Paediatric Hepatic International Tumour Trial
Belgium Study Initiation - 29 Janvier 2019
Pr Bénédicte BrichardGaëlle Dufour
Agenda
• General Information• Study Design• Study Objectives• Study Entry• Treatment Group• Treatment
• Biological Samples• Pharmacovigilance• Data Collection• Monitoring• Start-up: update
Chief investigator
Pr Bruce Morland
Cancer Research Clinical Trials Unit (CRCTU)
University of Birmingham - UK
+44 (0)121 333 8233
Trial Coordinators
Jennifer Laidler & Su Lee
Cancer Research Clinical Trials Unit (CRCTU)
University of Birmingham - UK
+44 (0)121 415 1061
General Information
Sponsor
Study Coordinators
Gaëlle Dufour
[email protected] +32 2 764 23 13
Mathilde Deligne, Caroline Martin, Michel Vanden Eynden
+32 2 764 23 76
General Information
National Coordinating Center (NCC): UCL Saint-Luc
Principal investigator
Pr Bénédicte Brichard
+32 2 764 23 50
General Information
• Expected number of patients: 300 in Europe / 1200 in total
• Study duration: 2 years of recruitment (end Dec 2020) - applied for extension
• Follow-up: 2 years
• 7 participating sites in Belgium:
UZ Leuven - Dr Marleen Renard
UZ Gent - Dr Bram De Wilde
UZ Brussel - Dr Machiel van den Akker
UZ Antwerpen - Dr Jaques van Heerden
Huderf - Dr Safiatou Diallo
CHU Liège - Dr Marie-Françoise Dresse
UCL Saint-Luc - Pr Bénédicte Brichard
• 15 participating countries
SIOPEL : 140 sites in totalUK, Ireland, France, Spain, Italy, Germany, Belgium, The Netherlands, Poland, Switzerland, Sweden, Norway, Czech Republic COG JCCG
• Recruitment in Europe (Dec. 2018)
35 opened sites: 17 UK, 1 Ireland, 6 Spain, 1 Norway, 8 Switzerland and 2 France30 recruited patients: 24 UK, 6 Spain
• Funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 668596
General Information
• International, multicenter, Phase III, 4 randomized comparisons (therapeutic questions)
• Paediatric and young adults hepatic tumours: hepatoblastoma (HB) and hepatocellularcarcinoma (HCC)
• HCC stratified into 2 groups : Completely resected at diagnosis and unresectable/metastaticdisease at diagnosis
• HB stratified into 4 groups : Very Low, Low, Intermediate and High Risk
Study Design
Group Stratification (HB)
Study Design
• PRETEXT Factors• VPEFR factors• Metastases• Age• AFP
4 different groups: Very Low (Group A), Low (Group B), Intermediate (Group C) and High (Group D) risk
Group Stratification (HB)
Study Design
Study Design
Primary
• To evaluate if the treatment of Low Risk hepatoblastoma (HB) can be reduced (Group B1)
• To compare different treatment regimens for Intermediate risk HB (Group C)
• To compare different post induction treatment regimens for High Risk HB (Group D2)
• To determine if the outcome is improved when GEMOX is added to PLADO in the treatment of unresected hepatocellular carcinoma HCC (Group F)
• To collect samples for biological and toxicities studies (all groups)
Study Objectives
• To report outcome (EFS, FFS, OS, toxicity and surgical outcome) in all patient groups
• To validate a new global risk stratification, by Children’s Hepatic Tumours International Collaboration (CHIC)
• To evaluate clinically relevant factors: To provide panel of diagnostic and prognostic biomarkers To determine paediatric HCC is biologically different to adult HCC To develop genomic and/or biomarker analysis to predict toxicity with chemotherapy
• To establish a collection of biological samples
• To evaluate a surgical planning tool in POST-TEXT III and IV HB
Study Objectives
Secondary
Study Entry
Study Entry ICF
Eligibility confirmation
First Part
• All patients sign Study Entry Informed Consent
• Informed consent must be obtained before any trial specific procedures can taken place
• Take consent before biopsy/surgery
Study Entry Informed Consent (version 1.2 - 15 November 2018)
Study Entry
• Clinical diagnosis of HB and histologically defined diagnosis of HB or HCC.• Age ≤30 years• Written informed consent for study entry
Inclusion criteria
Exclusion criteria
Study Entry
Eligibility
