A Study of the Safety and Preliminary Efficacy of Oral Midostaurin (PKC412) in Relapsed or Refractory Pediatric Leukemia

Phase 1

Terminated

Conditions: Acute Lymphoblastic Leukemia
Acute Myeloid Leukemia

Interventions: Drug: midostaurin

Registration Number: NCT00866281

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: This is a phase I/II pediatric dose-ranging study that will evaluate the safety, tolerability, clinical response, pharmacokinetics and pharmacodynamics of midostaurin in patients \<18 years of age who have relapsed or refractory acute leukemias that may benefit from administration of midostaurin, including MLL-rearranged ALL and FLT3 positive AML.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 22

Inclusion Criteria

Mixed-lineage leukemia (MLL) gene rearranged Acute Lymphoblastic Leukemia (ALL), that does not respond to treatment or has relapsed from prior treatment; or FLT3 mutated Acute Myeloid Leukemia (AML) that does not respond to a second treatment or has relapsed from 2 prior treatments
Normal organ function, and chest x-ray
Expected survival greater than 8 weeks
Can care for most of personal needs and perform at least minimum activity

Exclusion Criteria

Patients with symptomatic leukemic central nervous system involvement or isolated extramedullary leukemia
Patients must not have received other treatments for leukemia within a predefined time period, 72 hours for medications, 2 months for transplants
Patients with heart function that is not normal
Patients with HIV or hepatitis
Patients with another severe disease or medical condition besides leukemia Other protocol-defined inclusion/exclusion criteria may apply

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
60 mg/m^2 bid	midostaurin	Participants received bodyweight and BSA stratified dose of midostaurin 60 mg/m\^2 bid through oral route. The total daily dose in 60 mg/m\^2 bid cohort was 120 mg/m\^2.
30 mg/m^2 bid	midostaurin	Participants received bodyweight and body surface area (BSA) stratified dose of midostaurin 30 mg/m\^2 twice daily (bid) through oral route. The total daily dose in 30 mg/m\^2 bid cohort was 60 mg/m\^2.

Primary Outcome Measures

Name	Time	Method
Maximum Tolerated Dose (MTD) of Midostaurin- Posterior Probability of DLT	Baseline, End of dose escalation phase (6 months)	MTD was defined as highest dose level for which no more than 1 participant in a dose cohort experienced dose limiting toxicity (DLT), based on a Bayesian logistic regression model (BLRM) employing the escalation with overdose control (EWOC) principle. A DLT was defined as a grade 3 or 4 non-hematological adverse event (AE) or abnormal laboratory value related to study drug. Mean and the 95% posterior probability estimates of having a DLT by age strata and dose is presented. Estimation of MTD and/or recommended dose for expansion (RDE) at the dose-escalation phase of the study was based upon the estimation of the probability of DLT for participants in the dose-determining set (DDS).

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Best Overall Response by Indication	Baseline, Day 15 (Day 1 of Cycle 2), Day 22 (Day 8 of Cycle 2), Day 29(Day 1 of Cycle 9), End of treatment (up to 24 months after last dose or until death whichever occurred first)	The best overall clinical response was determined as per the clinical assessment done by the investigator. Responders were defined as all participants with a best clinical response of leukemia free state, morphological complete remission, incomplete morphological complete remission, partial remission, bone marrow blast response, bone marrow minor blast response, peripheral blood blast response, minor peripheral blood blast response. Participants with stable disease, progressive disease and with missing tumour assessment or who discontinued the study or who died before having their first assessment were considered as non-responders. Stable disease was defined as failure to achieve any of the above response. Progressive disease was defined as doubling of the bone marrow blast percentage from baseline in participants with \<40% bone marrow blasts at baseline, or a 50% increase in bone marrow blast percentage from baseline in participants with \>40% bone marrow blasts at baseline,
Time to Response With Midostaurin	Baseline, End of treatment (up to 24 months after last dose or until death whichever occurred first)	Time to response was defined as the time from the date of start of midostaurin treatment to the date of first response. The best overall clinical response was determined as per the clinical assessment done by the investigator. Responders were defined as all participants with a best clinical response of leukemia free state, morphological complete remission, incomplete morphological complete remission, partial remission, bone marrow blast response, bone marrow minor blast response, peripheral blood blast response, minor peripheral blood blast response. Time to response was calculated by using the formula = (date of first response -date of start of midostaurin) +1 day.
Overall Survival With Midostaurin	Baseline, End of treatment (up to 24 months after last dose or until death whichever occurred first)	Overall survival (OS) was defined as the time from start of treatment to date of death due to any cause. The percentage (%) event-free probability estimates were obtained from the Kaplan-Meier survival estimates.
Plasma Concentrations of Midostaurin and Its Metabolites CGP52421 and CGP62221	Day 1, Day 5, Day 7, Day 15 (Day 1 of Cycle 2), Day 29 (Day 1 of Cycle 3)	The plasma concentrations of midostaurin (PKC412) and its two major metabolites, CGP62221 and CGP52421 were determined by using a validated liquid chromatography/tandem mass spectrometry method.
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment Related AEs or SAEs and Death During the Study	Baseline (start of study treatment) up to End of treatment (up to 24 months after last dose or until death whichever occurred first)	An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not related to study drug. A SAE was defined as an event which was fatal or life threatening, required or prolonged hospitalization, was significantly or permanently disabling or incapacitating, constituted a congenital anomaly or a birth defect, or encompassed any other clinically significant event that could jeopardize the participant or require medical or surgical intervention to prevent one of the aforementioned outcomes. Treatment related AEs or SAEs were defined as AEs or SAEs that were suspected to be related to study treatment as per investigator. On treatment death was a fatal event leading to permanent cessations of all vital functions of the body.