<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/NCT04478292</url>
  </required_header>
  <id_info>
    <org_study_id>NCMC-SH-HEP-2020</org_study_id>
    <nct_id>NCT04478292</nct_id>
  </id_info>
  <brief_title>A Multi-institutional Study for Treatment of Children With Newly Diagnosed Hepatoblastoma Using a Modified PHITT Strategy</brief_title>
  <official_title>A Phase 3 Multi-institutional Study for Treatment of Children With Newly Diagnosed Hepatoblastoma Using a Modified PHITT Strategy Incorporating a Randomized Assessment of Sodium Thiosulfate as Otoprotection for Children With Localized Disease, and Response Adapted Therapy for Patients With Metastatic Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Shanghai Children's Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Children's Hospital of Fudan University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Shanghai Children's Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Shanghai Children's Medical Center</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      A Phase 3 multi-institutional study for treatment of children with newly diagnosed&#xD;
      hepatoblastoma using a modified Paediatric Hepatic International Tumour Trial (PHITT)&#xD;
      strategy incorporating a randomized assessment of sodium thiosulfate as auditory protection&#xD;
      for children with localized disease, and response adapted therapy for patients with&#xD;
      metastatic disease&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Primary aims:&#xD;
&#xD;
        1. Localized Disease: Groups B and C: To evaluate and validate the efficacy of sodium&#xD;
           thiosulfate (STS) to reduce the hearing impairment caused by a cisplatin monotherapy in&#xD;
           non-metastatic patients without adverse features (localized PRETEXT I-III tumors without&#xD;
           positive VPEFR annotation factors) (Group B - treated with cisplatin mono-therapy) or&#xD;
           with adverse features (localized PRETEXT I-III tumors with positive VPEFR annotation&#xD;
           factors) (Group C - treated with regimen C5VD)&#xD;
&#xD;
        2. Metastatic Disease: Group D: To determine the 3-year Event-free survival (EFS) in&#xD;
           patients with metastatic disease treated with International Society of Paediatric&#xD;
           Oncology (SIOPEL 4) induction therapy followed by response adapted consolidation&#xD;
           therapy.&#xD;
&#xD;
        3. To determine the 3-year EFS in patients with HB whose tumor is completely resected at&#xD;
           diagnosis (Group A) and either receive no adjuvant chemotherapy (Group A1, completely&#xD;
           resected well differentiated fetal (WDF) histology HB) or 2 cycles of standard dose&#xD;
           cisplatin monotherapy (Group A2, completely resected non-well differentiated fetal&#xD;
           histology HB)&#xD;
&#xD;
      Secondary aims:&#xD;
&#xD;
        1. To determine any impact of STS on chemotherapy response and survival in children with&#xD;
           localized hepatoblastoma&#xD;
&#xD;
        2. To assess the feasibility of complete resection after 2 cycles of interval compressed&#xD;
           lower dose cisplatin monotherapy (80 mg/m2/cycle) in non-metastatic patients and without&#xD;
           adverse features&#xD;
&#xD;
        3. To assess the feasibility of complete resection after 2 cycles of C5VD in non-metastatic&#xD;
           patients with adverse features.5. To determine the adherence to PRETEXT and&#xD;
           Post-treatment extent of disease (POSTTEXT) based surgical guidelines&#xD;
&#xD;
        4. To determine the prognostic relevance in HB of a &quot;small cell undifferentiated&quot;, tumor&#xD;
           component, percentage of tumor necrosis in post chemotherapy specimens, and the&#xD;
           relevance of a positive microscopic margin in resected HB specimens.&#xD;
&#xD;
        5. To determine the concordance between institutional, regional expert panel (prospective)&#xD;
           and international expert panel (retrospective) review assessment of PRETEXT and POSTTEXT&#xD;
           stage, and correlate with outcome variables.&#xD;
&#xD;
        6. To prospectively collect patient HB tumor, peripheral blood and urine specimens, for&#xD;
           translational biology studies.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">March 1, 2021</start_date>
  <completion_date type="Anticipated">September 30, 2027</completion_date>
  <primary_completion_date type="Anticipated">March 31, 2026</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>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Audiogram</measure>
    <time_frame>From diagnosis through study completion, an average of 1 year</time_frame>
    <description>The grade (from 0 to 4, higher scores mean a worse outcome) of audiograms evaluated by Boston Grading Scale for Ototoxicity.To evaluate and validate the efficacy of sodium thiosulfate (STS) to reduce the hearing impairment caused by a cisplatin monotherapy in non- metastatic patients without adverse features (localized PRETEXT I-III tumors without positive VPEFR annotation factors) (Group B - treated with cisplatin mono-therapy) or with adverse features (localized PRETEXT I-III tumors with positive VPEFR annotation factors) (Group C - treated with regimen C5VD).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>3 -year Event-free survival (EFS)</measure>
