prima investigator meeting sunday, september 12, 2004 corinthia towers hotel, prague

PRIMAPRIMAInvestigator MeetingInvestigator Meeting

Sunday, September 12, 2004Sunday, September 12, 2004

Corinthia Towers Hotel, PragueCorinthia Towers Hotel, Prague

PRIMAPRIMAInvestigator MeetingInvestigator MeetingAgenda Agenda Welcome and IntroductionWelcome and Introduction

– Bertrand Coiffier, Robert Marcus, Michael HeroldBertrand Coiffier, Robert Marcus, Michael Herold Design of the study and ProtocolDesign of the study and Protocol

– Gilles SallesGilles Salles General organization, financesGeneral organization, finances

– Bertrand Coiffier, Gilles Salles, Myriam MendilaBertrand Coiffier, Gilles Salles, Myriam Mendila Organization and regulationsOrganization and regulations

– Stephanie Baulu & Delphine GermainStephanie Baulu & Delphine Germain Path Review and BiologyPath Review and Biology

– Gilles SallesGilles Salles DiscussionDiscussion

PRIMA :PRIMA :Primary Rituximab and Primary Rituximab and Maintenance Maintenance

No standard first line chemotherapy in follicular No standard first line chemotherapy in follicular lymphomalymphoma

Rituximab when combined with chemotherapy Rituximab when combined with chemotherapy (CVP, CHOP, CHVP+IFN, MCP, FCM…) does improve (CVP, CHOP, CHVP+IFN, MCP, FCM…) does improve CR rate end EFSCR rate end EFS

Rituximab maintenance improves EFS in rituximab Rituximab maintenance improves EFS in rituximab (alone) or chemo (CVP alone) treated patients(alone) or chemo (CVP alone) treated patients

Primary objective : Primary objective : To evaluate in patients with To evaluate in patients with advanced follicular lymphoma the benefit of advanced follicular lymphoma the benefit of maintenance therapy with rituximab after induction maintenance therapy with rituximab after induction of response with chemotherapy plus rituximab in of response with chemotherapy plus rituximab in comparison with no maintenance therapy comparison with no maintenance therapy

PRIMA :PRIMA :Primary Rituximab and Primary Rituximab and Maintenance Maintenance First contacts : First contacts :

- End of August 2003- End of August 2003 Steering Committee in ParisSteering Committee in Paris : : - - November 6th 2003November 6th 2003 Investigator Meeting in San Diego during ASHInvestigator 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 2004June 1st 2004 Final draft after approval by the Steering committee Final draft after approval by the Steering committee

:: - - July 30th 2004July 30th 2004 Investigator Launch Meeting in Prague :Investigator Launch Meeting in Prague : - - September 10th 2004September 10th 2004


A multicentre, phase III, open-label, A multicentre, phase III, open-label, randomized study in patients with randomized study in patients with

advanced follicular lymphoma evaluating advanced follicular lymphoma evaluating the benefit of maintenance therapy with the benefit of maintenance therapy with

Rituximab (MabThera®) after induction of Rituximab (MabThera®) after induction of response with chemotherapy plus response with chemotherapy plus Rituximab in comparison with no Rituximab in comparison with no

maintenance therapymaintenance therapy

Principal Investigator : Gilles SallesPrincipal Investigator : Gilles SallesCo-Investigators : Robert Marcus & Michael HeroldCo-Investigators : Robert Marcus & Michael Herold


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

PRIMA Study PRIMA Study FinalFinal DesignDesign

PDs/SDsoff study

MabThera Maintenance1 dose every 8 weeks

for 24 months

Observation

R CR/PR

Chairs : G Salles, R Marcus & M HeroldChairs : G Salles, R Marcus & M Herold

R-CVP x 8 or R-CHOP x 6 + 2Ror R-FCM x 6 + 2Ror R-MCP x 6 +2R

Untreated Follicular NHLstages III–IV


Study design and protocolStudy design and protocol

Key clinical issuesKey clinical issues

Gilles Salles : [email protected]

PRIMAPRIMAScientific design of the studyScientific design of the study (1)(1) Primary objective: Primary objective: To evaluate in patients To evaluate in patients

with advanced follicular lymphoma with advanced follicular lymphoma the benefit of the benefit of maintenance therapy with rituximabmaintenance therapy with rituximab after after induction of response with chemotherapy plus induction of response with chemotherapy plus rituximab in comparison with no maintenance rituximab in comparison with no maintenance therapy therapy

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

ResponseEvaluation

Induction6 x FMC

8 x Rituximab

6 x CHOP8 x

Rituximab

8 x CVP8 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 MCP8 x

Rituximab

Maintenance

RANDOMIZATION

Follow-up

PRIMAPRIMAScientific design of the studyScientific design of the study (2)(2) The primary efficacy parameter is The primary efficacy parameter is event-event-

free survivalfree survival. Event-free survival will be . Event-free survival will be measured from the day of randomization measured from the day of randomization to the date of first documented disease to the date of first documented disease progression, death by any cause or progression, death by any cause or institution of new treatmentinstitution of new treatment. Responding . Responding patients and patients who are lost to patients and patients who are lost to follow up will be censored at their last follow up will be censored at their last tumor assessment date.tumor assessment date.

