PRIMA Investigator Meeting Saturday, December 9th, 2006 Orlando – ASH meeting

PRIMAInvestigator Meeting

Saturday, December 9th, 2006Saturday, December 9th, 2006

Orlando – ASH meetingOrlando – ASH meeting

AgendaAgenda

Status of the studyStatus of the study Study UpdateStudy Update Protocol AmendmentProtocol Amendment CT-scan reviewCT-scan review Monitoring / Administration / ContractsMonitoring / Administration / Contracts QuestionsQuestions

PRIMA had became PRIMA had became a registration triala registration trial

Agreement between GELA, Roche and GenentechAgreement between GELA, Roche and Genentech- First contacts end of May, decision in JulyFirst contacts end of May, decision in July

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

New responsabilities: New responsabilities: - For the sponsor (GELA)For the sponsor (GELA)- For the investigatorsFor the investigators- For the coordinating centersFor the coordinating centers- For monitoring the studyFor monitoring the study- For the partners (Roche, Genentech)For the partners (Roche, Genentech)- For the DSMCFor the DSMC- ……

Status on August 2006Status on August 2006

. 25 countries were active for recruitment. 25 countries were active for recruitment

. The 900 registered pts target (2. The 900 registered pts target (2ndnd amendment, early 2006) amendment, early 2006)

- reached on August 11th 2006- reached on August 11th 2006

. 406 pts at the time of randomization:. 406 pts at the time of randomization:- 176 maintenance- 176 maintenance

- 163 observation- 163 observation- 67 failed randomization (16.5%)- 67 failed randomization (16.5%)

ArgentinaAustraliaBelgium

BrazilChina

ColombiaCroatia

Czech republicDenmarkFinlandFranceIndiaIsrael

MexicoNetherlands

PeruPortugalSerbia /

MontenegroSpain

ThailandTurkeyUnited

KingdomUruguay

VenezuelaNew Zealand

To become a registration trialTo become a registration trial New protocol version (version 4.0, amendment 3) needed with several New protocol version (version 4.0, amendment 3) needed with several

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

GLSG studies (patients number)GLSG studies (patients number) Changes in protocol and ICF for new and already registered patientsChanges in protocol and ICF for new and already registered patients

Approval of the DSMCApproval of the DSMC August 4th 2006August 4th 2006

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

Approval by french authorities september 2006Approval by french authorities september 2006

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

Accrual resumed in France on October 9thAccrual resumed in France on October 9th

AgendaAgenda


Current STATUSCurrent STATUS

88 countries received approval to countries received approval to register patients againregister patients again

977977 patients registered (04/12/06) patients registered (04/12/06)601601 patients randomized (04/12/06) patients randomized (04/12/06)

Randomization rate Randomization rate ± 84 %± 84 %

Estimated end of recruitment : March, 2007Estimated end of recruitment : March, 2007

PRIMA RECRUITMENTPRIMA RECRUITMENT

Global World Recruitment - PRIMA Study

1 10 20 39 60 78108

136174

211257

307356

429

491

579638

707

790

872907 907

941970 978

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

Dec-04

Jan-

05

Feb-0

5

Mar

-05

Apr-0

5

May

-05

Jun-

05

Jul-0

5

Aug-0

5

Sep-0

5

Oct-05

Nov-05

Dec-05

Jan-

06

Feb-0

6

Mar

-06

Apr-0

6

May

-06

Jun-

06

Jul-0

6

Aug-0

6

Sep-0

6

Oct-06

Nov-06

Dec-06

Jan-

07

Feb-0

7

Mar

-07

Date

Incl

ud

ed P

atie

nts

Real Recruitment

Estimated World Recruitment

PRIMA RECRUITMENTPRIMA RECRUITMENTCountry Recruitment - PRIMA study

15

111

65

5 2 8 736 37

14 5 15 17 16 10 12 742

15 7 6 2 9

7845

4 26 7 6 7 4 6

977

13

501

19 4 22 99 183877

314

8 1

597

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 included Patients Nb of randomized patients

AgendaAgenda


Major Changes – 3rd AmendmentMajor Changes – 3rd Amendment(1)(1)

