PNET 5 STUDY INITIATION
Prof Sandra Jacobs / An Michiels15 December 2015
An International prospective study on clinically standard-risk
medulloblastoma in children older than 3 to 5 years with low-risk biological
profile (PNET 5 MB-LR) or average-risk biological profile (PNET5 MB-SR)
International study team
• Sponsor: University Medical Center Hamburg
• Coordinating investigator: Prof Stefan Rutkowski
• Co-coordinating investigator: Prof Francois Doz (PNET5-LR)
• Deputy coordinating investigator: Prof Katja von Hoff
• Biometrician: Prof Andreas Faldum, Dr Robert Kwiecien
• Datamangment: Regine Riechers [email protected]
National study team
• Principal Investigator
Prof Sandra Jacobs UZ Leuven [email protected]
Back-up: Dr Stefan Schifflers [email protected]
• National reviewer pathology/ biology
Prof Sciot / Prof Debiec (UZ Leuven)
• National reviewer radiology
Prof Demaerel/ Prof Heye (UZ Leuven)
• National reviewer radiotherapy
Prof Menten/ Prof Van Beek (UZ Leuven)
• National reviewer QOS
Jurgen Lemiere (UZ Leuven)
• Datamanagment
Diane Delaplace , Danielle Lemmens, An Michiels – UZ Leuven
Agenda
• Design
• Objectives
• In – and exclusion criteria
• Eligibility and review process
• National review pathology/biology
• National review radiology
• Registration/randomisation
• National review radiotherapy
• Treatment/ 2 years after diagnosis/ At relapse
• National review QOS
• Flowchart
• CRF
• SAE reporting
• Monitoring
• Conclusion
International, prospective study - 17 countries
Stratification according to clinical and biological criteria
PNET LR PNET SR
Phase II open III randomized
Recruitment 6 years 6 years
Follow-up 3 years 4 years
Expected N° patients 60 300
Design
Design
WNT subgroup status
Design
WNT + WNT + WNT - WNT -
A: Cisplatin 70mg/m² D1, CCNU 75mg/m² D1, VCR 1,5 mg/m² D1,8,15
B: Cyclophosphamide 1g/m² D1-2, VCR 1,5mg/m² D1
Design
Rando ± carbo,
8 chemo cycles
Treatment de-escalation
(reduced RT, only 6
chemo cycles)
Primary objectives
PNET5-LR
• To confirm 3 year EFS remains in excess of 80% when patients
are treated with 18,0 Gy neuraxis irradiation plus boost to primary
tumor and reduced-intensity chemotherapy
PNET5-SR
• To test whether EFS is different with or without carboplatin
concomitantly with radiotherapy (23,4 Gy neuraxis irradiation plus
boost to the primary tumor)
Secondary objectives
• Overall survival
• Progression free survival
• Pattern of relapse
• Late effects of therapy
• Endocrine function
• Audiology
• Neurology
• Standardized patients/parents measurements of health status,
executive function, behavioural outcome and quality of life
• Prognostic relevance of biological tumor markers
• PNET5 SR: Feasibility of carboplatin treatment concomitantly to
radiotherapy
Main Inclusion criteria
• Age 3-5 years according to national policy - age cut off 5 years for Belgium- to less
than 16 years (LR) or less than 22 years (SR)
• Histological proven MB (classical of desmoplastic/nodular MB)
– Central pathology review mandatory before start treatment!!
• Clinically confirmed standard risk MB
• Total or near total resection (≤ 1,5cm² residual tumor)
• No CNS metastasis on cranial and spinal MRI - central review
• No tumor cells in CSF –central review
• No evidence of extra CNS metastasis
• Submission of tumor material (FFPE slides and fresh-frozen tissue), blood , CFS
and pre/post-OP MRI images for central review in UZ Leuven
• No amplification of MYC/MYCN
• PNET5 LR: Low-risk biological profile = WNT positive
PNET5-SR: Average risk biological profile = WNT negative or WNT
positive in patients ≥ 16 years
Main Inclusion criteria
• No prior treatment for MB other than surgery
• Radiotherapy aiming to start no more than 28 days after surgery (start RT after
more than 40 days after surgery -> patient ineligible!)
• Screening for eligibility (including review!) should be completed within 22
days, patient should be included in the study within 28 days after surgery!
