Clinical Trial Results:
A Novel Single Arm Phase II Study for Relapsed Germ Cell Tumours with Poor Prognosis
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Summary
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EudraCT number |
2010-022795-31 |
Trial protocol |
GB |
Global end of trial date |
05 May 2021
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Results information
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Results version number |
v1 |
This version publication date |
19 May 2024
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First version publication date |
19 May 2024
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Other versions |
v2 |
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 |
TE 2010-12
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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 |
Barts Health NHS Trust
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Sponsor organisation address |
Joint Research and Management Office, 5 Walden Street, London, United Kingdom, E1 2EF
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Public contact |
Dr Jonathan Shamash, Barts Health NHS Trust, +44 02078827260, sponsorrep@bartshealth.nhs.net
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Scientific contact |
Dr Jonathan Shamash, Barts Health NHS Trust, +44 2078827260, sponsorrep@bartshealth.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 |
05 May 2021
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
05 May 2021
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Global end of trial reached? |
Yes
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Global end of trial date |
05 May 2021
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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 determine objective response rate (ORR). ORR is defined as the number of patients with an objective response (OR) divided by the number of patients analysed.
Objective response (OR) is defined as the number of patients with either (1) a complete response (CR) or partial response marker negative (PRm-) using the end of treatment overall response data, or (2) marker negative at screening who are operable with a post-surgery outcome of CR or PR, or (3) marker negative at screening who are not operable but survive and remain radiologically progression-free for one year from the date of enrolment.
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Protection of trial subjects |
Since both the combination of oxaliplatin and paclitaxel or of oxaliplatin and irinotecan have similar activity in relapsed patients in the phase two setting [3] [6], this protocol was designed using pegylated filgrastim, actinomycin D, high dose methotrexate and weekly paclitaxel.
Patients received combination therapy for four cycles of 21 days each with weekly paclitaxel on days 8 and 15. The substitution was expected to lead to benefits in terms of toxicity reduction.
Sadeghi et al observed improved overall survival with acceptable neurotoxicity with an increase in oxaliplatin dose [10]. In the GAMMA trial oxaliplatin was initially administered at 100 mg/m2 on day 3 of each cycle with acceptable toxicity observed. To optimise the treatment the oxaliplatin dose was then increased to 170mg/m2 per 3 week cycle delivered as 85mg/m2 on day 4 and 85/g/m2 on day 8. Splitting the dose in to two gives greater control and avoids any theoretical increase in nephrotoxicity following methotrexate compared to giving the whole dose on day 3 (immediately after the methotrexate.
For this trial we assessed response using FDG-PET scans. FDG-PET scanning has a predictive role in several tumour types and has been used to demonstrate a rapid normalisation in metastatic germ cell tumours [2]. The additional radiation over diagnostic CT (as standard care) is minimal. A PET–CT scan was carried out before cycle two (between day 15-21 of cycle 1) and the results look to see whether early changes in glucose activity proved superior to early tumour marker decline to predict eventual outcome.
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Background therapy |
- | ||
Evidence for comparator |
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Actual start date of recruitment |
14 Nov 2012
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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: 44
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Worldwide total number of subjects |
44
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EEA total number of subjects |
0
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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) |
0
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Adults (18-64 years) |
44
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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 |
45 patients were enrolled between 14Nov2012 and 18Feb2020. 44 patients received study medication. | ||||||
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Pre-assignment
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Screening details |
45 patients with relapsed GCT (germ cell tumours) were enrolled between 14Nov2012 and 18Feb2020. | ||||||
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Period 1
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Period 1 title |
Recruitment (overall period)
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Is this the baseline period? |
Yes | ||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||
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Arms
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Arm title
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Recruitment | ||||||
Arm description |
This is a single arm phase II clinical study in patients with relapsed GCT. Patients received combination therapy for four cycles of 21 days each with weekly paclitaxel on days 8 and 15. | ||||||
Arm type |
Experimental | ||||||
Investigational medicinal product name |
Paclitaxel
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Paclitaxel 80mg/m2 will be given on Day 1, Day 8 and Day 15 of 21 day cycles for 4 cycles.
