Paediatric Hepatic International Tumour Trial

NCT03017326 | Active Not Recruiting Phase 3 DMC

• 1 other identifier: RG_15-114
• Study Type: interventional
• Target: 450
• Locations: 14 countries
• Sites: 32

Brief Summary

The PHITT trial is an over-arching study for patients with Hepatoblastoma (HB) and Hepatocellular Carcinoma (HCC). This trial will use a risk-adapted approach to the treatment of children diagnosed with HB. Children with HCC will be included as a separate cohort.

Conditions

Hepatoblastoma; Carcinoma, Hepatocellular

Outcome Measures

Primary Outcomes (2)

• Event-free survival (EFS)

  Event-free survival (EFS) is defined as the time from randomisation (or registration into the trial for non-randomised patients) to 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.

  From date of randomisation (or registration into the trial for non-randomised patients), until date of first failure event, assessed up to 6 years.

• Response in HCC is defined as complete (CR) or partial (PR) response according to RECIST version 1.1 criteria

  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 who are not assessable for response - e.g. because of early stopping of treatment or death - will be assumed to be non-responders.

  From date of screening assessment until date of first response assessment, up to 63 days in Group F

Secondary Outcomes (8)

• Failure-free survival (FFS)

  From date of randomisation (or registration into the trial for non-randomised patients) until date of first failure event, or date of last follow up assessment, assessed up to 6 years.

• Overall survival (OS)

  From date of randomisation (or registration for non-randomised patients) until date of death from any cause, or date of last follow up assessment, assessed up to 6 years.

• Toxicity categorized and graded using Common Terminology Criteria for Adverse Events (CTCAE)

  From date of start of randomised treatment until date 30 days after last treatment.

• Chemotherapy-related cardiac, nephro- and oto-toxicity using Common Terminology Criteria for Adverse Events (CTCAE)

  From date of start of randomised treatment until date 30 days after last treatment.

• Hearing loss according to the SIOP Boston Scale

  From date of registration until date of last follow up assessment, or date of death, assessed up to 6 years.

Study Arms (6)

Group A Very Low Risk HB

OTHER

Patients with well differentiated foetal histology will receive 2 cycles of Cisplatin (2x 100mg/m2). Patients will non-well differentiated histology will be followed up only (no intervention).

Drug: Cisplatin

Group B Low Risk HB

ACTIVE COMPARATOR

Patients who are resected after 2 cycles of Cisplatin will be randomised to receive 4 or 6 cycles of Cisplatin overall (80mg/m2). Patients who are not resected will continue to receive up to 6 cycles of Cisplatin (80mg/m2) until resection.

Drug: Cisplatin

Group C Intermediate Risk HB

ACTIVE COMPARATOR

Patients will be randomised to receive Cisplatin (80mg/m2), Carboplatin (500mg/m2) and Doxorubicin (60mg/m2) as SIOPEL-3HR (5 cycles), Cisplatin (100mg/m2), Doxorubicin (60mg/m2) 5-Fluorouracil (600mg/m2) and Vincristine (4.5mg/m2) as C5VD (6 cycles), or 6 cycles of high dose Cisplatin (100mg/m2)

Drug: Cisplatin; Drug: Doxorubicin; Drug: Carboplatin; Drug: 5Fluorouracil; Drug: Vincristine

Group D High Risk HB

ACTIVE COMPARATOR

Patients will receive SIOPEL-4 regimen (Cisplatin 70mg/m2, Doxorubicin 30mg/m2) then have surgery. Post surgery, patients with remaining metastases will be randomised to receive 6 cycles of either Carboplatin (500mg/m2) and Doxorubicin (40mg/m2) alternating with Carboplatin (800mg/m2) and Etoposide (400mg/m2), or Carboplatin (500mg/m2) and Doxorubicin (40mg/m2) alternating with Vincristine (3mg/m2) and Irinotecan (250mg/m2). Patients with no metastases will receive the standard treatment of 3 cycles of Carboplatin (500mg/m2) and Doxorubicin (40mg/m2).

