Clinical trial NCT04478292: A Multi-institutional Study for Treatment of Children With Newly Diagnosed Hepatoblastoma Using a Modified PHITT Strategy
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Hepatoblastoma
Keywords: hepatoblastoma, sodium thiosulfate, auditory protection
Lead sponsor: Shanghai Children's Medical Center
Sponsor class: OTHER
Collaborators: name: Shanghai Children's Hospital
First posted: 2020-07-20
Enrollment: 330
Sex: ALL
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* 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)

Exclusion Criteria:

* 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.

Primary outcomes:
measure: Audiogram
timeFrame: From diagnosis through study completion, an average of 1 year
measure: 3 -year Event-free survival (EFS)
timeFrame: UP to 3years
Secondary outcomes:
measure: Treatment-related adverse events
timeFrame: UP to 3years
measure: Response to chemotherapy
timeFrame: UP to 3years
Other outcomes:
Locations:
city: Shanghai
country: China
facility: Shanghai Children's Medical Center
state: Shanghai
Study officials:
affiliation: Shanghai Children's Medical Center
name: Yi-Jin Gao, MD
role: PRINCIPAL_INVESTIGATOR
References:
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