    <time_frame>UP to 3years</time_frame>
    <description>Calculated from the time of randomisation to the first of the following events: progression, relapse, secondary malignancy or death.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Treatment-related adverse events</measure>
    <time_frame>UP to 3years</time_frame>
    <description>Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v5.0</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Response to chemotherapy</measure>
    <time_frame>UP to 3years</time_frame>
    <description>Complete response (CR):&#xD;
no evidence of disease and normal serum AFP value (for age).&#xD;
Partial response (PR):&#xD;
any tumour volume shrinkage associated with a decreasing serum AFP value, &gt; 1 log below the original measurement.&#xD;
Stable disease (SD):&#xD;
no tumour volume change and no change, or &lt; 1 log fall of the serum AFP concentration.&#xD;
Progressive disease (PD):&#xD;
unequivocal increase in 1 or more dimensions and/or any unequivocal increase of the serum AFP concentration (three successive 1-2 weekly determinations) even without clinical (physical and/or radiological) evidence of tumour re-growth.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Anticipated">330</enrollment>
  <condition>Hepatoblastoma</condition>
  <arm_group>
    <arm_group_label>Group A</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Group A1： tumor is completely resected at diagnosis and receives no adjuvant chemotherapy（well differentiated fetal [WDF] histology HB) ；&#xD;
Group A2：tumor is completely resected followed by 2 cycles of standard dose cisplatin monotherapy （non-well differentiated fetal histology HB)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group B</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will be randomized to one of 2 arms: Arm CDDP or Arm CDDP plus STS. In each arm, patients will be stratified by resectablity after completion of 2 cycles of protocol therapy (6 cycles of standard dose cisplatin monotherapy with or without STS). All the patients in 2 arms will receive 6 cycles chemotherapy in total.&#xD;
Resection of the primary tumor will be performed after completing the 2nd cycle of chemotherapy.&#xD;
Those patients whose tumors after 2 cycles do not meet criteria for definitive surgical, 2nd resectablity evaluation will be scheduled after 4 cycles of chemotherapy.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group C</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients in Group C will have locally advanced tumors including PRETEXT I-III tumors with a positive VPEFR annotation factor and all PRETEXT IV tumors.&#xD;
Patients will be randomized to one of 2 arms: Arm C5VD or Arm C5VD plus STS. In each arm, patients will be stratified by resectablity after completion of 2 cycles of protocol therapy. All the patients in 2 arms will receive 6 cycles chemotherapy in total.&#xD;
Resection of the primary tumor will be performed after completing the 2nd cycle of chemotherapy.&#xD;
Those patients whose tumors after 2 cycles do not meet criteria for definitive surgical, 2nd resectablity evaluation will be scheduled after 4 cycles of chemotherapy.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group D</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>These patients have metastatic disease, suspected HB patients ≥ 8 years of age, or have an AFP ≤ 100 at diagnosis.&#xD;
Patients will receive initial chemotherapy according to the cisplatin-intensive SIOPEL-4 induction regimen. Resection (including transplant) of the primary tumor should be completed after induction Block 3, but primary tumor resection can be planned any time after completing induction therapy.&#xD;
Following 3 blocks of induction chemotherapy, patients will be stratified into 2 risk groups: Group D1 includes patients who either have a chemotherapy-induced lung CR or are rendered a lung CR by surgical metastasectomy. These patients will have chemotherapy consolidation with carboplatin/doxorubicin. In Group D2, patients will have not yet achieved a lung CR at the end of induction Block 3. These patients will get intensified consolidation therapy of carboplatin/doxorubicin with vincristine/irinotecan.&#xD;
Resection of pulmonary nodules should be considered in Group D2.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sodium Thiosulfate Injection</intervention_name>
    <description>Weight ≥ 10 kg: 20 g/m2/dose STS or Weight 5-10 kg: 15 g/m2/dose STS or Weight &lt; 5 kg: 10 g/m2/dose STS will be administered by IV over 2 hours beginning 6 hours after the completion of each cisplatin infusion.</description>
    <arm_group_label>Group B</arm_group_label>
    <arm_group_label>Group C</arm_group_label>
