Clinical Trial Results:
An Evaluation of the Tolerability and Feasibility of combining 5-Amino-Levulinic Acid (5-ALA) with Carmustine Wafers (Gliadel) in the Surgical Management of Primary Glioblastoma (GALA-5 Trial)
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Summary
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EudraCT number |
2010-022496-66 |
Trial protocol |
GB |
Global end of trial date |
07 Mar 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
26 Oct 2016
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First version publication date |
26 Oct 2016
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Other versions |
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Summary report(s) |
End of trial report submitted to REC. Publication is being drafted at the time of EMA submission |
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 |
UCL/09/0398
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Additional study identifiers
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ISRCTN number |
ISRCTN77105850 | ||
US NCT number |
NCT01310868 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
University College London
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Sponsor organisation address |
Joint Research Office, Gower Street, London, United Kingdom, WC1E6BT
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Public contact |
Public contact, CRUK and UCL Cancer Trials Centre, ctc.sponsor@ucl.ac.uk
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Scientific contact |
Scientific contact, CRUK and UCL Cancer Trials Centre, ctc.sponsor@ucl.ac.uk
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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 |
19 Jan 2015
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
07 Mar 2014
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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 |
Treatments for patients with glioblastoma are limited. It accounts for around 60% of brain tumours and life expectancy in optimally managed patients is 12-14 months. Treatment options for patients with glioblastoma represents a major unmet need.
To establish that the combined use of 5-ALA and Carmustine wafers is safe and does not compromise a patient from receiving or completing standard chemo-radiotherapy.
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Protection of trial subjects |
Patients were closely monitored for site effects following surgery/treatment so they could be treated quickly.
There was a chance patients may have died after surgery following 5-ALA administration and therefore all surgeons using 5-ALA in this trial had to receive training by Medac to minimise this risk.
Treatment for cancer is inherently toxic and like all medication can cause side effects. Many of the anticipated side effects of the two trial drugs were no different to those of other chemotherapy drugs that might be offered to patients off-trial but patients were closely monitored for side effects (including monitoring blood pressure, blood results etc.).
Because 5-ALA should be used in caution in patients with low blood pressure/ cardiac/renal impairment patients with active liver disease, or significant comorbidity precluding radical aggressive therapy were not eligible for the trial. Patients were kept away from UV light sources (e.g windows) for 24 hours after surgery to prevent photosensitivity reactions.
Stopping criteria were in place so that the trial would be recommended to stop if >5% patients failed to start chemoRT due to surgical complications.
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Background therapy |
Treatment with temozolomide and RT was to continue as normal based on standard clinical protocols determined by the neuro-oncologist. For patients which the neuro-oncologists judged to be fit enough, the standard Stupp chemoRT regimen was followed: • Radiotherapy: 60Gy in 30 fractions (2Gy per fraction given once daily, five days per week (Monday-Friday) over 6 weeks. Radiotherapy delivered to gross tumour volume with 2-3cm margin • Concomitant chemotherapy: temozolomide given alongside the radiotherapy at 75mg/m2 daily from the first day of radiotherapy, until the last day of radiotherapy, but for no longer than 49 days • 4 week break • Adjuvant chemotherapy: temozolomide given 150-200mg/m2 TMZ 5/28* days for 6 cycles (dosage increase to 200mg/m2 on second and subsequent cycles dependent on haematological toxicity. Sites should follow local guidelines if different.). *TMZ to be given on 5 consecutive days followed by 23 days with no TMZ, per cycle. | ||
Evidence for comparator |
not applicable - no comparitor used | ||
Actual start date of recruitment |
07 Jul 2011
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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: 72
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Worldwide total number of subjects |
72
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EEA total number of subjects |
72
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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) |
54
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From 65 to 84 years |
18
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85 years and over |
0
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Recruitment
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Recruitment details |
Date first site open: 22/06/2011 Date first patient entered: 08/07/2011 Date final patient entered: 05/05/2013 72 patients were recruited across 10 sites in the UK. | ||||||||||||||
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Pre-assignment
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Screening details |
Screening was performed to confirm eligibility - see reporting group description | ||||||||||||||
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Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||
Blinding implementation details |
Single arm trial. Blinding not required.
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Arms
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Arm title
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5-ALA and Carmustine wafers | ||||||||||||||
Arm description |
Patients drank up to 20mg/kg of 5-aminolevulinic acid hydrochloride 3-5 hours prior to the beginning of anesthesia. Carmustine wafers (Gliadel implants) are small discs containing carmustine 7.7mgs (a cytotoxic chemotherapeutic agent) and an inactive ingredient, proliferosan 20. Carmustine implants were inserted (as a single episode) into the cavity left on completion of brain tumour resection. During surgery up to eight discs may have been used to line the resection cavity. | ||||||||||||||
Arm type |
Experimental | ||||||||||||||
Investigational medicinal product name |
Carmustine Wafers
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Investigational medicinal product code |
L01AD0I
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Other name |
Gliadel
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Pharmaceutical forms |
Implant
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Routes of administration |
Intracerebral use
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Dosage and administration details |
Max 61.6 mg carmustine - i.e. max 8 wafers each containing 7.7mg carmustine plus 192.3mg polifeprosan 20 (exipient) may have been placed in the resection cavity. The number of wafers dispensed depended on clinical judgement.
Oxidised regenerated cellulose (Surgicel) may have been placed over the implants to secure them to the cavity surface. After placement of the implants, the resection cavity should have been irrigated and the dura closed in a water-tight fashion.
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Investigational medicinal product name |
5-ALA
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Investigational medicinal product code |
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Other name |
5-aminolevulinic acid hydrochloride or Gliolan
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Pharmaceutical forms |
Powder for oral solution
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Routes of administration |
Oral use
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Dosage and administration details |
The patient drank up to 20mg/kg* of 5-aminolevulinic acid hydrochloride 3-5 hours prior to the beginning of anesthesia - with 5% dose rounding permitted.
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Baseline characteristics reporting groups
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Reporting group title |
Overall trial
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Reporting group description |
Inclusion criteria Patient reviewed by MDT and judged fit for treatment Stealth MRI (neuronavigation) prior to surgery and judged to have typical appearances of a primary GBM WHO performance status 0 or 1 Age ≥18 Exclusion criteria GBM thought to be transformed low grade or secondary disease There is uncertainty about the radiological diagnosis 5-ALA or Carmustine wafers is contra-indicated Pregnant or lactating women Known or suspected HIV or other significant infection or comorbidity that would preclude radical aggressive therapy for GBM Active liver disease (ALT or AST ≥5 x ULRR) Concomitant anti-cancer therapy except steroids History of other malignancies (except for adequately treated basal or squamous cell carcinoma or carcinoma in situ) within 5 years Previous brain surgery (including biopsy) or cranial radiotherapy Platelets <100 x109/L Mini mental status score <15 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
5-ALA and Carmustine wafers
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Reporting group description |
Patients drank up to 20mg/kg of 5-aminolevulinic acid hydrochloride 3-5 hours prior to the beginning of anesthesia. Carmustine wafers (Gliadel implants) are small discs containing carmustine 7.7mgs (a cytotoxic chemotherapeutic agent) and an inactive ingredient, proliferosan 20. Carmustine implants were inserted (as a single episode) into the cavity left on completion of brain tumour resection. During surgery up to eight discs may have been used to line the resection cavity. | ||
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End point title |
Proportion of 5-ALA resected patients receiving Carmustine wafers [1] | ||||||||
End point description |
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End point type |
Primary
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End point timeframe |
% 5-ALA resected patients receiving Carmustine wafers
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This is a single arm descriptive study. As advised by chersoni raffaella on 23/06/2016 for another study, we cannot post the results without entering the details of the statistical analysis as the system cannot accommodate one arm studies. |
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| Notes [2] - 59 patients eligible (glioblastoma confirmed peri/post-op, received 5-ALA and carmustine wafers) |
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of patients with post operative complication [3] | ||||||||||
End point description |
Number of patients with a new post-operative deficit or surgical complication (wound infection, CSF leakage, intracranial hypertension)
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End point type |
Primary
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End point timeframe |
post-surgery
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This is a single arm descriptive study. As advised by chersoni raffaella on 23/06/2016 for another study, we cannot post the results without entering the details of the statistical analysis as the system cannot accommodate one arm studies. |
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| Notes [4] - 59 patients eligible (glioblastoma confirmed peri/post-op, received 5-ALA and carmustine wafers) |
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| No statistical analyses for this end point | |||||||||||
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End point title |
Number of patients with chemoRT delay [5] | ||||||||||||||
End point description |
Number of patients with chemoRT delay (i.e number who do not begin chemoRT 6 weeks after surgery) due to surgical complications.
