<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03017326</url>
  </required_header>
  <id_info>
    <org_study_id>RG_15-114</org_study_id>
    <nct_id>NCT03017326</nct_id>
  </id_info>
  <brief_title>Paediatric Hepatic International Tumour Trial</brief_title>
  <acronym>PHITT</acronym>
  <official_title>Paediatric Hepatic International Tumour Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Birmingham</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Fundació Institut Germans Trias i Pujol</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University Hospital Munich</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University Hospital, Bonn</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Kiel</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University Hospital Tuebingen</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Padova</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Ludwig-Maximilians - University of Munich</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Medical University of Gdansk</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Cliniques universitaires Saint-Luc- Université Catholique de Louvain</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Motol University Hospital, Prague</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Rennes University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Children's University Hospital, Ireland</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Oslo</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Princess Maxima Center for Pediatric Oncology</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Andaluz Health Service</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Swiss Pediatric Oncology Group</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Gothia Forum - Center for Clinical Trial</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>St James's University Hospital, Leeds</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Bambino Gesù Hospital and Research Institute</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Newcastle University Centre for Cancer, Newcastle</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Experimental Cancer Medicine Centres</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>XenTech, Evry</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Birmingham</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The PHITT trial is an over-arching study for patients with Hepatoblastoma (HB) and&#xD;
      Hepatocellular Carcinoma (HCC). This trial will use a risk-adapted approach to the treatment&#xD;
      of children diagnosed with HB.&#xD;
&#xD;
      Children with HCC will be included as a separate cohort.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The trial will evaluate whether reducing treatment for low risk HB patients maintains their&#xD;
      excellent event free survival (EFS) and decreases acute and long-term toxicity.&#xD;
      Intensification of therapy with the use of novel agents will be evaluated in the high risk&#xD;
      group. The trial will also compare three different regimens in intermediate risk HB.&#xD;
&#xD;
      Patients with HCC will be divided into groups based on whether the tumour is resectable or&#xD;
      unresectable and/or metastatic.&#xD;
&#xD;
      Evaluation of the biology of HB and HCC, using the identification/validation of novel and&#xD;
      already reported prognostic biomarkers as well as toxicity biomarkers is a key strand of this&#xD;
      trial, so patients in all risk groups can be registered. The trial is also designed to&#xD;
      optimise the collection of clinically annotated biologic specimens and establish the world's&#xD;
      largest repository of blood and tissue samples from paediatric patients with HB and HCC.&#xD;
&#xD;
      The trial includes 4 randomised comparisons addressing therapeutic questions. For low risk HB&#xD;
      patients, outcome with a total of 4 cycles of treatment is not inferior to those receiving a&#xD;
      total of 6 cycles of treatment.&#xD;
&#xD;
      For intermediate risk patients, 3 regimens will be compared for outcome and toxicity.&#xD;
&#xD;
      For high risk patients, 2 post induction regimens will be compared for outcome. For resected&#xD;
      HCC patients, the addition of GEMOX to PLADO regimen will be compared.&#xD;
&#xD;
      In addition the following will be assessed:&#xD;
&#xD;
        -  To validate a new global risk stratification, defined by Children's Hepatic Tumours&#xD;
           International Collaboration (CHIC)&#xD;
&#xD;
        -  To evaluate clinically relevant factors, including the following:&#xD;
&#xD;
             -  Provide a comprehensive and highly-validated panel of diagnostic and prognostic&#xD;
                biomarkers&#xD;
&#xD;
             -  Determine if paediatric HCC is a biologically different entity to adult HCC&#xD;
&#xD;
             -  Develop genomic and/or biomarker analysis to predict children who may have an&#xD;
                increased risk of developing toxicity with chemotherapy.&#xD;
&#xD;
        -  To establish a collection of clinically and pathologically-annotated biological samples.&#xD;
&#xD;
        -  Evaluate a surgical planning tool for an impact on decision making processes in&#xD;
           POST-TEXT III and IV HB&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">August 24, 2017</start_date>
  <completion_date type="Anticipated">December 2025</completion_date>
  <primary_completion_date type="Anticipated">December 2024</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Factorial Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Event-free survival (EFS)</measure>
    <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.</time_frame>
    <description>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.&#xD;
Failure events are:&#xD;
progression of existing disease or occurrence of disease at new sites,&#xD;
death from any cause prior to disease progression,&#xD;
diagnosis of a second malignant neoplasm.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Response in HCC is defined as complete (CR) or partial (PR) response according to RECIST version 1.1 criteria</measure>
    <time_frame>From date of screening assessment until date of first response assessment, up to 63 days in Group F</time_frame>
