Clinical Trial Results:
An open label, multi-centre, randomised, parallel group phase II selection trial to identify the optimal starting dose of bendamustine (60 vs 100 mg/m2) when given in combination with thalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma
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Summary
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EudraCT number |
2010-021451-12 |
Trial protocol |
GB |
Global end of trial date |
11 Apr 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
08 Jul 2016
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First version publication date |
05 Aug 2015
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Other versions |
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Summary report(s) |
MUK01 End of Trial Report |
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 |
HM10/9422
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Additional study identifiers
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ISRCTN number |
ISRCTN90889843 | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
University of Leeds
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Sponsor organisation address |
Hyde Terrace, Leeds, United Kingdom, LS2 9LN
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Public contact |
QA department, Leeds Institute of Clinical Trials Research, ctruq@leeds.ac.uk
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Scientific contact |
QA department, Leeds Institute of Clinical Trials Research, ctruq@leeds.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 |
09 Jul 2013
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
09 Jul 2013
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Global end of trial reached? |
Yes
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Global end of trial date |
11 Apr 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 |
The primary objective of this study is to determine the optimum dose of bendamustine when combined with thalidomide and dexamethasone (BTD) in the treatment of relapsed/refractory multiple myeloma, based on response rates, tolerability, and progression-free survival (PFS).
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Protection of trial subjects |
Patients will be monitored closely throughout the trial and will be asked to attend regular outpatient appointments.
Some visits will involve taking extra blood, urine and bone marrow samples. The additional samples will be taken at the same time as routine samples so will not involve additional needle punctures. Bone marrow tests are potentially painful. The potential side effects of the treatments used in this trial are explained within the patient information sheet. Treatment modifications will be made and supportive care given to minimise the side effects.
The frequency of the outpatient appointments during the follow up phase to monitor for disease progression will be
more than standard care. These visits will involve taking a blood and urine sample. Sites will endeavour to fast track
patients through clinics or day units where possible.
CTRU will prepare safety reports at least annually to the following: MHRA, main REC, Sponsor and the DMEC. All data will be anonymised. SAEs related to some of the IMPs will be shared with the relevant pharmaceutical company, who may pass this information outside the EEA. This is made explicit in the patient information sheet.
Trial data collected on paper will be sent to the CTRU and filed in locked filing cabinets. The CTRU reserve the option
of sharing anonymised data to evaluate safety, if required (eg. MHRA) and to develop new research including meta analysis.
Data is entered onto a trial database application, MACRO. The database is stored on a private network protected by a
firewall. Access to the database is restricted to trials staff by login and password.
The CTRU will comply with all aspects of Data Protection Act 1998. All information collected during the course of the
trial will be kept strictly confidential. All data collection forms, except consent forms, that are transferred to or from the
CTRU will be coded
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
03 Jan 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: 95
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Worldwide total number of subjects |
95
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EEA total number of subjects |
95
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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) |
51
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From 65 to 84 years |
44
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85 years and over |
0
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Recruitment
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Recruitment details |
Between January 2011 and July 2012 a total of 95 patients were entered into the MUK one trial. Recruitment was temporarily halted in September 2011 to allow the interim analysis to take place. As a result of this analysis all patients recruited from March 2012 were registered to receive 60mg/m2 Bendamustine with thalidomide and dexamethasone. | |||||||||
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Pre-assignment
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Screening details |
Patients will be approached during standard clinic visits for management of their disease and will be provided with verbal and written details about the trial. This will include detailed information about the rationale, design and personal implications of the trial. | |||||||||
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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 |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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B60TD 60mg/m2 | |||||||||
Arm description |
60mg/m2 Bendamustine with thalidomide and dexamethasone (B60TD) This was given over a 28 day cycle. Bendamustine given by IV on days 1 and 8, thalidomide given orally continuously, dexamethasone given orally on days 1, 8, 15 and 22. Treatment was given for a minimum of 6 cycles and up to 9 cycles, unless the treatment was not tolerated. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Bendamustine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
25mg bendamustine hydrochloride.
