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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