Clinical Trial Results:
A RANDOMISED, CROSS-OVER, PHASE II STUDY, TO INVESTIGATE THE EFFICACY AND SAFETY OF GLUCARPIDASE FOR ROUTINE USE AFTER HIGH DOSE METHOTREXATE IN PATIENTS WITH BONE SARCOMA
Summary
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EudraCT number |
2006-003203-40 |
Trial protocol |
GB |
Global end of trial date |
13 Apr 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
15 Jul 2018
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First version publication date |
15 Jul 2018
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
06/085
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
University College London Joint Research Office
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Sponsor organisation address |
1st Floor Maple House, Suite A 149 Tottenham Court Rd , London, United Kingdom, W1T 7DN
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Public contact |
Prof Jeremy Whelan, University College London Joint research Office, 44 0203447 9346, jeremy.whelan@nhs.net
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Scientific contact |
Prof Jeremy Whelan, University College London Joint Research Office, 44 0203447 9346, jeremy.whelan@nhs.net
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
14 Mar 2018
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
13 Apr 2015
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Global end of trial reached? |
Yes
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Global end of trial date |
13 Apr 2015
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To investigate whether glucarpidase rescue after high-dose methotrexate reduces delay to subsequent cycle of chemotherapy due to methotrexate toxicity
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Protection of trial subjects |
Written informed consent taken
Safety measures to enable appropriate patient assessment pre-chemotherapy and timely reporting of treatment related adverse reactions/events.
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Background therapy |
MAP chemotherapy (methotrexate, doxorubicin, cisplatin) for high-grade bone osteosarcoma | ||
Evidence for comparator |
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Actual start date of recruitment |
13 Jun 2007
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 34
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Worldwide total number of subjects |
34
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EEA total number of subjects |
34
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
14
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Adults (18-64 years) |
20
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Patients with osteosarcoma undergoing standard first line chemotherapy -> Enter recruitement dates etc, hoover over 'i' on the right to get the info | ||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
Written informed consent from patient or parent/guardian Diagnosis of high grade osteosarcoma, localised or metastatic or high grade osteosarcoma as a second malignancy or spindle cell sarcoma of bone or relapsed high grade osteosarcoma Age: 5-50 years at registration Ability to comply with study and follow up procedures (WHO performance 0-2) | ||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Period 1
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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A (M-GluM) | ||||||||||||||||||||||||||||||
Arm description |
Cycle 1 methotrexate alone Day 1 and Day 8. Cycle 2 Methotrexate plus glucarpidase Day 1 and Day 8 | ||||||||||||||||||||||||||||||
Arm type |
No intervention | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Arm title
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B (GluM-M) | ||||||||||||||||||||||||||||||
Arm description |
Cycle 1 Methotrexate plus glucarpidase Day 1 and Day 8. Cycle 2 methotrexate alone Day 1 and Day 8. | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Glucarpidase
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate and solvent for suspension for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
50u/kg by slow iv injection
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Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: 2 patients were not randomised |
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Period 2
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Period 2 title |
Period 2
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Is this the baseline period? |
No | ||||||||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
No
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Arm title
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A (M-GluM) | ||||||||||||||||||||||||||||||
Arm description |
Glucarpidace plus Methotrexate | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Glucarpidase
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate and solvent for suspension for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
50u/kg by slow iv injection
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Arm title
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B (GluM-M) | ||||||||||||||||||||||||||||||
Arm description |
Methotrexate only | ||||||||||||||||||||||||||||||
Arm type |
No intervention | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Arm title
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GluM | ||||||||||||||||||||||||||||||
Arm description |
Outcomes for patients when on Glucarpidace (aggregated over both periods) | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Glucarpidase
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate and solvent for suspension for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
50u/kg by slow iv injection
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Arm title
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No Glu | ||||||||||||||||||||||||||||||
Arm description |
Outcomes for patients when not on Glucarpidace (aggregated over both periods) | ||||||||||||||||||||||||||||||
Arm type |
No intervention | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Baseline characteristics reporting groups
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Reporting group title |
A (M-GluM)
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Reporting group description |
Cycle 1 methotrexate alone Day 1 and Day 8. Cycle 2 Methotrexate plus glucarpidase Day 1 and Day 8 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
B (GluM-M)
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Reporting group description |
Cycle 1 Methotrexate plus glucarpidase Day 1 and Day 8. Cycle 2 methotrexate alone Day 1 and Day 8. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
A (M-GluM)
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Reporting group description |
Cycle 1 methotrexate alone Day 1 and Day 8. Cycle 2 Methotrexate plus glucarpidase Day 1 and Day 8 | ||
Reporting group title |
B (GluM-M)
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Reporting group description |
Cycle 1 Methotrexate plus glucarpidase Day 1 and Day 8. Cycle 2 methotrexate alone Day 1 and Day 8. | ||
Reporting group title |
A (M-GluM)
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Reporting group description |
Glucarpidace plus Methotrexate | ||
Reporting group title |
B (GluM-M)
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Reporting group description |
Methotrexate only | ||
Reporting group title |
GluM
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Reporting group description |
Outcomes for patients when on Glucarpidace (aggregated over both periods) | ||
Reporting group title |
No Glu
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Reporting group description |
Outcomes for patients when not on Glucarpidace (aggregated over both periods) | ||
Subject analysis set title |
Fitness for chemotherapy at day 15
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
The McNemar’s test considers the null hypothesis that the proportions of patients fit for chemotherapy after Glu and no Glu are equal.