    <other_name>STS</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Primary surgery resection</intervention_name>
    <description>Resection of the primary tumor up-front</description>
    <arm_group_label>Group A</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>mono CDDP-Group A2</intervention_name>
    <description>Cisplatin 100 mg/m2/dose Day 1 . All non-WDF patients (A2) will receive 2 cycles of mono cisplatin (100 mg/m2/dose) chemotherapy. Each cycle lasts 3 weeks (21 days).</description>
    <arm_group_label>Group A</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cisplatin, 5-Fluorouracil, Vincristine, Doxorubicin-Group C</intervention_name>
    <description>All the patients in Group C (2 arms) will receive 6 cycles chemotherapy in total. Cisplatin 100 mg/m2/dose Day 1; 5-Fluorouracil 600 mg/m2/dose Day 1; Vincristine 1.5 mg/m2/dose Day 1,8 and 15; Doxorubicin 30 mg/m2/dose Day 1 and 2; (Dexrazoxane : 300 mg/m2/dose Day 1 and 2, where is available)</description>
    <arm_group_label>Group C</arm_group_label>
    <other_name>C5VD Group C</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Biopsy</intervention_name>
    <description>Tumors are deemed unresectable at diagnosis.</description>
    <arm_group_label>Group B</arm_group_label>
    <arm_group_label>Group C</arm_group_label>
    <arm_group_label>Group D</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Resection or transplant</intervention_name>
    <description>Ideal timing to resect of the primary tumors or transplant if if excellent response achieved at 1st or 2nd evaluation timepoint. But surgery timing is not mandated. Irrespective of the timing of surgery, patients should complete all planned protocol cycles of chemotherapy (including post transplantation). If surgical resection of the primary tumor is delayed until the end of therapy, no further post-operative chemotherapy should be given.</description>
    <arm_group_label>Group B</arm_group_label>
    <arm_group_label>Group C</arm_group_label>
    <arm_group_label>Group D</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Resection of pulmonary nodules</intervention_name>
    <description>Resection of pulmonary nodules should be considered in Group D2, patients at any cycle if continuing to respond to consolidation therapy.</description>
    <arm_group_label>Group D</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>mono CDDP- Group B</intervention_name>
    <description>Cisplatin 80 mg/m2/dose Day 1. All patients in Group B (2 arms) will receive 6 cycles of mono cisplatin chemotherapy. Each cycle lasts 2 weeks (14 days).</description>
    <arm_group_label>Group B</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Block 1 to 3 (Cisplatin, Doxorubicin) Group D</intervention_name>
    <description>Block 1 and 2: Cisplatin 70 mg/m2/dose Day1, 8 and 15; Doxorubicin 30 mg/m2/dose, Day 8 and 9; (Dexrazoxane: 300 mg/m2/dose Day 1 and 2, where is available); Block 3: Cisplatin 70 mg/m2/dose Day1and 8; Doxorubicin 30 mg/m2/dose Day 8 and 9; (Dexrazoxane BSA ≥ 0.6 m2/dose: 300 mg/m2/dose Day 8 and 9, where is available) All patients in Group D will receive 3 blocks in induction, followed by consolidation therapy. Block 1 and 2 last 28 days. Block 3 is 21 cycles.</description>
    <arm_group_label>Group D</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Consolidation (Carboplatin, Doxorubicin) -Group D1</intervention_name>
    <description>Following Block 1-3 of induction therapy, Group D1 patients will receive 3 cycles of Carboplatin + Doxorubicin consolidation therapy. Each cycle lasts 3 weeks (21 days). Carboplatin 500 mg/m2/dose Day 1; Doxorubicin 20 mg/m2/dose Day 1 and 2; (Dexrazoxane: 200 mg/m2/dose Day 1 and 2, where is available).</description>
    <arm_group_label>Group D</arm_group_label>
    <other_name>Group D1 CD</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Consolidation (Carboplatin +Doxorubicin/Vincristine + Irinotecan)-Group D2</intervention_name>
    <description>Following Block 1-3 of induction therapy, patients in Group D2, will receive 6 cycles of consolidation chemotherapy with Carboplatin + Doxorubicin in Cycles 1, 3, and 5 alternating with Vincristine + irinotecan in Cycles 2, 4, and 6. One cycle of therapy lasts 3 weeks (21 days). Cycle 1, 3 and 5: Carboplatin 500 mg/m2/dose Day 1; Doxorubicin 20 mg/m2/dose Day 1 and 2; (Dexrazoxane: 200 mg/m2/dose Day 1 and 2, where is available).&#xD;
Cycle 2, 4 and 6: Vincristine 1.5 mg/m2/dose, Day 1 and 8; Irinotecan 50 mg/m2/dose, Day 1 to 5;</description>
    <arm_group_label>Group D</arm_group_label>
    <other_name>Group D2 CD/VI</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Performance Level Patients must have a performance status corresponding to ECOG scores&#xD;
             0, 1, or 2. Use Karnofsky for patients &gt;16 years of age and Lansky for patients ≤16&#xD;
             years of age.&#xD;
&#xD;
          -  Diagnosis Patients must be newly diagnosed with histologically-proven primary&#xD;
             pediatric HB&#xD;
&#xD;
          -  Emergent Treatment for HB In emergency situation when a patient meets all other&#xD;
