Paediatric Hepatic International Tumour Trial

• Register: EUCTR
• Last refreshed on: 1 February 2020
• Main ID: EUCTR2016-002828-85-AT
• Date of registration: 24/07/2019
• Prospective Registration: Yes
• Primary sponsor: University of Birmingham
• Public title: Paediatric Hepatic International Tumour Trial
• Scientific title: Paediatric Hepatic International Tumour Trial - PHITT
• Date of first enrolment: 17/09/2019
• Target sample size: 300
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-002828-85
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: yes; Placebo: no; Other: no; Number of treatment arms in the trial: 6
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Austria, Belgium, Czech Republic, France, Germany, Ireland, Italy, Netherlands, Norway, Poland, Spain, Sweden, Switzerland, United Kingdom

Contacts

• Name: Sean Jennings
• Affiliation: University of Birmingham

• Name: Sean Jennings
• Affiliation: University of Birmingham

Key inclusion & exclusion criteria

Inclusion criteria:
For Trial Entry:
• Clinical diagnosis of HB or histologically defined diagnosis of HB or HCC.
• Age =30 years
• Written informed consent for trial entry

For Allocation/Randomisation to Treatment Group:
All Groups
• Written Informed Consent for trial treatment participation
• Patient assessed as fit to receive group specific treatment
• For females of child-bearing potential, a negative pregnancy test prior to trial entry is required. Any patient who is of reproductive age must agree to use adequate contraception for the duration of the trial.

Group A (no treatment arm)
At diagnosis:
• Resected Tumour.
• Patient meets Very Low Risk definition according to CHIC guidelines.
Group A1 – No treatment arm
• Central pathology review confirming WDF histology.
Group A2 - Treatment arm
• Central pathology review confirming non-WDF histology.
• Adequate renal function determined by:
o Serum creatinine in the normal range based on age appropriate local reference values or glomerular filtration rate (GFR) =60mL/min/1.73m2
• Adequate haematology:
o Absolute neutrophil count (ANC) >0.75 x 109/L
o Platelet count >75 x 109/L
o Prothrombin time (PT) <1.2x ULN for age-based local reference values

Group B
• Patient meets Low Risk definition according to CHIC Guidelines
• Adequate renal function determined by:
o Serum creatinine in the normal range based on age appropriate local reference values or glomerular filtration rate (GFR) =60mL/min/1.73m2
• Adequate haematology:
o Absolute neutrophil count (ANC) >0.75 x 109/L
o Platelet count >75 x 109/L
o Prothrombin time (PT) <1.2x ULN for age-based local reference values

Group C
• Patient meets Intermediate Risk definition according to CHIC Guidelines
• Adequate renal function determined by:
o Serum creatinine in the normal range based on age appropriate local reference values or glomerular filtration rate (GFR) =60mL/min/1.73m2
• Adequate cardiac function determined by:
o Shortening fraction =28% by local assessment method
o OR Ejection fraction =47% by local assessment method
• Adequate haematology:
o Absolute neutrophil count (ANC) >0.75 x 109/L
o Platelet count >75 x 109/L
o Prothrombin time (PT) <1.2x ULN for age-based local reference values

Group D
• Patient meets High Risk definition according to CHIC Guidelines
• Adequate renal function determined by:
o Serum creatinine in the normal range based on age appropriate local reference values or glomerular filtration rate (GFR) =60mL/min/1.73m2
• Adequate cardiac function determined by:
o Shortening fraction =28% by local assessment method

Exclusion criteria:
• Any previous chemotherapy or currently receiving anti-cancer agents
• Recurrent disease
• Previously received a solid organ transplant
• Uncontrolled infection
• Unable to follow the protocol for any reason
• Second malignancy
• Pregnant or breastfeeding women



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Hepatoblastoma and Hepatocellular Carcinoma.
MedDRA version: 20.0 Level: PT Classification code 10062001 Term: Hepatoblastoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 20.0 Level: LLT Classification code 10019828 Term: Hepatocellular carcinoma non-resectable System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 20.0 Level: LLT Classification code 10019830 Term: Hepatocellular carcinoma resectable System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Product Name: Cisplatin
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Cisplatin
CAS Number: 15663-27-1
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 1-

Product Name: Carboplatin
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Carboplatin
CAS Number: 41575-94-4
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 10-

