Clinical Trial Results:
A Phase II Trial of Sequential treatment with Cytoreductive therapy and Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation for Relapsed/ Refractory Acute Myeloid Leukemia, High Risk Myelodysplasia, or other High Risk Myeloid Malignancies
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Summary
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EudraCT number |
2007-000806-64 |
Trial protocol |
GB |
Global end of trial date |
09 Dec 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
08 Sep 2017
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First version publication date |
08 Sep 2017
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Other versions |
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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 |
BLT004973
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Additional study identifiers
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ISRCTN number |
ISRCTN32336114 | ||
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 |
JRMO, 5 Walden Street, London, United Kingdom, E1 2EF
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Public contact |
CECM Trials Team, Queen Mary University of London, 0044 02078828197, bci-cecmmonitoring@qmul.ac.uk
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Scientific contact |
CECM Trials Team, Queen Mary University of London, 0044 02078828197, bci-cecmmonitoring@qmul.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 Dec 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 |
09 Dec 2014
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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 determine whether it is safer and more effective, in treating high risk Myeloid Malignancies, to immediately follow chemotherapy with Allogeneic Haemopoietic Stem Cell Transplantation than to treat in two distinct phases, with a break to determine remission status.
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Protection of trial subjects |
Side effects were closely monitored during and after the study. The patient information sheet included details on expected adverse events for patients and clinicians to look out for and also detailed that unexpected events may occur. The independent data monitoring committee for the trial was in place throughout to closely assess the side effects of the interventiohn on a regular basis to make sure there were no excess risks to patients. Monitoring was performed throughout the study to provide real-time review of source data to allow for early detection of signals.
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Background therapy |
- | ||
Evidence for comparator |
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Actual start date of recruitment |
02 Jul 2007
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 54
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Worldwide total number of subjects |
54
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EEA total number of subjects |
54
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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) |
53
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From 65 to 84 years |
1
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85 years and over |
0
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Recruitment
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Recruitment details |
Between 24.7.07 and 9.12.14, 54 patients with refractory or relapsed Acute Myeloid Leukaemia, High Risk Myelodysplasia or other high risk Myeloid Malignancy were recruited within the United Kingdom. | ||||||||||
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Pre-assignment
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Screening details |
Inclusion criteria included patients with histologically documented AML (any WHO type), MDS or other high risk myeloid malignancy, with primary induction failure, or at relapse where the patient was not a candidate for a myeloablative transplant. | ||||||||||
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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 |
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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Study Intervention | ||||||||||
Arm description |
Sequential treatment with cytoreductive therapy and reduced inetnsity conditioning allogeneic stem cell transplantation | ||||||||||
Arm type |
Experimental | ||||||||||
Investigational medicinal product name |
Cytarabine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Low Dose Cytarabine(10mg/m2 sc bd for 14 days to be repeated at 28 day intervals if necessary) can be administered at the Investigator’s discretion for disease control in patients with rapidly progressive disease when conditioning has to be delayed (e.g awaiting unrelated donor clearance).
D-15: Cytarabine 1.5g/m2 (1 dose-pm) IV
D-14: Cytarabine 1.5g/m2 BD IV
D-13: Cytarabine 1.5g/m2 BD IV
D-12: Cytarabine 1.5g/m2 BD IV
D-11: Cytarabine 1.5g/m2 BD IV
D-10: Cytarabine 1.5g/m2 BD IV
D-9: Cytarabine 1.5g/m2 (1 dose-am) IV
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Investigational medicinal product name |
Daunorubicin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
D-15: Daunorubicin 45mg/m2 OD IV
D-14: Daunorubicin 45mg/m2 OD IV
D-13: Daunorubicin 45mg/m2 OD IV
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Investigational medicinal product name |
Cyclophosphamide
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
D-3: Cyclophosphamide 1 g/m2 IV in 500ml N/saline
D-2: Cyclophosphamide 1 g/m2 IV in 500ml N/saline
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Investigational medicinal product name |
Fludarabine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
D-6: Fludarabine 25 mg/m2 i.v. OD
D-5: Fludarabine 25 mg/m2 i.v. OD
D-4: Fludarabine 25 mg/m2 i.v OD
D-3: Fludarabine 25 mg/m2 IV
D-2: Fludarabine 25 mg/m2 IV
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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 |
Intravenous use
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Dosage and administration details |
D+1 Methotrexate 5mg/m2 IV OD
D+3 Methotrexate 5mg/m2 IV OD
D+6 Methotrexate 5mg/m2 IV OD
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Baseline characteristics reporting groups
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Reporting group title |
Overall Trial
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Study Intervention
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Reporting group description |
Sequential treatment with cytoreductive therapy and reduced inetnsity conditioning allogeneic stem cell transplantation | ||
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End point title |
Overall Survival (OS) at 1 and 2 years [1] | ||||||||||||||||||||||||||||||||
End point description |
Median OS for AML=11.64 months, median OS for MDS (not reached but lower limit of 95%CI is 3.96) >3.96 months, median OS for high-risk malignancy=3.6 months; p=0.25.
Median OS for over 60=4.1 months, median OS for under 60=1 year 3.24 months; p=0.34.
