| Eligibility |
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 with or without Midostaurin
(failure to respond to 1 or more cycles of daunorubicin and cytarabine) or to
re-induction.
- Patients with relapse after HSCT (non-preventive) and pretransplant treatment with
Midostaurin (FLT3-ITD or FLT3-TKD at diagnosis) or without Midostaurin (acquired FLT3
mutation).
- 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
registration
- Vaccinated with live, attenuated vaccines within 4 weeks prior to trial registration
- History of stroke or intracranial hemorrhage within 6 months prior to trial
registration.
- 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 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 and/or HDM201.
- 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
contraception
- 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.
Women are considered post-menopausal and not of child bearing potential if they have had 2
years of natural (spontaneous) amenorrhea with an appropriate clinical profile (i.e., age
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy
(with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks
ago. In the case of oophorectomy alone, only when the reproductive status of the woman has
been confirmed by follow up hormone level assessment is she considered not of child bearing
potential.
- Sexually active males unless they use a condom during intercourse while taking the
drug during treatment, and for at least 12 months after stopping treatment and should
not father a child in this period. A condom is required to be used also by
vasectomized men as well as during intercourse with a male partner in order to prevent
delivery of the drug via semen.
- Unwillingness or inability to comply with the protocol.
|
