Clinical Trial Results:
A single-arm phase II trial to assess the efficacy of Midostaurin (PKC412) added to standard primary therapy in patients with newly diagnosed c-KIT or FLT3-ITD mutated t(8;21) AML
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Summary
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EudraCT number |
2011-002567-17 |
Trial protocol |
DE |
Global end of trial date |
30 Oct 2019
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Results information
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Results version number |
v1(current) |
This version publication date |
24 Nov 2021
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First version publication date |
24 Nov 2021
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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 |
TUD-MIDOKI-052
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01830361 | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
Novartis Study code: CPKC412ADE01T | ||
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Sponsors
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Sponsor organisation name |
Technische Universität Dresden
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Sponsor organisation address |
Helmholtzstraße 10, Dresden, Germany, 01069
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Public contact |
Head of Clinical Trial Dept., Medizinische Fakultät C. G. Carus, +49 03514583775, christoph.roellig@uniklinikum-dresden.de
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Scientific contact |
Head of Clinical Trial Dept., Medizinische Fakultät C. G. Carus, +49 03514583775, christoph.roellig@uniklinikum-dresden.de
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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 |
23 Oct 2020
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
30 Oct 2019
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Global end of trial reached? |
Yes
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Global end of trial date |
30 Oct 2019
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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 |
To assess the efficacy of tyrosine-kinase inhibitor midostaurin in c-KIT or FLT3-ITD mutated t(8;21) AML
To assess the efficacy of midostaurin depending on the type of c-KIT mutation
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Protection of trial subjects |
The ECG recordings for the assessment of safety were performed as 12-lead standard ECGs. Echocardiography assessment were done for the determination of LVEF in M-Mode technique. A regular toxicity assessment was obtained as outlined in the study evaluations. Furthermore, the primary endpoint of this trial, event-free survival was a combined efficacy and safety endpoint and was therefore also used for the assessment of safety.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
13 Mar 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 |
Germany: 18
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Worldwide total number of subjects |
18
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EEA total number of subjects |
18
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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) |
17
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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 March 2013 and December 2017, 18 patients were enrolled, displaying 15 KIT (88%) and 4 FLT3-ITD (20%) mutations. | ||||||
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Pre-assignment
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Screening details |
Sreening examinations were done to determine the patients eligibility for the study within 7 days before study entry. | ||||||
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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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Midostaurin | ||||||
Arm description |
After inclusion in the study, patients received one cycle of standard DA (days 1-7) in combination with midostaurin treatment (days 8-21). After confirmation of responsive disease and complete remission, patients continued with three cycles of high-dose cytarabine (HiDAC, days 1, 3, 5) in combination with midostaurin (days 8-21), which was administered depending on adequate blood counts and sufficient organ function. After a minimum of 14 days after the last midostaurin application in the last cycle of MidoHiDAC, i.e. earliest on day 36 after the beginning of the last cycle of MidoHiDAC, patients had to start maintenance treatment. | ||||||
Arm type |
Experimental | ||||||
Investigational medicinal product name |
Midostaurin
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Investigational medicinal product code |
PKC412
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Other name |
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Pharmaceutical forms |
Capsule, soft
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Routes of administration |
Oral use
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Dosage and administration details |
- second cycle of induction therapy: one cycle of standard DA (days 1-7) in combination with midostaurin treatment (50 mg oral, twice a day, days 8-21)
- consolidation therapy: three cycles of high-dose cytarabine (HiDAC, days 1, 3, 5) in combination with midostaurin (50 mg oral, twice a day, days 8-21)
- maintenance therapy: midostaurin (50 mg oral, twice a day) continuously for 12 cycles with 28 days per cycle (max. total of 336 days)
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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 |
Midostaurin
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Reporting group description |
After inclusion in the study, patients received one cycle of standard DA (days 1-7) in combination with midostaurin treatment (days 8-21). After confirmation of responsive disease and complete remission, patients continued with three cycles of high-dose cytarabine (HiDAC, days 1, 3, 5) in combination with midostaurin (days 8-21), which was administered depending on adequate blood counts and sufficient organ function. After a minimum of 14 days after the last midostaurin application in the last cycle of MidoHiDAC, i.e. earliest on day 36 after the beginning of the last cycle of MidoHiDAC, patients had to start maintenance treatment. | ||
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End point title |
2-year event-free survival [1] | ||||||||
End point description |
The primary endpoint is a binary variable indicating event-free-survival at 2 years. The nullhypothesis of this trial was that the 2-year-EFS rate is worse or equal to 0.5 under the experimental treatment. The alternate hypothesis was that the 2-year-EFS rate is equal to 0.8 or greater. In an exact single stage phase 2 design, 18 patients have to be enrolled to be able to detect the critical difference in the EFS rates of 0.3 with a power of 80% and a one-sided significance level of 5%. The nullyhpothesis could be rejected if after 2 years, 13 or more patients were without an event. The calculation is based on the exact binomial distribution as described in A’Hern (2001).
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End point type |
Primary
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End point timeframe |
2-year Event-free Survival (EFS)
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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: further information can be found in the publication (see online references) |
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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 |
AEs were documented from the first administration of study drug up to 30 days after the last administration.
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Assessment type |
Systematic | ||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||
Dictionary version |
15.1
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| 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 publication (see online references) |
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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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14 Feb 2014 |
- It can be assumed that patients who acquired a translocation t(8; 21) with c-KIT or FLT-ITD mutation secondary to chemotherapy or radiotherapy for another malignant disease will benefit from midostaurin just as much as patients who such a genetic constellation primary, ie without prior antineoplastic therapy. For this reason, previous radio or chemotherapy was deleted as an exclusion criterion.
- Sections were added to the protocol that describe the interactions with the substances that enhance and inhibit the effect.
- The interactions between midostaurin and CYP3A4 attenuating / enhancing substances have been described in more detail. |
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29 Jun 2015 |
- The recommendations for control and the required dose adjustments in the event of an increase in lipase and possibly occurring pancreatitis during the individual therapy phases have been supplemented according to Investigator’s Brochure Version 18.
- The prescribed storage temperature of midostaurin has been changed to "not above 25 ° C". |
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13 Jul 2018 |
- Change of LKP: From 05/01/2018 on, Prof. Röllig took over the tasks of the previous LKP of Prof. Ehninger.
- In the Investigator’s Brochure Edition 21, the times for the necessary contraception have been significantly extended. This was included as an additional point in the inclusion and exclusion criteria.
- The protocol section 5.4 Pregnancy, breast-feeding, contraception and fertility was supplemented according to the changes and requirements to prevent pregnancy from the investigator's brochure Edition 21. Safe birth control times have been extended from 4 weeks to at least 4 months after the last dose of midostaurin for women and men.
- Since, according to the Investigator’s brochure, a pregnancy test must be carried out in women of childbearing potential within 7 days before the start of Midostaurin administration, the determination of ß-HCG was added on day 1 of the 2nd induction and every consolidation cycle and before the start of maintenance therapy. |
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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. | |||
| None reported | |||
