Clinical Trial Results:
A randomized placebo-controlled phase 2 study of decitabine with or without eltrombopag in AML patients ≥65 years of age not eligible for intensive chemotherapy
|
Summary
|
|
EudraCT number |
2014-003150-13 |
Trial protocol |
DE |
Global end of trial date |
26 Dec 2020
|
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
27 Jun 2024
|
First version publication date |
27 Jun 2024
|
Other versions |
|
Summary report(s) |
Clinical Study Report |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
|
Trial identification
|
|||
Sponsor protocol code |
TUD-DELTA1-063
|
||
|
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
NCT02446145 | ||
WHO universal trial number (UTN) |
- | ||
|
Sponsors
|
|||
Sponsor organisation name |
Technische Universität Dresden
|
||
Sponsor organisation address |
Helmholtzstraße 10, Dresden, Germany, 01069
|
||
Public contact |
Coordinating investigator, Coordinating investigator, MK1, Bereich Klinische Studien,, +49 3514585198, mk1-klinische-studien@ukdd.de
|
||
Scientific contact |
Coordinating investigator, Coordinating Investigator, MK1, Bereich Klinische Studien,, +49 3514585198, mk1-klinische-studien@ukdd.de
|
||
|
Paediatric regulatory details
|
|||
Is trial part of an agreed paediatric investigation plan (PIP) |
No
|
||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
|
Results analysis stage
|
|||
Analysis stage |
Final
|
||
Date of interim/final analysis |
26 Jun 2023
|
||
Is this the analysis of the primary completion data? |
Yes
|
||
Primary completion date |
26 Dec 2020
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
26 Dec 2020
|
||
Was the trial ended prematurely? |
Yes
|
||
|
General information about the trial
|
|||
Main objective of the trial |
To assess whether the addition of eltrombopag improves efficacy and tolerability of the standard treatment with hypomethylating agents in thrombocytopenic AML patients who are ≥65 years of age and nonfit for intensive chemotherapy
|
||
Protection of trial subjects |
An independent Data safety monitoring board (DSMB) was set in order to oversee the safety
of the trial subjects by periodic safety assessments of the trial therapy . The DSMB followed specific guidelines outlined in the
DSMB charter.
|
||
Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
18 Jun 2015
|
||
Long term follow-up planned |
Yes
|
||
Long term follow-up rationale |
Safety, Efficacy | ||
Long term follow-up duration |
60 Months | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
|
||
|
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
Germany: 132
|
||
Worldwide total number of subjects |
132
|
||
EEA total number of subjects |
132
|
||
Number of subjects enrolled per age group |
|||
In utero |
0
|
||
Preterm newborn - gestational age < 37 wk |
0
|
||
Newborns (0-27 days) |
0
|
||
Infants and toddlers (28 days-23 months) |
0
|
||
Children (2-11 years) |
0
|
||
Adolescents (12-17 years) |
0
|
||
Adults (18-64 years) |
0
|
||
From 65 to 84 years |
120
|
||
85 years and over |
12
|
||
|
||||||||||
|
Recruitment
|
||||||||||
Recruitment details |
Adult subjects (≥65 years of age) with newly-diagnosed AML defined by ≥20% blasts in the bone marrow or blood and not eligible for intensive induction therapy and planned therapy with DAC (decitabine) or AZA (azacitidine) | |||||||||
|
Pre-assignment
|
||||||||||
Screening details |
The screening tests outlined in the protocol are standard practice and could be conducted before obtaining consent. Patients who fulfilled the eligibility criteria for trial participation were provided with the approved patient information sheet by the investigator, allowing them to make an informed decision regarding their participation. | |||||||||
|
Period 1
|
||||||||||
Period 1 title |
overall trial (overall period)
|
|||||||||
Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
|
|||||||||
Blinding used |
Double blind | |||||||||
Roles blinded |
Subject, Investigator | |||||||||
|
Arms
|
||||||||||
Are arms mutually exclusive |
Yes
|
|||||||||
|
Arm title
|
Verum | |||||||||
Arm description |
EPAG will be given in combination with standard-dose DAC or AZA treatment as concomitant medication | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Eltrombopag
|
|||||||||
Investigational medicinal product code |
||||||||||
Other name |
||||||||||
Pharmaceutical forms |
Film-coated tablet
|
|||||||||
Routes of administration |
Oral use
|
|||||||||
Dosage and administration details |
Dose:
Starting dose 200 mg/d p.o.; escalation up to 300 mg/d p.o
East Asian patients: Starting dose 100 mg/d p.o.; escalation up to 150 mg/d p.o
Duration: cycle days 12-25 q4w (max. 12 cycles)
Concomitant medication (both treatment arms):
Treatment with standard-dose DAC
Decitabine 20 mg/m² i.v. d 1-5 q4w
or
Treatment with standard-dose AZA
Azacitidine 75 mg/m2 s.c. d 1-7 q4w
|
|||||||||
|
Arm title
|
Control | |||||||||
Arm description |
Placebo will be given in combination with standard-dose DAC or AZA treatment as concomitant medication | |||||||||
Arm type |
Placebo | |||||||||
Investigational medicinal product name |
Placebo
|
|||||||||
Investigational medicinal product code |
||||||||||
Other name |
||||||||||
Pharmaceutical forms |
Film-coated tablet
|
|||||||||
Routes of administration |
Oral use
|
|||||||||
Dosage and administration details |
Dose: number of tablets according to Verum arm
Duration: cycle days 12-25 q4w (max. 12 cycles)
Concomitant medication (both treatment arms):
Treatment with standard-dose DAC
Decitabine 20 mg/m² i.v. d 1-5 q4w
or
Treatment with standard-dose AZA
Azacitidine 75 mg/m2 s.c. d 1-7 q4w
|
|||||||||
|
||||||||||
