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

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).

Time frame: Baseline, End of dose escalation phase (6 months)

Population: The analysis was performed in dose determining set (DDS) population. Here, 'n' signifies the number of evaluable participants for this measure.

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.

Time frame: Baseline (start of study treatment) up to End of treatment (up to 24 months after last dose or until death whichever occurred first)

Population: The analysis was performed in safety set population, defined as the participants who received at least one dose of midostaurin.

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.

Time frame: Baseline, End of treatment (up to 24 months after last dose or until death whichever occurred first)

Population: The analysis was performed in FAS population.

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 frame: 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)

Population: The analysis was performed in full analysis set (FAS) population, defined as all participants to whom study treatment was assigned.

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.

Time frame: Day 1, Day 5, Day 7, Day 15 (Day 1 of Cycle 2), Day 29 (Day 1 of Cycle 3)

Population: The analysis was performed in pharmacokinetic (PK) set population defined as all safety set participants who had at least one valid (measurable) PK sample of midostaurin, and who had no significant restricted co-medications.

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.

Time frame: Baseline, End of treatment (up to 24 months after last dose or until death whichever occurred first)

Population: The analysis was performed in FAS population. Here, Number of participants analysed signifies number of responders at specified time points for each arm, respectively.