Managed Access Programs for PKC412, Midostaurin

This is an expanded access trial for FMS-Like Tyrosine Kinase 3 (FLT3)-Mutated Acute Myeloid Leukemia focused on measuring FLT3-mutated AML, AML, Aggressive systemic mastocytosis, Mast cell leukemia, Systemic mastocytosis with an associated hematologic neoplasm, MAP, Manage access program, PKC412, Midostaurin Read More

Inclusion Criteria:

Patients eligible for inclusion in this Treatment Plan have to meet all of the following criteria:

1. Patients must be 18 years of age or older; elderly patients must be fit to receive intensive induction and consolidation chemotherapy.
2. Patients must have a documented unequivocal diagnosis of AML according to WHO 2016 classification. A bone marrow or blood blast count of ≥20% is required.
3. Patients must have a documented FLT3-mutation (ITD and/or TKD).
4. Patients may enroll at any time point provided that they receive at least one consolidation cycle before maintenance phase.
5. Patients requiring intrathecal chemotherapy must have a minimum washout of 48 hours prior to the first dose of midostaurin.
6. Azacitidine, decitabine or any drug not considered part of the current treatment plan must have been discontinued for a period of at least 30 days or 5 half-lives of the drug before midostaurin can be administered
7. Secondary AML are eligible, e.g. AML patients with antecedent history of treatment for a prior malignancy. AML patients with a history of antecedent treatment for myelodysplasia (MDS) remain eligible for treatment on Midostaurin MAP.

8. Patients must have the following laboratory values:

   • Direct Bilirubin ≤ 2.5 x ULN
   • Serum Creatinine ≤ 2.5 x ULN
9. Patients must be able to swallow capsules. Written patient informed consent must be obtained prior to start of treatment.

Exclusion Criteria:

Patients eligible for this Treatment Plan must not meet any of the following criteria:

1. History of hypersensitivity to any drugs or metabolites of similar chemical classes as the product.
2. Patients with LVEF less than 45% (by echocardiogram or MUGA) or symptomatic congestive heart failure, Class III or IV according to New York Heart Association (NYHA) classification.

3. Patient with another known malignant disease which is considered life-threatening or concurrent severe and/or uncontrolled medical condition as, but not limited to:

   • Uncontrolled diabetes,
   • Active chronic pancreatitis
   • Active uncontrolled infection
4. Patients with Acute promyelocytic leukemia APL (M3).
5. Patients with symptomatic CNS leukemia and/or patients whose CSF is positive for AML blasts
6. QTcF ≥470 msec on screening ECG
7. Abnormal chest X-ray unless the abnormality represents a non-active, or non-clinically significant finding, such as scarring or a lung infection which is controlled by treatment.
8. Patient requires treatment with strong CYP3A4 inhibitors and strong CYP3A4 inducer unless they can be discontinued or replaced prior to enrollment

9. Female patient is pregnant or nursing (lactating). Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they are using two birth control methods. The two methods can be a double barrier method or a barrier method plus a hormonal method.

   Adequate barrier methods of contraception include: diaphragm, condom (by the partner), intrauterine device (copper or hormonal), sponge or spermicide. Hormonal contraceptives include any marketed contraceptive agent that includes an estrogen and/or a progestational agent.

   Reliable contraception should be maintained throughout the period of treatment and for 4 months after treatment discontinuation.

   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 (e.g. age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL [for US only: and estradiol < 20 pg/mL] or have had surgical bilateral oophorectomy (with or without hysterectomy) 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.

10. Sexually active males unless they use a condom during intercourse while taking drug and for 4 months after stopping midostaurin medication. They should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid.
11. Participation in a prior investigational study within 30 days prior to enrollment or within 5 half-lives of the investigational product, whichever is longer (except for patients coming from parents studies with midostaurin).
12. Not able to understand and to comply with treatment instructions and requirements.