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: Completed

Sex: Not specified

Target Recruitment: 5

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 quardian and/or patient must give written informed consent, according to local law and regulations

Exclusion Criteria

1. Patients with symptomatic leukemic CNS involvement.
2. Patients with isolated extramedullary leukemia.
3. Patients must have recovered from prior cytotoxic chemotherapy, and a
minimum wash-out time of previous chemotherapy of 72 hours should be
taken into account. For intrathecal chemotherapy, the minimum wash-out time is 48 hours
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.
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 the protocol 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 or patients of
reproductive potential not employing an effective method of birth control.
Barrier contraceptives must be used throughout the trial by both sexes, if
applicable.
17. Males of reproductive potential unwilling to comply with contraceptive
requirements
18. Patients/parents unwilling or unable to comply with the protocol

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>To determine the maximum tolerated dose (MTD) or to identify the recommended<br /><br>dose for expansion (RDE) for two age groups (>=3 months to <=2 years: >2years to<br /><br><18 years) of pediatric patients with AML or MLL based on the rate of<br /><br>dose-limiting toxicity (DLT) of midostaurin administered orally in dose ranges<br /><br>studied in adults.</p><br>

Secondary Outcome Measures

Name	Time	Method
<p>• To characterize the safety and tolerability of midostaurin, including acute<br /><br>and chronic toxicities<br /><br>• To characterize the population PK of single and repeated doses of midostaurin<br /><br>and its metabolite(s),<br /><br>• To determine the response rates, time to relapse and overall survival of<br /><br>patients treated with midostaurin.</p><br>