             eligibility criteria and has had baseline required observations, but is too ill to&#xD;
             undergo a biopsy safely, the patient may be enrolled without a biopsy.&#xD;
&#xD;
          -  Prior Therapy Patients may have had surgical resection of the hepatic malignancy prior&#xD;
             to enrollment. All other anti-cancer therapy for the current liver lesion is&#xD;
             prohibited.&#xD;
&#xD;
          -  Organ Function Requirements&#xD;
&#xD;
        I) Adequate renal function defined as:&#xD;
&#xD;
        Creatinine clearance or radioisotope Glomerular Filtration Rate (GFR) ≥ 70 mL/min/1.73 m2&#xD;
&#xD;
        II) Adequate liver function defined as:&#xD;
&#xD;
        Total bilirubin ≤ 5 x upper limit of normal (ULN) for age, and Aspartate aminotransferase&#xD;
        (AST) or Alanine transaminase (ALT) &lt; 10 x upper limit of normal (ULN) for age.&#xD;
&#xD;
        III) Adequate pulmonary function defined as:&#xD;
&#xD;
        Normal pulmonary function tests (including DLCO) if there is clinical indication for&#xD;
        determination (e.g. dyspnea at rest, known requirement for supplemental oxygen)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Prior chemotherapy or tumor directed therapy expect for surgical resection of the&#xD;
             hepatic malignancy (i.e. radiation therapy, biologic agents, local therapy&#xD;
             (embolization, radiofrequency ablation, and laser)). Therefore, patients with a&#xD;
             pre-disposition syndrome who have a prior malignancy are not eligible.&#xD;
&#xD;
          -  Patients who are currently receiving another investigational drug.&#xD;
&#xD;
          -  Patients who are currently receiving other anticancer agents.&#xD;
&#xD;
          -  Patients with uncontrolled infection.&#xD;
&#xD;
          -  Patients who previously received a solid organ transplant.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>18 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Yi-Jin Gao, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Shanghai Children's Medical Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Min Xu, MD</last_name>
    <phone>+8613816116777</phone>
    <email>xumin@scmc.com.cn</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Hongxiang Gao</last_name>
    <phone>+8615216606578</phone>
    <email>gaohongxiang@scmc.com.cn</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Shanghai Children's Medical Center</name>
      <address>
        <city>Shanghai</city>
        <state>Shanghai</state>
        <zip>200127</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Hongxiang Gao, M.D.</last_name>
      <phone>+8615216606578</phone>
      <email>gaohongxiang@scmc.com.cn</email>
    </contact>
    <investigator>
      <last_name>YiJin Gao, Ph.D.</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <results_reference>
    <citation>Brock PR, Maibach R, Childs M, Rajput K, Roebuck D, Sullivan MJ, Laithier V, Ronghe M, Dall'Igna P, Hiyama E, Brichard B, Skeen J, Mateos ME, Capra M, Rangaswami AA, Ansari M, Rechnitzer C, Veal GJ, Covezzoli A, Brugieres L, Perilongo G, Czauderna P, Morland B, Neuwelt EA. Sodium Thiosulfate for Protection from Cisplatin-Induced Hearing Loss. N Engl J Med. 2018 Jun 21;378(25):2376-2385. doi: 10.1056/NEJMoa1801109.</citation>
    <PMID>29924955</PMID>
  </results_reference>
  <results_reference>
    <citation>Freyer DR, Chen L, Krailo MD, Knight K, Villaluna D, Bliss B, Pollock BH, Ramdas J, Lange B, Van Hoff D, VanSoelen ML, Wiernikowski J, Neuwelt EA, Sung L. Effects of sodium thiosulfate versus observation on development of cisplatin-induced hearing loss in children with cancer (ACCL0431): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2017 Jan;18(1):63-74. doi: 10.1016/S1470-2045(16)30625-8. Epub 2016 Dec 1. Erratum In: Lancet Oncol. 2017 Jun;18(6):e301.</citation>
    <PMID>27914822</PMID>
  </results_reference>
  <results_reference>
    <citation>Freyer DR, Brock P, Knight K, Reaman G, Cabral S, Robinson PD, Sung L. Interventions for cisplatin-induced hearing loss in children and adolescents with cancer. Lancet Child Adolesc Health. 2019 Aug;3(8):578-584. doi: 10.1016/S2352-4642(19)30115-4. Epub 2019 May 31.</citation>
    <PMID>31160205</PMID>
  </results_reference>
  <results_reference>
    <citation>Meyers RL, Maibach R, Hiyama E, Haberle B, Krailo M, Rangaswami A, Aronson DC, Malogolowkin MH, Perilongo G, von Schweinitz D, Ansari M, Lopez-Terrada D, Tanaka Y, Alaggio R, Leuschner I, Hishiki T, Schmid I, Watanabe K, Yoshimura K, Feng Y, Rinaldi E, Saraceno D, Derosa M, Czauderna P. Risk-stratified staging in paediatric hepatoblastoma: a unified analysis from the Children's Hepatic tumors International Collaboration. Lancet Oncol. 2017 Jan;18(1):122-131. doi: 10.1016/S1470-2045(16)30598-8. Epub 2016 Nov 22.</citation>
    <PMID>27884679</PMID>
  </results_reference>
  <results_reference>
    <citation>Brock PR, Knight KR, Freyer DR, Campbell KC, Steyger PS, Blakley BW, Rassekh SR, Chang KW, Fligor BJ, Rajput K, Sullivan M, Neuwelt EA. Platinum-induced ototoxicity in children: a consensus review on mechanisms, predisposition, and protection, including a new International Society of Pediatric Oncology Boston ototoxicity scale. J Clin Oncol. 2012 Jul 1;30(19):2408-17. doi: 10.1200/JCO.2011.39.1110. Epub 2012 Apr 30.</citation>
    <PMID>22547603</PMID>
  </results_reference>
  <results_reference>
    <citation>Zsiros J, Brugieres L, Brock P, Roebuck D, Maibach R, Zimmermann A, Childs M, Pariente D, Laithier V, Otte JB, Branchereau S, Aronson D, Rangaswami A, Ronghe M, Casanova M, Sullivan M, Morland B, Czauderna P, Perilongo G; International Childhood Liver Tumours Strategy Group (SIOPEL). Dose-dense cisplatin-based chemotherapy and surgery for children with high-risk hepatoblastoma (SIOPEL-4): a prospective, single-arm, feasibility study. Lancet Oncol. 2013 Aug;14(9):834-42. doi: 10.1016/S1470-2045(13)70272-9. Epub 2013 Jul 4.</citation>
    <PMID>23831416</PMID>
  </results_reference>
  <verification_date>September 2023</verification_date>
  <study_first_submitted>June 8, 2020</study_first_submitted>
  <study_first_submitted_qc>July 15, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 20, 2020</study_first_posted>
  <last_update_submitted>September 1, 2023</last_update_submitted>
  <last_update_submitted_qc>September 1, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 5, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>hepatoblastoma, sodium thiosulfate, auditory protection</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hepatoblastoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Sodium thiosulfate</mesh_term>
    <mesh_term>Cisplatin</mesh_term>
    <mesh_term>Carboplatin</mesh_term>
    <mesh_term>Doxorubicin</mesh_term>
    <mesh_term>Liposomal doxorubicin</mesh_term>
    <mesh_term>Fluorouracil</mesh_term>
    <mesh_term>Irinotecan</mesh_term>
    <mesh_term>Vincristine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Study protocol, SAP and ICF were shared before study initiation. Patient data and the information about the process of the study will be shared within the 3 participants annually after enrollment patients.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_time_frame>The data will be shared within the 3 hospital every 12 months after enrollment of patients.</ipd_time_frame>
    <ipd_access_criteria>Scheduled meeting and paper transferring.</ipd_access_criteria>
  </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/NCT04478292
org study id: NCMC-SH-HEP-2020
nct id: NCT04478292
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
A Phase 3 multi-institutional study for treatment of children with newly diagnosed
      hepatoblastoma using a modified Paediatric Hepatic International Tumour Trial (PHITT)
      strategy incorporating a randomized assessment of sodium thiosulfate as auditory protection
      for children with localized disease, and response adapted therapy for patients with
      metastatic disease
Primary aims:

        1. Localized Disease: Groups B and C: To evaluate and validate the efficacy of sodium
           thiosulfate (STS) to reduce the hearing impairment caused by a cisplatin monotherapy in
           non-metastatic patients without adverse features (localized PRETEXT I-III tumors without
           positive VPEFR annotation factors) (Group B - treated with cisplatin mono-therapy) or
           with adverse features (localized PRETEXT I-III tumors with positive VPEFR annotation
           factors) (Group C - treated with regimen C5VD)

        2. Metastatic Disease: Group D: To determine the 3-year Event-free survival (EFS) in
           patients with metastatic disease treated with International Society of Paediatric
           Oncology (SIOPEL 4) induction therapy followed by response adapted consolidation
           therapy.

        3. To determine the 3-year EFS in patients with HB whose tumor is completely resected at
           diagnosis (Group A) and either receive no adjuvant chemotherapy (Group A1, completely
           resected well differentiated fetal (WDF) histology HB) or 2 cycles of standard dose
           cisplatin monotherapy (Group A2, completely resected non-well differentiated fetal
           histology HB)

      Secondary aims:

        1. To determine any impact of STS on chemotherapy response and survival in children with
           localized hepatoblastoma

        2. To assess the feasibility of complete resection after 2 cycles of interval compressed
           lower dose cisplatin monotherapy (80 mg/m2/cycle) in non-metastatic patients and without
           adverse features

        3. To assess the feasibility of complete resection after 2 cycles of C5VD in non-metastatic
           patients with adverse features.5. To determine the adherence to PRETEXT and
           Post-treatment extent of disease (POSTTEXT) based surgical guidelines

        4. To determine the prognostic relevance in HB of a "small cell undifferentiated", tumor
           component, percentage of tumor necrosis in post chemotherapy specimens, and the
           relevance of a positive microscopic margin in resected HB specimens.

        5. To determine the concordance between institutional, regional expert panel (prospective)
           and international expert panel (retrospective) review assessment of PRETEXT and POSTTEXT
           stage, and correlate with outcome variables.

        6. To prospectively collect patient HB tumor, peripheral blood and urine specimens, for
           translational biology studies.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Audiogram
time frame: From diagnosis through study completion, an average of 1 year
description: The grade (from 0 to 4, higher scores mean a worse outcome) of audiograms evaluated by Boston Grading Scale for Ototoxicity.To evaluate and validate the efficacy of sodium thiosulfate (STS) to reduce the hearing impairment caused by a cisplatin monotherapy in non- metastatic patients without adverse features (localized PRETEXT I-III tumors without positive VPEFR annotation factors) (Group B - treated with cisplatin mono-therapy) or with adverse features (localized PRETEXT I-III tumors with positive VPEFR annotation factors) (Group C - treated with regimen C5VD).
measure: 3 -year Event-free survival (EFS)
time frame: UP to 3years
description: Calculated from the time of randomisation to the first of the following events: progression, relapse, secondary malignancy or death.
measure: Treatment-related adverse events
time frame: UP to 3years
description: Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v5.0
measure: Response to chemotherapy
time frame: UP to 3years
description: Complete response (CR):
no evidence of disease and normal serum AFP value (for age).
Partial response (PR):
any tumour volume shrinkage associated with a decreasing serum AFP value, > 1 log below the original measurement.
Stable disease (SD):
no tumour volume change and no change, or < 1 log fall of the serum AFP concentration.
Progressive disease (PD):
unequivocal increase in 1 or more dimensions and/or any unequivocal increase of the serum AFP concentration (three successive 1-2 weekly determinations) even without clinical (physical and/or radiological) evidence of tumour re-growth.
arm group label: Group A
arm group type: Experimental
description: Group A1： tumor is completely resected at diagnosis and receives no adjuvant chemotherapy（well differentiated fetal [WDF] histology HB) ；
Group A2：tumor is completely resected followed by 2 cycles of standard dose cisplatin monotherapy （non-well differentiated fetal histology HB)
arm group label: Group B
arm group type: Experimental
description: Patients will be randomized to one of 2 arms: Arm CDDP or Arm CDDP plus STS. In each arm, patients will be stratified by resectablity after completion of 2 cycles of protocol therapy (6 cycles of standard dose cisplatin monotherapy with or without STS). All the patients in 2 arms will receive 6 cycles chemotherapy in total.
Resection of the primary tumor will be performed after completing the 2nd cycle of chemotherapy.
Those patients whose tumors after 2 cycles do not meet criteria for definitive surgical, 2nd resectablity evaluation will be scheduled after 4 cycles of chemotherapy.
arm group label: Group C
arm group type: Experimental
description: Patients in Group C will have locally advanced tumors including PRETEXT I-III tumors with a positive VPEFR annotation factor and all PRETEXT IV tumors.
Patients will be randomized to one of 2 arms: Arm C5VD or Arm C5VD plus STS. In each arm, patients will be stratified by resectablity after completion of 2 cycles of protocol therapy. All the patients in 2 arms will receive 6 cycles chemotherapy in total.
Resection of the primary tumor will be performed after completing the 2nd cycle of chemotherapy.
Those patients whose tumors after 2 cycles do not meet criteria for definitive surgical, 2nd resectablity evaluation will be scheduled after 4 cycles of chemotherapy.
arm group label: Group D
arm group type: Experimental
description: These patients have metastatic disease, suspected HB patients ≥ 8 years of age, or have an AFP ≤ 100 at diagnosis.
Patients will receive initial chemotherapy according to the cisplatin-intensive SIOPEL-4 induction regimen. Resection (including transplant) of the primary tumor should be completed after induction Block 3, but primary tumor resection can be planned any time after completing induction therapy.
Following 3 blocks of induction chemotherapy, patients will be stratified into 2 risk groups: Group D1 includes patients who either have a chemotherapy-induced lung CR or are rendered a lung CR by surgical metastasectomy. These patients will have chemotherapy consolidation with carboplatin/doxorubicin. In Group D2, patients will have not yet achieved a lung CR at the end of induction Block 3. These patients will get intensified consolidation therapy of carboplatin/doxorubicin with vincristine/irinotecan.
Resection of pulmonary nodules should be considered in Group D2.
intervention type: Drug
intervention name: Sodium Thiosulfate Injection
description: Weight ≥ 10 kg: 20 g/m2/dose STS or Weight 5-10 kg: 15 g/m2/dose STS or Weight < 5 kg: 10 g/m2/dose STS will be administered by IV over 2 hours beginning 6 hours after the completion of each cisplatin infusion.
arm group label: Group B
arm group label: Group C
other name: STS
intervention type: Procedure
intervention name: Primary surgery resection
description: Resection of the primary tumor up-front
arm group label: Group A
intervention type: Drug
intervention name: mono CDDP-Group A2
description: Cisplatin 100 mg/m2/dose Day 1 . All non-WDF patients (A2) will receive 2 cycles of mono cisplatin (100 mg/m2/dose) chemotherapy. Each cycle lasts 3 weeks (21 days).
arm group label: Group A
intervention type: Drug
intervention name: Cisplatin, 5-Fluorouracil, Vincristine, Doxorubicin-Group C
description: All the patients in Group C (2 arms) will receive 6 cycles chemotherapy in total. Cisplatin 100 mg/m2/dose Day 1; 5-Fluorouracil 600 mg/m2/dose Day 1; Vincristine 1.5 mg/m2/dose Day 1,8 and 15; Doxorubicin 30 mg/m2/dose Day 1 and 2; (Dexrazoxane : 300 mg/m2/dose Day 1 and 2, where is available)
arm group label: Group C
other name: C5VD Group C
intervention type: Procedure
intervention name: Biopsy
description: Tumors are deemed unresectable at diagnosis.
arm group label: Group B
arm group label: Group C
arm group label: Group D
intervention type: Procedure
intervention name: Resection or transplant
description: Ideal timing to resect of the primary tumors or transplant if if excellent response achieved at 1st or 2nd evaluation timepoint. But surgery timing is not mandated. Irrespective of the timing of surgery, patients should complete all planned protocol cycles of chemotherapy (including post transplantation). If surgical resection of the primary tumor is delayed until the end of therapy, no further post-operative chemotherapy should be given.
arm group label: Group B
arm group label: Group C
arm group label: Group D
intervention type: Procedure
intervention name: Resection of pulmonary nodules
description: Resection of pulmonary nodules should be considered in Group D2, patients at any cycle if continuing to respond to consolidation therapy.
arm group label: Group D
intervention type: Drug
intervention name: mono CDDP- Group B
description: Cisplatin 80 mg/m2/dose Day 1. All patients in Group B (2 arms) will receive 6 cycles of mono cisplatin chemotherapy. Each cycle lasts 2 weeks (14 days).
arm group label: Group B
intervention type: Drug
intervention name: Block 1 to 3 (Cisplatin, Doxorubicin) Group D
description: Block 1 and 2: Cisplatin 70 mg/m2/dose Day1, 8 and 15; Doxorubicin 30 mg/m2/dose, Day 8 and 9; (Dexrazoxane: 300 mg/m2/dose Day 1 and 2, where is available); Block 3: Cisplatin 70 mg/m2/dose Day1and 8; Doxorubicin 30 mg/m2/dose Day 8 and 9; (Dexrazoxane BSA ≥ 0.6 m2/dose: 300 mg/m2/dose Day 8 and 9, where is available) All patients in Group D will receive 3 blocks in induction, followed by consolidation therapy. Block 1 and 2 last 28 days. Block 3 is 21 cycles.
arm group label: Group D
intervention type: Drug
intervention name: Consolidation (Carboplatin, Doxorubicin) -Group D1
description: Following Block 1-3 of induction therapy, Group D1 patients will receive 3 cycles of Carboplatin + Doxorubicin consolidation therapy. Each cycle lasts 3 weeks (21 days). Carboplatin 500 mg/m2/dose Day 1; Doxorubicin 20 mg/m2/dose Day 1 and 2; (Dexrazoxane: 200 mg/m2/dose Day 1 and 2, where is available).
arm group label: Group D
other name: Group D1 CD
intervention type: Drug
intervention name: Consolidation (Carboplatin +Doxorubicin/Vincristine + Irinotecan)-Group D2
description: Following Block 1-3 of induction therapy, patients in Group D2, will receive 6 cycles of consolidation chemotherapy with Carboplatin + Doxorubicin in Cycles 1, 3, and 5 alternating with Vincristine + irinotecan in Cycles 2, 4, and 6. One cycle of therapy lasts 3 weeks (21 days). Cycle 1, 3 and 5: Carboplatin 500 mg/m2/dose Day 1; Doxorubicin 20 mg/m2/dose Day 1 and 2; (Dexrazoxane: 200 mg/m2/dose Day 1 and 2, where is available).