• Any previous chemotherapy or currently receiving anti-cancer agents• Recurrent disease• Previously received a solid organ transplant; other than orthotopic liver transplantation (OLT)• Uncontrolled infection• Unable to follow or comply with the protocol for any reason• Second malignancy• Pregnant or breastfeeding women
Electronic Remote Data Entry (eRDE) - The PHITT Trial Online Database
• Log on to:www.chilternproject.eu
• Complete the Trial Entry Eligibility form online• System will allocate a TNO identifier and email a registration confirmation
Study Entry
Registration procedure (PHITT Database User Manual v1.0)
If the system is out of use, registration can be done by phoning the Trials Office on +44 (0) 121 415 1061 or +44 (0) 121 415 8211If registering by phone, return a copy of the Eligibility form to the trial office as soon as possible
PLEASE ENSURE THAT ALL PATIENT IDENTIFIERS (NAME, ADDRESS, AGE, SEX) ARE REMOVED FROM ALL CORRESPONDENCE
Treatment Group
Second Part Study Treatment ICF
Treatment group allocation
• All patients who will receive treatment• Patients who will not receive treatment (HB Grp A1 and
HCC Grp E1) only need to sign Study Entry Consent
• Informed consent must be obtained before any trial specific procedures can taken place
Treatment Group
Treatment Group Informed Consent (version 1.2 - 15 November 2018)
Treatment Group
Screening (within 28 days prior to treatment group allocation)
• Full physical examination (including blood pressure, weight, height and body surface area)• Performance status (Lansky or Karnofsky)• Blood tests:
Haematology Biochemistry: including serum creatinine and alpha-fetoprotein (AFP) Coagulation Hepatitis B and C serology Pregnancy test (serum or urine): if applicable
• Radiological assessments Tumour evaluation of primary tumour disease: MRI or CT Tumour evaluation of metastases: Chest CT
• Cardiology assessments: for Groups C, D, E and F (local institution assessment)• Tissue sample for Pathology/Biology studies• Blood samples for Pathology/Biology and Toxicity studies
• Written informed consent for study treatment• Score of ≥50% Lansky scale for patients <16 years, or Karnofsky scale for patients ≥16 years• For patients of reproductive potential, agreement to use adequate contraception for the
duration of the trial• Patient meets specific eligibility criteria for their allocated treatment group:
Treatment Group
Treatment Group Eligibility
Treatment Group
Treatment Group Eligibility - Specific eligibility criteriaGROUP TUMOUR RISK DEFINITION PATHOLOGY RENAL FUNCTION1 HAEMATOLOGY2 CARDIOLOGY3
A1 Resected Very Low Risk HBReal time review required–WDF histological result
N/A N/A N/A
A2 Resected Very Low Risk HBReal time review required– Non-WDF histological result
serum creatinine in the normal range OR GFR
≥60mL/min/1.73m2
ANC >0.75x109/L
Platelet count >75x109/L
PT <1.2x ULN
N/A
B1B2
N/A Low Risk HB N/A
serum creatinine in the normal range OR GFR
≥60mL/min/1.73m2
ANC >0.75x109/L
Platelet count >75x109/L
PT <1.2x ULN
N/A
C(all
treatments)
N/AIntermediate Risk HB
N/A
serum creatinine in the normal range OR GFR
≥60mL/min/1.73m2
ANC >0.75x109/L
Platelet count >75x109/L
PT <1.2x ULN
Shortening fraction ≥28% OR Ejection fraction ≥47%
D (all
treatments)
N/A High Risk HB N/A
serum creatinine in the normal range OR GFR
≥60mL/min/1.73m2
ANC >0.75x109/L
Platelet count >75x109/L
PT <1.2x ULN
Shortening fraction ≥28% OR Ejection fraction ≥47%
E1
Resected
HCC secondary to underlying liver disease
N/A N/A N/A N/A N/A
E2
Resected
HCC de novo, including fibrolamellar
N/A N/A
serum creatinine in the normal range OR GFR
≥60mL/min/1.73m2
ANC >0.75x109/L
Platelet count >75x109/L
PT <1.2x ULN
Shortening fraction ≥28% OR Ejection fraction ≥47%
FNot resected or metastatic HCC
N/A N/A
serum creatinine in the normal range OR GFR
≥60mL/min/1.73m2
ANC >0.75x109/L
Platelet count >75x109/L
PT <1.2x ULN
Shortening fraction ≥28% OR Ejection fraction ≥47%
Treatment Group
Treatment Group allocation
• Decision rests with responsible clinician, using the treatment group eligibility criteria
• Depends of disease (HB or HCC) and Risk group according to CHIC Risk Stratification.