Primary objective : PFS instead of EFSPrimary objective : PFS instead of EFS Increase in the follow-up period : 3 to 5 yearsIncrease in the follow-up period : 3 to 5 years Increase in patients number : 1200 (instead of 900)Increase in patients number : 1200 (instead of 900)

Exclusion criteria : patient with any history of hepatitis B or Exclusion criteria : patient with any history of hepatitis B or hepatitis B virus infectionhepatitis B virus infection

Eligibility for randomization : Eligibility for randomization : Patients should have received at least : Patients should have received at least :

4 R-CHOP + 2R 4 R-CHOP + 2R or 6 R-CVP or 6 R-CVP or 4 R-FCMor 4 R-FCM

Induction chemotherapy regimen : R-MCP deletedInduction chemotherapy regimen : R-MCP deleted

EORTC 20981: K-M curves for PFSEORTC 20981: K-M curves for PFSSubgroup analysis according to inductionSubgroup analysis according to induction

(years)

0 1 2 3 4 5

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Treatment55 98 59 31 13 4

34 91 65 48 27 8

Observation

Mabthera

Progression free survivalafter R-CHOP

Overall Logrank test: p=0.004

median: 23.1 months

median: 51.9 months

H.R. 0.54

Major Changes – 3rd AmendmentMajor Changes – 3rd Amendment(2)(2)

Additional visits and CT-scan in the 2Additional visits and CT-scan in the 2ndnd year after the year after the end of maintenance/observationend of maintenance/observation

New ICF for new patientsNew ICF for new patients (ICF and information letter (ICF and information letter version 2.0)version 2.0)

An additional ICFAn additional ICF to be signed by patients already to be signed by patients already registered (ICF and information letter version 2.1)registered (ICF and information letter version 2.1)

CT-scan collection and reviewCT-scan collection and review Induction Chemotherapy doses required by FDAInduction Chemotherapy doses required by FDA Changes in the CRF for new patients, specific Changes in the CRF for new patients, specific

additional forms for those already registeredadditional forms for those already registered

Regulatory UpdateRegulatory Update Belgium, Croatia, Denmark, Finland, France, Thailand, Belgium, Croatia, Denmark, Finland, France, Thailand,

Venezuela and one site of Australia received approval for Venezuela and one site of Australia received approval for 3rd amendment3rd amendment

Before starting recruitment, to be provided to GELARC :Before starting recruitment, to be provided to GELARC : CV of Principal Investigator and Co-investigators in each centerCV of Principal Investigator and Co-investigators in each center PD 35 form for Inv. And Co-InvPD 35 form for Inv. And Co-Inv Page of protocol (v3.2 and 4.0) signed by PIPage of protocol (v3.2 and 4.0) signed by PI Approvals (Ethics Committee and Health Authorities) for Approvals (Ethics Committee and Health Authorities) for

amendment n°2 and n°3 + regulatory certification document amendment n°2 and n°3 + regulatory certification document New Informed consent in local languageNew Informed consent in local language

After reception of all documents, GELARC will send to After reception of all documents, GELARC will send to the local coordinator the new Registration formthe local coordinator the new Registration form

AgendaAgenda

Status of the studyStatus of the study Study UpdateStudy Update Protocol AmendmentProtocol Amendment CT-scan reviewCT-scan review Administration / contractAdministration / contract QuestionsQuestions

AgendaAgenda


CRFs FLOW CHARTCRFs FLOW CHART Baseline part (p1 to 9)Baseline part (p1 to 9) => sent to GELARC before => sent to GELARC before

randomizationrandomization Induction / randomization parts (p10 to 18)Induction / randomization parts (p10 to 18) => sent as soon => sent as soon

as possible after randomization or premature withdrawalas possible after randomization or premature withdrawal Maintenance partMaintenance part => every 4 visits (with evaluation and => every 4 visits (with evaluation and

toxicity pages), likely after each visit in the near futuretoxicity pages), likely after each visit in the near future Progression, event, deathProgression, event, death : : to be faxed to GELARC and to be faxed to GELARC and

sent as soon as possiblesent as soon as possible AE and original forms of SAEAE and original forms of SAE => sent after each => sent after each

monitoring visitmonitoring visit

All parts have to be monitored All parts have to be monitored before being sent to the GELARCbefore being sent to the GELARC