Standard chemoRT refers to the Stupp regimen as described earlier.
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End point type |
Primary
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End point timeframe |
Following surgery until the beginning of chemoRT
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| Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This is a single arm descriptive study. As advised by chersoni raffaella on 23/06/2016 for another study, we cannot post the results without entering the details of the statistical analysis as the system cannot accommodate one arm studies. |
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| Notes [6] - 59 patients eligible (glioblastoma confirmed peri/post-op, received 5-ALA and carmustine wafers) |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Number of patients failing to complete chemoRT without interruption [7] | ||||||||||||||||||||
End point description |
Number of patients failing to complete chemoRT without interruption (RT with concomitant chemotherapy, and RT with concomitant plus adjuvant chemotherapy)
Standard chemoRT refers to the Stupp regimen as described earlier.
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End point type |
Primary
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End point timeframe |
Duration of chemoRT
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| Notes [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This is a single arm descriptive study. As advised by chersoni raffaella on 23/06/2016 for another study, we cannot post the results without entering the details of the statistical analysis as the system cannot accommodate one arm studies. |
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| Notes [8] - 59 patients eligible (glioblastoma confirmed peri/post-op, received 5-ALA and carmustine wafers) |
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Proportion of patients with a lower WHO performance status after surgery with Carmustine wafers [9] | ||||||||||||||
End point description |
Proportion of patients with a lower WHO performance status after surgery with Carmustine wafers (at first post-operative clinic visit)
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End point type |
Primary
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End point timeframe |
Measured at first post-operative clinic visit
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| Notes [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This is a single arm descriptive study. As advised by chersoni raffaella on 23/06/2016 for another study, we cannot post the results without entering the details of the statistical analysis as the system cannot accommodate one arm studies. |
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| Notes [10] - 59 patients eligible (glioblastoma confirmed peri/post-op, received 5-ALA and carmustine wafers) |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Number of patients failing to start chemoRT due to surgical complications [11] | ||||||||||
End point description |
Number of patients failing to start chemoRT due to surgical complications.
Standard chemoRT refers to the Stupp regimen as described earlier.
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End point type |
Primary
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End point timeframe |
Post-surgery until decision to not administer chemoRT
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| Notes [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This is a single arm descriptive study. As advised by chersoni raffaella on 23/06/2016 for another study, we cannot post the results without entering the details of the statistical analysis as the system cannot accommodate one arm studies. |
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| Notes [12] - 59 patients eligible (glioblastoma confirmed peri/post-op, received 5-ALA and carmustine wafers) |
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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 |
All AEs that occurred between informed consent and 8 weeks post surgery or the end of all radiotherapy and concomitant and adjuvant chemotherapy, whichever is later (or after this date if the site investigator felt the event was trial treatment related)
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Adverse event reporting additional description |
As per publication, AEs have only been reported for the 59 eligible patients. SAEs are listed in full. Non-serious adverse events includes all events (including SAEs) of grade 3 or higher with a 5% threshold frequency.
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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 |
4.03
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Reporting groups
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Reporting group title |
All eligible patients (59)
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Reporting group description |
Patients received up to 20mg/kg 5-ALA prior to surgery and up to 8 carmustine wafers inserted into the resected cavity. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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10 Feb 2011 |
Response to REC comments: Protocol v2.0 with minor amendments & statistics section updated, Amended PIS v2.0 and consent form v2.0 as per RECs comments, IRAS form questions regarding loss of capacity answered |
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22 Feb 2011 |
Amendment to site IMP labelling requirements to meet Annex 13 clause 32 |
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25 May 2011 |
Change to IRAS filter question 7 (capacity to consent) in response to change to the IRAS wording. |
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24 Jun 2011 |
Protocol v3.0. Amendment to Pregnant Partner Information Sheet & ICF. New document: Pregnant Patient Information Sheet & ICF. |
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14 Feb 2012 |
5.1 MRI no longer ideally to be conducted on either no or stable steroids
5.1. MRI registration assessment date extended from 2 to 4 weeks. The MRI scan date given must correspond to the scan discussed at a recent MDT meeting from which a provisional diagnosis has been made.
5.3.1. Clarification that Stealth MRI (neuronavigation) will be performed prior to surgery. |
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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. | |||
| -non-serious AEs: 'occurrences all number' cannot be provided as only highest grade experienced by patients collected on CRF; subjects affected number is entered instead -serious AEs & non-serious AEs are listed under non-serious adverse event. | |||
