Clinical Trial Results:
A phase Ib/II, open label study of siremadlin monotherapy and in combination with donor lymphocyte infusion as a treatment for patients with acute myeloid leukemia postallogeneic stem cell transplantation who are in complete remission but at high risk for relapse.
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Summary
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EudraCT number |
2021-003596-34 |
Trial protocol |
ES DE IT |
Global end of trial date |
26 Oct 2023
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Results information
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Results version number |
v1(current) |
This version publication date |
21 Sep 2024
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First version publication date |
21 Sep 2024
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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 |
CHDM201K12201
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT05447663 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Novartis Pharma, AG
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Sponsor organisation address |
CH-4002, Basel, Switzerland,
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Public contact |
Clinical Disclosure Office, Novartis Pharma, AG, 41 613241111, novartis.email@novartis.com
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Scientific contact |
Clinical Disclosure Office, Novartis Pharma, AG, 41 613241111, novartis.email@novartis.com
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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 |
26 Oct 2023
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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 |
26 Oct 2023
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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 the dose and schedule of siremadlin monotherapy that are tolerable without unacceptable toxicities (recommended dose for Part 2) [Part 1 - siremadlin monotherapy].
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Protection of trial subjects |
The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
23 Feb 2023
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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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: 5
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Country: Number of subjects enrolled |
Italy: 2
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Country: Number of subjects enrolled |
Spain: 1
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Worldwide total number of subjects |
8
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EEA total number of subjects |
8
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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) |
5
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From 65 to 84 years |
3
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85 years and over |
0
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Recruitment
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Recruitment details |
38 participants were planned to be enrolled; 12 participants in Part 1 and 26 participants in Part 2; however, due to permanent recruitment halt, the enrollment was stopped after the 1st dose escalation meeting. The study was conducted in 6 centers in 3 countries: Germany, Italy and Spain. | ||||||||||||||||||
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Pre-assignment
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Screening details |
Prior to dosing at Cycle 1 Day 1, participants who fulfilled all the inclusion/exclusion criteria were enrolled via IRT and a treatment number was provided for the study treatment siremadlin. | ||||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||
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Arms
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Arm title
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Siremadlin (HDM201) 30mg | ||||||||||||||||||
Arm description |
Participants with AML post allogeneic stem cell transplantation (allo-SCT) received 30mg siremadlin monotherapy in part 1 | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Siremadlin
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Investigational medicinal product code |
HDM201
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Other name |
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
10 mg, 20mg and 30 mg* (During the study, siremadlin (HDM201) 30mg capsule was included as additional strength which was globally supplied), administered orally (PO).
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Baseline characteristics reporting groups
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Reporting group title |
Siremadlin (HDM201) 30mg
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Reporting group description |
Participants with AML post allogeneic stem cell transplantation (allo-SCT) received 30mg siremadlin monotherapy in part 1 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Siremadlin (HDM201) 30mg
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Reporting group description |
Participants with AML post allogeneic stem cell transplantation (allo-SCT) received 30mg siremadlin monotherapy in part 1 | ||
Subject analysis set title |
Siremadlin (HDM201) 10mg
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants with AML post allogeneic stem cell transplantation (allo-SCT) received 10mg siremadlin monotherapy in part 1
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Subject analysis set title |
Seremadlin (HDM201) 30mg
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants with AML post allogeneic stem cell transplantation (allo-SCT) received 30mg siremadlin monotherapy in part 1
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Subject analysis set title |
Siremadlin (HDM201) 30mg
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants with AML post allogeneic stem cell transplantation (allo-SCT) received 30mg siremadlin monotherapy in part 1
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Subject analysis set title |
Siremadlin (HDM201) 10mg
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants with AML post allogeneic stem cell transplantation (allo-SCT) received 10mg siremadlin monotherapy in part 1
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Subject analysis set title |
Siremadlin (HDM201) 30mg
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants with AML post allogeneic stem cell transplantation (allo-SCT) received 30mg siremadlin monotherapy in part 1
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End point title |
Rate of Dose Limiting Toxicities (DLTs) with siremadlin monotherapy in part 1 (dose confirmation with siremadlin monotherapy) [1] | ||||||
End point description |
To determine the dose and schedule of siremadlin monotherapy that are tolerable without unacceptable toxicities as defined by the incidence of DLT during the first cycle of treatment in part 1. 'A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value assessed, by the Investigator, to be at least possibly related to study treatment (siremadlin monotherapy and/or siremadlin in combination with DLI), and as unrelated to disease, disease progression, inter-current illness, or concomitant medications, that occurs during the DLT observation period and meets severity criteria as per protocol.