    <description>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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Failure-free survival (FFS)</measure>
    <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.</time_frame>
    <description>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.&#xD;
Failure events are:&#xD;
progression of existing disease or occurrence of disease at new sites,&#xD;
death from any cause prior to disease progression,&#xD;
diagnosis of a second malignant neoplasm. failure to go to resection.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS)</measure>
    <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.</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Toxicity categorized and graded using Common Terminology Criteria for Adverse Events (CTCAE)</measure>
    <time_frame>From date of start of randomised treatment until date 30 days after last treatment.</time_frame>
    <description>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)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Chemotherapy-related cardiac, nephro- and oto-toxicity using Common Terminology Criteria for Adverse Events (CTCAE)</measure>
    <time_frame>From date of start of randomised treatment until date 30 days after last treatment.</time_frame>
    <description>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)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hearing loss according to the SIOP Boston Scale</measure>
    <time_frame>From date of registration until date of last follow up assessment, or date of death, assessed up to 6 years.</time_frame>
    <description>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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Best Response</measure>
    <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.</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Surgical resectability defined as complete resection, partial resection or transplant</measure>
    <time_frame>From date of registration until date of last follow up assessment, or date of death, assessed up to 6 years.</time_frame>
    <description>Surgical resectability is defined as complete resection, partial resection or transplant</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adherence to surgical guidelines</measure>
    <time_frame>From date of registration until date of last follow up assessment, or date of death, assessed up to 6 years.</time_frame>
    <description>Adherence to surgical guidelines is defined as the local clinician's surgical decision to resect or not compared to the current SIOPEL surgical guidelines.</description>
  </secondary_outcome>
  <number_of_arms>6</number_of_arms>
  <enrollment type="Anticipated">450</enrollment>
  <condition>Hepatoblastoma</condition>
  <condition>Carcinoma, Hepatocellular</condition>
  <arm_group>
    <arm_group_label>Group A Very Low Risk HB</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <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).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group B Low Risk HB</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group C Intermediate Risk HB</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <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)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group D High Risk HB</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <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).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group E Resected HCC</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group F Unresected HCC</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <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)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cisplatin</intervention_name>
    <description>Arms A and B - cisplatin is used alone Arms C, D, E and F - cisplatin us used in combination</description>
    <arm_group_label>Group A Very Low Risk HB</arm_group_label>
    <arm_group_label>Group B Low Risk HB</arm_group_label>
    <arm_group_label>Group C Intermediate Risk HB</arm_group_label>
    <arm_group_label>Group D High Risk HB</arm_group_label>
    <arm_group_label>Group E Resected HCC</arm_group_label>
    <arm_group_label>Group F Unresected HCC</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Doxorubicin</intervention_name>
    <description>Arms C, D and E used in combination</description>
    <arm_group_label>Group C Intermediate Risk HB</arm_group_label>
    <arm_group_label>Group D High Risk HB</arm_group_label>
    <arm_group_label>Group E Resected HCC</arm_group_label>
    <arm_group_label>Group F Unresected HCC</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Carboplatin</intervention_name>
    <description>Arms C and D used in combination</description>
    <arm_group_label>Group C Intermediate Risk HB</arm_group_label>
    <arm_group_label>Group D High Risk HB</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>5Fluorouracil</intervention_name>
    <description>Arm C used alone</description>
    <arm_group_label>Group C Intermediate Risk HB</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Vincristine</intervention_name>
    <description>Arms C and D used in combination</description>
    <arm_group_label>Group C Intermediate Risk HB</arm_group_label>
    <arm_group_label>Group D High Risk HB</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Etoposide</intervention_name>
    <description>Arm D used in combination</description>
    <arm_group_label>Group D High Risk HB</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Irinotecan</intervention_name>
    <description>Arm D used in combination</description>
    <arm_group_label>Group D High Risk HB</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Gemcitabine</intervention_name>
    <description>Arm F used in combination</description>
    <arm_group_label>Group F Unresected HCC</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Oxaliplatin</intervention_name>
    <description>Arm F used in combination</description>
    <arm_group_label>Group F Unresected HCC</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sorafenib</intervention_name>
    <description>Arm used in combination</description>
    <arm_group_label>Group F Unresected HCC</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Clinical diagnosis of HB* and histologically defined diagnosis of HB or HCC.&#xD;
