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 relapsed/refractory acute myeloid leukemia (AML) with FLT3mut
applying an accelerated titration design.
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.
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.
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.
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.
- AML with FLT3-ITD or FLT3-TKD and TP53wt.
- Age over 18 years
- Patient must give written informed consent before registration indicating that the
patient understands the purpose of the procedures required for the trial and is
willing to participate in the trial.
- Patients with relapsed/refractory disease must have morphologic proof (from bone
marrow aspirate, smears or touch preps of bone marrow biopsy) of AML with >= 10%
blasts within two weeks (14 days) prior to initiation of therapy.
- Patients must demonstrate one of the following: Relapse after first complete remission
or refractory to conventional induction chemotherapy (failure to respond to 1 or more
cycles of daunorubicin and cytarabine) or to re-induction.
- Patients with previously untreated AML are candidates if they are unable to receive an
anthracyclin, and have documented AML with ≥ 20% blasts within one week prior to
- Laboratory values that indicate adequate organ function assessed locally at the
- AST ≤ 3 times ULN
- Alanine aminotransferase (ALT) ≤ 3 times ULN
- Serum total bilirubin ≤ 1.5 times ULN, unless in case of hyperbilirubinemia due
to an isolated Gilbert syndrome
- Estimated (by Cockcroft-Gault) creatinine clearance ≥ 30ml/min
- ECOG score performance status 0-2.
- Patients may have received therapy for other malignancies, as long as they have
completed therapy at least 6 months prior to study entry.
- Subjects must have a life expectancy of 3 or more months.
- AML with FLT3wt or TP53mut
- Ongoing adverse event drug-induced neuropathy of prior therapy grade ≥2 (according to
CTCAE criteria Version 5.0) at registration
- Previous malignancy within 2 years with the exception of adequately treated in situ
cervical cancer or localized non-melanoma skin cancer.
- Evidence of ongoing uncontrolled systemic infections.
- Major surgery within 4 weeks prior to trial registration
- Concurrent treatment with other experimental drugs or treatment in a clinical trial
within 30 days prior to trial registration.
- Treatment with chemotherapy and radiotherapy within 3 weeks prior to trial
- Vaccinated with live, attenuated vaccines within 4 weeks prior to trial registration
- History of stroke or intracranial hemorrhage within 6 months prior to trial
- Clinically significant cardiovascular disease such as congestive heart failure NYHA
III or IV (as defined by the New York Heart Association Functional Classification),
uncontrolled or symptomatic arrhythmias, unstable angina pectoris, myocardial
infarction within 6 months of prior to registration
- Prior allogeneic bone marrow or solid organ transplantation
- Any life-threatening illness, medical condition, or organ system dysfunction which, in
the investigator's opinion,
- could impair the ability of the patient to participate in the trial
- could compromise the patient's safety,
- could interfere with the absorption or metabolism of midostaurin or HDM201,
- could put the trial outcomes at undue risk,
- could prevent compliance with trial treatment.
- Psychiatric disorder precluding understanding of trial information, giving informed
consent, or interfering with compliance for oral drug intake.
- Known hypersensitivity to trial drug(s) or hypersensitivity to any other component of
the trial drugs.
- Any concomitant drugs contraindicated for use with the trial drugs according to the
approved product information.
- Any psychological, familial, sociological or geographical condition potentially
hampering compliance with the trial protocol and follow‐up.
- Impairment of gastrointestinal (GI) function or GI disease that might alter
significantly the absorption of midostaurin.
- Known confirmed diagnosis of HIV infection or active viral hepatitis (testing is not
mandatory to exclude these viral infections).
- Pregnant or nursing (lactating) women
- Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception
during dosing and for at least 12 months after stopping medication. Highly effective
contraception methods include:
- Total abstinence (when this is in line with the preferred and usual lifestyle of
the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal,
post-ovulation methods) and withdrawal are not acceptable methods of
- Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before
taking study treatment. In case of oophorectomy alone, only when the reproductive
status of the woman has been confirmed by follow up hormone level assessment
- Male sterilization (at least 12 months prior to screening). The vasectomized male
partner should be the sole partner for that subject
- Use of oral, injected or implanted hormonal methods of contraception or placement
of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of
hormonal contraception that have comparable efficacy (failure rate <1%), for
example hormone vaginal ring or transdermal hormone contraception.
- Midostaurin may reduce the effectiveness of hormonal contraceptives; therefore,
females using systemically active hormonal contraceptives should add a barrier
method of contraception.