Studie zur Behandlung von Patienten mit akuter myeloischer Leukämie (AML) ohne FLT3-Mutation mit Standard-Chemotherapie in Kombination mit Midostaurin (PKC412) oder Placebo

Trade Name: Rydapt
Product Code: PKC412
Pharmaceutical Form: Capsule, soft
INN or Proposed INN: midostaurin
CAS Number: 120685-11-2
Other descriptive name: MIDOSTAURIN
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 25-
Pharmaceutical form of the placebo: Capsule, soft
Route of administration of the placebo: Oral use

Inclusion criteria:
1. Diagnosis of AML (=20% blasts in the bone marrow based on WHO 2016 classification). Patients with APL (acute promyelocytic leukemia) with PML-RARA are not eligible.
2. Suitability for intensive induction chemotherapy in the judgment of the investigator
3. Documented absence of an ITD and TKD activating mutation at codons D835 and I836 in the FLT3 gene, as determined by analysis in a Novartis designated FLT3 screening laboratory using a validated clinical trial assay with clinical cutoff of 0.05 mutant to wild type ratio.
4. Age = 18 years
5. 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
6. Written informed consent must be obtained prior to any screening procedures.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 452
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 50

Exclusion criteria:
1. Central nervous system (CNS) leukemia
2. Therapy-related secondary AML
3. Isolated extramedullary leukemia
4. Prior therapy for leukemia or myelodysplasia with the following exceptions:
a) Emergency leukapheresis
b) Emergency treatment for hyperleukocytosis with hydroxyurea or low-dose cytarabine for = 7 days
c) Cranial RT for CNS leukostasis (one dose only)
d) Hematopoietic Growth factor/cytokine support
e) Other supportive therapy including antibiotics at the discretion of the investigator
5. AML after antecedent myelodysplasia (MDS) with prior cytotoxic treatment (e.g., azacytidine or decitabine)
6. Any investigational agent within 30 days or 5 half-lives, whichever is greater, prior to Day 1. An investigational agent is defined as an agent with no approved medical use in adults or in pediatric patients.
7. Prior treatment with a FLT3 inhibitor (e.g., midostaurin, quizartinib, sorafenib)
8. Strong CYP3A4/5 enzyme inducing drugs unless they can be discontinued or replaced prior to enrollment.
9. Any other known disease or concurrent severe and/or uncontrolled medical condition (e.g., cardiovascular disease including congestive heart failure or active uncontrolled infection) that could compromise participation in the study.
10. Abnormal chest X-ray with corresponding clinical symptoms or findings that indicate an active infection, or other pulmonary conditions that are currently clinically significant.
11. Impairment of gastrointestinal (GI) function or GI disease that might alter significantly the absorption of midostaurin.
12. Known confirmed diagnosis of HIV infection or active viral hepatitis (testing is not mandatory to exclude these viral infections).
13. Cardiovascular abnormalities, including any of the following:
• History of MI, angina pectoris, CABG within 6 months prior to starting study treatment
• Clinically uncontrolled cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block)
• Uncontrolled congestive heart failure
• Left ventricular ejection fraction of <50%,
• Poorly controlled hypertension
14. Pregnant or nursing (lactating) women
15. 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 4 months after stopping medication.
Women are considered post-menopausal and not of child bearing potential if they have had 12 months 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.
16. Sexually active males unless they use a condom during intercourse while taking the drug during treatment, and for at least 4 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.
17. Unwillingness or inability to comply with the protocol.
18. Known hypersensitivity to midostauri