PRIMAPRIMAScientific design of the study Scientific design of the study (3)(3) New anti-lymphoma treatment is New anti-lymphoma treatment is

defined :defined :

– as the institution of as the institution of anyany radiation therapy radiation therapy (even focal) or chemotherapy or (even focal) or chemotherapy or immunotherapy, alone or in any immunotherapy, alone or in any combination of them, which is instituted for combination of them, which is instituted for lymphoma treatment.lymphoma treatment.

Any new anti-lymphoma treatment not Any new anti-lymphoma treatment not planed in the protocol will be considered planed in the protocol will be considered as an eventas an event..

PRIMAPRIMAScientific design of the study Scientific design of the study (4)(4) New anti-lymphoma treatment should be started:New anti-lymphoma treatment should be started:

– if a patient does demonstrate disease progression if a patient does demonstrate disease progression during during induction treatment;induction treatment;

– at the discretion of the physician if a patient does not reach at at the discretion of the physician if a patient does not reach at least a partial response or a complete (either confirmed or least a partial response or a complete (either confirmed or unconfirmed) unconfirmed) at the end of the induction treatment;at the end of the induction treatment;

– during the maintenance phaseduring the maintenance phase, , for patients in both armsfor patients in both arms (rituximab maintenance or observation), at any time of (rituximab maintenance or observation), at any time of documented disease progression if this progression is documented disease progression if this progression is symptomatic and/or if the physician consider that a new symptomatic and/or if the physician consider that a new treatment is necessary for patients benefit. The disease treatment is necessary for patients benefit. The disease progression should be documented (see above)progression should be documented (see above)

– during the 3 year follow-up periodduring the 3 year follow-up period, at any time of documented , at any time of documented disease progression if this progression is symptomatic and/or if disease progression if this progression is symptomatic and/or if the physician consider that a new treatment is necessary for the physician consider that a new treatment is necessary for patients benefit. The disease progression should be patients benefit. The disease progression should be documented (see above)documented (see above)

PRIMAPRIMAScientific design of the studyScientific design of the study (5)(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 according to the FLIPI index at patient registration (study

entry)entry)– according to each arm of chemotherapy (CVP, CHOP, FCM and according to each arm of chemotherapy (CVP, CHOP, FCM and

MCP)MCP)


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.


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)

24 18 432 576 62 68 51

24 20 480 640 55 61 46

24 22 528 704 50 56 42

Assumption: required number of events is 236Based on the above considerations 480 patients will be randomized over 24 months. This implies that approximately 640 patients will receive the induction R-CHEMO.


PDs/SDsoff study


for 24 months

Observation

R CR/PR



PRIMAPRIMAInclusion criteriaInclusion criteria (1) (1) Histologically confirmed follicular lymphoma grade 1, 2 or Histologically confirmed follicular lymphoma grade 1, 2 or

3a3a Patients previously Patients previously untreateduntreated.. Patients with at least one of the following Patients with at least one of the following symptomssymptoms

requiring initiation of treatment:requiring initiation of treatment:– Bulky disease at study entry according to the GELF criteria: Bulky disease at study entry according to the GELF criteria:

nodal or extranodal mass > 7cm in its greater diameter nodal or extranodal mass > 7cm in its greater diameter – B symptoms B symptoms – Elevated serum LDH or Elevated serum LDH or 2-microglobulin2-microglobulin– involvement of at least 3 nodal sites (each with a diameter involvement of at least 3 nodal sites (each with a diameter

greater than 3 cm) greater than 3 cm) – symptomatic splenic enlargement symptomatic splenic enlargement – compressive syndrome compressive syndrome – pleural/peritoneal effusionpleural/peritoneal effusion

PRIMAPRIMAInclusion criteriaInclusion criteria (2) (2) Age must be Age must be >> 18 years 18 years.. Performance status Performance status << 2 on the ECOG scale (see appendix 2 on the ECOG scale (see appendix

E).E). Adequate hematological function within 28 days prior to Adequate hematological function within 28 days prior to

registration (unless those abnormalities are related to registration (unless those abnormalities are related to lymphoma extension), this includes:lymphoma extension), this includes:– Hemoglobin ≥ 8.0 g/dl (5.0 mmol/L)Hemoglobin ≥ 8.0 g/dl (5.0 mmol/L)– Absolute neutrophil count (ANC) ≥ 1.5 109/LAbsolute neutrophil count (ANC) ≥ 1.5 109/L– Platelet count ≥ 100 109/LPlatelet count ≥ 100 109/L

Women are not breast feeding, are using effective Women are not breast feeding, are using effective contraception, are not pregnant and agree not to become contraception, are not pregnant and agree not to become pregnant during participation in the trial and during the 12 pregnant during participation in the trial and during the 12 months thereafter. Men agree not to father a child during months thereafter. Men agree not to father a child during participation in the trial and during the 12 months participation in the trial and during the 12 months thereafter.thereafter.