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End point type |
Primary
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End point timeframe |
Overall Survival (OS) at 1 and 2 years
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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 study and hence statistical analysis is not needed except the survival rate . |
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Attachments |
Untitled (Filename: Overall survival for patients that underwent RIC-AlloHSCT.jpg) Untitled (Filename: Overall survival for patients that underwent RIC-AlloHSCT for high-risk myeloid malignancy, MDS and relapsed refractory AML.jpg) Untitled (Filename: Overall survival for patients below the age of 60 and for patients 60 and above following RIC-AlloHSCT.jpg) |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||
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End point title |
Event Free Survival (EFS) at 1 and 2 years | ||||||||||||||||||||||||||||||||||||||||
End point description |
EFS is defined as the time between day 1 and relapse or death. Any patients to reach neither relapse nor death were censored at the last date of follow-up.
Median EFS for AML=9.4 months, median EFS for MDS (not reached but lower limit of 95%CI is 4) >4 months, median EFS for high-risk malignancy=2.3 months; p=0.25.
Median EFS for MUD=11.2 months, median EFS for MFD=8.5 months; p=0.98.
Median EFS for over 60=4.1 months, median EFS for under 60=9.4 months; p=0.67.
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End point type |
Secondary
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End point timeframe |
Event Free Survival (EFS) at 1 and 2 years
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Attachments |
Untitled (Filename: EFS of patients that underwent RIC-alloHSCT.jpg) Untitled (Filename: EFS of patients that underwent RIC-alloHSCT for high-risk myeloid malignancy, MDS and relapsed refractory AML.jpg) Untitled (Filename: EFS of patients that underwent RIC-alloHSCT with matched family donor and matched unrelated donor.jpg) Untitled (Filename: EFS of patients below the age of 60 and for patients 60 and above following RIC-AlloHSCT.jpg) |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||
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End point title |
Engraftment and Chimerism Analysis (Full Split Chimerism at Days 30, 60, 100 and 1 year following RIC Allo-HSCT) | ||||||||||||||||||||||||||||||||
End point description |
Neutrophil Engraftment and Platelet Engraftment are calculated as time between day 1 to first of two consecutive days with a neutrophil count exceeding 500/μ and to the first day of three consecutive days with an unsupported platelet count exceeding 20 x 109 / L respectively.
37 patients experienced complete haematologic recovery after RIC-allogeneic SCT. The median time to achieve more than 0.5x109/L neutrophils in the peripheral blood was 18.5 days (range, 10–30) after transplantation; a sustained platelet count greater than 20x109/L was achieved at 14.5 days (range, 6-39), 12 patients did not reach this count by the time of death or censoring) after transplantation.
Chimerism studies demonstrate that by one year median engraftment was 97%. Full split chimerism studies confirmed over 98% donor engraftment in both CD3 and CD15 at 1 year.
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End point type |
Secondary
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End point timeframe |
Time to Engraftment is categorised as Neutrophil Engraftment and Platelet Engraftment.
Full Split Chimerism at Days 30, 60, 100 and 1 year following RIC Allo-HSCT.
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Attachments |
Untitled (Filename: Neutrophil engraftment following transplantation.jpg) Untitled (Filename: Platelet engraftment following transplantation.jpg) |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||
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End point title |
Incidence and Grade of Acute Graft versus Host Disease (GVHD) | ||||||||||||||||||||||||
End point description |
Grades were only recorded for acute GVHD where available.
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End point type |
Secondary
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End point timeframe |
GVHD in patients following RIC Allo-HSCT.
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Treatment Related Mortality (TRM) at d100, 1 and 2 years and cause of mortality | ||||||||||||||||||
End point description |
Treatment Related Mortality Rate is calculated for deaths when there is no evidence of leukaemia within 100 days of treatment and then within 1 and 2 year.
Median TRM rates for MFD > 8.63 months.
Median TRM rates for MUD > 1 year 5.8 months.
Cause of mortality was mainly categorised as AML, GVHD or infection related.
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End point type |
Secondary
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End point timeframe |
Cumulative incidence of TRM at 100 days, 1 year and 2 years.
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Attachments |
Untitled (Filename: Treatment related mortality following RIC Allo-HSCT.jpg) Untitled (Filename: TRM following RIC-alloHSCT with matched family donor and matched unrelated donor.jpg) Untitled (Filename: Cause of mortality.jpg) |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Opportunistic Infections | ||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Incidence of opportunistic infections.
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| No statistical analyses for this end point | |||||||||||
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End point title |
Duration of Hospitalisation | ||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Median hospital stay.
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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 |
All serious adverse events recorded during the study are recorded. Non-serious adverse events are not recorded in this trial
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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 |
Overall trial
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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: No Non-serious adverse events are recorded in this trial. |
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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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08 Oct 2008 |
Alterations to chemotherapy schedule and supportive medications to ensure consistency with site standard practice. Redefined early closing rule of 'unacceptble toxicity'. Expanded AE reporting requirements. |
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09 Jul 2011 |
Implementation of temporary halt while DSMB reviewed data to confirm if stopping rule had been met. |
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20 Sep 2011 |
Re-open to recruitment following confirmation from DSMB. Exclusion criteria amended to prevent entry of patients >60 years. Introduction of regular DSMB monit9oring. Re-classifcation of MENSA, cyclosporine, and allogeneic blood stem cells as non-IMPs. |
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15 May 2012 |
Change of sponsor from Barts and the London NHS Trust to Barts Health NHS Trust following institutional mergers. |
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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. | |||||||
| A sample of 93 patients was aimed to establish a 95% CI of 0.1 but only 54 patients were accrued for the trial, with 49 undergoing transplant. | |||||||
