PRIMAInvestigator Meeting

Gilles SallesGilles Salles

Vienna, June 07

PRIMA investigator meetingPRIMA investigator meeting

Introduction and WelcomeIntroduction and Welcome

Study & Patients Study & Patients

Prima is a Registration trial = changes & Prima is a Registration trial = changes & regulatory aspectsregulatory aspects

Next stepsNext steps

Vienna, June 07

STATUSSTATUS

From 24/12/2004 until 11/04/07From 24/12/2004 until 11/04/07

12171217 patients registered patients registered

2525 active countries (with at least 1 patient) active countries (with at least 1 patient)

PRIMA : an international PRIMA : an international collaborative effortcollaborative effort

Country Recruitment - PRIMA study

15

132

75

13 8 11 736 48

14 9 15 18 26 10 16 9

5418 7 16 3 9

9452

7 31 11 14 9 6 6 2 8

1217

24

624

113 5 42 99 30

412915

400

9 5

788

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

Country

Num

ber

of In

clud

ed P

atie

nts

Nb of Registered Patients Nb of randomized patients

PRIMA RECRUITMENTPRIMA RECRUITMENT

PRIMA recruitmentPRIMA recruitmentGlobal World Recruitment - PRIMA Study

1 10 20 39 60 78108

136174

211257

307356

429

491

579638

707

790

872907 907

941970

1003

1217

10671122

1206

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

Date

Incl

ud

ed P

atie

nts

Real Recruitment

Estimated World Recruitment

PRIMA RECRUITMENTPRIMA RECRUITMENT

Chemo regimen chosen (all pts)

R-CHOP 900 74%R-CVP 272 22%R-FCM 45 4%

Vienna, June 07

STATUSSTATUS

On June 5th, 821 patients (84% or those that reached the time of randomization) were effectively randomized:

Maintenance 417 pts

Observation 404 pts

Randomization failureRandomization failure

For the 146 patients (15.6%) that failed to be randomized:

Major violation (inclusion criteria) 10 pts (3 Hbs +)pathology review 12 ptsBM only 3 pts

Major protocol violation (treatment) 11 pts2nd cancer discovered during induction 7 pts 29%

Toxicity and premature withdrawal 24 ptsDelay during induction or at randomisation 20 pts 30%

Treatment failure 32 ptsDeath 14 pts 33%

Consent withdrawal 6 ptsInvestigator decision 4 pts 7%

Vienna, June 07

Patients characteristicsPatients characteristics (CRF registered, medical review ongoing)

Total 1071 ptsTotal 1071 pts Nb PatientsNb Patients %

MaleMale 559559 53

FemaleFemale 508508 47

PS ECOG 0-1PS ECOG 0-1 10051005 94

PS ECOG 2-3PS ECOG 2-3 4747 6

AA Stage I-IIAA Stage I-II 130130 14

AA Stage III-IVAA Stage III-IV 920920 86

Vienna, June 07

Total 1071 patientsTotal 1071 patients Nb PatientsNb Patients %Nodal or ex-nodal > 7 cmNodal or ex-nodal > 7 cm 465465 43

B symptoms presenceB symptoms presence 315315 29

Elevated LDH or Elevated LDH or ββ2-micro2-micro 603603 56 *

Involvement 3 nodal sites > 3 cmInvolvement 3 nodal sites > 3 cm 333333 31

Splenic enlargementSplenic enlargement 226226 21

Compressive syndromeCompressive syndrome 180180 17

Pleural / peritoneal effusionPleural / peritoneal effusion 124124 12

(only 112 patients - 10% - had those sole criteria)

Patients characteristicsPatients characteristics (CRF registered, medical review ongoing)

Vienna, June 07

Total 1048 ptsTotal 1048 pts Nb PatientsNb Patients %%

FLIPI 0-1FLIPI 0-1 226226 2222

FLIPI 2FLIPI 2 376376 3636

FLIPI 3-5FLIPI 3-5 446446 4343

Patients characteristicsPatients characteristics (CRF registered, medical review ongoing)

Vienna, June 07

PRIMA had became PRIMA had became a registration triala registration trial

Agreement between GELA, Roche and GenentechAgreement between GELA, Roche and Genentech

The results will be used for registration filingThe results will be used for registration filing- in EU, US and rest of the world- in EU, US and rest of the world

New responsibilities New responsibilities - For the sponsor (GELA)For the sponsor (GELA)- For the investigatorsFor the investigators- For the coordinating centersFor the coordinating centers- For the partners (Roche, Genentech)For the partners (Roche, Genentech)- For the DSMBFor the DSMB- ……

Vienna, June 07

To become a registration trialTo become a registration trial New protocol version (version 4.0, amendment 3) needed some changes:

Compliance with Health Authorities (EMEA, FDA) requirements (PFS, etc…) Update statistical hypothesis taking into account the results of the EORTC and