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

PRIMAPRIMAExclusion criteriaExclusion criteria (1) (1) Transformation to high-grade lymphoma (secondary to Transformation to high-grade lymphoma (secondary to

“low-grade” follicular lymphoma).“low-grade” follicular lymphoma). Grade 3b follicular lymphomaGrade 3b follicular lymphoma.. Presence or history of CNS disease (either CNS Presence or history of CNS disease (either CNS

lymphoma or lymphomatous meningitis).lymphoma or lymphomatous meningitis). Patients regularly taking corticosteroids during the last Patients regularly taking corticosteroids during the last

4 weeks, unless administered at a dose equivalent to 4 weeks, unless administered at a dose equivalent to << 20 mg/day prednisone. 20 mg/day prednisone.

Patients with prior or concomitant malignancies except Patients with prior or concomitant malignancies except non-melanoma skin cancer or adequately treated in situ non-melanoma skin cancer or adequately treated in situ cervical cancer. cervical cancer.

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

PRIMAPRIMAExclusion criteriaExclusion criteria (2) (2) Poor renal function: Serum creatinine > 2.0 mg/dl (197 Poor renal function: Serum creatinine > 2.0 mg/dl (197

μmol/L),μmol/L), Poor hepatic function: total bilirubin > 2.0 mg/dl (34 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 AST (SGOT) > 3 x the upper limit of normal unless these abnormalities are related to lymphoma.abnormalities are related to lymphoma.

Known HIV infection or active HBV or HCV infectionKnown HIV infection or active HBV or HCV infection.. Serious underlying medical conditions, which could impair Serious underlying medical conditions, which could impair

the ability of the patient to participate in the trial (e.g. the ability of the patient to participate in the trial (e.g. ongoing infection, uncontrolled diabetes mellitus, gastric ongoing infection, uncontrolled diabetes mellitus, gastric ulcers, active autoimmune disease). Judgment is up to the ulcers, active autoimmune disease). Judgment is up to the investigator. investigator.

Life expectancy < 6 monthsLife expectancy < 6 months Known sensitivity or allergy to murine productsKnown sensitivity or allergy to murine products Treatment within a clinical trial within 30 days prior to trial Treatment within a clinical trial within 30 days prior to trial

entryentry Adult patient under tutelage.Adult patient under tutelage.

PRIMAPRIMAPre-treatments assessments Pre-treatments assessments (1)(1)

Informed consent will be obtained before any Informed consent will be obtained before any procedures are undertakenprocedures are undertaken

All the following assessments should have All the following assessments should have been performed been performed – within within 28 days28 days before the first planned dose of trial before the first planned dose of trial

medication, medication, – excepted for histological diagnosis of FL which can excepted for histological diagnosis of FL which can

be obtained within be obtained within 3 months3 months before study before study registrationregistration

PRIMAPRIMAPre-treatments assessments Pre-treatments assessments (2)(2) Complete medical history and physical examinationComplete medical history and physical examination Histological diagnosis of Follicular Lymphoma including pathologic Histological diagnosis of Follicular Lymphoma including pathologic

assessment. The histological diagnosis of follicular lymphoma assessment. The histological diagnosis of follicular lymphoma should have been made within the last 3 months. Material should should have been made within the last 3 months. Material should be available for central pathology review (appendix F)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 CT scan (thorax, abdomen, pelvis), with description of nodal

locations according to the FLIPI index (appendix E3)locations according to the FLIPI index (appendix E3) Bone marrow biopsy Bone marrow biopsy Tumor lesion assessment: two dimensional diameters of all lymph Tumor lesion assessment: two dimensional diameters of all lymph

nodes, spleen and liver enlargementnodes, spleen and liver enlargement B- Symptoms B- Symptoms Ann Arbor stagingAnn Arbor staging ECOG performance status (see Appendix E1)ECOG performance status (see Appendix E1) Any important additional documentation according to physician Any important additional documentation according to physician

judgment (MRI for example) judgment (MRI for example)

PRIMAPRIMAPre-treatments assessments Pre-treatments assessments (3)(3)

Weight, height, BSA.Weight, height, BSA. Cardiac function evaluation by US echocardiography or Cardiac function evaluation by US echocardiography or

left VEF according to physician decision (if patient left VEF according to physician decision (if patient planned to receive anthracycline).planned to receive anthracycline).

Laboratory assessments:Laboratory assessments:– Hemoglobin, WBC with differentials, platelets,Hemoglobin, WBC with differentials, platelets,– Sodium, potassium, calcium, Sodium, potassium, calcium, – AST, ALT, total bilirubin, serum creatinine, alkaline AST, ALT, total bilirubin, serum creatinine, alkaline

phosphatase, total protein, albumin,phosphatase, total protein, albumin,– β2-microglobulin, LDH.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 Serum and DNA storage for ancillary studies (Appendix

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


PDs/SDsoff study


for 24 months

Observation

R CR/PR



PRIMAPRIMAInduction treatment (1)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 dayswith 8 cycles of CVP every 21 days– or 6 cycles of CHOP in 21-day cycles or 6 cycles of CHOP in 21-day cycles – or 6 cycles of FCM in 28-day cycles or 6 cycles of FCM in 28-day cycles – or 6 cycles of MCP in 28-day cycles.or 6 cycles of MCP in 28-day cycles.

PRIMAPRIMAInduction treatment (2)Induction treatment (2) After registration induction therapy has to be started within After registration induction therapy has to be started within

7 days from registration7 days from registration

The The assignment to one of the four chemotherapyassignment to one of the four chemotherapy groups (R- groups (R-CVP, R-CHOP, R-FCM and R-MCP) is CVP, R-CHOP, R-FCM and R-MCP) is on a per centre decisionon a per centre decision. . Every centre has to decide Every centre has to decide upfrontupfront ( (before initiation of the before initiation of the studystudy) which chemotherapy schedule is standard of care for ) which chemotherapy schedule is standard of care for follicular lymphoma patients in that center and therefore follicular lymphoma patients in that center and therefore will be given to all patients of that center throughout the will be given to all patients of that center throughout the studystudy (information will be reported on registration form) (information will be reported on registration form)

In France, only R-CVP and R-CHOP will be considered as In France, only R-CVP and R-CHOP will be considered as standard. In Germany, the regimen will be allocated to each standard. In Germany, the regimen will be allocated to each patient through randomization (OSHO/GLSG procedure).patient through randomization (OSHO/GLSG procedure).

PRIMAPRIMAInduction treatment (3)Induction treatment (3) 8 R-CVP / 21-day CYCLES (cycles 1 to 8)

Chemotheray regimen Dose Mode D1 D2 D3 D4 D5

Rituximab 375 mg/m2 IV

Cyclophosphamide 750 mg/m2 IV push

Vincristine 1.4 mg/m2

(2 mg max.)IV bolu

s

Prednisone 100 mg/day PO

PRIMAPRIMAInduction treatment (4)Induction treatment (4) 6 R-CHOP / 21-day CYCLES (cycles 1 to 6)

Chemotheray regimen Dose Mode D1 D2 D3 D4 D5


Cyclophosphamide 750 mg/m2 IV

Doxorubicin 50 mg/m2 IV push

Vincristine 1.4 mg/m2

(2 mg max.)IV push

Prednisone 100 mg/day PO

2 Rituximab / 21-day CYCLES (cycles 7 and 8)

Rituximab 375 mg/m2 IV 1 injection 21 days (3 weeks) after cycle 6 of R-CHOP

1 injection 42 days (6 weeks) after cycle 6 of R-CHOP

PRIMAPRIMAInduction treatment (5)Induction treatment (5)

6 R-FCM / 28- day cycles (cycles 1 to 6) C1 to C6

Chemotherapy regimen

Dose Mode D1 D2 D3

Rituximab 375mg/m2

IV

Cyclophosphamide 200mg/m2

IV – 4 hours infusion

Fludarabine 25 mg/m2

IV - 30 min. infusion

Mitoxantrone 6 mg/m2

IV – 30 min. infusion

2 Rituximab D15 of C1 D15 of C4


PRIMAPRIMAInduction treatment (6)Induction treatment (6) 6 R-MCP / 28-day cycles (cycles 1 to 6) C1 to C6

Chemotherapy regimen Dose Mode D1 D2 D3 D4

D5


Mitoxantrone 8 mg/m2 IV – 30 min. infusion

Chlorambucil 3 x 3 mg/m2

PO

Prednisolone 25 mg/m2 PO

2 Rituximab D15 of C1 D15 of C4


PRIMAPRIMAInduction period (7)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.


PDs/SDsoff study


for 24 months

Observation

R CR/PR



PRIMAPRIMAEvaluation of response after Evaluation of response after

inductioninduction After completion of the study medication a final restaging After completion of the study medication a final restaging

should be performed should be performed within 28 days (between 14 and 28 within 28 days (between 14 and 28 days) after the last immuno-chemotherapy coursedays) 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: Final restaging after induction therapy: CT scan of the chest, CT scan of the chest,

abdomen, and pelvis.abdomen, and pelvis. Tumor lesion assessment :Tumor lesion assessment : two dimensional diameters of all two dimensional diameters of all

lymph nodes, spleen and liver enlargementlymph nodes, spleen and liver enlargement Bone marrow biopsyBone marrow biopsy (unless initially negative). (unless initially negative). B-symptoms and ECOG performance status.B-symptoms and ECOG performance status. Any important additional documentation according to Any important additional documentation according to

physician judgment (MRI for example).physician judgment (MRI for example). Quality of life questionnairesQuality of life questionnaires FACT-G and QLQ-C30. FACT-G and QLQ-C30.