• HB patients assessed according to CHIC risk group: Very Low Risk, Low Risk, Intermediate Risk, High Risk
• HCC will be grouped according to primary tumour resection.
• Assessment will be done by the patient’s trial doctor according to the Protocol and Eligibility criteria andrecorded on the Treatment Group Registration Form
Treatment Group
Treatment Group registration & Randomisation procedure (PHITT Database User Manual v1.0)
Electronic Remote Data Entry (eRDE)
• Log on to:www.chilternproject.eu
• Complete the Treatment Group Registration Form online• For Treatment Groups which contain an immediate randomisation step (Group C and F), also
complete a Randomisation Form• The system will carry out the randomised allocation based on the completion of a
Randomisation Form
If the system is out of use, registration and randomisation can be done by phoning the Trials Office on +44 (0) 121 415 1061 or +44 (0) 121 415 8211
Treatment
Treatment aimTherapy reductionResection at diagnosis withreduction of chemotherapyin WDF patients
Group A - Very Low Risk Hepatoblastoma (HB)
Treatment
*WDF: Well Differentiated Fetal
Treatment Group Allocation:Group A Very Low Risk
Group A1 - WDF HistologyNo Chemotherapy
Group A2 - Non WDF Histology2 Cycles Cisplatin
100mg/m² every 21 days
Central Pathological Review
Online Registration/Randomisation
Assessment
Treatment
Treatment aimTherapy reductionReduction number of Cisplatin cycles from 6 to 4
Treatment
Group B - Low Risk HBTreatment Group Allocation:
Group B Low Risk
2 cycles of Cisplatin 80mg/m2 every 14 days
Group B2Not resected
Group B1Resect
2 cycles of Cisplatin 80mg/m2 every 14 days
2 cycles of Cisplatin80mg/m2 every 14 days
Treat patient according to local guidelines
2 cycles of Cisplatin 80mg/m2 every 14
days
4 cycles of Cisplatin 80mg/m2 every 14
days
Consider surgery
Not resected Resect
Consider surgery
Randomisation
Online Registration/Randomisation
Surgery
Assessment
Treatment
Treatment
Group C - Intermediate Risk HB
Treatment
Group C - Intermediate Risk HB
Treatment
Group C - Intermediate Risk HB
Treatment aimTherapy reductionReduction DoxorubicinElimination 5-fluorouracil and Vincristine
Treatment
Group C - Intermediate Risk HB
Treatment
Group D - High Risk HB
Treatment aimValidate SIOPEL-4 treatment for rapid lung respondersImprove outcomes for slow lung responders withconsolidation
Treatment Group Allocation:Group D High Risk
SIOPEL-4 3 blocks Cisplatin/Doxorubicin
(Induction)
Consolidation: Group D1Carboplatin + Doxorubicin (CD)
3 cycles
Consolidation: Group D2 Carboplatin + Doxorubicin (CD)/ Carboplatin + Etoposide (CE)
alternate cyclesto a total of 6 cycles
Consolidation: Group D3 Carboplatin + Doxorubicin (CD) /
Vincristine + Irinotecan (VI) alternate cycles
to a total of 6 cycles
Metastatic Disease Cleared Metastatic Disease Persists
Surgery
Response Assessment
Randomisation
Online Registration/Randomisation
Surgery
Assessment
Treatment
Treatment
Group E - Resected Hepatocellular carcinoma (HCC)
Treatment aimDetermine role of PLADO in de novo HCC
Treatment Group Allocation:Group E
Group E1HCC secondary to underlying disease
No further treatment (Follow Up)
Group E2de novo HCC
PLADO 4 cycles
Surgery
Online Registration/Randomisation
Surgery
Treatment
