Clinical Trial Results:
A randomised phase 2 trial investigating the additional benefit of hydroxychloroquine (HCQ) to short course radiotherapy (SCRT) in patients aged 70 years and older with high grade gliomas (HGG)
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Summary
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EudraCT number |
2012-000091-41 |
Trial protocol |
GB |
Global end of trial date |
25 Jul 2019
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Results information
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Results version number |
v1(current) |
This version publication date |
13 Aug 2020
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First version publication date |
13 Aug 2020
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Other versions |
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Summary report(s) |
Hydroxychloroquine and short-course radiotherapy |
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/11/0404
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01602588 | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
Cancer Research UK reference number: CR UK11/057, CTA number: 20363/0310/001-0001 | ||
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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,
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Public contact |
Public Contact, Cancer Research UK and UCL Cancer
Trials Centre,, ctc.sponsor@ucl.ac.uk
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Scientific contact |
Scientific Contact, Cancer Research UK 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 |
25 Feb 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
25 Dec 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
25 Jul 2019
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
To examine the effect on one-year survival of giving hydroxychloroquine with SCRT to HGG patients aged 70 yrs or older and to assess the toxicity of giving HCQ with SCRT.
Primary endpoint
•One-year survival
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Protection of trial subjects |
Hydroxychloroquine was being used outside of its marketing authorisation. However, it has been used successfully in a phase 2 CML trial and in small studies of brain tumours. Hydroxychloroquine will be given at the same dose and via the same route as per the marketing authorisation. Subjects were provided with a diary card which include instructions for how many tablets should have been taken in order to take the correct dose. Full drug accountability was recorded by site and provided to UCL CTC upon request.
Regular monitoring of safety data was conducted by IDMC and the trial conduct was overseen by the TMG and TSC. Patients were regularly assessed while on treatment and on follow up. Appropropriate entry criteria were in place to ensure only eligible and suitable patients entered the trial.
Assessments were carried out at different points of treatment and the trial to ensure safety of participants. Pre-treatment assessments included post-operative MRI scan and visual assessment by an opthalmologist for patients on Arm B. Assessments during treatment included review of adverse events and steroid dose. After completion of the trial, patients were assessed with a complete physical examination including full neurological examination, review of concomitant medication, review of steroid dose, review of any adverse events, ECOG performance status, mini-mental status examination, blood tests and an electrocardiogram (for Arm B patients).
The protocol also provided information on how to manage adverse events (including haematology, eye, metabolic and nutritional disorders) and possible supportive medication. As it was not known if there was a direct risk to pregnancy due to exposure to HCQ, male patients with female partners of child bearing potential were asked to use adequate contraception. As the inclusion criteria required patients to be over 70, it was anticipated that any female patients would not be of child bearing potential.
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Background therapy |
Radiotherapy Patients receive short course radiotherapy: Patients were planned using conformal radiotherapy. Radiotherapy started within 4 weeks of surgery (Day 28 post surgery). A window of +/- 3 days was permitted. Dose fractionation Short course radiotherapy was given as a total dose of 30Gy in 6 fractions given on alternate days (Monday, Wed and Friday) over 2 weeks prescribed to the intersection point (IP). | ||
Evidence for comparator |
Many centres recommend short course ‘high dose palliation’ radiotherapy (SCRT) using hypofractionated regimes, which have been shown to be as effective as prolonged treatment courses. Sources: Roa, W., et al., Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: A prospective randomized clinical trial. Journal of Clinical Oncology, 2004. 22(9): p. 1583-1588. Malmstrom, A., et al., Glioblastoma in Elderly Patients: Health-Related Quality of Life (Hrqol) in a Randomized Trial Comparing 6-Weeks of Tadiotherapy (Rt) Vs Hypofractionated Rt over 2 Weeks Vs Temozolomide Chemotherapy (Tmz). Neuro-Oncology, 2010. 12: p. 18-19. | ||
Actual start date of recruitment |
20 May 2013
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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: 53
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Worldwide total number of subjects |
53
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EEA total number of subjects |
53
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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) |
0
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From 65 to 84 years |
53