PRIMAPRIMARequirements for Requirements for

RandomizationRandomization Being registered in the trial before treatment Being registered in the trial before treatment andand

having filled / send the CRF having filled / send the CRF for baseline periodfor baseline period

All lesions reported in the on-study form have been re-All lesions reported in the on-study form have been re-evaluated. evaluated.

Patient must have reached a PR, CRu or CR. (According Patient must have reached a PR, CRu or CR. (According to appendix C).to appendix C).

Patient should have received all full doses of induction Patient should have received all full doses of induction treatment, excepted planned modifications.treatment, excepted planned modifications.

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


PDs/SDsoff study


for 24 months

Observation

R CR/PR



PRIMAPRIMAMaintenance period (1)Maintenance period (1)

Randomization to the second phase Randomization to the second phase will be will be stratified by chemotherapy and by response stratified by chemotherapy and by response (CR/PR).(CR/PR). All stratification factors must be All stratification factors must be verifiable at randomization. verifiable at randomization.

At randomization eligible patients will be At randomization eligible patients will be randomized in a 1:1 fashion to receive eitherrandomized in a 1:1 fashion to receive either– Arm A: one injection Arm A: one injection rituximab 375 mg/m2 rituximab 375 mg/m2 every 8 weeks for 24 months every 8 weeks for 24 months – Arm B: no treatmentArm B: no treatment

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


Study visits are foreseen every 8 weeks for all patients Study visits are foreseen every 8 weeks for all patients ((with or without rituximabwith or without rituximab)) in the maintenance period. in the maintenance period.

Patients randomized to maintenance therapy Patients randomized to maintenance therapy should start should start treatment with rituximab 8 weeks (56 +/- 7 days) after the treatment with rituximab 8 weeks (56 +/- 7 days) after the day 1 of the last treatment cycleday 1 of the last treatment cycle (chemo-immunotherapy (chemo-immunotherapy or rituximab, which ever last). or rituximab, which ever last).

Rituximab should be given every 8 weeks (56 +/- 7 days) Rituximab should be given every 8 weeks (56 +/- 7 days) until progression, relapse, institution of a new treatment, until progression, relapse, institution of a new treatment, death, or toxicity for a maximum period of 2 years.death, or toxicity for a maximum period of 2 years.

Any new treatment initiation unplanned in the protocol is Any new treatment initiation unplanned in the protocol is considered as an event.considered as an event.


Rituximab 375 mg/m2 :Rituximab 375 mg/m2 :– administered by IV infusion every 8 weeks administered by IV infusion every 8 weeks – starting 8 weeks after the last chemotherapy cyclestarting 8 weeks after the last chemotherapy cycle– dosage calculations for rituximab will be based on the dosage calculations for rituximab will be based on the

patient’s body surface area (BSA), using actual weight patient’s body surface area (BSA), using actual weight for calculationsfor calculations

– premedication consisting of an analgesic/antipyretic premedication consisting of an analgesic/antipyretic (e.g. paracetamol) and an antihistaminic agent (e.g. (e.g. paracetamol) and an antihistaminic agent (e.g. diphenhydramine) should diphenhydramine) should alwaysalways be administered be administered before each infusion of rituximab.before each infusion of rituximab.

No dose adjustement (except BSA)No dose adjustement (except BSA)


At each visit, every 2 months, for all patients:At each visit, every 2 months, for all patients:– Physical examination.Physical examination.– Recording of infusion-related toxicity within the first 24 hours Recording of infusion-related toxicity within the first 24 hours

after the start of study treatment.after the start of study treatment.– Recording of adverse events and serious adverse events.Recording of adverse events and serious adverse events.– Laboratory assessments: Hemoglobin, WBC with differential, Laboratory assessments: Hemoglobin, WBC with differential,

platelets, Sodium, potassium, Serum creatinine.platelets, Sodium, potassium, Serum creatinine. In addition,In addition, every 6 months,every 6 months, for all patients: for all patients:

– β2-microglobulin, LDH β2-microglobulin, LDH – Tumor lesion assessmentTumor lesion assessment: two dimensional diameters of all lymph : two dimensional diameters of all lymph

nodes, spleen and liver enlargementnodes, spleen and liver enlargement– CT scan of the chest, abdomen, and pelvisCT scan of the chest, abdomen, and pelvis – (Note: Use the same method of assessment for each lesion at (Note: Use the same method of assessment for each lesion at

every evaluation throughout the study. Patients with symptoms every evaluation throughout the study. Patients with symptoms suggestive of PD may have tumor assessments performed at suggestive of PD may have tumor assessments performed at times other than those described in the protocol at the times other than those described in the protocol at the investigator’s discretion).investigator’s discretion).

In addition, every 12 months,In addition, every 12 months, for all patients: for all patients: – Quality of life questionnaires FACT-G and QLQ-C30.Quality of life questionnaires FACT-G and QLQ-C30.

PRIMAPRIMAResponse assessment after Response assessment after maintenance (or no !)maintenance (or no !)

After completion of the maintenance period, After completion of the maintenance period, for all patients for all patients (with or without rituximab) a final restaging should be (with or without rituximab) a final restaging should be performedperformed within 28 days of the last rituximab course. 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 :Tumor lesion assessment : two dimensional diameters of two dimensional diameters of

all lymph nodes, spleen and liver enlargementall lymph nodes, spleen and liver enlargement Bone marrow biopsyBone marrow biopsy (unless initially negative). (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 Any important additional documentation according to

physician judgment (MRI for example).physician judgment (MRI for example). Quality of life questionnaires FACT-G and QLQ-C30.Quality of life questionnaires FACT-G and QLQ-C30.


PDs/SDsoff study


for 24 months

Observation

R CR/PR



PRIMAPRIMA3 years follow-up 3 years follow-up periodperiod ! ! Following assessments for response evaluation Following assessments for response evaluation

should be performed, should be performed, every three months every three months during the first year then every 6 months during the first year then every 6 months during two additional yearsduring two additional years::– Physical examinationPhysical examination– Tumor lesion assessment: two dimensional Tumor lesion assessment: two dimensional

diameters of all lymph nodes, spleen and liver diameters of all lymph nodes, spleen and liver enlargementenlargement

– B-symptoms and ECOG performance statusB-symptoms and ECOG performance status Every 6 monthsEvery 6 months: CT scan of the chest, : CT scan of the chest,

abdomen, and pelvisabdomen, and pelvis Every 12 monthsEvery 12 months: Quality of life questionnaires : Quality of life questionnaires

FACT-G and QLQ-C30.FACT-G and QLQ-C30.


General Organization and General Organization and FinancesFinances

PRIMAPRIMAGeneral organizationGeneral organization

The GELA-RC will organize and The GELA-RC will organize and coordinate all administrative and coordinate all administrative and financials items that relate to the PRIMA financials items that relate to the PRIMA studystudy

The randomization, CRF, data-base, trial The randomization, CRF, data-base, trial files, etc… will be collected by the files, etc… will be collected by the GELA-RCGELA-RC


In each country, a collaborative group or a In each country, a collaborative group or a center will coordinate the efforts for trial center will coordinate the efforts for trial implementation and organization :implementation and organization :– Contacts with Roche affiliates regarding Contacts with Roche affiliates regarding

Mabthera supply for maintenance and Mabthera supply for maintenance and regulatory issuesregulatory issues

– Regulatory issues, ethics, insuranceRegulatory issues, ethics, insurance– Choice and coordination of centersChoice and coordination of centers– Monitoring organizationMonitoring organization– Contact with the GELA-RCContact with the GELA-RC


The national collaborative group or the The national collaborative group or the coordinating center will coordinating center will sign a contractsign a contract with the GELA-RCwith the GELA-RC– Agreement with GCP, ICH, …Agreement with GCP, ICH, …– The GELA will support investigator and The GELA will support investigator and

national work by providing 500€ per national work by providing 500€ per observation (complete !)observation (complete !)

– Insurance fees to be coveredInsurance fees to be covered– Intellectual properties of dataIntellectual properties of data

PRIMAPRIMAGeneral organizationGeneral organization Drug supply during inductionDrug 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 maintenanceDrug 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


MonitoringMonitoring– 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

PRIMAPRIMAGeneral organizationGeneral organization PublicationPublication

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


Sunday, September 12, 2004Sunday, September 12, 2004

Corinthia Towers Hotel, PragueCorinthia Towers Hotel, Prague

Stéphanie Baulu & Delphine Stéphanie Baulu & Delphine GermainGermain

REGULATORY ASPECTREGULATORY ASPECT

PRIMA Study will be conducted in PRIMA Study will be conducted in accordance with :accordance with :– ICH-GCP (Topic E6)ICH-GCP (Topic E6)– Helsinki DeclarationHelsinki Declaration– Local laws and regulatory Local laws and regulatory

requirements as new European requirements as new European directive (2001/83 and 2002/98)directive (2001/83 and 2002/98)

PRIMA ORGANISATIONPRIMA ORGANISATION

How to validate your country’s How to validate your country’s participation?participation?

How to validate the center’s How to validate the center’s participation?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

regulationCenter

activationPatient

registration

Case ReportForm filing

SAEs declarationand AEs

How to validate your How to validate your country’s participation country’s participation

?? Define the country coordinatorDefine the country coordinator Define all centers that will participate to Define all centers that will participate to

the studythe study To be sent To be sent by Coordinator to the GELARCby Coordinator to the GELARC::

– ““Study agreement”Study agreement” (signed by coordinator) (signed by coordinator)– List of all centersList of all centers with principal investigator’s with principal investigator’s

name, address, phone number and E-mail name, address, phone number and E-mail – Curriculum VitaeCurriculum Vitae (1 page) of principal (1 page) of principal

investigator for each center investigator for each center – Name of the PathologistName of the Pathologist in charge of local in charge of local

review if applicablereview if applicable

How to validate your How to validate your country’s participation ? country’s participation ?