Drug: Cisplatin; Drug: Doxorubicin; Drug: Carboplatin; Drug: Vincristine; Drug: Etoposide; Drug: Irinotecan

Group E Resected HCC

OTHER

Patients with an underlying predisposition to HCC through genetic, viral or metabolic conditions will be followed up (no intervention). De novo or fibrolamellar HCC patients will receive 4 cycles of PLADO regimen (Cisplatin (80mg/m2) and Doxorubicin (60mg/m2)) over 4 cycles.

Drug: Cisplatin; Drug: Doxorubicin

Group F Unresected HCC

ACTIVE COMPARATOR

Patients will be randomised to receive up to 6 cycles of PLADO (Cisplatin 80mg/m2, Doxorubicin 60mg/m2) with Sorafenib (300mg/m2) or up to 8 cycles of PLADO with Sorafenib and GEMOX (Gemcitabine 1000mg/m2, Oxaliplatin 100mg/m2) with Sorafenib (300mg/m2)

Drug: Cisplatin; Drug: Doxorubicin; Drug: Gemcitabine; Drug: Oxaliplatin; Drug: Sorafenib

Interventions

Cisplatin DRUG

Arms A and B - cisplatin is used alone Arms C, D, E and F - cisplatin us used in combination

Group A Very Low Risk HB; Group B Low Risk HB; Group C Intermediate Risk HB; Group D High Risk HB; Group E Resected HCC; Group F Unresected HCC

Doxorubicin DRUG

Arms C, D and E used in combination

Group C Intermediate Risk HB; Group D High Risk HB; Group E Resected HCC; Group F Unresected HCC

Carboplatin DRUG

Arms C and D used in combination

Group C Intermediate Risk HB; Group D High Risk HB

5Fluorouracil DRUG

Arm C used alone

Group C Intermediate Risk HB

Vincristine DRUG

Arms C and D used in combination

Group C Intermediate Risk HB; Group D High Risk HB

Etoposide DRUG

Arm D used in combination

Group D High Risk HB

Irinotecan DRUG

Arm D used in combination

Group D High Risk HB

Gemcitabine DRUG

Arm F used in combination

Group F Unresected HCC

Oxaliplatin DRUG

Arm F used in combination

Group F Unresected HCC

Sorafenib DRUG

Arm used in combination

Group F Unresected HCC

Eligibility Criteria

• Age: Up to 30 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Clinical diagnosis of HB\* and histologically defined diagnosis of HB or HCC.
• \*Histological confirmation of HB is required except in emergency situations where:
• a) the patient meets all other eligibility criteria, but is too ill to undergo a biopsy safely, the patient may be enrolled without a biopsy.
• b) there is anatomic or mechanical compromise of critical organ function by tumour (e.g., respiratory distress/failure, abdominal compartment syndrome, urinary obstruction, etc.)
• c) Uncorrectable coagulopathy
• Age ≤30 years
• Written informed consent for trial entry

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Birmingham: lead
• Fundació Institut Germans Trias i Pujol: collaborator
• University Hospital Munich: collaborator
• University Hospital, Bonn: collaborator
• University of Kiel: collaborator
• University Hospital Tuebingen: collaborator
• University of Padova: collaborator
• Ludwig-Maximilians - University of Munich: collaborator
• Medical University of Gdansk: collaborator
• Cliniques universitaires Saint-Luc- Université Catholique de Louvain: collaborator
• Motol University Hospital: collaborator
• Rennes University Hospital: collaborator
• Children's University Hospital, Ireland: collaborator
• University of Oslo: collaborator
• Princess Maxima Center for Pediatric Oncology: collaborator
• Andaluz Health Service: collaborator
• Swiss Pediatric Oncology Group: collaborator
• Gothia Forum - Center for Clinical Trial: collaborator
• The Leeds Teaching Hospitals NHS Trust: collaborator
• Bambino Gesù Hospital and Research Institute: collaborator
• Newcastle University Centre for Cancer, Newcastle: collaborator
• Experimental Cancer Medicine Centres: collaborator
• XenTech, Evry: collaborator