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85 years and over |
0
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Recruitment
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Recruitment details |
54 patients were recruited onto the trial from May 2013 to September 2016 of which 1 patient was inelgibile and therefore excluded. There were 17 sites activated in the trial. 16 recruited patients and 2 did not. | |||||||||
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Pre-assignment
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Screening details |
No screening information to provide for this trial. Patients were screened for eligibility for inclusion into the trial as per trial protocol. | |||||||||
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Period 1
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Period 1 title |
Main trial (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||
Blinding implementation details |
N/A
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Arm A - SCRT alone | |||||||||
Arm description |
4 weeks post surgery (day 28 post surgery +/- 3 days) patients will commence short course radiotherapy (30 Gy, 5Gy/day, 6 fractions Mon, Weds, Fri) over a 2 week period. 2 of the 18 patients did not receive radiotherapy but still included in the ITT analysis | |||||||||
Arm type |
control | |||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Arm title
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Arm B - SCRT + HCQ | |||||||||
Arm description |
Patients randomised to Arm B will commence Hydroxychloroquine 200mg per oral twice daily starting from day 14-20 post surgery until radiological or clinical progression. At 4 weeks post surgery (day 28 with a window of +/- 3days), patients will commence short course radiotherapy of 30 Gy in total over 2 weeks. (5 Gy/day, 6 fractions on Monday, Wednesday and Friday). Patients should have been taking HCQ for at least 7 days before receiving radiotherapy treatment. 36 patients were randomised to this arm. 1 was ineligible. Of the 35 eligible patients all received SCRT and HCQ but 2 did not receive the protocol radiotherapy dose (one received 30Gy over 7 fractions and one received 2 fractions). They are included in the IIT analysis. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Plaquenil
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
200mg HCQ should be taken twice daily starting from between day 14 to day 20 post surgery until radiological or clinical progression.
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Baseline characteristics reporting groups
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Reporting group title |
Arm A - SCRT alone
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Reporting group description |
4 weeks post surgery (day 28 post surgery +/- 3 days) patients will commence short course radiotherapy (30 Gy, 5Gy/day, 6 fractions Mon, Weds, Fri) over a 2 week period. 2 of the 18 patients did not receive radiotherapy but still included in the ITT analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Arm B - SCRT + HCQ
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Reporting group description |
Patients randomised to Arm B will commence Hydroxychloroquine 200mg per oral twice daily starting from day 14-20 post surgery until radiological or clinical progression. At 4 weeks post surgery (day 28 with a window of +/- 3days), patients will commence short course radiotherapy of 30 Gy in total over 2 weeks. (5 Gy/day, 6 fractions on Monday, Wednesday and Friday). Patients should have been taking HCQ for at least 7 days before receiving radiotherapy treatment. 36 patients were randomised to this arm. 1 was ineligible. Of the 35 eligible patients all received SCRT and HCQ but 2 did not receive the protocol radiotherapy dose (one received 30Gy over 7 fractions and one received 2 fractions). They are included in the IIT analysis. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Arm A - SCRT alone
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Reporting group description |
4 weeks post surgery (day 28 post surgery +/- 3 days) patients will commence short course radiotherapy (30 Gy, 5Gy/day, 6 fractions Mon, Weds, Fri) over a 2 week period. 2 of the 18 patients did not receive radiotherapy but still included in the ITT analysis | ||
Reporting group title |
Arm B - SCRT + HCQ
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Reporting group description |
Patients randomised to Arm B will commence Hydroxychloroquine 200mg per oral twice daily starting from day 14-20 post surgery until radiological or clinical progression. At 4 weeks post surgery (day 28 with a window of +/- 3days), patients will commence short course radiotherapy of 30 Gy in total over 2 weeks. (5 Gy/day, 6 fractions on Monday, Wednesday and Friday). Patients should have been taking HCQ for at least 7 days before receiving radiotherapy treatment. 36 patients were randomised to this arm. 1 was ineligible. Of the 35 eligible patients all received SCRT and HCQ but 2 did not receive the protocol radiotherapy dose (one received 30Gy over 7 fractions and one received 2 fractions). They are included in the IIT analysis. | ||
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End point title |
Overall survival | ||||||||||||
End point description |
From Kaplan-Meier estimates
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End point type |
Primary
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End point timeframe |
One year
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Statistical analysis title |
Primary outcome | ||||||||||||
Statistical analysis description |
The OS rates at 1 year came from Kaplan-Meier estimates (life tables).
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Comparison groups |
Arm B - SCRT + HCQ v Arm A - SCRT alone
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Number of subjects included in analysis |
53
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Analysis specification |
Pre-specified
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Analysis type |
superiority [1] | ||||||||||||
P-value |
< 0.05 | ||||||||||||
Method |
Regression, Cox | ||||||||||||
Confidence interval |
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| Notes [1] - We used a single-arm phase II A’Hern design, with a target 1-year OS rate of 40% using hydroxychloroquine, assuming 25% for radiotherapy alone. With one-sided 15% statistical significance and 80% power, we required 13 patients to be alive at 1 year out of 38 patients given hydroxychloroquine to justify further investigation. We also compared OS between the two trial arms using Cox regression to produce hazard ratio, though the trial was not powered for this direct comparison. |
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End point title |
Progression free survival | ||||||||||||
End point description |
Radiological progression free survival at 6 months as defined from the day of randomisation to the day of local tumour progression or recurrence based on the modified RANO response criteria for MRI, or the day of death of any cause.
Clinical progression free survival at 6 months as defined from the day of randomization to the day of local tumour progression or recurrence based on clinical evaluation, or the day of death of any cause.
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End point type |
Secondary
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End point timeframe |
From the day of randomisation to 6 months post randomisation.
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Adverse events information
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Timeframe for reporting adverse events |
All adverse events that occur between informed consent and 30 days post last trial treatment administration. Non-serious AEs: not presented in line with manuscript
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Adverse event reporting additional description |
Adverse events were recorded in the patient notes and reported to the coordinating centre via the trial CRFs. Those meeting the definition of a Serious Adverse Event (SAE) were reported using the trial specific SAE Report. Causality assessment to study IMPs was performed by site investigator and study CI.
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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 |
Arm A - SCRT alone
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Reporting group description |
4 weeks post surgery (day 28 post surgery +/- 3 days) patients will commence short course radio therapy (30 Gy, 5Gy/day, 6 fractions Mon, Weds, Fri) over a 2 week period. Serious adverse events below is defined as all grade 3-5 events. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Arm B - SCRT + HCQ
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Reporting group description |
Patients randomisedto Arm B will commence Hydroxychloroquine 200mg per oral twice daily from day 14-20 post surgery until radiological or clinical progression. At 4 weeks post surgery (day 28 with a window of +/- 3days), patients will commence short course radio therapy of 30 Gy in total over 2 weeks. (5 Gy/day, 6 fractions on Monday, Wednesday and Friday). Patients should have been taking HCQ for at least 7 days before receiving radiotherapy treatment. Serious adverse events is defined as all grade 3-5 events. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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11 Aug 2014 |
The protocol amendment was primarily to make changes in 1) the randomisation period to give greater flexibility for sites to assess/screen potential subjects and 2) addition of management of a potential adverse event ‘hypoglycaemia’ to the protocol due to the updated version of the SPC for trial IMP ‘hydroxychloroquine’. The amendment will changed the version number of the Protocol from v1.1 to v2.0.
Main cahnges include:
• To clarify the radiotherapy treatment should start within 4 weeks of surgery (Day 28 post surgery). A window of +/- 3 days is permitted
• Arm B patients should have been taking HCQ for at least 7 days prior to receiving SCRT (A window of +/- 3 days is permitted)
• Randomisation can be taken place between day 1 to day 19 post surgery.
• Review of concomitant medications to identify those patients taking anti-diabetic medications is added to pre-randomisation evaluations. Diabetic patients should be made aware of the risk of hypoglycaemia and the associated clinical signs and symptoms and that their requirements for diabetic medication may decrease and that they should actively monitor their glucose measurements.
• Management of adverse events due to treatment – hydroxychloroquine has been added. Actions to be taken in the event of haematological toxicities, eye disorders and hypoglycaemia
• Visual assessment should be repeated every 12 months whilst patient is still taking hydroxychloroquine after their visual assessments at 6 and 12 months post completion of radiotherapy.
• Sites which are participating the translational research will consent to patients to translational research in order to carry out follicle and blood sample collections.
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Interruptions (globally) |
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| Were there any global interruptions to the trial? Yes | |||||||
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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. | |||||||
| Serious AEs: occurrences all number can't be provided as only highest grade experienced by patients are collected on CRFs; subjects affected is entered instead (only grade 3-5 reported) Treatment related death/relatedness to SAEs not presented | |||||||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/32642699 |
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