(2)(2) Send Send by GELARC to Coordinatorby GELARC to Coordinator (by email):(by email):

– Last version of protocolLast version of protocol– English version of synopsisEnglish version of synopsis– English model of informed consentEnglish model of informed consent– Quality of life questionnaire in local Quality of life questionnaire in local

languagelanguage– Quotation proposal for insurance Quotation proposal for insurance

(eventually)(eventually)– Case Report FormCase Report Form Apply to ethics and national health Apply to ethics and national health

authoritiesauthorities

How to validate your How to validate your country’s participation ? country’s participation ?

(3)(3) Send Send by Coordinator to GELARCby Coordinator to GELARC::

– Ethic Committee approvalEthic Committee approval– Health Authorities approvalHealth Authorities approval– Insurance Insurance – ““Regulatory Documents Certification” Regulatory Documents Certification”

signed by Coordinatorsigned by Coordinator Any local amendment must be approved Any local amendment must be approved

by GELARC before local submissionby GELARC before local submission

Your country is ready to start the Your country is ready to start the studystudy


How to validate your country’s How to validate your country’s participationparticipation ? ?

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?

How to validate the How to validate the center’s participation ?center’s participation ?

GELARC will send by mail to each center GELARC will send by mail to each center an Investigator’s Study File containing:an Investigator’s Study File containing:

– 2 copies of the protocol 2 copies of the protocol – 1 copy of ICH1 copy of ICH– 1 copy of CTCAE (v3)1 copy of CTCAE (v3)– 5 kits (paper forms) for inclusion5 kits (paper forms) for inclusion– 4 Serious Adverse Event Report Forms4 Serious Adverse Event Report Forms– 2 copies of “Study Protocol Agreement”2 copies of “Study Protocol Agreement”– An electronic version of the IB An electronic version of the IB

How to validate theHow to validate the center’s participation ? center’s participation ?

(2)(2) The country coordinator will send all local The country coordinator will send all local

regulatory documents and informed regulatory documents and informed consent in local language to each centerconsent in local language to each center

The PI of each center must sign The PI of each center must sign 2 copies 2 copies of “Study Protocol Agreement”of “Study Protocol Agreement” (1 for (1 for him, 1 for the GELA-RC) and send one him, 1 for the GELA-RC) and send one back to the GELA-RCback to the GELA-RC

Each center is ready to start the studyEach center is ready to start the study



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?

How to register a patient How to register a patient ??

Obtain consent of patient : the patient must sign Obtain consent of patient : the patient must sign 3 copies3 copies of the informed consent form (1 for of the informed consent form (1 for him, 1 for investigator and 1 for GELARC)him, 1 for investigator and 1 for GELARC)

Complete and fax the registration form to the Complete and fax the registration form to the GELA randomization center GELA randomization center withwith informed informed consentconsent

GELARC will send it back in 24 hours GELARC will send it back in 24 hours (Monday to (Monday to Friday)Friday) with patient trial number with patient trial number

Country Coordinator informed of country Country Coordinator informed of country inclusions by emailinclusions by email

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

Registration FormRegistration Form

Center’s and Patient’s

Informations

Inclusion and Exclusion Criteria

For Registration

Investigator’s signatureGELA’s validation and patient’s registration number

How to randomize a How to randomize a patient ?patient ?

Your patient has received all the induction Your patient has received all the induction treatment and has reached a PR, CRu or CRtreatment and has reached a PR, CRu or CR

Baseline period (from CRF) has been Baseline period (from CRF) has been monitored and sent to GELARCmonitored and sent to GELARC

Complete and fax randomization form to Complete and fax randomization form to GELA randomization centerGELA randomization center

GELARC will send it back in 24 hours GELARC will send it back in 24 hours – Arm for maintenance treatment assignedArm for maintenance treatment assigned

Coordinator informed of country Coordinator informed of country randomizations by emailrandomizations by email

Randomization FormRandomization Form

Center’s Informations

Patient’s Informations :-Identification-Treatment (regimen and last administration)-Response

Inclusion and Exclusion Criteria For Randomization

Investigator’s signatureGELA’s validation and Arm for Maintenance

Treatment

GELA Randomization GELA Randomization CenterCenter

Registration and Randomization Registration and Randomization Forms have to be faxed to : Forms have to be faxed to :

GELA randomization centerGELA randomization center

St Louis Hospital – Centre HayemSt Louis Hospital – Centre Hayem

Fax : +33 1 42 49 99 72Fax : +33 1 42 49 99 72Monday to Friday - 09:00 am to 05:00 Monday to Friday - 09:00 am to 05:00

pmpm(local time)(local time)



How to validate the center’s How to validate the center’s participation?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?

How to complete How to complete a Case Report Form ?a Case Report Form ?

