A phase I/II, open-label, dose-escalating study to evaluate the safety, tolerability and pharmacokinetics of twice daily oral midostaurin and to evaluate the preliminary clinical and pharmacodynamic response in pediatric patients with relapsed or refractory leukemia

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 22

Inclusion Criteria

1. Patients must have a documented diagnosis of one of the following leukemias:
• MLL-rearranged ALL, refractory to standard induction treatment or in first or subsequent relapse
• FLT3-mutated AML refractory to standard induction (after failure of at least 2 different induction chemotherapy regimens) or refractory to reinduction at 1st relapse (after failure of the first re-induction course), or in second or greater relapse
2. Patients must be less than 18 years of age and =3 months of age.
3. Patients must have a Lansky/Karnofsky performance status = 60.
4. Patients must have the following laboratory values reflecting
appropriate organ function:
• AST and ALT = 5x Upper Limit of Normal (ULN),
• Serum Bilirubin = 1.5 x ULN,
• Serum Creatinine = 2 x ULN.
5. Patients must have an expected survival of greater than 8 weeks.
6. Parent or legal guardian and/or the patient must give written
informed consent, according to local law and regulations.
Are the trial subjects under 18? yes
Number of subjects for this age range:
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion Criteria

1. Patients with symptomatic leukemic CNS involvement.
2. Patients with isolated extramedullary leukemia.
3. Patients must have recovered from prior cytotoxic chemotherapy, with a minimum wash-out time of previous chemotherapy of 72 hours. For intrathecal chemotherapy, the minimum wash-out time is 48 hours (other exceptions for intrathecal chemotherapy are noted in Section 6.6.5)
4. Patients who had prior allogeneic, syngeneic or autologous bone
marrow or stem cell transplant less than 2 months from Day 1
5. Patients who have received any investigational agent within 30 days or 5 half-lives, whichever is greater, prior to Day 1. An investigational agent is an agent with no approved medical uses in adults or pediatrics.
6. Patients who have had prior treatment with a FLT3 inhibiting drug or investigational agent; except for sorafenib.
7. Use of CYP3A4/5 enzyme inducing or inhibiting drugs or CYP3A4/5 enzyme inducing or inhibiting herbal supplements while on study treatment
8. The use of corticosteroids while on study drug (exceptions are noted in Section 6.6.5)
9. Patients who have had any surgical procedure, excluding central
venous catheter placement or other minor procedures (e.g. skin or bone marrow biopsy), within 14 days of Day 1.
10. Patients with any other known disease concurrent severe and/or uncontrolled medical condition (e.g. cardiovascular disease including congestive heart failure or active uncontrolled infection) which could compromise participation in the study.
11. Patients with an abnormal chest X-ray and/or any pulmonary
infiltrate including those suspected to be of infectious origin. In
particular, patients with resolution of clinical symptoms of pulmonary infection but with residual pulmonary infiltrates on chest x-ray are not eligible until pulmonary infiltrates have completely resolved.
12. Patients with known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of midostaurin, including active graft-versus-host disease of the liver or the gut.
13. Patients with a known confirmed diagnosis of HIV infection or active viral hepatitis.
14. Patients with a left ventricular shortening fraction < 27% as
determined by MUGA scan or echocardiogram
15. Patients with abnormal ECG including:
• QTcF = 450 ms, PR = 200 msec, QRS complex = 110 msec, at screening or prior to first dosing
• Any cardiac conduction abnormality
• Any morphologic abnormality
• Any ST/T wave abnormality
• Any atrial or ventricular arrhythmia
16. Female patients who are pregnant or breast feeding. Women of childbearing 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 3 months after the last exposure to midostaurin.
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) 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 partner sterilization (at least 6 months prior to

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method

Secondary Outcome Measures

Name	Time	Method

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