Paediatric Hepatic International Tumour T · • Patients who will not receive treatment (HB Grp A1 and HCC Grp E1) only need to sign Study Entry Consent • Informed consent must

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

[email protected]

+44 (0)121 415 1061

General Information

Sponsor

mailto:[email protected]

Study Coordinators

Gaëlle Dufour

[email protected] +32 2 764 23 13

Mathilde Deligne, Caroline Martin, Michel Vanden Eynden

[email protected]

+32 2 764 23 76

General Information

National Coordinating Center (NCC): UCL Saint-Luc

Principal investigator

Pr Bénédicte Brichard

[email protected]

+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


≥60mL/min/1.73m2

ANC >0.75x109/L


PT <1.2x ULN

N/A

C(all

treatments)

N/AIntermediate Risk HB

N/A


≥60mL/min/1.73m2

ANC >0.75x109/L


PT <1.2x ULN

Shortening fraction ≥28% OR Ejection fraction ≥47%

D (all

treatments)

N/A High Risk HB N/A


≥60mL/min/1.73m2

ANC >0.75x109/L


PT <1.2x ULN


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


≥60mL/min/1.73m2

ANC >0.75x109/L


PT <1.2x ULN


FNot resected or metastatic HCC

N/A N/A


≥60mL/min/1.73m2

ANC >0.75x109/L


PT <1.2x ULN


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


Surgery

Assessment

Treatment

Treatment

Group C - Intermediate Risk HB

Treatment


Treatment


Treatment aimTherapy reductionReduction DoxorubicinElimination 5-fluorouracil and Vincristine

Treatment


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


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


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

http://www.chilternproject.eu/


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)


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


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



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


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


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.

https://webmail.saintluc.be/owa/redir.aspx?C=iiYwmraROqolLEgDsaxuwweReZ3MmKw-OVZG4qBuVgcwoUB-UYXWCA..&URL=mailto:[email protected]

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

http://www.chilternproject.eu/

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!

Documents

Paediatric Hepatic International Tumour T · • Patients who will not receive treatment (HB Grp A1 and HCC Grp E1) only need to sign Study Entry Consent • Informed consent must