Ignite Creation Date:
2024-05-06 @ 3:01 PM
Last Modification Date:
2024-10-26 @ 1:41 PM
Study NCT ID:
NCT04496999
Status:
TERMINATED
Last Update Posted:
2022-10-06
First Post:
2020-07-29
Brief Title:
HDM201 and Midostaurin HDMM in RelapsedRefractory AML With FLT3mut and TP53wt
Sponsor:
Insel Gruppe AG University Hospital Bern
Organization:
Insel Gruppe AG University Hospital Bern
Study Overview
Official Title:
HDM201 and Midostaurin HDMM in RelapsedRefractory AML With FLT3mut and TP53wt a Phase I Study
Status:
TERMINATED
Status Verified Date:
2022-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Insufficient recruitment
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
HDMM
Brief Summary:
This is a non-randomized prospective open-label single-arm clinical phase I trial investigating dose finding feasibility and safety of the combined treatment of HDM201 and midostaurin in patients with relapsedrefractory acute myeloid leukemia AML with FLT3mut applying an accelerated titration design
Detailed Description:
Background and Rationale
Acute myeloid leukemia AML is a clonal hematopoietic malignant disease characterized by genetic and epigenetic alterations leading to inactivation of the tumor suppressor p53 This contributes to a block in normal differentiation of the various blood type lineages and to an accumulation of leukemic blasts in the blood and bone marrow The disease variants have been grouped into favorable intermediate and poor risk categories The largest group of poor risk AML is characterized by the genetic alterations of the FLT3 receptor gene termed FLT3-ITD or FLT3-TKD The prognosis for this specific subset which comprises 25-35 of all AML patients is generally poor particularly in elderly or in relapsed patients highlighting the unmet need for novel treatments
Targeting the mutated FLT3 receptor is a promising approach to treat this specific poor risk AML subset Midostaurin is particularly effective to induce cell death in FLT3-ITD-TKD and TP53wt cells Targeting MDM2 is a novel approach to restore the crucial p53 tumor suppressor function in AML cells Preliminary data indicate that the MDM2 inhibitor HDM201 is active in AML cell lines in vitro and in vivo Like midostaurin HDM201 is specifically effective to induce cell death in FLT3-ITD and TP53wt cells The combination of midostaurin and HDM201 targets FLT3-ITD AML cells with little effect on FLT3 wt cells and healthy blood cells Both compounds induce apoptosis and cell death in a dose-dependent manner in FLT3-ITD TP53wt AML cells with enhanced effects in the combination treatment The combination treatment with midostaurin and HDM201 ought to be superior to the current best available treatment which utilizes intensive genotoxic induction therapy In order to confirm inhibition of mutated FLT3 receptor and restoration of p53 tumor suppressor function blood samples will be analyzed in this trial before during and after treatment with HDM201 and midostaurin for changes in the expression of FLT3 and p53 target genes as well as induction of pro- apoptotic genes These gene expression levels will be correlated with clinical response and outcome
Objectives
Primary objective
The primary objective of this trial is to establish the recommended dose for a subsequent phase II RP2D of HDM201 in combination with midostaurin in patients with relapsed or refractory FLT3mut TP53wt AML
Secondary objectives
The secondary objectives are to determine the safety and tolerability of HDM201 in combination with midostaurin and to assess the preliminary antitumor activity of HDM201 in combination with midostaurin in patients with relapsed or refractory FLT3mut TP53wt AML and in newly diagnosed AML with FLT3mut and TP53wt
Study Duration
The trial study duration encompasses the time from when the first participant signs the informed consent until the last protocol-specific procedure of the last patient in the trial has been completed
This phase I trial involves a minimum of 3 and a maximum of 24 subjects Accordingly the Investigator anticipate a duration of recruitment of between 3 and 18 months
All patients will be followed up for up to 12 months after end of treatment adding to a total study duration of between 15 and 33 months depending on the effective number of patients in the various dose cohorts
Acute myeloid leukemia AML is a clonal hematopoietic malignant disease characterized by genetic and epigenetic alterations leading to inactivation of the tumor suppressor p53 This contributes to a block in normal differentiation of the various blood type lineages and to an accumulation of leukemic blasts in the blood and bone marrow The disease variants have been grouped into favorable intermediate and poor risk categories The largest group of poor risk AML is characterized by the genetic alterations of the FLT3 receptor gene termed FLT3-ITD or FLT3-TKD The prognosis for this specific subset which comprises 25-35 of all AML patients is generally poor particularly in elderly or in relapsed patients highlighting the unmet need for novel treatments
Targeting the mutated FLT3 receptor is a promising approach to treat this specific poor risk AML subset Midostaurin is particularly effective to induce cell death in FLT3-ITD-TKD and TP53wt cells Targeting MDM2 is a novel approach to restore the crucial p53 tumor suppressor function in AML cells Preliminary data indicate that the MDM2 inhibitor HDM201 is active in AML cell lines in vitro and in vivo Like midostaurin HDM201 is specifically effective to induce cell death in FLT3-ITD and TP53wt cells The combination of midostaurin and HDM201 targets FLT3-ITD AML cells with little effect on FLT3 wt cells and healthy blood cells Both compounds induce apoptosis and cell death in a dose-dependent manner in FLT3-ITD TP53wt AML cells with enhanced effects in the combination treatment The combination treatment with midostaurin and HDM201 ought to be superior to the current best available treatment which utilizes intensive genotoxic induction therapy In order to confirm inhibition of mutated FLT3 receptor and restoration of p53 tumor suppressor function blood samples will be analyzed in this trial before during and after treatment with HDM201 and midostaurin for changes in the expression of FLT3 and p53 target genes as well as induction of pro- apoptotic genes These gene expression levels will be correlated with clinical response and outcome
Objectives
Primary objective
The primary objective of this trial is to establish the recommended dose for a subsequent phase II RP2D of HDM201 in combination with midostaurin in patients with relapsed or refractory FLT3mut TP53wt AML
Secondary objectives
The secondary objectives are to determine the safety and tolerability of HDM201 in combination with midostaurin and to assess the preliminary antitumor activity of HDM201 in combination with midostaurin in patients with relapsed or refractory FLT3mut TP53wt AML and in newly diagnosed AML with FLT3mut and TP53wt
Study Duration
The trial study duration encompasses the time from when the first participant signs the informed consent until the last protocol-specific procedure of the last patient in the trial has been completed
This phase I trial involves a minimum of 3 and a maximum of 24 subjects Accordingly the Investigator anticipate a duration of recruitment of between 3 and 18 months
All patients will be followed up for up to 12 months after end of treatment adding to a total study duration of between 15 and 33 months depending on the effective number of patients in the various dose cohorts
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None