| 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: In total 132 patients were enrolled, but 27 patients had to be excluded from the analysis. Exclusions included patients enrolled before protocol version 5.0 (N=19), withdrawal of consent before the first adm. of study med. (N=2), patient death before the first adm. of study med. (N=1), no adm. of study med. or placebo (N=4), and one patient whose diagnosis was changed from AML to MDS after randomization (N=1). 105 randomized patients have started treatment with Eltrombopag/Placebo. |
||||||||||
|
|||||||||||||||||||||||||||||||||||||||||
|
Baseline characteristics reporting groups
|
|||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Verum
|
||||||||||||||||||||||||||||||||||||||||
Reporting group description |
EPAG will be given in combination with standard-dose DAC or AZA treatment as concomitant medication | ||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Control
|
||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Placebo will be given in combination with standard-dose DAC or AZA treatment as concomitant medication | ||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||
|
|||
|
End points reporting groups
|
|||
Reporting group title |
Verum
|
||
Reporting group description |
EPAG will be given in combination with standard-dose DAC or AZA treatment as concomitant medication | ||
Reporting group title |
Control
|
||
Reporting group description |
Placebo will be given in combination with standard-dose DAC or AZA treatment as concomitant medication | ||
|
|||||||||||||
End point title |
Treatment change-free survival (TCFS) [1] | ||||||||||||
End point description |
TCFS is defined as time interval from day of randomisation to the day of death or until day one of the new disease modifying treatment (all chemotherapeutic and disease modifying agents except
hydrea, including when given within subsequent clinical trials). For a patient who is not known to have died or changed disease modifying treatment by the end of observational period (Treatment period + follow-up period), observation of TCFS will be censored on the date the patient was last
known to be alive.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
Treatment change free survival (TCFS) defined as time from randomisation until day one of the new disease modifying treatment or death as the primary endpoint of this study
|
||||||||||||
| 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: further information can be found in the attached clinical study report |
|||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||
|
Adverse events information [1]
|
|||
Timeframe for reporting adverse events |
During the trial all adverse events CTCAE ≥ grade 3 have been documented in the eCRF. AEs
needed to be documented from the date of randomisation until 28 days after the date of study
termination.
|
||
Assessment type |
Systematic | ||
|
Dictionary used for adverse event reporting
|
|||
Dictionary name |
MedDRA | ||
Dictionary version |
25.0
|
||
| Frequency threshold for reporting non-serious adverse events: 5% | |||
| 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: further information can be found in the attached clinical study report |
|||
|
|||||||||||||
Substantial protocol amendments (globally) |
|||||||||||||
| Were there any global substantial amendments to the protocol? Yes | |||||||||||||
Date |
Amendment |
||||||||||||
12 May 2016 |
During the trial, a significant protocol amendment took place in May 2016 for the following reasons. Despite positive results from a phase 1 trial indicating the viability and tolerance of the EPAG and AZA combination in high-risk MDS15, the subsequent placebo-controlled multi-center trial (SUPPORT trial, NCT02158936) evaluating EPAG in MDS patients with IPSS int-1/int-2/high-risk and thrombocytopenia was prematurely terminated in January 2016. Due to the data of the SUPPORT trial, we cannot exclude that these results have a direct implications for the DELTA study. Although the interim results of the SUPPORT trial are not completely transferable to the DELTA study (use of AZA, inclusion of lower-risk MDS patients) we believed that the data was strong enough to support an amendment of the DELTA study, which had recruited only a limited number of 19 patients at the time of submission. Within the SUPPORT trial, EPAG was given concomitantly to AZA therapy which might, at least partly, explain the presented results. In fact, TPO specifically activates Erk and NF-ĸB pathway that directly affects the double-strand break repair machinery through increased DNA-protein kinase phosphorylation and nonhomologous end-joining repair efficiency and fidelity.16;17 As a matter of fact, EPAG, when given at the same time, might alleviate the desired effects of an HMA-based therapy. Therefore, the DELTA trial was amended in two ways.
1. We changed the concomitant EPAG administration to a sequential approach with no overlap in order to omit interactions between both agents.
2. Additionally, meanwhile AZA has become available as a treatment option for elderly AML patients comparable to DAC. Therefore, the use of AZA (or DAC) was allowed within the study as well. As a consequence of the amendment, the sample size was increased by 19 patients to account for the patients which have had enroled already. Futher information can be found in the attached clinical trial report. |
||||||||||||
Interruptions (globally) |
|||||||||||||
| Were there any global interruptions to the trial? Yes | |||||||||||||
|
|||||||||||||
Limitations and caveats |
|||||||||||||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||||||||
| None reported | |||||||||||||