GLSG studies (sample size) Changes in protocol and ICF for new and already registered patients

Approval of the DSMC August 4th 2006

Submission to the ethics and health authorities in the lead sponsor country : August 18th 2006

Approval by French authorities September 2006

Dissemination of new protocol and ICF versions to other countries: September 18th

Accrual resumed from October 9th until January in most countries

Vienna, June 07

Regulatory aspectsRegulatory aspects

3rd amendment approval needed even if no additional patient was included (regulatory, follow-up, etc…) No CT scan collection without this approval

Additional ICF to be signed by patients registered before the 3rd amendment

New contract between GELA – cooperative group/Roche affiliate

Vienna, June 07

Monitoring and follow-upMonitoring and follow-up Close monitoring of centers (every 2 months) to

complete and clean the data base - 89% of baseline received (2% incomplete) - 72% of induction / response received (11% incomplete) - 65% of first follow-up received (40% incomplete)

Assure timely follow-up of patients and events

Answer queries

CT-scan review process with Bio-Imaging (only for randomized patients)

Vienna, June 07

Some clinical aspectsSome clinical aspects“maintenance or observation”“maintenance or observation”

1) Please follow the protocol recommendations for

- visits every 8 weeks during the 2 years arm A & B

then - clinical visits every 3 months (2 y) and 6 months (3 y)- CT scans every 6 months (3 y) and 12 months (2 y)

2) For women in age of being pregnant:- please recommend contraceptives in the maintenance arm

Vienna, June 07

PRIMAPRIMAsafetysafety

No obvious safety issues reported during inductionNo obvious safety issues reported during induction - next DSMB meeting in 2007- next DSMB meeting in 2007

Follow carefully AE and SAE during maintenanceFollow carefully AE and SAE during maintenance Document well what happensDocument well what happens Follow-up of patients with side effectsFollow-up of patients with side effects

EORTC intergroup study dataEORTC intergroup study data

Any clinical study has to weight the risk/benefit ratioAny clinical study has to weight the risk/benefit ratio

Vienna, June 07

PRIMAPRIMAefficacyefficacy

Progression:Progression:

1) Fast track declaration of progressions after 1) Fast track declaration of progressions after randomization by FAXrandomization by FAX2) Document well :2) Document well :

Tumor measurements (CT scans)Tumor measurements (CT scans) BiopsyBiopsy Treatment (can be delayed) Treatment (can be delayed)

3) Follow subsequent events : Death3) Follow subsequent events : Death

Adequate follow-up for all patientsAdequate follow-up for all patients Respect planed visits and evaluationRespect planed visits and evaluation

Vienna, June 07

Financial agreementsFinancial agreements Patient fees were changed Patient fees were changed

After randomizationAfter randomization Time of final analysisTime of final analysis End of studyEnd of study + CT-scan review+ CT-scan review

First payments to the country coordinating group in First payments to the country coordinating group in GELA-sponsored country will be done in timely manner GELA-sponsored country will be done in timely manner June 07 (if the amended contract signed)June 07 (if the amended contract signed) Then once a yearThen once a year Final analysisFinal analysis End of studyEnd of study

Vienna, June 07

Next steps for PRIMANext steps for PRIMA

- With 1217 pts recruited, PRIMA is the With 1217 pts recruited, PRIMA is the largest trial ever performed in first line largest trial ever performed in first line follicular lymphoma patientsfollicular lymphoma patients

- An opportunity for answering a very An opportunity for answering a very important question with a high standard important question with a high standard quality trial : quality trial : - Rituximab maintenance benefit after R-chemoRituximab maintenance benefit after R-chemo

Vienna, June 07

Results of R-CHOP maintenance Results of R-CHOP maintenance in the EORTC intergroup studyin the EORTC intergroup study

Overall log-rank test: p=0.004; HR: 0.54

Progression-free survivalafter R-CHOP

O N Number of patients at risk :

55 98 59 31 13 4

34 91 65 48 27 8 MabThera

Treatment

100

90

80

70

60

50

40

30

20

10

0

Years

0 1 2 3 4 5

Median 23.1 months

Median 51.9 months

Pro

gre

ssio

n-f

ree

surv

ival

(%

)

Vienna, June 07

Time for analysisTime for analysis

Estimated number of event to confirm the Estimated number of event to confirm the hypothesis (45% increase of PFS) : 344 eventshypothesis (45% increase of PFS) : 344 events

First interim analysis to be performed when 172 First interim analysis to be performed when 172 events will have occurredevents will have occurred Close tracking of events – Close tracking of events –

- fax progression /death pages to gelarc “on line”

Expected first semester of 2008 ?Expected first semester of 2008 ?

Will be blinded and presented to the DSMCWill be blinded and presented to the DSMC

Vienna, June 07

Thanks to all of youThanks to all of you

for your cooperationfor your cooperation

Vienna, June 07