Study Sites (32)

St. Anna Kinderspital

Vienna, 1090, Austria

Location

Cliniques Universitaires Saint-Luc

Brussels, Woluwe-Saint-Lambert, 1200, Belgium

Location

University Hospital Motol

Prague, 150 06 Prague 5, Czechia

Location

Kuopio University Hospital

Kuopio, FI20029 KYS, Finland

Location

CHU de Rennes

Rennes, 35033, France

Location

Ludwig-Maximillians-University Munich

Munich, 80337 Munich, Germany

Location

Children's Health Ireland Crumlin

Dublin, 12 N512, Ireland

Location

Schneider Children's Medical Center

Petah Tikva, 4920235, Israel

Location

Prinses Maxima Center

Utrecht, 3584 CS, Netherlands

Location

Oslo University Hospital

Nydalen, 0424 Oslo, Norway

Location

Medical University of Gdansk

Gdansk, 80-803, Poland

Location

University Hospital Reina Sofia

Córdoba, 14004, Spain

Location

Hopitaux Universitaires de Geneve

Geneva, CH 1211, Switzerland

Location

Royal Aberdeen Children's Hospital

Aberdeen, AB25 2ZG, United Kingdom

Location

Royal Belfast Hospital for Sick Children

Belfast, BT12 6BE, United Kingdom

Location

Birmingham Children's Hospital

Birmingham, B4 6NH, United Kingdom

Location

Bristol Royal Hospital for Children

Bristol, BS2 8BJ, United Kingdom

Location

Addenbrooke's Hospital

Cambridge, CB2 0QQ, United Kingdom

Location

Noah's Ark Children's Hospital for Wales

Cardiff, CF14 4XW, United Kingdom

Location

Royal Hospital for Children

Edinburgh, EH9 1LW, United Kingdom

Location

Royal Hospital for Children

Glasgow, G51 4TF, United Kingdom

Location

Leeds General Infirmary

Leeds, LS1 3EX, United Kingdom

Location

Leicester Royal Infirmary

Leicester, LE1 5WW, United Kingdom

Location

Alder Hey Children's Hospital

Liverpool, L12 2AP, United Kingdom

Location

Great Ormond Street Hospital

London, WC1N 3JH, United Kingdom

Location

Royal Manchester Children's Hospital

Manchester, M13 9WL, United Kingdom

Location

Great North Children's Hospital

Newcastle upon Tyne, NE1 4LP, United Kingdom

Location

Nottingham Children's Hospital

Nottingham, NG7 2UH, United Kingdom

Location

Oxford Children's Hospital

Oxford, OX3 9DU, United Kingdom

Location

Sheffield Children's Hospital

Sheffield, S10 2TH, United Kingdom

Location

University Hospital Southampton

Southampton, SO16 6YD, United Kingdom

Location

The Royal Marsden Hospital

Sutton, SM2 5PT, United Kingdom

Location

MeSH Terms

Conditions

Hepatoblastoma; Carcinoma, Hepatocellular

Interventions

Cisplatin; Doxorubicin; Carboplatin; Fluorouracil; Vincristine; Etoposide; Irinotecan; Gemcitabine; Oxaliplatin; Sorafenib

Condition Hierarchy (Ancestors)

Neoplasms, Complex and Mixed; Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Intervention Hierarchy (Ancestors)

Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Coordination Complexes; Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Glucosides; Camptothecin; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Phenylurea Compounds; Urea; Amides; Benzene Derivatives; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Pyridines

Study Officials

• Madhumita Dandapani, MD PhD

  University of Nottingham

  PRINCIPAL INVESTIGATOR

• Marc Ansari, MD

  University of Geneva

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 14, 2016
• First Posted: January 11, 2017
• Study Start: August 24, 2017
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): August 1, 2027
• Last Updated: May 13, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will not share

Locations

AU (1); IE (1); NO (1); CH (1); FI (1); IL (1); NL (1); ES (1); BE (1); CZ (1); PL (1); FR (1); DE (1); GB (19)