Reconstitute each vial of bendamustine containing 25mg bendamustine hydrochloride in 10 ml water for injection by shaking. The reconstituted concentrate contains 2.5mg bendamustine hydrochloride per ml and appears as a clear colourless solution.
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Investigational medicinal product name |
Thalidomide
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Oral 100mg/day Days 1 to 28. It is recommended that thalidomide is administered as a single dose at bedtime to reduce the impact of somnolence.
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Investigational medicinal product name |
Dexamethasone
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Oral 20mg/day Days 1, 8, 15, 22. It is recommended that dexamethasone is administered as a single dose in the morning.
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Arm title
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B100TD 100mg/m2 | |||||||||
Arm description |
100mg/m2 Bendamustine with thalidomide and dexamethasone (B100TD). This was given over a 28 day cycle. Bendamustine given by IV on days 1 and 8, thalidomide given orally continuously, dexamethasone given orally on days 1, 8, 15 and 22. Treatment was given for a minimum of 6 cycles and up to 9 cycles, unless the treatment was not tolerated. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Bendamustine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Reconstitute each vial of bendamustine containing 100mg bendamustine hydrochloride in 40ml water for injection by shaking. The reconstituted concentrate contains 2.5mg bendamustine hydrochloride per ml and appears as a clear colourless solution.
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Investigational medicinal product name |
Thalidomide
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
100mg/day Days 1 to 28, It is recommended that thalidomide is administered as a single dose at bedtime to reduce the impact of somnolence.
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Investigational medicinal product name |
Dexamethasone
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
20mg/day Days 1, 8, 15, 22. It is recommended that dexamethasone is administered as a single dose in the morning.
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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: One patient was randomised to receive B60TD but the patient withdrew from the trial prior to starting treatment. |
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Baseline characteristics reporting groups
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Reporting group title |
B60TD 60mg/m2
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Reporting group description |
60mg/m2 Bendamustine with thalidomide and dexamethasone (B60TD) This was given over a 28 day cycle. Bendamustine given by IV on days 1 and 8, thalidomide given orally continuously, dexamethasone given orally on days 1, 8, 15 and 22. Treatment was given for a minimum of 6 cycles and up to 9 cycles, unless the treatment was not tolerated. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
B100TD 100mg/m2
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Reporting group description |
100mg/m2 Bendamustine with thalidomide and dexamethasone (B100TD). This was given over a 28 day cycle. Bendamustine given by IV on days 1 and 8, thalidomide given orally continuously, dexamethasone given orally on days 1, 8, 15 and 22. Treatment was given for a minimum of 6 cycles and up to 9 cycles, unless the treatment was not tolerated. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
B60TD 60mg/m2
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Reporting group description |
60mg/m2 Bendamustine with thalidomide and dexamethasone (B60TD) This was given over a 28 day cycle. Bendamustine given by IV on days 1 and 8, thalidomide given orally continuously, dexamethasone given orally on days 1, 8, 15 and 22. Treatment was given for a minimum of 6 cycles and up to 9 cycles, unless the treatment was not tolerated. | ||
Reporting group title |
B100TD 100mg/m2
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Reporting group description |
100mg/m2 Bendamustine with thalidomide and dexamethasone (B100TD). This was given over a 28 day cycle. Bendamustine given by IV on days 1 and 8, thalidomide given orally continuously, dexamethasone given orally on days 1, 8, 15 and 22. Treatment was given for a minimum of 6 cycles and up to 9 cycles, unless the treatment was not tolerated. | ||
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End point title |
The proportion of patients achieving at least a partial response [1] | |||||||||||||||
End point description |
This forms one of the joint primary endpoints of the trial: the proportion of patients achieving at least a partial response (as defined by the Modified International Working Group (IWG) Uniform Response Criteria) within six cycles of treatment, and the proportion of patients successfully able to receive both doses of their second cycle of bendamustine at full dose with no more than a 2 week delay.
The proportion of patients achieving at least a partial response is based on independently assessed response data.
