Clinical trial NCT00652132: Cisplatin With or Without Sodium Thiosulfate in Treating Young Patients With Stage I, II, or III Childhood Liver Cancer
Official title: A Multi-centre Open-label Randomised Phase III Trial of the Efficacy of Sodium Thiosulphate in Reducing Ototoxicity in Patients Receiving Cisplatin Chemotherapy for Standard Risk Hepatoblastoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Liver Cancer
Ototoxicity
Keywords: ototoxicity
childhood hepatoblastoma
stage I childhood liver cancer
stage II childhood liver cancer
stage III childhood liver cancer
Lead sponsor: University of Birmingham
Sponsor class: OTHER
Collaborators: name: Childhood Liver Tumours Strategy Group - SIOPEL
First posted: 2008-04-03
Enrollment: 116
Sex: ALL
Minimum age (years): 1
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: RATIONALE: Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Chemoprotective drugs, such as sodium thiosulfate, may protect normal cells from the side effects of chemotherapy. It is not yet known whether giving sodium thiosulfate is effective in reducing hearing damage caused by cisplatin in treating young patients with liver cancer.

PURPOSE: This randomized phase III trial is studying how well sodium thiosulfate works to decrease hearing loss caused by cisplatin in treating young patients with stage I, stage II, or stage III childhood liver cancer.

Detailed description: OBJECTIVES:

Primary

* To assess the efficacy of sodium thiosulfate (STS) to reduce the hearing impairment caused by cisplatin chemotherapy.

Secondary

* To carefully monitor any potential impact of STS on response to cisplatin and survival.
* To assess the short- and long-term tolerability of the combination of STS and cisplatin
* To prospectively evaluate and validate biological, radiological and pathological features of standard-risk hepatoblastoma for future risk adapted management
* To investigate the effect of STS on the formation of cisplatin-DNA adducts.
* To prospectively collect patient DNA specifically for the analysis of possible genetic factors that may contribute to the development of treatment-related ototoxicity and nephrotoxicity

OUTLINE: This is a multicenter study. Patients are stratified according to country, median age (\< 15 months vs ≥ 15 months), and PRETEXT tumor classification (I vs II vs III). Patients are randomized to 1 of 2 treatment arms.

* Arm I (Neoadjuvant and adjuvant cisplatin): Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 2 weeks for 4 courses. Patients with progressive disease after course 4 are taken off study. Patients without evidence of disease progression proceed to surgery. Beginning within 3 weeks after surgery, patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 2 weeks for 2 courses in the absence of disease progression or unacceptable toxicity.
* Arm II (Neoadjuvant and adjuvant cisplatin and sodium thiosulphate): Patients receive cisplatin IV over 6 hours and sodium thiosulphate IV over 15 minutes (beginning 6 hours after completion of cisplatin) on day 1. Treatment repeats every 2 weeks for 4 courses. Patients with progressive disease after course 4 are taken off study. Patients without evidence of disease progression proceed to surgery. Beginning within 3 weeks after surgery, patients receive cisplatin IV over 6 hours and sodium thiosulphate IV over 15 minutes (as in neoadjuvant therapy) on day 1. Treatment repeats every 2 weeks for 2 courses in the absence of disease progression or unacceptable toxicity.

Patients undergo blood collection and tumor biopsies periodically for biological and pharmacological studies consisting of biomarker analysis, gene expression profiling, IHC, proteomic analysis, and gene rearrangement analysis. Patients undergo auditory evaluations at baseline, and at the completion of study treatment or at an age of at least 3.5 years to measure ototoxicity and hearing impairment.

After completion of study treatment, patients are followed periodically for at least 5 years.

Eligibility criteria: Inclusion Histologically confirmed newly diagnosed hepatoblastoma

* Standard risk hepatoblastoma (Pretext I,II,III)
* Age ≤ 18 years and \> 1 month
* Written informed consent and national/local ethics committee and regulatory approval
* Centre/country willing and able to organise audiometry at the minimum required quality standard and to provide the contact details of the Consultant Audiologist or Ear Nose and Throat Surgeon who will take the responsibility for seeing that this is done
* Ability to comply with requirements for submission of material for central review
* For females of child-bearing potential, a negative pregnancy test prior to study treatment is required.
* Any patient who is of reproductive age should agree to use adequate contraception for the duration of the trial.

Exclusion:

High risk hepatoblastoma

* Hepatocellular carcinoma
* Treatment starting more than 15 days from written biopsy report
* Abnormal renal function
* Any previous chemotherapy
* Recurrent disease
* Previous hypersensitivity to STS
* Patient unable to follow the protocol for any reason

Primary outcomes:
measure: Rate of Brock grade ≥ 1 hearing loss
timeFrame: End of trial treatment or at an age of 3.5 years, whichever is later
Secondary outcomes:
measure: Response to preoperative chemotherapy
timeFrame: Following completion of preoperative chemotherapy
measure: Complete resection
timeFrame: Within 2 weeks after surgery.
measure: Complete remission
timeFrame: End of trial treatment
measure: Event-free survival (EFS)
timeFrame: Until first event or up to 5 years
measure: Overall survival (OS)
timeFrame: Until event or up to 5 years
measure: Toxicity as graded by CTCAE v 3.0
timeFrame: 30 days post treatment
measure: Long-term renal clearance
timeFrame: Until event or up to 5 years
measure: Feasibility of central audiology review
timeFrame: End of trial treatment or at an age of 3.5 years, whichever is later
Other outcomes:
Locations:
city: Birmingham
country: United Kingdom
facility: Birmingham Children's Hospital
state: England
city: Bristol
country: United Kingdom
facility: Bristol Royal Hospital for Childre
state: England
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
state: England
city: London
country: United Kingdom
facility: Royal Marsden - London
state: England
city: London
country: United Kingdom
facility: Great Ormond Street Hospital for Children
state: England
city: Manchester
country: United Kingdom
facility: Royal Manchester Children's Hospital
state: England
city: Nottingham
country: United Kingdom
facility: Queen's Medical Centre
state: England
city: Sheffield
country: United Kingdom
facility: Sheffield Hallam University - City Campus
state: England
city: Aberdeen
country: United Kingdom
facility: Royal Aberdeen Children's Hospital
state: Scotland
city: Glasgow
country: United Kingdom
facility: Royal Hospital for Sick Children
state: Scotland
city: Cardiff
country: United Kingdom
facility: The Noah's Ark Children's Hospital for Wales
city: Edinburgh
country: United Kingdom
facility: Royal Hospital For Sick Children
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
city: Liverpool
country: United Kingdom
facility: Alder Hey Children's Hospital Trust
city: Oxford
country: United Kingdom
facility: John Radcliffe Hospital
city: Southampton
country: United Kingdom
facility: Southampton Children's Hospital
Study officials:
affiliation: Royal Hospital for Sick Children
name: Milind D. Ronghe, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.