Clinical Trials /

HDM201 and Midostaurin (HDMM) in Relapsed/Refractory AML With FLT3mut and TP53wt.



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.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:



Phase 1

Trial Eligibility



  • Brief Title: HDM201 and Midostaurin (HDMM) in Relapsed/Refractory AML With FLT3mut and TP53wt.
  • Official Title: HDM201 and Midostaurin (HDMM) in Relapsed/Refractory AML With FLT3mut and TP53wt; a Phase I Study.

Clinical Trial IDs

  • NCT ID: NCT04496999


  • AML, Adult


HDM201Dose findingMidostaurin with HDM201 dose escalation.
MidostaurinMidostaurin with HDM201 dose escalation.


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.

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.


      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.

Trial Arms

Midostaurin with HDM201 dose escalation.ExperimentalMidostaurin 50mg bid d1-28 (morning, evening) and HDM201
  • HDM201
  • Midostaurin

Eligibility Criteria

        Inclusion Criteria:

          -  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
             screening visit:

               -  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.

        Exclusion Criteria:

          -  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.
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose finding
Time Frame:30 days
Safety Issue:
Description:To identify the maximum tolerated dose of HDM201 added to standard Midostaurin

Secondary Outcome Measures

Measure:Adverse Event
Time Frame:12 months
Safety Issue:
Description:Number of patient experiencing toxicity (Adverse Events)
Measure:Complete Remission
Time Frame:30 days
Safety Issue:
Description:Number of patient showing complete remission in bone marrow aspirate/biopsy


Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University Hospital Inselspital, Berne

Trial Keywords

  • AML with FLT3-ITD or FLT3-TKD and TP53wt
  • relapsed/refractory AML

Last Updated

August 5, 2021