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End point type |
Primary
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End point timeframe |
within six cycles of treatment
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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: There was no formal comparison of the treatment arms. The trial was not designed to make any formal comparisons but to look at the arms independently, with focus on the lower limit of the 80% confidence intervals around the proportions. it has not been possible to add these values to the system as this is a countable outcome. |
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| No statistical analyses for this end point | ||||||||||||||||
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End point title |
Progression-free survival at 12 months post-randomisation/registration [2] | ||||||||||||
End point description |
The primary endpoint of progression-free survival at 12 months post-randomisation/registration is used to allow treatment selection should both dosing schedules be determined sufficiently efficacious and tolerable.
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End point type |
Primary
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End point timeframe |
12 months post-randomisation/registration.
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| Notes [2] - 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: At the outset of the trial it was originally planned that the PFS endpoint would be used as a secondary selection criterion in the event that both B60TD and B100TD arms passed the activity and tolerability boundaries. Since the B100TD arm was closed to recruitment due to unacceptable tolerability this was not required. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
The proportion of patients successfully able to receive both doses of their second cycle of bendamustine at full dose with no more than a 2 week delay [3] | |||||||||||||||
End point description |
This forms on of the joint primary endpoints of the trial: the proportion of patients achieving at least a partial response (as defined by the Modified International Working Group (IWG) Uniform Response Criteria) within six cycles of treatment, and the proportion of patients successfully able to receive both doses of their second cycle of bendamustine at full dose with no more than a 2 week delay.
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End point type |
Primary
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End point timeframe |
2 cycles of treatment
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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: There was no formal comparison of the treatment arms. The trial was not designed to make any formal comparisons but to look at the arms independently, with focus on the lower limit of the 80% confidence intervals around the proportions. it has not been possible to add these values to the system as this is a countable outcome. |
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| Notes [4] - Two patients were not assessable for tolerability. |
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| No statistical analyses for this end point | ||||||||||||||||
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End point title |
Maximum response rate | |||||||||||||||||||||||||||||||||
End point description |
Maximum response summaries are based on independently assessed response.
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End point type |
Secondary
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End point timeframe |
Within 6 cycles of treatment
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||
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End point title |
Proportion of patients successfully receiving 6 cycles of treatment with no dose reductions or delays of more than 2 weeks | |||||||||||||||
End point description |
The proportion of patients successfully receiving six cycles of treatment with no dose reductions (with the exception of day 8, cycle 1) or delays of more than 2 weeks
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End point type |
Secondary
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End point timeframe |
6 cycles of treatment
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| No statistical analyses for this end point | ||||||||||||||||
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End point title |
Response duration | ||||||||||||
End point description |
Response duration is defined as the time from date of achieving at least a PR within six cycles of treatment to the date of disease progression.
Patients who do not achieve at least a PR (including who have died without achieving a PR) are not included in this endpoint. Patients who achieve at least a PR and who die from causes other than disease progression are censored at the date of death. Patients who achieve at least a PR and who do not progress by the time of analysis will be censored at the last date they were known to be alive and progression free.
Response duration is based on locally assessed response therefore numbers of patients with at least a PR differ to those for the primary endpoint and maximum response summaries.
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End point type |
Secondary
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End point timeframe |
From the date of achieving a partial response until the date of disease progression
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Time to next treatment | ||||||||||||
End point description |
Time to next treatment is defined as time from randomisation/registration to the date patient receives new treatment due to disease progression. Patients not receiving further treatment due to disease progression by the time of analysis will be censored at the last date known to be alive and not receiving further treatment. Patients who have died prior to receiving any further treatment will be censored at the date of death. Patients who receive further treatment but not due to disease progression will be censored at the date new treatment was received; if there are any cases where this information is not available patients will be censored at the last time they were known to have not received any new treatment.
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End point type |
Secondary
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End point timeframe |
Time from registration to the date patient receives further treatment due to disease progression
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| No statistical analyses for this end point | |||||||||||||
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End point title |
overall survival | ||||||||||||
End point description |
Patients alive at the time of analysis will be censored at the last date known to be alive.