• CTC grade <2 for liver, renal and hematological function
• No significant sensineural hearing deficit (pure tone audiometry; if not possible
normal otoacoustic emissions are acceptable if no history of hearing deficit)
• No medical contraindication for radiotherapy or chemotherapy such as DNA
breakage syndromes, Gorlin syndrome or other
• No known turcot and Li Fraumeni syndrome
(-> turcot and Li Fraumeni syndrome testing will be mandatory at next protocol
amendment)
• Written informed consent
Main Exclusion criteria
• Brainstem of supratentorial PNET, ATRT, medulloepithelioma,
Ependymoblastoma, large-cell MB, anaplastic MB, MBEN
• Unfavourable or undeterminable biological profile (amplicfication of MYC or MYCN
or WNT status not determiable)
• Metastatic MB
• Previously treated for a brain tumor or any type of malignant disease
Eligibility and review process
Diagnosis Fossa posterior tumor
Pre-Op cranial and spinal MRI
Surgery
-> FFPE and Fresh frozen tissue mandatory for review
Post-Op MRI (24-72h post-OP)
LP within 14 days after surgery
-> frozen CSF (2 aliquots) mandatory for review
-> if CSF positive repeat LP at day 15 or later
Eligibility and review process
Local Diagnosis Medulloblastoma
1st ICF (central review/scientific research)
Email “screening for eligiblilty form” (form 1 paper CRF) to
Eligibility and review process
Central Review
Send material/images/forms
Pathology Biology Radiology RT
Review and biological stratification within 22 days Post-OP!!!
Reviewers: Prof Sciot [email protected]/
Prof Debiec [email protected]
At local confirmation Medulloblastoma and signing first ICF
-> please send the following as soon as possible:
Frozen: 1) aliquot snap frozen tissue
2)10ml EDTA whole blood frozen
3) CSF frozen (2 aliquots)
Ambient: 30 FFPE slides 5µm
Local pathology report , ˝to pathology form ˝ and ˝ to biology form ˝ (form 3A and
4A paper CRF)- please indicate full name/health insurance company number !!!
Address: UZ Leuven - Pathology Department
Prof Sciot/Prof Debiec/Marleen Franssens/ Peter Leemans
Herestraat 49
3000 Leuven
Please email ˝ to pathology form ˝ and ˝ to biology form ˝ to national datacenter
Review results will be returned to local site as soon as possible
(within 22 days after surgery)
National review pathology/biology
Please note full name and health insurance data on pathology and biology form
(required for reimbursment of some review test)
Reviewer: Prof Demaerel [email protected] /
Prof Heye [email protected]
At local confirmation Medulloblastoma and signing first ICF
-> please send electronically (lamp-dropbox) as soon as possible:
Anonymized Pre and Post-Op MRI images
˝to neuroradiology form ˝ (form 2A paper CRF)
Dropbox (lamp) system is preferred to send images electronically for review*
Each center will receive link and login/password for dropbox (lamp)
-Send test images before to make sure there is no problem
Send anonymized uncompressed DICOM images
Please email ˝ to neuroradiology form ˝ to national datacenter [email protected]
Review results will be returned to local site as soon as possible
(within 22 days after surgery)
National review radiology
*If not possible to send images electronically send your CD to:
UZ Leuven, secretariaat kindergeneeskunde, Greet Vandeneynde/An Michiels, Herestraat 49, 3000 Leuven)
Registration / randomisation
Completed “Screening for eligibility form” is
sent to local center indicating eligibility for
PNET5 MB LR or PNET5 MB SR
2nd ICF (main study) signed
Registration in marvin by local center
Marvin ID
Day 22 Post-Op
Registration / randomisation
Email “registration form” (form 5A, for PNET5 MB-LR )
OR
“registration and randomisation” (form 5B, for PNET5 MB-SR) to:
further registration/randomisation by national datacenter in Marvin
completed registration/registration and randomisation form with
result of randomisation is sent to local center
RT planning according to stratification PNET5 MB-LR or SR
Reviewer: Prof Menten [email protected] /
Prof Van Beek [email protected]
If radiotherapy planning is ready
-> please send electronically (lamp-dropbox) as soon as possible:
Anonymized RT planning images/documents
˝central prospective review of RT form ˝ (form 7A paper CRF)
See electronically (lamp-dropbox) system review radiology*
Send anonymized uncompressed DICOM images
Please email ˝ central prospective review of RT form ˝ to national datacenter
Review results will be returned to local site before start RT (no later than 1st week RT)
National review radiotherapy
*If not possible to send images electronically send your CD to:
UZ Leuven, secretariaat kindergeneeskunde, Greet Vandeneynde/An Michiels, Herestraat 49, 3000 Leuven)
Treatment
Radiotherapy should start 28 days Post-Op
Patient is ineligible if RT starts more than 40 days after surgery
Start radiotherapy treatment (28 days post-op)
Treatment
Treatment
Treatment
• Carboplatin (SR-arm)
35mg/m2/d over 15-20 minutes IV
1 to 4 hours before RT