CRFs Reception / MonitoringCRFs Reception / Monitoring

638 CRF must should have been registered at the 638 CRF must should have been registered at the end of induction treatment as today :end of induction treatment as today : 97 % of complete baselines received !97 % of complete baselines received ! 53 % of complete induction received53 % of complete induction received

- 23 % = incomplete induction part- 23 % = incomplete induction part- 24 % = missing induction part- 24 % = missing induction part

Monitoring frequency will be increased in 2007 : Monitoring frequency will be increased in 2007 : every 8 weeksevery 8 weeks instead of twice a year. instead of twice a year.

Many thanks for your effort to send the induction Many thanks for your effort to send the induction treatment before the end of this year !!!treatment before the end of this year !!!

QUERY & DATA MANAGEMENTQUERY & DATA MANAGEMENT

CRFs validationCRFs validation parametered tests + medical reviewparametered tests + medical review

CRFs are validated as followCRFs are validated as follow : : Baseline + induction treatmentBaseline + induction treatment Maintenance (every 4 visits) : increased Maintenance (every 4 visits) : increased

frequency in the near futurefrequency in the near future Follow-up / progression / death / AEs (at Follow-up / progression / death / AEs (at

reception)reception)

Clinical data correction Forms will be sent by Clinical data correction Forms will be sent by GELARC after the validation of each partGELARC after the validation of each part

QUERY & DATA MANAGEMENTQUERY & DATA MANAGEMENT Clinical data correction Forms will be sent by e-Clinical data correction Forms will be sent by e-

mail to the local coordinator (study group, Roche mail to the local coordinator (study group, Roche or other)or other)

Answers must be completed directly on the form Answers must be completed directly on the form by the investigator (by the investigator (do not forget to sign and do not forget to sign and date form ! date form ! ) )

One copy must be kept in the CRFOne copy must be kept in the CRF Each completed form has to be faxed to Each completed form has to be faxed to

GELARC (ASAP) and original forms have to be GELARC (ASAP) and original forms have to be sent after the next monitoring visit (with CRF sent after the next monitoring visit (with CRF pages)pages)

SAE s (1)SAE s (1) A serious adverse event is any experience that suggests A serious adverse event is any experience that suggests

a significant hazard, contraindication, side effect or a significant hazard, contraindication, side effect or precaution. It is any adverse event that at any dose fulfils precaution. It is any adverse event that at any dose fulfils at least one of the following criteria:at least one of the following criteria:

is fatal (results in death) (is fatal (results in death) (notenote:: death is an outcome, not an death is an outcome, not an event)event)

is life-threatening (is life-threatening (notenote:: the term “life-threatening” refers to an the term “life-threatening” refers to an event in which the patient was at risk of death at the time of the event in which the patient was at risk of death at the time of the event; it does not refer to an event which could hypothetically event; it does not refer to an event which could hypothetically have caused death had it been more severe)have caused death had it been more severe)

required patient hospitalization or prolongation of existing required patient hospitalization or prolongation of existing hospitalization (hospitalization (notenote: “inpatient hospitalization” refers to an : “inpatient hospitalization” refers to an unplanned, overnight hospitalization)unplanned, overnight hospitalization)

results in persistent or significant disability/incapacityresults in persistent or significant disability/incapacity is a congenital anomaly/birth defectis a congenital anomaly/birth defect is medically significant or requires intervention to prevent one or is medically significant or requires intervention to prevent one or

other of the outcomes listed aboveother of the outcomes listed above

SAE s (2)SAE s (2) During the induction phase, During the induction phase,

all SAEs have to be recorded up to 30 days after the last dose of all SAEs have to be recorded up to 30 days after the last dose of induction therapyinduction therapy

treatment related SAEs have to be reported at any time beyond treatment related SAEs have to be reported at any time beyond 30 days after the last dose of induction therapy.30 days after the last dose of induction therapy.