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End point type |
Primary
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End point timeframe |
from cycle 1 day 1 (C1D1) to end of Cycle 1 (cycle = 28days)
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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: No analysis was done for this endpoint |
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| No statistical analyses for this end point | |||||||
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End point title |
Participants who are alive and maintained CR or CRi with no evidence of hematologic relapse | ||||||||
End point description |
This involves evaluating the preliminary efficacy of siremadlin monotherapy at the recommended dose for part 2 on prevention of hematologic relapse
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End point type |
Secondary
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End point timeframe |
Over 6 months from start of siremadlin monotherapy (part 1)
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| Notes [2] - No participant was analyzed for this endpoint |
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| No statistical analyses for this end point | |||||||||
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End point title |
Incidence of Graft versus Host Disease (GvHD) | ||||||||
End point description |
Incidence of grade III or IV acute GvHD, and moderate to severe chronic GvHD in part 1 and 2.
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End point type |
Secondary
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End point timeframe |
From start of study treatment to up to 24 months from last patient first treatment
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| Notes [3] - No participant was analyzed for this endpoint |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of participants with permanent study treatment discontinuation due to GvHD or other adverse events | ||||||
End point description |
Percentage of participants with permanent discontinuation of study treatment due to GvHD or other adverse events in part 1 and 2.
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End point type |
Secondary
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End point timeframe |
From start of study treatment to up to 24 months from last patient first treatment
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| No statistical analyses for this end point | |||||||
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End point title |
Time from start of study treatment to the date of death from any cause | ||||||||
End point description |
Assessment of Overall survival (OS) in part 2
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End point type |
Secondary
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End point timeframe |
From start of study treatment to up to 36 months from last patient first treatment
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| Notes [4] - No participant was analyzed for this endpoint |
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| No statistical analyses for this end point | |||||||||
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End point title |
Cumulative incidence of AML relapse | ||||||||
End point description |
Cumulative incidence of Acute Myeloid Leukemia (AML) relapse at one year and 2 years after the start of study treatment in part 1 and 2. Cumulative incidence of relapse (CIR) is defined as the time from start of study treatment to the date of first documented hematologic relapse. CIR was to be analyzed in the FAS population who initiated priming phase at siremadlin recommended dose (RD) in Part 2 and participants at the RD in Part 1.
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End point type |
Secondary
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End point timeframe |
at 1 year and at 2 years after start of study treatment
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| Notes [5] - No participant was analyzed for this endpoint |
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| No statistical analyses for this end point | |||||||||
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End point title |
Time from start of study treatment to the date of first documented occurrence or worsening of treatment emergent grade III or IV acute GvHD, or chronic GvHD requiring initiation of systemic immunosuppressive treatment | ||||||||
End point description |
Assessment of GvHD-free/relapse-free survival (GRFS) in part 1 and 2.
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End point type |
Secondary
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End point timeframe |
From start of treatment to up to 36 months from last patient first treatment
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| Notes [6] - No participant was analyzed for this endpoint |
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| No statistical analyses for this end point | |||||||||
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End point title |
Pharmacokinetic (PK) characteristic AUC of siremadlin | ||||||||||||||||||||||||
End point description |
AUC is the area under the concentration vs. time curve in part 1. Part 2 did not open for enrollment due to recruitment halt and so no data was analyzed.
