Paediatric Hepatic International Tumour Trial (PHITT)

University of Birmingham

Status and phase: Active, not recruiting; Phase 3

Conditions: Carcinoma, Hepatocellular; Hepatoblastoma

Treatments: Drug: Oxaliplatin; Drug: Doxorubicin; Drug: Carboplatin; Drug: Sorafenib; Drug: Etoposide; Drug: Irinotecan; Drug: Vincristine; Drug: Cisplatin; Drug: Gemcitabine; Drug: 5Fluorouracil

Study type: Interventional

Funder types: Other

Identifiers

NCT03017326

RG_15-114

Details and patient eligibility

About

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.

Full description

The trial will evaluate whether reducing treatment for low risk HB patients maintains their excellent event free survival (EFS) and decreases acute and long-term toxicity. Intensification of therapy with the use of novel agents will be evaluated in the high risk group. The trial will also compare three different regimens in intermediate risk HB.

Patients with HCC will be divided into groups based on whether the tumour is resectable or unresectable and/or metastatic.

Evaluation of the biology of HB and HCC, using the identification/validation of novel and already reported prognostic biomarkers as well as toxicity biomarkers is a key strand of this trial, so patients in all risk groups can be registered. The trial is also designed to optimise the collection of clinically annotated biologic specimens and establish the world's largest repository of blood and tissue samples from paediatric patients with HB and HCC.

The trial includes 4 randomised comparisons addressing therapeutic questions. For low risk HB patients, outcome with a total of 4 cycles of treatment is not inferior to those receiving a total of 6 cycles of treatment.

For intermediate risk patients, 3 regimens will be compared for outcome and toxicity.

For high risk patients, 2 post induction regimens will be compared for outcome. For resected HCC patients, the addition of GEMOX to PLADO regimen will be compared.

In addition the following will be assessed:

• To validate a new global risk stratification, defined by Children's Hepatic Tumours International Collaboration (CHIC)

• To evaluate clinically relevant factors, including the following:

  • Provide a comprehensive and highly-validated panel of diagnostic and prognostic biomarkers
  • Determine if paediatric HCC is a biologically different entity to adult HCC
  • Develop genomic and/or biomarker analysis to predict children who may have an increased risk of developing toxicity with chemotherapy.

• To establish a collection of clinically and pathologically-annotated biological samples.

• Evaluate a surgical planning tool for an impact on decision making processes in POST-TEXT III and IV HB

Enrollment: 450 estimated patients

Sex: All

Ages: Under 30 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• 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

Exclusion criteria

• 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Factorial Assignment

Masking: None (Open label)

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450 participants in 6 patient groups

Group A Very Low Risk HB

Other group

Description:

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).

Treatment:

Drug: Cisplatin

Group B Low Risk HB

Active Comparator group

Description:

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.

Treatment:

Drug: Cisplatin

Group C Intermediate Risk HB

Active Comparator group

Description:

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)

Treatment:

Drug: Carboplatin

Drug: Doxorubicin

Drug: Cisplatin

Drug: 5Fluorouracil

Drug: Vincristine

Group D High Risk HB

Active Comparator group

Description:

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).

Treatment:

Drug: Carboplatin

Drug: Doxorubicin

Drug: Etoposide

Drug: Cisplatin

Drug: Irinotecan

Drug: Vincristine

Group E Resected HCC

Other group

Description:

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.

Treatment:

Drug: Doxorubicin

Drug: Cisplatin

Group F Unresected HCC

Active Comparator group

Description:

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)

Treatment:

Drug: Doxorubicin

Drug: Cisplatin

Drug: Oxaliplatin

Drug: Gemcitabine

Drug: Sorafenib