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

• Status: Recruiting
• Trial end date: 2023-06-01
• Target enrollment: 0
• Participant gender: All

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 relapsed/refractory acute myeloid leukemia (AML) with FLT3mut applying an accelerated titration design.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University Hospital Inselspital, Berne
• Treatments: Midostaurin

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 enrollment.

• 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 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 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.