CRF will be send after each inclusion to CRF will be send after each inclusion to the investigator of each centerthe investigator of each center

CRF must be completed CRF must be completed in Englishin English,, using using a black ball point pena black ball point pen

Pages of CRF are Triplicate FormsPages of CRF are Triplicate Forms

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

Case Report Form Case Report Form (1)(1)

CRF contains 8 parts:CRF contains 8 parts:– Baseline periodBaseline period– Induction Treatment (with response)Induction Treatment (with response)– Maintenance Treatment (with Maintenance Treatment (with

randomization)randomization)– End of Treatment Evaluation / WithdrawalEnd of Treatment Evaluation / Withdrawal– Follow-up visitsFollow-up visits– Progression / relapse form - Death formProgression / relapse form - Death form– Adverse Events forms Adverse Events forms – Follow-up of Adverse Events formsFollow-up of Adverse Events forms

Case Report Form Case Report Form (2)(2)

Monitoring of data reported on CRF is Monitoring of data reported on CRF is planned planned on key parameterson key parameters, twice a , twice a yearyear

Each country may organize monitoring Each country may organize monitoring as its convenienceas its convenience

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

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


How to validate your country’s How to validate your country’s participation ?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 ?

SAFETY OPERATIONSSAFETY OPERATIONS

DistinctionDistinction between simple toxicity, between simple toxicity, toxicity reported as AE and toxicity toxicity reported as AE and toxicity reported as SAEreported 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

SAFETY OPERATIONSSAFETY OPERATIONS

Adverse eventsAdverse events are recorded are recorded only only during the maintenance treatment and during the maintenance treatment and up to 6 monthsup to 6 months after the last study drug after the last study drug administrationadministration

All Adverse events are reported on All Adverse events are reported on specific pages in CRF (initial and follow-specific pages in CRF (initial and follow-up)up)

Serious Adverse Event Serious Adverse Event (SAE) Definition (SAE) Definition

An Adverse Event is An Adverse Event is SeriousSerious if it: if it:– Results in Results in deathdeath– Is Is life-threateninglife-threatening– Require patient Require patient hospitalizationhospitalization or or

prolongation of existing prolongation of existing hospitalizationhospitalization

– Results in persistent or significant Results in persistent or significant disabilitydisability/incapacity/incapacity

– Is a Is a congenital anomalycongenital anomaly/birth defect/birth defect– Is Is medically significantmedically significant

Serious Adverse Event Serious Adverse Event (SAE) Reporting (SAE) Reporting

TimeframeTimeframe SAEs should be reported from SAEs should be reported from registration until registration until

6 months after the last drug administration 6 months after the last drug administration (chemotherapy or rituximab)(chemotherapy or rituximab)

Fatal/Life-threatening SAEs should be reported Fatal/Life-threatening SAEs should be reported as soon as possible and as soon as possible and no later than 7 no later than 7 calendar days from first knowledge by calendar days from first knowledge by investigatorinvestigator

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

SAE Reporting (1)SAE Reporting (1)

Complete SAE report form with as many informations as possible

SAE report form included : diagnosis and SAE report form included : diagnosis and intensity of adverse event, relationship intensity of adverse event, relationship with study drug, action taken, outcome …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

SAE Reporting (2)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

Let’s start the study !Let’s start the study !

We expect a lot of inclusions !!!We expect a lot of inclusions !!!

We expect an excellent tracking of We expect an excellent tracking of data !!!data !!!

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200

300400

500

600

700

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ati

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Planned RecruitmentReal Recruitment


QoL QoL Pathology ReviewPathology ReviewAncillary studiesAncillary studies

PRIMAPRIMAQoLQoL study study

Questionnaires with FACT-G and QLQ-C30 will be Questionnaires with FACT-G and QLQ-C30 will be distributed distributed – by the clinician to the patient by the clinician to the patient – at diagnosis, at the end of induction therapy and then at diagnosis, at the end of induction therapy and then

every year in both arms and for all follow-up period (7 every year in both arms and for all follow-up period (7 questionnaires per patient). questionnaires per patient).

– The patient will be encouraged to fill in the questionnaire The patient will be encouraged to fill in the questionnaire within one week after the physician visit. An anonymous within one week after the physician visit. An anonymous envelope will be provided to send back the questionnaire envelope will be provided to send back the questionnaire directly to the GELA-RC data center.directly to the GELA-RC data center.

– (GELARC will provide both questionnaires in every (GELARC will provide both questionnaires in every language !)language !)

PRIMAPRIMAPathological reviewPathological review (1) (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.

PRIMAPRIMAPathological reviewPathological review (2) (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).

PRIMAPRIMA Pathological review Pathological review (3) (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.

PRIMAPRIMA Pathological review Pathological review (4)(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.

PRIMAPRIMAAncillary studiesAncillary studies (1) (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.

PRIMAPRIMAAncillary studiesAncillary studies (2) (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.

PRIMAPRIMAAncillary studiesAncillary studies (3) (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 !

PRIMAPRIMAPrimary Rituximab and Primary Rituximab and Maintenance Maintenance

A unique A unique challengechallenge– an important clinical issue for patientsan important clinical issue for patients– an international clinical trial an international clinical trial – an opportunity for further clinical and an opportunity for further clinical and

scientific collaborations scientific collaborations

The success of The success of our projectour project depends on depends on the commitment and the quality of the the commitment and the quality of the work of everybody !work of everybody !