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

• ClinicalTrials.gov Identifier: NCT00652132
• Recruitment Status: Completed
• First Posted: April 3, 2008
• Last Update Posted: May 29, 2018
• Sponsor: University of Birmingham
• Collaborator: Childhood Liver Tumours Strategy Group - SIOPEL
• Information provided by (Responsible Party): University of Birmingham

Tracking Information

• First Submitted Date: April 2, 2008
• First Posted Date: April 3, 2008
• Last Update Posted Date: May 29, 2018
• Actual Study Start Date: December 15, 2007
• Actual Primary Completion Date: September 4, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 24, 2018)

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

• Original Primary Outcome Measures (submitted: April 2, 2008): Rate of Brock grade ≥ 1 hearing loss determined after end of trial treatment or at an age of at least 3.5 years

Current Secondary Outcome Measures (submitted: May 24, 2018)

• 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.
• 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
• 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.
• 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.
• Overall survival (OS) [ Time Frame: Until event or up to 5 years ]
  Calculated from the time of randomisation to death.
• 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.
• Long-term renal clearance [ Time Frame: Until event or up to 5 years ]
  By clearance method either EDTA, iohexol or inulin.
• 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

Original Secondary Outcome Measures (submitted: April 2, 2008)

• Response to preoperative chemotherapy
• Complete resection
• Complete remission
• Event free survival (EFS)
• Overall survival (OS)
• Toxicity as graded by CTCAE v 3.0
• Long-term renal clearance
• Feasibility of central audiology review

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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

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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Liver Cancer
• Ototoxicity

Intervention

• Drug: cisplatin
• Drug: sodium thiosulfate

Study Arms

• 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.
  Intervention: 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.
  Interventions:

  • Drug: cisplatin
  • Drug: sodium thiosulfate

• Publications *: 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 24, 2018): 116
• Original Enrollment (submitted: April 2, 2008): 115
• Actual Study Completion Date: February 28, 2018
• Actual Primary Completion Date: September 4, 2017 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 1 Month to 18 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United Kingdom

Administrative Information

• NCT Number: 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 )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: University of Birmingham
• Original Responsible Party: Not Provided
• Current Study Sponsor: University of Birmingham
• Original Study Sponsor: Children's Cancer and Leukaemia Group
• Collaborators: Childhood Liver Tumours Strategy Group - SIOPEL

Investigators

• Principal Investigator: Milind D. Ronghe, MD; Royal Hospital for Sick Children

• PRS Account: University of Birmingham
• Verification Date: May 2018