During the maintenance phase, During the maintenance phase, all serious adverse events encountered up to all serious adverse events encountered up to 6 months after 6 months after

the last dose of rituximab or last observation visit the last dose of rituximab or last observation visit have to be have to be reportedreported

treatment related SAEs have to be reported at any time beyond treatment related SAEs have to be reported at any time beyond 6 months after the last dose of maintenance therapy/last 6 months after the last dose of maintenance therapy/last observation visit.observation visit.

SAE s (3)SAE s (3)

All Serious Adverse Events (SAE) must be All Serious Adverse Events (SAE) must be reported to the respective Group Principal reported to the respective Group Principal Investigator or Data Manager by fax Investigator or Data Manager by fax within 24 within 24 hours of the initial observation of the eventhours of the initial observation of the event. .

Any adverse event that is considered SERIOUS Any adverse event that is considered SERIOUS must be reported within one working day must be reported within one working day (IMMEDIATELY) by the investigator to the (IMMEDIATELY) by the investigator to the GELARC Safety Desk. GELARC Safety Desk.

It is a legal requirement to report serious It is a legal requirement to report serious adverse events. adverse events.

SAEs report and follow-upSAEs report and follow-upo Please be precise in the description of the medical Please be precise in the description of the medical

event : provide one event, but detail the presence event : provide one event, but detail the presence of absence of relevant conditions, specially when of absence of relevant conditions, specially when the outcome is fatal : the outcome is fatal :

o Ex : if pneumonia after chemo: describe blood counts at onset, Ex : if pneumonia after chemo: describe blood counts at onset, any microbiology results, etc… ; any microbiology results, etc… ;

o Ex : if cardiovascular, describe previous history, treatments, etc…Ex : if cardiovascular, describe previous history, treatments, etc…

o Please respect the delays (1 day)Please respect the delays (1 day)

o Please follow-up the eventsPlease follow-up the events

o Please answer the queriesPlease answer the queries

PRIMA = timelinesPRIMA = timelines

according to the assumptions in the protocol the according to the assumptions in the protocol the analyses are planned at the following timepoints:analyses are planned at the following timepoints:

1st interim analysis (172 events) - 29 months after the 1st interim analysis (172 events) - 29 months after the first patient has been randomized to maintenance first patient has been randomized to maintenance

2nd interim analysis (258 events) - 37 months after the 2nd interim analysis (258 events) - 37 months after the first patient has been randomized to maintenance first patient has been randomized to maintenance

final analysis (344 events) - 46 months after the first final analysis (344 events) - 46 months after the first patient has been randomized to maintenance patient has been randomized to maintenance

end of study: 5 years after the last patient has finished end of study: 5 years after the last patient has finished maintenance therapymaintenance therapy

- 11/07

- 07/08

- 05/09

- 09/14 !

Administration / ContractAdministration / Contract All contracts will be updated : All contracts will be updated :

with Cooperative Groups in EU + Australia/NZ + Brazil + Israelwith Cooperative Groups in EU + Australia/NZ + Brazil + Israel with Roche Affiliates outside EU (were Roche is the sponsor)with Roche Affiliates outside EU (were Roche is the sponsor)

Substantial increase in investigator fee Substantial increase in investigator fee Paid by GELA to cooperative groups in EU, Au/NZ, Brazil, IsraelPaid by GELA to cooperative groups in EU, Au/NZ, Brazil, Israel Paid by Roche affiliates in Roche sponsor countriesPaid by Roche affiliates in Roche sponsor countries

Monitoring Plan + SDV Plan will be attached to the new Monitoring Plan + SDV Plan will be attached to the new contractcontract

1st batch of Investigator’s fees will be paid at the 1st batch of Investigator’s fees will be paid at the beginning of 2007 (if contract is signed)beginning of 2007 (if contract is signed)

PRIMA : a collaborative effort for PRIMA : a collaborative effort for the largest follicular lymphoma trialthe largest follicular lymphoma trial

AgendaAgenda


Documents

PRIMA Investigator Meeting Saturday, December 9th, 2006 Orlando – ASH meeting