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Investigational medicinal product name |
Actinomycin D
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Actinomycin D 1mg/m2 on Day1 of 21day cycle for 4 cycles
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Investigational medicinal product name |
Methotrexate
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Infusion
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Dosage and administration details |
Methotrexate bolus loading dose in 250ml 0.9% sodium chloride followed by 12-hour infusion in 1000ml 0.9% sodium chloride on Day 1 of 21day cycle for 4 cycles. Doses are titrated against renal function. If serum creatinine rises by >15% the creatinine clearance should be recalculated.
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Investigational medicinal product name |
Oxaliplatin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Infusion
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Dosage and administration details |
Oxaliplatin 85mg/m2 in 500 ml 0.9% sodium chloride over 2 hours on Day 4 of 21day cycle for 4 cycles.
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Baseline characteristics reporting groups
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Reporting group title |
Recruitment
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Evaluable Population
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
This population includes all patients enrolled into the trial who completed at least 2 cycles of study medication, regardless of whether they were later found to be ineligible or a protocol violator. All efficacy analysis will also be performed on the evaluable population.
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End points reporting groups
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Reporting group title |
Recruitment
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Reporting group description |
This is a single arm phase II clinical study in patients with relapsed GCT. Patients received combination therapy for four cycles of 21 days each with weekly paclitaxel on days 8 and 15. | ||
Subject analysis set title |
Evaluable Population
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
This population includes all patients enrolled into the trial who completed at least 2 cycles of study medication, regardless of whether they were later found to be ineligible or a protocol violator. All efficacy analysis will also be performed on the evaluable population.
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End point title |
Objective Response Rate | ||||||||||||
End point description |
Objective response (OR) is defined as the number of patients with either (1) a CR or PRm- using the end of treatment overall response data, or (2) marker negative at screening who are operable with a post-surgery outcome of CR or PR, or (3) marker negative at screening who are not operable but survive and remain radiologically progression-free for one year from the date of enrolment. ORR is defined as the number of patients with an OR divided by the number of patients analysed.
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End point type |
Primary
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End point timeframe |
Baseline to maximum of 1-year post treatment
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Statistical analysis title |
Objective Response Rate | ||||||||||||
Comparison groups |
Recruitment v Evaluable Population
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Number of subjects included in analysis |
83
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Analysis specification |
Pre-specified
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Analysis type |
other [1] | ||||||||||||
Method |
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Parameter type |
Objective response rate | ||||||||||||
Point estimate |
0.5897
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Confidence interval |
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95% | ||||||||||||
sides |
2-sided
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lower limit |
0.4209 | ||||||||||||
upper limit |
0.7446 | ||||||||||||
| Notes [1] - ORR is defined as the number of patients with an OR divided by the number of patients analysed. |
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End point title |
Progression Free Survival | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline to end of treatment PET scan
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| No statistical analyses for this end point | |||||||||
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End point title |
Overall Survival Rate at 2 years | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline to 2 years
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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 |
From informed consent to 28 days after the last treatment dose
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
CTCAE | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
4
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Reporting groups
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Reporting group title |
Combination Therapy in GCT Patients
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Reporting group description |
This is a single arm phase II clinical study in patients with relapsed GCT. Patients will receive combination therapy for four cycles of 21 days each with weekly paclitaxel on days 8 and 15. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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21 Nov 2011 |
PIS Updated as per REC comments in initial submission rejection letter dated 07Mar2012 |
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30 Apr 2012 |
Documents updated to reflect the change in sponsor to Barts Health NHS Trust following a merger of trusts. |
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27 Aug 2013 |
Updated list of concomitant medications |
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13 Sep 2013 |
- Changes to the inclusion/exclusion criteria
- Pegfilgrastim reclassified as a supportive agent
- Clarification on the administration of omitted paclitaxel dose in the first 3 patients |
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02 Jan 2014 |
- Change in dosing schedule for Oxaliplatin
- PIS & Consent Form amended to clarify use of anonymised study data in future ethically approved projects |
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27 Oct 2015 |
- Oxaliplatin to be administered on day 4 instead of day 3
- Trial specific ICF created for collected of samples for future research |
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16 May 2016 |
Expansion of the inclusion criteria to include patients with very low risk |
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22 Feb 2021 |
- To update the end of study definition (reduce from 2 years to 12months following completion of treatment).
- Addition of remote monitoring to the protocol.
- Minor updates to rectify errors in the statistical analysis sections as well as formatting errors. |
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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. | |||
| None reported | |||