5 days per week for 6 weeks (Mo-Fri with RT)
No carboplatin if RT is not given
Total 30 applications of carbo
Adjust carboplatin dose weekly to weight
RT and carboplatin not to be withheld for myelosuppresion or fever in
clinically stable patients
• G-CSF
5µg/kg/d Fri-sun (3d) if ANC ≤1000 on Fridays
5µg/kg/d for 2d after RT if ANC<500 on Mon/Wed
Treatment
All used chemotherapeutic drugs are:
-used in current standard of care for MB in children
-licensed and commercially avialable
-from hospital stock
2 years after diagnosis
Please send electronically (lamp-dropbox) :
Anonymized MRI images
˝to follow-up neuroradiology review form ˝ (form 15A
paper CRF)
Dropbox (lamp) system is preferred to send images
electronically for review*
Send anonymized uncompressed DICOM images
Please email ˝ to follow-up neuroradiology form ˝ to national
datacenter [email protected]
Review results will be returned to local site as soon as
possible
*If not possible to send images electronically send your CD to:
UZ Leuven, secretariaat kindergeneeskunde, Greet Vandeneynde/An Michiels, Herestraat 49, 3000 Leuven)
National review radiology
At relapse
National review radiology(see previous slide)
National review radiotherapy
Send electronically (lamp-dropbox):
Anonymized RT planning images/documents
˝Posterior Fossa relapse/progression form˝
(form 16 paper CRF)
Send anonymized uncompressed DICOM images
Please email ˝ Posterior Fossa relapse/progression
form“ to national datacenter [email protected]
Review results will be returned to local site
• National Reviewer: Jurgen Lemiere [email protected]
• QOL paper version submitted and approved by EC
• Online Health tracker module:
Admin portal https://pnet5-admin.healthtracker.co.uk/
Patient portal https://pnet5-patient.healthtracker.co.uk/
• QOS Data collection / review Belgium
– Patient completes questionnaires directly into Health tracker OR
Psychologist/studycoordinator enters questionnaires (from paper version if applicable) in
health tracker
– The national QOS reviewer Jurgen Lemiere will coordinate and review data
• Please provide name of local psychologist/studycoordinator who will enter
questionnaires in Health tracker if applicable login and password will be sent)
National review QOS
National review QOS
Flowchart
• Paper CRF – version adapted for Belgium
(forms national review, radiotherpy, radiology, …)
• Documentation in Marvin (e-CRF)
– Local center
• registers new patient when 2nd ICF is signed
• Completes all forms such as demographics, treatment, toxicities,….
– National datacenter
• further registers (LR arm) or randomizes (SR arm) in Marvin after receiving
the randomisation/registration form from the local center
• Marvin e-CRF https://gpoh-1.xclinical.net
• log in and passwords will be sent by international
datamangment
CRF
SAE reporting
Reporting period
• Immediate SAE reporting NOT required for:
– Expected hospitalisation for procedures such as
• Blood transfusion for hematological toxicity grade 1-4 without
complications
• Antibiotic treatment for neutropenic fever or grade 1-3 infections
• Nutritional support for weight loss grade 1-3
• Other expected toxicity grade 1-3
– Hospitalisation due to progressive disease unless outcome leads to death
before last protocol treatment +30 days
– Hospitalisation within FU period (after last protocol treatment + 30 days)
without causal relationship to protocol treatment
Only documentation in marvin toxicity form necessary
SAE reporting
Safety Desk University Hospital Munster
Phone: +49 (0)251 83 57109
Fax: +49 (0)251 83 57112
Email: [email protected]
SAE reporting
Fax SAE form within 24 hours to the safety desk
SAE reporting
SAE reporting
SAE reporting
• By Bimetra UZ Ghent [email protected]
• Frequency
– First visit at the end of therapy first patient (earlier in case of poor compliance)
– Second visit
• Sites with 2 or more registered patients
• Sites with poor or late documentation
• 10% of other sites chosen randomly
• Tasks
– Check ISF (Investigator Site File)
– SDV (Source data verification)
• First one or 2 patients: complete (100%) review
• Other patients: review key data (ISF, in and exclusion, reference results, treatment, EOT,
demographics, diagnostic data, SAEs, toxicities
– Monitoring visit report with pending issues to local site and national coordinator
Monitoring
Conclusion
• Almost green light to start enrolling patients in PNET5 study
• Intersite contracts need to be signed
• Review radiology/radiotherapy
– dropbox (lamp) system link with password will be sent
– Please send test transfer as soon as possible
• Center ID and login for marvin (and health tracker )will be sent
• Final documents will be sent by dropbox / BSPHO website
– Table of content ISF, final protocol and ICFs, CRF, manuals, …
• Document further training at your center (training log)
National review Pathology/Biology/Radiology/RT
before day 22 after surgery is challenge!
Feasibility study Germany
Conclusion
Thank you and good luck!