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End point title |
Fitness for chemotherapy at Day 15 following Glu or no Glu | ||||||||||||||||||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Day 15 fitness post chemotherapy
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Statistical analysis title |
Fitness for chemotherapy at Day 15 | ||||||||||||||||||||||||||||
Statistical analysis description |
The McNemar’s test considers the null hypothesis that the proportions of patients fit for chemotherapy after Glu and no Glu are equal.
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Comparison groups |
A (M-GluM) v B (GluM-M)
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Number of subjects included in analysis |
29
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Analysis specification |
Pre-specified
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Analysis type |
equivalence [1] | ||||||||||||||||||||||||||||
P-value |
< 0.05 | ||||||||||||||||||||||||||||
Method |
Mcnemar | ||||||||||||||||||||||||||||
Confidence interval |
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Notes [1] - The sample size calculation is based on a McNemar’s test with an assumption that the responses to glucarpidase and folinic acid rescue are independent. With anticipated proportions of responses to standard rescue and glucarpidase+folinic acid of 55% and 90% respectively, the study will require 38 patients to give 80% power at a significance level of 5% and to allow for up to 30% drop-out during the study.The O’Brien and Flemming boundary method will be used for testing significance of effe |
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End point title |
Mucositis assessment | |||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Assessment at Day 15
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No statistical analyses for this end point |
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End point title |
Renal toxicity | |||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
DAy 15
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No statistical analyses for this end point |
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End point title |
Neutropenia | |||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Day 15
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No statistical analyses for this end point |
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End point title |
Liver toxicity | |||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Day 15
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No statistical analyses for this end point |
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End point title |
Thromobcytopenia | |||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Day 15
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
AE related to IMP followed up until resolution. AE not related to IMP followed up until the end of the study (Day 21 of cycle 2)
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Assessment type |
Systematic | ||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
CTCAE | ||||||||||||||||||||||
Dictionary version |
3
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Reporting groups
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Reporting group title |
Data analysis
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Reporting group description |
- | ||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 3% | |||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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04 Dec 2006 |
Inclusion of new study site and clarifications on administration of care |
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17 Apr 2007 |
Manufacturer's data amending timing of folinic acid administration post glucarpidase to minimise competition |
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08 Sep 2009 |
To provide real-time stability data for IMP
To provide new safety data for IMP
Change of study design to double blind, randomised to unblind, randomised
Revision of sample size to allow drop-out rate of 30%
Administrative changes to contact details
Study solely sponsored by UCL |
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03 Nov 2010 |
Notification of additional laboratory conducting anti-glucarpidase antibody analysis
Change in co-investigator
Updated hydration details of methotrexate
addition of safety reporting procedures to protocol |
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02 Feb 2011 |
IMP updated to new batch
Updated methotrexate hydration details |
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24 May 2012 |
ALT and albumin measurement ranges removed from inclusion criteria
Platelet count reduced to 75 for inclusion
IMP shelf life changed to 4 hours
ASR replaced with DSUR
Clarifications to reporting of SAEs |
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23 Aug 2013 |
Change of Chief Investigator title
Notification of new Co-investigator
New contact details
Updated protocol and appendices |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
Results are preliminary and unpublished |