**NB the upper limit of the 95% confidence interval for median OS in the B60TD has been given as 99999 as the upper limit was not calculated due to the last patient being censored. This would ordinarily be set to '.', i.e. not calculated
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End point type |
Secondary
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End point timeframe |
From date of randomisation/registration to date of death from any cause.
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| No statistical analyses for this end point | |||||||||||||
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Adverse events information [1]
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Timeframe for reporting adverse events |
Adverse reactions will be collected for all patients from the time of start of protocol treatment until 30 days post cessation of trial therapy.
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Assessment type |
Systematic | ||
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Dictionary used for adverse event reporting
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Dictionary name |
body system coding | ||
Dictionary version |
1
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| Frequency threshold for reporting non-serious adverse events: 0% | |||
| Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: See attached End of Trial Report submitted to the MHRA in February 2015 for details of adverse events. Leeds Institute of Clinical Trials Research is an academic trials unit where full MedDRA coding is not the standard. It has therefore not been possible for adverse event data to be accurately entered into the full data view within EudraCT as all mandatory categories cannot be completed. |
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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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24 Mar 2011 |
As part of the trial,patients will get the opportunity to take part in the King’s College London Haemato-Oncology
Tissue Bank Project (REC ref 08/H0906/94). Participation will be entirely optional and patients will be provided with a separate information sheet and consent form specific to the tissue bank.
An additional stipulation that any brand of dexamethasone can be used in the trial in accordance with the protocol and section D2-2 in the EudraCT application form, that section D2-1 should not be completed. |
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18 Jul 2011 |
Exclusion criteria in the Protocol was updated to include:
G-CSF is permitted for no more than 7 days prior to enrolment.
Steroid treatment totalling greater than 160mg in the 14 days prior to enrolment.
Additional indemnity statements were also included. |
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07 Nov 2011 |
Following a review by the DMEC the 100 mg arm of this study was closed and further recruitment temporarily suspended. The DMEC are currently reviewing further data from the 60 mg arm and will advise further |
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08 Nov 2011 |
The inclusion criteria was updated to include:
Unsupported platelet count >75 x 109/L within 48 hours before enrolment (unless solely attributable to the myeloma in the opinion of the local investigator).
Absolute neutrophil count >1.5 x109/L within 48 hours before enrolment (unless solely attributable to the myeloma in the opinion of the local investigator). G-CSF is permitted for no more than 7 days prior to enrolment.
The exclusion criteria was updated to remove:
Unsupported platelet count <75 x 10/9L within 14 days before enrolment (unless attributable solely to myeloma in the opinion of the local investigator)
Absolute neutrophil count <105 x 109L within 14 days before enrolement. G-CSF is permitted for no more than 7 days prior to enrolment.
Study definition of the protocol updated to include:
' If a patient is unable to receive both day 1 and day 8 of cycle 2 bendamustine at full dose, with no more than a 2 week delay, due to a low neutrophil count, this patient’s data will be independently assessed to incorporate response assessments and all marker data in order to determine whether a low neutrophil count is likely due to disease or intolerability of bendamustine treatment. Only those patients for whom the independent review deems intolerability of bendamustine treatment will be classed as not able to tolerate treatment.'
Primary Endpoint Analyses updated to include:
An independent assessment of those patients unable to receive both day 1 and day 8 of cycle 2 bendamustine at full dose, with no more than a 2 week delay, due to a low neutrophil count, will be performed to incorporate response assessments and all marker data in order to determine whether a low neutrophil count is likely due to disease or intolerability of bendamustine treatment. The number of patients to which this applies, and the outcome of the independent assessment, will be summarized. |
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06 Jan 2012 |
Following a temporary suspension to the trial upon the advice of the DMEC and TSC the trial was reopened in the 60mg bendamustine arm only. |
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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. | |||||||
| The results presented are the ITT population only. The analysis was also performed for a per protocol population and study eligible population, as outlined in the attached end of trial report | |||||||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/25891006 |
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