAE) Definition

  • 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


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Serious Adverse Event (SAE) Reporting Timeframe

  • 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

  • Other SAEs should be reported as soon as possible and no later than 15 days from first knowledge by investigator


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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 …

  • 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


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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


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Let’s start the study !

We expect a lot of inclusions !!!

We expect an excellent tracking of data !!!


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PRIMAInvestigator Meeting

QoL

Pathology Review

Ancillary studies


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PRIMAQoL study

  • 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 !)


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PRIMAPathological 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.


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PRIMAPathological 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).


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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.


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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: [email protected]

  • 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.


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PRIMAAncillary 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.


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PRIMAAncillary 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.


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PRIMAAncillary 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 !


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PRIMAPrimary Rituximab and Maintenance

  • 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 !


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