Treatment aimCompare resectability and survival with interval-compressed PLADO + GEMOX
Treatment
Group F - Unresected / Metastatic HCC
Treatment
Study IMPs
• Routine hospital stock : stored and handled according to local institutional policy
• Treatment should be prepared and administered according to the relevant Summary of Product Characteristics (SmPC) and local practice unless the trial protocol requires otherwise
• Drug accountability can be done according to local practice - ensuring appropriate traceability
• Labels will be provided but sites may use own if in accordance with Annex 13 guidelines and national legislation. Sorafenib must be labelled at point of dispensing. IV IMPs may be labelled when IMP is designated as trial drug
• Pharmacy Manual (version 1.0) is provided
Treatment
• Upcoming STS supportive care Amendment to the PHITT protocol
Recommended for localized HB: Groups A, B, C
Investigator discretion Prohibited for the disseminated HB (Group D), Groups E and F
once hearing loss is present STS is not as effective (Neuwelt et al. 1998) upfront preventive use
• Named Patient Program : Fennec Pharma
STS as supportive care
Biological Samples (Lab Manual version 4.0)
Sampling process and shipments
• Sites provided with box containing: lab kits (tubes, forms), material required
• All shipments arranged and paid by the receiving lab
• Record receipt and shipment in www.chilternproject.eu
Biological Samples (Lab Manual version 4.0)
Biology & Pathology
To develop a large scale Europeanbiorepository: Childhood Liver Cancer Network (CLCN) collection
Biology samples to be stored in -80°C and shipped by batch to IGTP in Spain
* Collect bloodsamples just before
surgery (exceptGroup A - not
necessary)
Biological Samples (Lab Manual version 4.0)
Pathology: URGENT Review
MANDATORY: Group ARECOMMENDED:- Group D with AFP < 100ng/ml- Group E & F
International Pathologist
Shipment between 2-5 daysResults in 14 days
Samples for pathology review and pathology studies
Samples for biology studies
Biological Samples (Lab Manual version 4.0)
Pathology: STANDARD Review
Group B, C, D*, E* & F*
*Urgent review recommended(in D only if AFP<100ng/ml)
National Pathologist Review
Pr Mina KomutaService Anatomie PathologieTour Franklin -1Cliniques Universitaires Saint-LucAvenue Hippocrate 101200 Bruxelles
[email protected] +32 2 764 68 57
Contact NCC min. 24h before to organise the shipment
Biological Samples (Lab Manual version 4.0)
Pathology: At SURGERY
PDX only for patients (HIV, HBV & HCV neg):- Group D, E and F- Neg. AFP at Baseline and are not pure fœtal at diagnosis- Recurrent disease- SCU Histology
Biological Samples (Lab Manual version 4.0)
Toxicity sampling
Blood and urine samples collected from all patients receiving Cisplatin
• Pharmacogenetic1 whole blood 5mlprior to treatment
• Cardiac toxicity1 EDTA blood 5 mlpriot to treatment + ECG assessment
Biological Samples (Lab Manual version 4.0)
Toxicity sampling
• Pharmacokinetics* & kidney toxicity**
* PK on first and last treatment cycle** Kidney toxicity taken on 3 cycles of Cisplatin treatment
(including 1st and cycle immediately prior to surgery)
Pharmacovigilance
Adverse Events (AE)
• Only selected AEs (occurring during treatment and 30 days after the last treatment) are recordedon the Treatment Forms.