&#xD;
             *Histological confirmation of HB is required except in emergency situations where:&#xD;
&#xD;
               -  a) the patient meets all other eligibility criteria, but is too ill to undergo a&#xD;
                  biopsy safely, the patient may be enrolled without a biopsy.&#xD;
&#xD;
               -  b) there is anatomic or mechanical compromise of critical organ function by&#xD;
                  tumour (e.g., respiratory distress/failure, abdominal compartment syndrome,&#xD;
                  urinary obstruction, etc.)&#xD;
&#xD;
               -  c) Uncorrectable coagulopathy&#xD;
&#xD;
          -  Age ≤30 years&#xD;
&#xD;
          -  Written informed consent for trial entry&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any previous chemotherapy or currently receiving anti-cancer agents&#xD;
&#xD;
          -  Recurrent disease&#xD;
&#xD;
          -  Previously received a solid organ transplant; other than orthotopic liver&#xD;
             transplantation (OLT).&#xD;
&#xD;
          -  Uncontrolled infection&#xD;
&#xD;
          -  Unable to follow or comply with the protocol for any reason&#xD;
&#xD;
          -  Second malignancy&#xD;
&#xD;
          -  Pregnant or breastfeeding women&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>30 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Madhumita Dandapani, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Nottingham</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Marc Ansari, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Geneva</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Stephen Baker, BEng (Hons)</last_name>
    <phone>0121 4151061</phone>
    <email>phitt@trials.bham.ac.uk</email>
  </overall_contact>
  <location>
    <facility>
      <name>St. Anna Kinderspital</name>
      <address>
        <city>Vienna</city>
        <zip>1090</zip>
        <country>Austria</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Eva Sorz</last_name>
      <phone>01401704380</phone>
      <email>eva.sorz@ccri.at</email>
    </contact>
    <investigator>
      <last_name>Heidrun Boztug</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Cliniques Universitaires Saint-Luc</name>
      <address>
        <city>Brussels</city>
        <state>Woluwe-Saint-Lambert</state>
        <zip>1200</zip>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Georgia Demarteau</last_name>
      <phone>027642376</phone>
      <email>georgia.demateau@uclouvain.be</email>
    </contact>
    <investigator>
      <last_name>Benedicte Brichard</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University Hospital Motol</name>
      <address>
        <city>Prague</city>
        <zip>150 06 Prague 5</zip>
        <country>Czechia</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Eva AL Jamal</last_name>
      <phone>0224431017</phone>
      <email>eva.aljamal@fnmotol.cz</email>
    </contact>
    <investigator>
      <last_name>Josef Malis, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>CHU de Rennes</name>
      <address>
        <city>Rennes</city>
        <zip>35033</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Valerie Visseiche</last_name>
      <phone>0299289747</phone>
      <email>valerie.visseiche@chu-rennes.fr</email>
    </contact>
    <investigator>
      <last_name>Sophie Taque</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Ludwig-Maximillians-University Munich</name>
      <address>
        <city>Munich</city>
        <zip>80337 Munich</zip>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Rebecca Maxwell</last_name>
      <phone>015254889395</phone>
      <email>rebecca.maxwell@med-uni-muenchen.de</email>
    </contact>
    <investigator>
      <last_name>Irene Schmid</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Children's Health Ireland Crumlin</name>
      <address>
        <city>Dublin</city>
        <zip>12 N512</zip>
        <country>Ireland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Aishling Ryan</last_name>
      <phone>014096651</phone>
      <email>aishling.ryan@olchc.ie</email>
    </contact>
    <investigator>
      <last_name>Michael Capra</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Schneider Children's Medical Center</name>
      <address>
        <city>Petach Tikva</city>
        <zip>4920235</zip>
        <country>Israel</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Mical Rada</last_name>
      <phone>02524643166</phone>
      <email>michalra6@clalit.org.il</email>
    </contact>
    <investigator>
      <last_name>Helen Toledano</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Prinses Maxima Center</name>
      <address>
        <city>Utrecht</city>
        <zip>3584 CS</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jaap Mur</last_name>
      <phone>0889729536</phone>
      <email>j.mur@prinsesmaximacentrum.nl</email>
    </contact>
    <investigator>
      <last_name>Jozef Zsiros</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Oslo University Hospital</name>
      <address>
        <city>Nydalen</city>
        <zip>0424 Oslo</zip>
        <country>Norway</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Anne Gro Wesenberg Rognlien</last_name>
      <phone>023074560</phone>
      <email>rogann@ous-hf.no</email>
    </contact>
    <investigator>
      <last_name>Anne Gro Wesenberg Rognlien</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Medical University of Gdansk</name>
      <address>
        <city>Gdańsk</city>
        <zip>80-803</zip>
        <country>Poland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Hanna Garnier</last_name>
      <phone>0513870100</phone>
      <email>hanna.garnier@gumed.edu.pl</email>
    </contact>
    <investigator>
      <last_name>Piotr Czauderna</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University Hospital Reina Sofia</name>
      <address>
        <city>Córdoba</city>
        <zip>14004</zip>
        <country>Spain</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>José Carlos Garrido Gracia</last_name>
      <phone>0957213831</phone>
      <email>josecarlos.garrido@imibic.org</email>
    </contact>
    <investigator>
      <last_name>Maria Mateos</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Hopitaux Universitaires de Geneve</name>
      <address>
        <city>Geneva</city>
        <zip>CH 1211</zip>
        <country>Switzerland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Nadja Enz</last_name>
      <phone>0315084237</phone>
      <email>Nadja.Enz@spog.ch</email>
    </contact>
    <investigator>
      <last_name>Marc Ansari</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Royal Aberdeen Children's Hospital</name>
      <address>
        <city>Aberdeen</city>
        <zip>AB25 2ZG</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Courtney Willis, MD PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Royal Belfast Hospital for Sick Children</name>
      <address>
        <city>Belfast</city>
        <zip>BT12 6BE</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Anthony McCarthy, MD PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Birmingham Children's Hospital</name>
      <address>
        <city>Birmingham</city>
        <zip>B4 6NH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Dave Hobin, MB ChB</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Bristol Royal Hospital for Children</name>
      <address>
        <city>Bristol</city>
        <zip>BS2 8BJ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Antony Ng, MBBS PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Addenbrooke's Hospital</name>
      <address>
        <city>Cambridge</city>
        <zip>CB2 0QQ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Amos Burke, MB ChB</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Noah's Ark Children's Hospital for Wales</name>
      <address>
        <city>Cardiff</city>
        <zip>CF14 4XW</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Catherine Morley-Jacob, MD MBBS</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Royal Hospital for Children</name>
      <address>
        <city>Edinburgh</city>
        <zip>EH9 1LW</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Mark Broughman, MD MBChB</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Royal Hospital for Children</name>
      <address>
        <city>Glasgow</city>
        <zip>G51 4TF</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Jairam Sastry, MD FRSM</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Leeds General Infirmary</name>
      <address>
        <city>Leeds</city>
        <zip>LS1 3EX</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Danielle Ingham, PhD MRCPCH</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Leicester Royal Infirmary</name>
      <address>
        <city>Leicester</city>
        <zip>LE1 5WW</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Emma Ross, MBBS MRCPCH</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Alder Hey Children's Hospital</name>
      <address>
        <city>Liverpool</city>
        <zip>L12 2AP</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Barry Pizer, MD ChB FRCPCH</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Great Ormond Street Hospital</name>
      <address>
        <city>London</city>
        <zip>WC1N 3JH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Catriona Duncan, MBBS MRCP</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Royal Manchester Children's Hospital</name>
      <address>
        <city>Manchester</city>
        <zip>M13 9WL</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Bernadette Brennan, MBChB FRCPCH</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Great North Children's Hospital</name>
      <address>
        <city>Newcastle Upon Tyne</city>
        <zip>NE1 4LP</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Gail Halliday, BSc MRCPCH</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Nottingham Children's Hospital</name>
      <address>
        <city>Nottingham</city>
        <zip>NG7 2UH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Madhumita Dandapani, MBBS MRCPCH</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Oxford Children's Hospital</name>
      <address>
        <city>Oxford</city>
        <zip>OX3 9DU</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Esther Blanco, BSc MRCPCH</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Sheffield Children's Hospital</name>
      <address>
        <city>Sheffield</city>
        <zip>S10 2TH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Anna Jenkins, MBBS MRCPCH</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University Hospital Southampton</name>
      <address>
        <city>Southampton</city>
        <zip>SO16 6YD</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Jessica Bate, MBBS MRCPCH</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>The Royal Marsden Hospital</name>
      <address>
        <city>Sutton</city>
        <zip>SM2 5PT</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Paola Angelini, MD PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Austria</country>
    <country>Belgium</country>
    <country>Czechia</country>
    <country>France</country>
    <country>Germany</country>
    <country>Ireland</country>
    <country>Israel</country>
    <country>Netherlands</country>
    <country>Norway</country>
    <country>Poland</country>
    <country>Spain</country>
    <country>Switzerland</country>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>September 2022</verification_date>
  <study_first_submitted>December 14, 2016</study_first_submitted>
  <study_first_submitted_qc>January 10, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 11, 2017</study_first_posted>
  <last_update_submitted>September 5, 2022</last_update_submitted>
  <last_update_submitted_qc>September 5, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">September 9, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma, Hepatocellular</mesh_term>
    <mesh_term>Hepatoblastoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carboplatin</mesh_term>
    <mesh_term>Gemcitabine</mesh_term>
    <mesh_term>Doxorubicin</mesh_term>
    <mesh_term>Fluorouracil</mesh_term>
    <mesh_term>Oxaliplatin</mesh_term>
    <mesh_term>Irinotecan</mesh_term>
    <mesh_term>Etoposide</mesh_term>
    <mesh_term>Vincristine</mesh_term>
    <mesh_term>Sorafenib</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03017326
org study id: RG_15-114
nct id: NCT03017326
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has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
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.
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
allocation: Randomized
intervention model: Factorial Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: 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.
description: 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.
measure: 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
description: 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.
measure: 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.
description: 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.
measure: 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.
description: 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.
measure: 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.
description: 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)
measure: 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.
description: 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)
measure: 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.
description: 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
measure: 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.
description: 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.
measure: 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.
description: Surgical resectability is defined as complete resection, partial resection or transplant
measure: 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.
description: Adherence to surgical guidelines is defined as the local clinician's surgical decision to resect or not compared to the current SIOPEL surgical guidelines.
arm group label: Group A Very Low Risk HB
arm group type: Other
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).
arm group label: Group B Low Risk HB
arm group type: Active Comparator
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.
arm group label: Group C Intermediate Risk HB
arm group type: Active Comparator
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)
arm group label: Group D High Risk HB
arm group type: Active Comparator
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).
arm group label: Group E Resected HCC
arm group type: Other
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.
arm group label: Group F Unresected HCC
arm group type: Active Comparator
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)
intervention type: Drug
intervention name: Cisplatin
description: Arms A and B - cisplatin is used alone Arms C, D, E and F - cisplatin us used in combination
arm group label: Group A Very Low Risk HB
arm group label: Group B Low Risk HB
arm group label: Group C Intermediate Risk HB
arm group label: Group D High Risk HB
arm group label: Group E Resected HCC
arm group label: Group F Unresected HCC
intervention type: Drug
intervention name: Doxorubicin
description: Arms C, D and E used in combination
arm group label: Group C Intermediate Risk HB
arm group label: Group D High Risk HB
arm group label: Group E Resected HCC
arm group label: Group F Unresected HCC
intervention type: Drug
intervention name: Carboplatin
description: Arms C and D used in combination
arm group label: Group C Intermediate Risk HB
arm group label: Group D High Risk HB
intervention type: Drug
intervention name: 5Fluorouracil
description: Arm C used alone
arm group label: Group C Intermediate Risk HB
intervention type: Drug
intervention name: Vincristine
description: Arms C and D used in combination
arm group label: Group C Intermediate Risk HB
arm group label: Group D High Risk HB
intervention type: Drug
intervention name: Etoposide
description: Arm D used in combination
arm group label: Group D High Risk HB
intervention type: Drug
intervention name: Irinotecan
description: Arm D used in combination
arm group label: Group D High Risk HB
intervention type: Drug
intervention name: Gemcitabine
description: Arm F used in combination
arm group label: Group F Unresected HCC
intervention type: Drug
intervention name: Oxaliplatin
description: Arm F used in combination
arm group label: Group F Unresected HCC
intervention type: Drug
intervention name: Sorafenib
description: Arm used in combination
arm group label: Group F Unresected HCC
criteria: 
gender: All
minimum age: N/A
maximum age: 30 Years
healthy volunteers: No
last name: Madhumita Dandapani, MD PhD
role: Principal Investigator
affiliation: University of Nottingham
last name: Marc Ansari, MD
role: Principal Investigator
affiliation: University of Geneva
last name: Stephen Baker, BEng (Hons)
phone: 0121 4151061
email: phitt@trials.bham.ac.uk
facility: 
status: Recruiting
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investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
country: Austria
country: Belgium
country: Czechia
country: France
country: Germany
country: Ireland
country: Israel
country: Netherlands
country: Norway
country: Poland
country: Spain
country: Switzerland
country: United Kingdom
responsible party type: Sponsor
mesh term: Carcinoma, Hepatocellular
mesh term: Hepatoblastoma
mesh term: Carboplatin
mesh term: Gemcitabine
mesh term: Doxorubicin
mesh term: Fluorouracil
mesh term: Oxaliplatin
mesh term: Irinotecan
mesh term: Etoposide
mesh term: Vincristine
mesh term: Sorafenib
sharing ipd: No