Cycle 2, 4 and 6: Vincristine 1.5 mg/m2/dose, Day 1 and 8; Irinotecan 50 mg/m2/dose, Day 1 to 5;
arm group label: Group D
other name: Group D2 CD/VI
criteria: 
gender: All
minimum age: N/A
maximum age: 18 Years
healthy volunteers: No
last name: Yi-Jin Gao, MD
role: Principal Investigator
affiliation: Shanghai Children's Medical Center
last name: Min Xu, MD
phone: +8613816116777
email: xumin@scmc.com.cn
last name: Hongxiang Gao
phone: +8615216606578
email: gaohongxiang@scmc.com.cn
facility: 
status: Recruiting
contact: 
investigator: 
country: China
citation: Brock PR, Maibach R, Childs M, Rajput K, Roebuck D, Sullivan MJ, Laithier V, Ronghe M, Dall'Igna P, Hiyama E, Brichard B, Skeen J, Mateos ME, Capra M, Rangaswami AA, Ansari M, Rechnitzer C, Veal GJ, Covezzoli A, Brugieres L, Perilongo G, Czauderna P, Morland B, Neuwelt EA. Sodium Thiosulfate for Protection from Cisplatin-Induced Hearing Loss. N Engl J Med. 2018 Jun 21;378(25):2376-2385. doi: 10.1056/NEJMoa1801109.
PMID: 29924955
citation: Freyer DR, Chen L, Krailo MD, Knight K, Villaluna D, Bliss B, Pollock BH, Ramdas J, Lange B, Van Hoff D, VanSoelen ML, Wiernikowski J, Neuwelt EA, Sung L. Effects of sodium thiosulfate versus observation on development of cisplatin-induced hearing loss in children with cancer (ACCL0431): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2017 Jan;18(1):63-74. doi: 10.1016/S1470-2045(16)30625-8. Epub 2016 Dec 1. Erratum In: Lancet Oncol. 2017 Jun;18(6):e301.
PMID: 27914822
citation: Freyer DR, Brock P, Knight K, Reaman G, Cabral S, Robinson PD, Sung L. Interventions for cisplatin-induced hearing loss in children and adolescents with cancer. Lancet Child Adolesc Health. 2019 Aug;3(8):578-584. doi: 10.1016/S2352-4642(19)30115-4. Epub 2019 May 31.
PMID: 31160205
citation: Meyers RL, Maibach R, Hiyama E, Haberle B, Krailo M, Rangaswami A, Aronson DC, Malogolowkin MH, Perilongo G, von Schweinitz D, Ansari M, Lopez-Terrada D, Tanaka Y, Alaggio R, Leuschner I, Hishiki T, Schmid I, Watanabe K, Yoshimura K, Feng Y, Rinaldi E, Saraceno D, Derosa M, Czauderna P. Risk-stratified staging in paediatric hepatoblastoma: a unified analysis from the Children's Hepatic tumors International Collaboration. Lancet Oncol. 2017 Jan;18(1):122-131. doi: 10.1016/S1470-2045(16)30598-8. Epub 2016 Nov 22.
PMID: 27884679
citation: Brock PR, Knight KR, Freyer DR, Campbell KC, Steyger PS, Blakley BW, Rassekh SR, Chang KW, Fligor BJ, Rajput K, Sullivan M, Neuwelt EA. Platinum-induced ototoxicity in children: a consensus review on mechanisms, predisposition, and protection, including a new International Society of Pediatric Oncology Boston ototoxicity scale. J Clin Oncol. 2012 Jul 1;30(19):2408-17. doi: 10.1200/JCO.2011.39.1110. Epub 2012 Apr 30.
PMID: 22547603
citation: Zsiros J, Brugieres L, Brock P, Roebuck D, Maibach R, Zimmermann A, Childs M, Pariente D, Laithier V, Otte JB, Branchereau S, Aronson D, Rangaswami A, Ronghe M, Casanova M, Sullivan M, Morland B, Czauderna P, Perilongo G; International Childhood Liver Tumours Strategy Group (SIOPEL). Dose-dense cisplatin-based chemotherapy and surgery for children with high-risk hepatoblastoma (SIOPEL-4): a prospective, single-arm, feasibility study. Lancet Oncol. 2013 Aug;14(9):834-42. doi: 10.1016/S1470-2045(13)70272-9. Epub 2013 Jul 4.
PMID: 23831416
responsible party type: Sponsor
mesh term: Hepatoblastoma
mesh term: Sodium thiosulfate
mesh term: Cisplatin
mesh term: Carboplatin
mesh term: Doxorubicin
mesh term: Liposomal doxorubicin
mesh term: Fluorouracil
mesh term: Irinotecan
mesh term: Vincristine
sharing ipd: Yes
ipd description: Study protocol, SAP and ICF were shared before study initiation. Patient data and the information about the process of the study will be shared within the 3 participants annually after enrollment patients.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd info type: Clinical Study Report (CSR)
ipd time frame: The data will be shared within the 3 hospital every 12 months after enrollment of patients.
ipd access criteria: Scheduled meeting and paper transferring.