Product Name: Doxorubicin
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Doxorubicin hydrochloride
CAS Number: 25316-40-9
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 2-

Product Name: Etoposide
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Etoposide
CAS Number: 33419-42-0
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 20-

Product Name: Fluorouracil
Pharmaceutical Form: Solution for injection/infusion
INN or Proposed INN: Fluorouracil
CAS Number: 51-21-8
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 50-

Produc

Primary Outcome(s)

Secondary Objective: - to report event free survival in all patient groups
- to evaluate prognostic factors, including the following:
> to provide a comprehensive and highly validated panel of diagnostic and prognostic biomarkers
> to determine if paediatric HCC is a biologically different entity to adult HCC
> to validate prospectively a clinical risk stratification
> to develop genomic and/or biomarker analysis to predict children who may have an increased risk of developing toxicity with chemotherapy

Primary end point(s): Event Free Survival (EFS) as defined as the time from randomisation (or registration into the trial for non-randomised patients) to the first failure event. Patients who have not had an event will be censored at their last follow-up date.
Failure events are:
• progression of existing disease or occurrence of disease at new sites,
• death from any cause prior to disease progression,
• diagnosis of a second malignant neoplasm.

Response in HCC is defined as complete (CR) or partial (PR) response according to RECIST version 1.1 criteria. The assessment will be performed after 3 cycles of PLADO, or 4 cycles of PLADO+S/GEMOx+S in Group F patients. Patients who are not assessable for response, e.g. because of early stopping of treatment or death, will be assumed to be non-responders.

Timepoint(s) of evaluation of this end point: Evaluation of EFS will be until first failure event.
Evaluation of Response in HCC will be until end of treatment.

Main Objective: - To evaluate if the outcome with 4 cycles of treatment is not inferior to the outcome with 6 cycles of treatment, for patients with Low Risk HB, resectable tumours.
- To compare outcome and toxicity in patients with Intermediate Risk HB, treated with one of three treatment regimens: C5VD (cisplatin/5-fluorouracil/vincristine/doxorubicin), SIOPEL-3 high risk (cisplatin, carboplatin and doxorubicin) and cisplatin monotherapy.
- To compare the outcomes in patients with High Risk HB with metastatic disease, treated with one of two post induction treatments (carboplatin and doxorubicin alternating with carboplatin and etoposide, carboplatin and doxorubicin alternating with vincristine and irinotecan)
- to determine whether the addition of gemcitabine and oxaliplatin (GEMOX) to cisplatin, doxorubicin and sorafenib improves outcome in unresectable HCC patients
- to collect biology in all HB and HCC patients

Secondary Outcome(s)

Secondary end point(s): Failure-Free Survival (FFS) is defined as per EFS (primary endpoint above) with the addition of failure to go to resection.
Overall Survival (OS) is defined as the time from randomisation (or registration for non-randomised patients) to death from any cause.
Toxicity will be recorded in relation to each cycle of randomised treatment and will be categorised and graded using Common Terminology Criteria for Adverse Events (CTCAE)
Chemotherapy-related cardiac, nephro- and oto- toxicity will be recorded in relation to each cycle of non-randomised treatment and will be categorised by CTCAE.
Hearing loss is defined as Grade 4 Boston grade oto-toxicity compared to baseline.
Best Response is defined as Complete Response (CR) or Partial Response (PR) and is defined in the protocol based on radiological (RECIST) response and AFP decline.Patients who are not assessable for response (e.g. because of early stopping of treatment or death) will be assumed to be non-responders.
Surgical resectability id defined as complete resection, partial resection or transplant following randomisation (or enrolement for non-randomised patients).
Adherence to surgical guidelines is defined as the local clinician's surgical decision to resect or not compared to the current SIOPEL surgical guidelines.

Timepoint(s) of evaluation of this end point: Evaluation of FFS will be until first failure event, including failure to resect.
Evaluation of OS and Best Response will be until the last follow up.
Evaluation of Toxicity and Chemotherapy-related toxicity will be until 30 days after End of Treatment.
Evaluation of Hearing Loss, Surgical resectability and Adherence to surgical guidelines will be until End of Treatment.

Secondary ID(s)

2016-002828-85-GB

RG_15-114

NCT03017326

Source(s) of Monetary Support

European Commission

Ethics review

Status: Approved
Approval date: 17/09/2019
Contact: