Liver CancerPhase 3SIOPEL6NCT00652132
Cisplatin With or Without Sodium Thiosulfate in Treating Young Patients With Stage I, II, or III Childhood Liver Cancer
A Phase 3 study testing cisplatin and sodium thiosulfate in people with Liver Cancer and Ototoxicity, run by University of Birmingham at 16 sites in United Kingdom.
Trial 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. Read more about this study
- Who is it for?
- Ages 1 month to 18 years
- Conditions the study is for
- Liver Cancer, Ototoxicity
- What is being tested?
- cisplatin and sodium thiosulfate
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 116 participants
- Where
- 16 sitesUnited Kingdom
- Study dates
- 15 Dec 2007to 28 Feb 2018
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 month to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
None listed.
Who cannot join
- 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
Trial locations and contacts
16 sites in 1 country.
16 sites in 1 country
United Kingdom16 sites
Royal Aberdeen Children's Hospital
Aberdeen, Scotland, AB25 2ZG
Birmingham Children's Hospital
Birmingham, England, B4 6NH
Bristol Royal Hospital for Childre
Bristol, England, BS2 8AE
Addenbrooke's Hospital
Cambridge, England, CB2 2QQ
The Noah's Ark Children's Hospital for Wales
Cardiff
Royal Hospital For Sick Children
Edinburgh
Royal Hospital for Sick Children
Glasgow, Scotland, G3 8SJ
Leicester Royal Infirmary
Leicester
Alder Hey Children's Hospital Trust
Liverpool
Royal Marsden - London
London, England, SW3 6JJ
Great Ormond Street Hospital for Children
London, England, WC1N 3JH
Royal Manchester Children's Hospital
Manchester, England, M27 4HA
Queen's Medical Centre
Nottingham, England, NG7 2UH
John Radcliffe Hospital
Oxford
Sheffield Hallam University - City Campus
Sheffield, England, S1 1WB
Southampton Children's Hospital
Southampton
About this study
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
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.
Read the 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.
- Conditions
- Liver Cancer, Ototoxicity
- Being tested
- cisplatin, sodium thiosulfate
- Keywords
- ototoxicity, childhood hepatoblastoma, stage I childhood liver cancer, stage II childhood liver cancer, stage III childhood liver cancer
- Medical subject headings
- Liver Neoplasms, Ototoxicity, Hepatoblastoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
cisplatinDrug
sodium thiosulfateDrug
| Study group | Role | What they receive |
|---|---|---|
| Arm I (cisplatin) | Active comparator | 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. Receives: Drug: cisplatin |
| Arm II (cisplatin + STS) | Experimental | 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. Receives: Drug: cisplatin; Drug: sodium thiosulfate |
What is being measured
The primary outcome is the main question the study is designed to answer.
Rate of Brock grade ≥ 1 hearing loss
To investigate if the administration of sodium thiosulfate simultaneously with the administration of Cisplatin significantly reduces the hearing impairment
Measured: End of trial treatment or at an age of 3.5 years, whichever is later
Secondary outcomes (8)
Response to 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.
Measured: Following completion of preoperative chemotherapy
Complete resection
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
Measured: Within 2 weeks after surgery.
Complete remission
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.
Measured: End of trial treatment
Event-free survival (EFS)
Calculated from the time of randomisation to the first of the following events: progression, relapse, secondary primary malignancy or death.
Measured: Until first event or up to 5 years
Overall survival (OS)
Calculated from the time of randomisation to death.
Measured: Until event or up to 5 years
Toxicity as graded by CTCAE v 3.0
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.
Measured: 30 days post treatment
Long-term renal clearance
By clearance method either EDTA, iohexol or inulin.
Measured: Until event or up to 5 years
Feasibility of central audiology review
The feasibility of central review
Measured: End of trial treatment or at an age of 3.5 years, whichever is later
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Apr 2008 (estimated)
- Study start15 Dec 2007
- Primary completion4 Sep 2017
- Study completion28 Feb 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Liver CancerStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 116 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Birmingham
- Sponsor type
- University, hospital or other
- Collaborators
- Childhood Liver Tumours Strategy Group - SIOPEL
- Responsible party
- Sponsor
- Investigators
- Milind D. Ronghe, MD, Principal investigator, Royal Hospital for Sick Children
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00652132
- Sponsor's protocol ID
- RG_09-205
- Other IDs
- CDR0000590649, 2007-002402-21, SIOP-CCLG-LT-2007-03
- Acronym
- SIOPEL6
- Status last verified
- May 2018
- First submitted
- 2 Apr 2008
- Last updated
- 29 May 2018
- Results posted
- No
- Data monitoring committee
- Yes
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.
PubMed 29924955
Study at a glance
From the registry record, last updated by the sponsor on 29 May 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT00652132
- Acronym / sponsor ID
- SIOPEL6 / RG_09-205
- Conditions
- Liver Cancer, Ototoxicity
- Keywords
- ototoxicity, childhood hepatoblastoma, stage I childhood liver cancer, stage II childhood liver cancer, stage III childhood liver cancer
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 116 participants (actual)
- Lead sponsor
- University of BirminghamUniversity, hospital or other
- Collaborators
- Childhood Liver Tumours Strategy Group - SIOPEL
- Study start
- 15 Dec 2007 (actual)
- Primary completion
- 4 Sep 2017 (actual)
- Study completion
- 28 Feb 2018 (actual)
- First posted
- 3 Apr 2008 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Arm I (cisplatin) | Active comparator | Drug: cisplatinNeoadjuvant 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 (cisplatin + STS) | Experimental | Drug: cisplatin, Drug: sodium thiosulfateNeoadjuvant 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. |
Who may qualify
- Ages
- 1 month to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (0 listed)
Key exclusion criteria (8 listed)
- High risk hepatoblastoma
- Hepatocellular carcinoma
- Treatment starting more than 15 days from written biopsy report
- Abnormal renal function
- Any previous chemotherapy
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| cisplatin | Drug | Arm I (cisplatin), Arm II (cisplatin + STS) |
| sodium thiosulfate | Drug | Arm II (cisplatin + STS) |
Primary outcome
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
8 secondary outcomes
Response to preoperative chemotherapy
Time frame: Following completion of preoperative chemotherapy
Complete resection
Time frame: Within 2 weeks after surgery.
Complete remission
Time frame: End of trial treatment
Event-free survival (EFS)
Time frame: Until first event or up to 5 years
Overall survival (OS)
Time frame: Until event or up to 5 years
Toxicity as graded by CTCAE v 3.0
Time frame: 30 days post treatment
Long-term renal clearance
Time frame: Until event or up to 5 years
Feasibility of central audiology review
Time frame: End of trial treatment or at an age of 3.5 years, whichever is later
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 May 2018.
- Derived from this study: PubMed 29924955Brock 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Milind D. Ronghe, MD principal investigator
Royal Hospital for Sick Children
16 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing cisplatin and sodium thiosulfate in people with Liver Cancer and Ototoxicity, run by University of Birmingham at 16 sites in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 0 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 29 May 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 16 sites in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Rate of Brock grade ≥ 1 hearing loss (time frame: End of trial treatment or at an age of 3.5 years, whichever is later). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00652132, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 May 2018.