SIOPEL6: Cisplatin With or Without Sodium Thiosulfate in Treating Young Patients With Stage I, II, or III Childhood Liver Cancer

Sponsor

University of Birmingham (Other)

Overall Status

Completed

CT.gov ID

NCT00652132

Collaborator

Childhood Liver Tumours Strategy Group - SIOPEL (Other)

116

Enrollment

Locations

Arms

122.5

Actual Duration (Months)

7.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Liver Cancer Ototoxicity	Drug: cisplatin Drug: sodium thiosulfate	Phase 3

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

116 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Dec 15, 2007

Actual Primary Completion Date :

Sep 4, 2017

Actual Study Completion Date :

Feb 28, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Arm I (cisplatin) 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.	Drug: cisplatin
Experimental: Arm II (cisplatin + STS) Neoadjuvant and adjuvant cisplatin and sodium thiosulphate (STS): 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.	Drug: cisplatin Drug: sodium thiosulfate

Arm

Intervention/Treatment

Active Comparator: Arm I (cisplatin)

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.

Drug: cisplatin

Experimental: Arm II (cisplatin + STS)

Neoadjuvant and adjuvant cisplatin and sodium thiosulphate (STS): 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.

Drug: cisplatin

Drug: sodium thiosulfate

Outcome Measures

Primary Outcome Measures

Rate of Brock grade ≥ 1 hearing loss [End of trial treatment or at an age of 3.5 years, whichever is later]
To investigate if the administration of sodium thiosulfate simultaneously with the administration of Cisplatin significantly reduces the hearing impairment

Secondary Outcome Measures

Response to preoperative chemotherapy [Following completion of preoperative chemotherapy]
Defined as: 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.
Complete resection [Within 2 weeks after surgery.]
Total macroscopic removal of the tumour as reported by the surgeon and pathologist. In case of any doubt the lack of residual tumour must be confirmed with imaging studies performed
Complete remission [End of trial treatment]
Lack of evidence of residual disease and normal (for age) alpha-foetal protein (AFP). To establish a complete remission all of the following requirements must be fulfilled: No evidence of tumour intra-abdominally: negative abdominal (including hepatic) ultrasound or CT scan or Magnetic resonance imaging No evidence of metastases: clear chest X-ray (PA and lateral) for non-metastatic patients. (Normal lung CT scan for patients with lung metastasis at diagnosis, who are high-risk by definition and not treated according to SIOPEL 6). Serum AFP level either normal or compatible with age for at least 4 weeks after normalisation.
Event-free survival (EFS) [Until first event or up to 5 years]
Calculated from the time of randomisation to the first of the following events: progression, relapse, secondary primary malignancy or death.
Overall survival (OS) [Until event or up to 5 years]
Calculated from the time of randomisation to death.
Toxicity as graded by CTCAE v 3.0 [30 days post treatment]
Adverse drug reactions are defined as adverse events, which are possibly, probably or definitely related to the trial treatment. They will be assessed according to NCI CTCAE v 3.0.
Long-term renal clearance [Until event or up to 5 years]
By clearance method either EDTA, iohexol or inulin.
Feasibility of central audiology review [End of trial treatment or at an age of 3.5 years, whichever is later]
The feasibility of central review

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Month to 18 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Birmingham Children's Hospital	Birmingham	England	United Kingdom	B4 6NH
2	Bristol Royal Hospital for Childre	Bristol	England	United Kingdom	BS2 8AE
3	Addenbrooke's Hospital	Cambridge	England	United Kingdom	CB2 2QQ
4	Royal Marsden - London	London	England	United Kingdom	SW3 6JJ
5	Great Ormond Street Hospital for Children	London	England	United Kingdom	WC1N 3JH
6	Royal Manchester Children's Hospital	Manchester	England	United Kingdom	M27 4HA
7	Queen's Medical Centre	Nottingham	England	United Kingdom	NG7 2UH
8	Sheffield Hallam University - City Campus	Sheffield	England	United Kingdom	S1 1WB
9	Royal Aberdeen Children's Hospital	Aberdeen	Scotland	United Kingdom	AB25 2ZG
10	Royal Hospital for Sick Children	Glasgow	Scotland	United Kingdom	G3 8SJ
11	The Noah's Ark Children's Hospital for Wales	Cardiff		United Kingdom
12	Royal Hospital For Sick Children	Edinburgh		United Kingdom
13	Leicester Royal Infirmary	Leicester		United Kingdom
14	Alder Hey Children's Hospital Trust	Liverpool		United Kingdom
15	John Radcliffe Hospital	Oxford		United Kingdom
16	Southampton Children's Hospital	Southampton		United Kingdom