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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00652132
Recruitment Status : Completed
First Posted : April 3, 2008
Last Update Posted : May 29, 2018
Sponsor:
Collaborator:
Childhood Liver Tumours Strategy Group - SIOPEL
Information provided by (Responsible Party):
University of Birmingham

Study Description
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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
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Study Type : Interventional  (Clinical Trial)
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 : December 15, 2007
Actual Primary Completion Date : September 4, 2017
Actual Study Completion Date : February 28, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Liver Cancer

Arms and Interventions
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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
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Primary Outcome Measures :
  1. Rate of Brock grade ≥ 1 hearing loss [ Time Frame: 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 :
  1. Response to preoperative chemotherapy [ Time Frame: 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.


  2. Complete resection [ Time Frame: 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

  3. Complete remission [ Time Frame: 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.

  4. Event-free survival (EFS) [ Time Frame: 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.

  5. Overall survival (OS) [ Time Frame: Until event or up to 5 years ]
    Calculated from the time of randomisation to death.

  6. Toxicity as graded by CTCAE v 3.0 [ Time Frame: 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.

  7. Long-term renal clearance [ Time Frame: Until event or up to 5 years ]
    By clearance method either EDTA, iohexol or inulin.

  8. Feasibility of central audiology review [ Time Frame: End of trial treatment or at an age of 3.5 years, whichever is later ]
    The feasibility of central review


Eligibility Criteria
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Ages Eligible for Study:   1 Month to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00652132


Locations
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United Kingdom
Birmingham Children's Hospital
Birmingham, England, United Kingdom, B4 6NH
Bristol Royal Hospital for Childre
Bristol, England, United Kingdom, BS2 8AE
Addenbrooke's Hospital
Cambridge, England, United Kingdom, CB2 2QQ
Royal Marsden - London
London, England, United Kingdom, SW3 6JJ
Great Ormond Street Hospital for Children
London, England, United Kingdom, WC1N 3JH
Royal Manchester Children's Hospital
Manchester, England, United Kingdom, M27 4HA
Queen's Medical Centre
Nottingham, England, United Kingdom, NG7 2UH
Sheffield Hallam University - City Campus
Sheffield, England, United Kingdom, S1 1WB
Royal Aberdeen Children's Hospital
Aberdeen, Scotland, United Kingdom, AB25 2ZG
Royal Hospital for Sick Children
Glasgow, Scotland, United Kingdom, G3 8SJ
The Noah's Ark Children's Hospital for Wales
Cardiff, United Kingdom
Royal Hospital For Sick Children
Edinburgh, United Kingdom
Leicester Royal Infirmary
Leicester, United Kingdom
Alder Hey Children's Hospital Trust
Liverpool, United Kingdom
John Radcliffe Hospital
Oxford, United Kingdom
Southampton Children's Hospital
Southampton, United Kingdom
Sponsors and Collaborators
University of Birmingham
Childhood Liver Tumours Strategy Group - SIOPEL
Investigators
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Principal Investigator: Milind D. Ronghe, MD Royal Hospital for Sick Children
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: University of Birmingham
ClinicalTrials.gov Identifier: NCT00652132    
Other Study ID Numbers: RG_09-205
CDR0000590649 ( Other Identifier: PDQ (Physician Data Query) )
2007-002402-21 ( EudraCT Number )
SIOP-CCLG-LT-2007-03 ( Other Identifier: CCLG - previous Sponsor )
First Posted: April 3, 2008    Key Record Dates
Last Update Posted: May 29, 2018
Last Verified: May 2018
Keywords provided by University of Birmingham:
ototoxicity
childhood hepatoblastoma
stage I childhood liver cancer
stage II childhood liver cancer
stage III childhood liver cancer
Additional relevant MeSH terms:
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Liver Neoplasms
Hepatoblastoma
Ototoxicity
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Liver Diseases
Neoplasms, Complex and Mixed
Neoplasms by Histologic Type
Ear Diseases
Otorhinolaryngologic Diseases
Pathologic Processes
Drug-Related Side Effects and Adverse Reactions
 Chemically-Induced Disorders
Radiation Injuries
Wounds and Injuries
Sodium thiosulfate
Antidotes
Protective Agents
Physiological Effects of Drugs
Antioxidants
Molecular Mechanisms of Pharmacological Action
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Chelating Agents
Sequestering Agents