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Paediatric Hepatic International Tumour Trial (PHITT)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03017326
Recruitment Status : Recruiting
First Posted : January 11, 2017
Last Update Posted : May 19, 2022
Sponsor:
Collaborators:
Fundació Institut Germans Trias i Pujol
University of Padova
University of Newcastle Upon-Tyne
University Hospital Munich
University Hospital, Bonn
University of Kiel
University Hospital Tuebingen
Medical University of Gdansk
Information provided by (Responsible Party):
University of Birmingham

Tracking Information
First Submitted Date  ICMJE December 14, 2016
First Posted Date  ICMJE January 11, 2017
Last Update Posted Date May 19, 2022
Actual Study Start Date  ICMJE August 24, 2017
Estimated Primary Completion Date December 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 10, 2017)
  • Event-free survival (EFS) [ Time Frame: From date of randomisation (or registration into the trial for non-randomised patients), until date of first failure event, assessed up to 6 years. ]
    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.
  • Response in HCC is defined as complete (CR) or partial (PR) response according to RECIST version 1.1 criteria [ Time Frame: From date of screening assessment until date of first response assessment, up to 63 days in Group F ]
    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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 10, 2017)
  • Failure-free survival (FFS) [ Time Frame: 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. ]
    Failure-free survival (FFS) 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. failure to go to resection.
  • Overall survival (OS) [ Time Frame: 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. ]
    Overall survival (OS) is defined as the time from randomisation (or registration for non-randomised patients) to death from any cause. Patients who have not died will be censored at their last follow-up date.
  • Toxicity categorized and graded using Common Terminology Criteria for Adverse Events (CTCAE) [ Time Frame: From date of start of randomised treatment until date 30 days after last treatment. ]
    Toxicity will be recorded in relation to each cycle of randomised treatment and will be categorized and graded using Common Terminology Criteria for Adverse Events (CTCAE)
  • Chemotherapy-related cardiac, nephro- and oto-toxicity using Common Terminology Criteria for Adverse Events (CTCAE) [ Time Frame: From date of start of randomised treatment until date 30 days after last treatment. ]
    Chemotherapy-related cardiac, nephro- and oto-toxicity will be recorded in relation to each cycle of treatment and will be categorized and graded using Common Terminology Criteria for Adverse Events (CTCAE)
  • Hearing loss according to the SIOP Boston Scale [ Time Frame: From date of registration until date of last follow up assessment, or date of death, assessed up to 6 years. ]
    Hearing loss will be measured according to the SIOP Boston Scale for oto-toxicity. The assessment will be performed at end of treatment (EOT) and follow up
  • Best Response [ Time Frame: From date of first treatment until the date of last treatment, or until the date of first documented progression or date of death, assessed up to 6 months. ]
    Best Response is defined as CR or PR and is based on radiological response (RECIST v1.1) and Alpha Fetoprotein (AFP) decline. Best Response will be measured throughout treatment period. 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 defined as complete resection, partial resection or transplant [ Time Frame: From date of registration until date of last follow up assessment, or date of death, assessed up to 6 years. ]
    Surgical resectability is defined as complete resection, partial resection or transplant
  • Adherence to surgical guidelines [ Time Frame: From date of registration until date of last follow up assessment, or date of death, assessed up to 6 years. ]
    Adherence to surgical guidelines is defined as the local clinician's surgical decision to resect or not compared to the current SIOPEL surgical guidelines.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Paediatric Hepatic International Tumour Trial
Official Title  ICMJE Paediatric Hepatic International Tumour Trial
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.

Detailed 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
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Hepatoblastoma
  • Carcinoma, Hepatocellular
Intervention  ICMJE
  • Drug: Cisplatin
    Arms A and B - cisplatin is used alone Arms C, D, E and F - cisplatin us used in combination
  • Drug: Doxorubicin
    Arms C, D and E used in combination
  • Drug: Carboplatin
    Arms C and D used in combination
  • Drug: 5Fluorouracil
    Arm C used alone
  • Drug: Vincristine
    Arms C and D used in combination
  • Drug: Etoposide
    Arm D used in combination
  • Drug: Irinotecan
    Arm D used in combination
  • Drug: Gemcitabine
    Arm F used in combination
  • Drug: Oxaliplatin
    Arm F used in combination
  • Drug: Sorafenib
    Arm used in combination
Study Arms  ICMJE
  • Group A Very Low Risk HB
    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).
    Intervention: Drug: Cisplatin
  • Active Comparator: Group B Low Risk HB
    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.
    Intervention: Drug: Cisplatin
  • Active Comparator: Group C Intermediate Risk HB
    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)
    Interventions:
    • Drug: Cisplatin
    • Drug: Doxorubicin
    • Drug: Carboplatin
    • Drug: 5Fluorouracil
    • Drug: Vincristine
  • Active Comparator: Group D High Risk HB
    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).
    Interventions:
    • Drug: Cisplatin
    • Drug: Doxorubicin
    • Drug: Carboplatin
    • Drug: Vincristine
    • Drug: Etoposide
    • Drug: Irinotecan
  • Group E Resected HCC
    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.
    Interventions:
    • Drug: Cisplatin
    • Drug: Doxorubicin
  • Active Comparator: Group F Unresected HCC
    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)
    Interventions:
    • Drug: Cisplatin
    • Drug: Doxorubicin
    • Drug: Gemcitabine
    • Drug: Oxaliplatin
    • Drug: Sorafenib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 10, 2017)
300
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2025
Estimated Primary Completion Date December 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 30 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Jennifer Laidler, BSc (hons) 0121 4151061 phitt@trials.bham.ac.uk
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03017326
Other Study ID Numbers  ICMJE RG_15-114
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Current Responsible Party University of Birmingham
Original Responsible Party Same as current
Current Study Sponsor  ICMJE University of Birmingham
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE
  • Fundació Institut Germans Trias i Pujol
  • University of Padova
  • University of Newcastle Upon-Tyne
  • University Hospital Munich
  • University Hospital, Bonn
  • University of Kiel
  • University Hospital Tuebingen
  • Medical University of Gdansk
Investigators  ICMJE
Principal Investigator: Bruce Morland, MD PhD University of Birmingham
PRS Account University of Birmingham
Verification Date May 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP