A Multi-institutional Study for Treatment of Children With Newly Diagnosed Hepatoblastoma Using a Modified PHITT Strategy

NCT04478292 | Recruiting Phase 3 DMC

• 1 other identifier: NCMC-SH-HEP-2020
• Study Type: interventional
• Target: 330
• Locations: 1 country
• Sites: 1

Brief Summary

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

Conditions

Hepatoblastoma

Keywords

hepatoblastoma, sodium thiosulfate, auditory protection

Outcome Measures

Primary Outcomes (2)

• Audiogram

  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).

  From diagnosis through study completion, an average of 1 year

• 3 -year Event-free survival (EFS)

  Calculated from the time of randomisation to the first of the following events: progression, relapse, secondary malignancy or death.

  UP to 3years

Secondary Outcomes (2)

• Treatment-related adverse events

  UP to 3years

• Response to chemotherapy

  UP to 3years

Study Arms (4)

Group A

EXPERIMENTAL

* 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)

Procedure: Primary surgery resection; Drug: mono CDDP-Group A2

Group B

EXPERIMENTAL

* 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.

Drug: Sodium Thiosulfate Injection; Procedure: Biopsy; Procedure: Resection or transplant; Drug: mono CDDP- Group B

Group C

EXPERIMENTAL

* 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.

Drug: Sodium Thiosulfate Injection; Drug: Cisplatin, 5-Fluorouracil, Vincristine, Doxorubicin-Group C; Procedure: Biopsy; Procedure: Resection or transplant

Group D

EXPERIMENTAL

* 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.

Procedure: Biopsy; Procedure: Resection or transplant; Procedure: Resection of pulmonary nodules; Drug: Block 1 to 3 (Cisplatin, Doxorubicin) Group D; Drug: Consolidation (Carboplatin, Doxorubicin) -Group D1; Drug: Consolidation (Carboplatin +Doxorubicin/Vincristine + Irinotecan)-Group D2

Interventions

Sodium Thiosulfate Injection DRUG

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.

Also known as: STS

Group B; Group C

Primary surgery resection PROCEDURE

Resection of the primary tumor up-front

Group A

mono CDDP-Group A2 DRUG

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).

Group A

Cisplatin, 5-Fluorouracil, Vincristine, Doxorubicin-Group C DRUG

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)

Also known as: C5VD Group C

Group C

Biopsy PROCEDURE

Tumors are deemed unresectable at diagnosis.

Group B; Group C; Group D

Resection or transplant PROCEDURE

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.

Group B; Group C; Group D

Resection of pulmonary nodules PROCEDURE

Resection of pulmonary nodules should be considered in Group D2, patients at any cycle if continuing to respond to consolidation therapy.

Group D

mono CDDP- Group B DRUG

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).

Group B

Block 1 to 3 (Cisplatin, Doxorubicin) Group D DRUG

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.

Group D

Consolidation (Carboplatin, Doxorubicin) -Group D1 DRUG

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).

Also known as: Group D1 CD

Group D

Consolidation (Carboplatin +Doxorubicin/Vincristine + Irinotecan)-Group D2 DRUG

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;

Also known as: Group D2 CD/VI

Group D

Eligibility Criteria

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

You may qualify if:

• Performance Level Patients must have a performance status corresponding to ECOG scores 0, 1, or 2. Use Karnofsky for patients \>16 years of age and Lansky for patients ≤16 years of age.
• Diagnosis Patients must be newly diagnosed with histologically-proven primary pediatric HB
• Emergent Treatment for HB In emergency situation when a patient meets all other eligibility criteria and has had baseline required observations, but is too ill to undergo a biopsy safely, the patient may be enrolled without a biopsy.
• Prior Therapy Patients may have had surgical resection of the hepatic malignancy prior to enrollment. All other anti-cancer therapy for the current liver lesion is prohibited.
• Organ Function Requirements
• I) Adequate renal function defined as:
• Creatinine clearance or radioisotope Glomerular Filtration Rate (GFR) ≥ 70 mL/min/1.73 m2
• II) Adequate liver function defined as:
• Total bilirubin ≤ 5 x upper limit of normal (ULN) for age, and Aspartate aminotransferase (AST) or Alanine transaminase (ALT) \< 10 x upper limit of normal (ULN) for age.
• III) Adequate pulmonary function defined as:
• Normal pulmonary function tests (including DLCO) if there is clinical indication for determination (e.g. dyspnea at rest, known requirement for supplemental oxygen)

You may not qualify if:

• Prior chemotherapy or tumor directed therapy expect for surgical resection of the hepatic malignancy (i.e. radiation therapy, biologic agents, local therapy (embolization, radiofrequency ablation, and laser)). Therefore, patients with a pre-disposition syndrome who have a prior malignancy are not eligible.
• Patients who are currently receiving another investigational drug.
• Patients who are currently receiving other anticancer agents.
• Patients with uncontrolled infection.
• Patients who previously received a solid organ transplant.

Sponsors & Collaborators

• Shanghai Children's Medical Center: lead
• Shanghai Children's Hospital: collaborator

Study Sites (1)

Shanghai Children's Medical Center

Shanghai, Shanghai Municipality, 200127, China

RECRUITING

Related Publications (6)

• 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 RESULT

• 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.

  PMID: 27914822 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

MeSH Terms

Conditions

Hepatoblastoma

Interventions

sodium thiosulfate; Cisplatin; Fluorouracil; Vincristine; Biopsy; Transplantation; Doxorubicin; Carboplatin

Condition Hierarchy (Ancestors)

Neoplasms, Complex and Mixed; Neoplasms by Histologic Type; Neoplasms

Intervention Hierarchy (Ancestors)

Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Specimen Handling; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Investigative Techniques; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Coordination Complexes

Study Officials

• Yi-Jin Gao, MD

  Shanghai Children's Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Haishan Ruan, MS

CONTACT

+8618801902467; ruanhaishan@scmc.com.cn

Yujia Tang, MD

CONTACT

+8618516342079; tangyuejia@scmc.com.cn

Study Design

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

Study Record Dates

• First Submitted: June 8, 2020
• First Posted: July 20, 2020
• Study Start: March 1, 2021
• Primary Completion (Estimated): March 31, 2027
• Study Completion (Estimated): September 30, 2027
• Last Updated: May 4, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: The data will be shared within the 3 hospital every 12 months after enrollment of patients.
• Access Criteria: Scheduled meeting and paper transferring.

Locations

CN (1)