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End point type |
Secondary
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End point timeframe |
From Cycle 1 Day 1 to Cycle 1 Day 5 in part 1 [each cycle is 28 days for monotherapy]
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
PK characteristic Cmax of siremadlin | ||||||||||||||||||
End point description |
The maximum (peak) observed plasma, blood, serum or other body fluid drug concentration following drug administration (mass x volume^-1) in part 1. Part 2 did not open for enrollment due to recruitment halt and so no data was analyzed.
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End point type |
Secondary
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End point timeframe |
From Cycle 1 Day 1 to Cycle 1 Day 5 in part 1 [each cycle is 28 days for monotherapy]
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
PK characteristic Ctrough of siremadlin | ||||||||
End point description |
Concentration that is just prior to the beginning of, or at the end of a dosing interval; corresponding to the pre-dose concentration in part 1 and 2.
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End point type |
Secondary
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End point timeframe |
From Cycle 1 Day 1 to Cycle 24 Day 1 in part 1 or from Cycle 1 Day 1 safety confirmation to Cycle 21 Day 1 maintenance in part 2; [each cycle is 28 days for monotherapy, and 42 days for combination]
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| Notes [7] - No participant was analyzed for this endpoint |
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| No statistical analyses for this end point | |||||||||
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End point title |
PK characteristic Tmax of siremadlin | ||||||||||||||||||
End point description |
The time to reach maximum (peak) plasma, blood, serum or other body fluid drug concentration after drug administration (time) in part 1. Part 2 did not open for enrollment due to recruitment halt and so no data was analyzed.
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End point type |
Secondary
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End point timeframe |
From Cycle 1 Day 1 to Cycle 1 Day 5 in part 1 [each cycle is 28 days for monotherapy]
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| No statistical analyses for this end point | |||||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after endo of treatment (EOT) (responders and non-responders, regardless of when treatment was d
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Adverse event reporting additional description |
Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Deaths in the post treatment survival follow-up are not considered Adverse Events.
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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 |
26.1
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Reporting groups
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Reporting group title |
SIREMADLIN 30 mg
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Reporting group description |
SIREMADLIN 30 mg | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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06 Jul 2022 |
As the release of this amendment, no sites had been initiated, and no subject had been screened or had received study treatment in this trial.
The main purpose of this amendment was to comply with health authority’s request to modify the protocol as follows:
To modify the study design by adding a siremadlin monotherapy dose confirmation part (Part 1) with at least 6 evaluable participants to evaluate the safety and tolerability of siremadlin monotherapy and determine the recommended dose before commencing the treatment strategy part (Part 2), which includes siremadlin/donor lymphocyte infusion (DLI) combination as well as priming and maintenance with siremadlin monotherapy; To specify that after the recommended siremadlin dose was determined in Part 1, enrollment in Part 2 would start after obtaining Health Authority’s approval as applicable. Enrollment in Part 2 would not have been applicable to the participating sites in the United States; To implement a larger dose reduction to 20% of siremadlin (instead of 30%) of the total planned dose when administered concomitantly with strong CYP3A inhibitors in the initial treatment cohort(s). Following the first safety review meeting and based on safety and siremadlin total exposure data, this could have changed to a dose reduction to 30% of the planned siremadlin dose with concomitant use of strong CYP3A inhibitors; To clarify that pre-allo-SCT participants with AML in morphologic complete remission at time of transplant but with evidence of residual leukemia had been removed from inclusion criteria 4. The assessment of this pre-transplant risk factor was based on retrospective test results and could not fulfill regulatory requirements of a MRD assay; To clarify that the decision about DLI administration in eligible participants in Part 2 would have been at the discretion of the treating investigator per the standard of practice. |
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18 Nov 2022 |
At the time of release of this amendment, no sites had been initiated, and no subject had been screened or received study treatment in this trial.
The main purpose of this amendment was to restrict the participation of the German sites to Part 1 of the study. The protocol specified that the participating sites in Germany will enroll patients only in Part 1 with siremadlin monotherapy. The German sites were not permitted to enroll patients in Part 2, which included Donor Lymphocyte Infusion (DLI) in combination with siremadlin. |
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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 | |||