• SAEs of any kind should be recorded on the SAE form by the site SAEs must be reported by the site to the sponsor, University of Birmingham, immediately upon
knowledge of the event and within 24 hours. The site Investigator will define the causality and the severity of the AE which should be documented
using the CTCAE v4
• SAEs must be reported by faxing the SAE form and SAE fax cover sheet to the trial office on+44 (0) 121 414 9520 or +44 (0) 121 414 3700 (or at [email protected] if fax not available)
PLEASE ENSURE THAT ALL PATIENT IDENTIFIERS (NAME, ADDRESS, AGE, GENDER) ARE REMOVED FROM ALLCORRESPONDENCE.
Pharmacovigilance
Serious Adverse Events (SAE)
• Hospitalisation for:
Protocol defined treatment Pre-planned elective procedures unless the condition worsens Treatment for the symptoms/ progression of the patient’s cancer
• Progression or death as a result of the patient’s cancer
This information is captured elsewhere on the CRFs
Not to be reported on a SAE Form
Pharmacovigilance
• Neutropenia• Fever• Febrile neutropenia• Infections• Haematological toxicity (haemoglobin increased, lymphocyte count decreased, neutrophil count
decreased, platelet count decreased, white blood cell decreased, …)
• Gut toxicity (diarrhoea, nausea, vomiting, mucositis, …)
To be reported on an Expected Serious Adverse Reaction (SAR) Form - not on SAE Form(unless the condition is life threatening or proves fatal)
Expected SAR Forms (paper) should be completed and sent to the CRCTU as soon as possible via email.
Serious Adverse Events (SAE)
Data Collection (PHITT Trial Online Database User Manual version 1.0)
• Data entered into the PHITT online database:
www.chilternproject.eu
• Access (username and password) will be given by sponsor once site is activated
• CRF completion is aimed to be > 80%• Missing CRFS will be requested monthly by NCC• DCFs raised by sponsor
CLCN Kit Management
CLCN Kit Shipment/Reception
CLCN Kits shipmentlab kits sent to NCCNCC redistributes to sites
CLCN Kits redistribution Sample shipment
Data Collection (PHITT Trial Online Database User Manual version 1.0)
Monitoring
By Bimetra Clinics (UZ Gent) according to monitoring plan
Frequency• Only randomised patients need to be monitored (Groups B1, C, D2 and F)• Following the recruitment of the 1st patient• After completion of 2 treatment cycles and post cycle 2 tumour assessment of 1st patient• After 2 additional patients recruitment• If any particular reason for concern or in response to increased recruitment
Tasks• Investigator Site Files (ISF)• Review of completed ICFs, ICF procedure and patient recruitment• Eligibility criteria at registration and randomisation• Safety reporting (AE and SAE)• Study specific procedures• Drug accountability• Pharmacy
Monitoring
Contact person at Bimetra for monitoring:
Leen Geets
Bimetra - Clinical Research Centre Ghent-1K5 - Entrance 81 ‐route 810‐813De Pintelaan 1859000 Gent
[email protected] or [email protected] +32 9 332 05 01
• PHITT study is opened in Belgium
Approval Authorities: 08 June 2018
Approval Central Ethics Committee: 29 November 2018
• Intersite contract needs to be signed before patient first inclusion
• Current version of study documents (final versions will be sent to you):
Protocol version 2.0a - 17 January 2018
Informed Consent Forms version 1.2 - 15 November 2018
Parents, Patient 18y+, Children 12-17y, Children 8-11y
Study Entry and Study Treatment groups A-F
Lab Manual version 4.0 - 28 August 2018 , Biological Samples Schedule version 1.0 - 21 July 2017
Pathology Guidelines version 2.0 - 01 December 2017
Pharmacy Manual version 1.0 - 11 April 2017
• Sponsor will provide access to eCRF
• Please, further train the staff of your center
Start-up: update
Paediatric Hepatic International Tumour Trial
Thanks for your attention!