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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: midostaurin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 3 Months
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 30 mg/m^2 bid<br>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. | Drug: midostaurin<br>* Midostaurin 25 mg/mL oral solution was provided in bottles of 50 mL, administered with water. The pediatric starting dose of midostaurin was set at 30 mg/m2 bid and was not to exceed 60 mg/m2 bid.<br>* Other names: PKC412;|
| Experimental: 60 mg/m^2 bid<br>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. | Drug: midostaurin<br>* Midostaurin 25 mg/mL oral solution was provided in bottles of 50 mL, administered with water. The pediatric starting dose of midostaurin was set at 30 mg/m2 bid and was not to exceed 60 mg/m2 bid.<br>* Other names: PKC412;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of Midostaurin- Posterior Probability of DLT | 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). | Baseline, End of dose escalation phase (6 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Best Overall Response by Indication | 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, | 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) | 
| Time to Response With Midostaurin | 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. | Baseline, End of treatment (up to 24 months after last dose or until death whichever occurred first) | 
| Overall Survival With 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. | Baseline, End of treatment (up to 24 months after last dose or until death whichever occurred first) | 
| Plasma Concentrations of Midostaurin and Its Metabolites CGP52421 and CGP62221 | 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. | Day 1, Day 5, Day 7, Day 15 (Day 1 of Cycle 2), Day 29 (Day 1 of Cycle 3) | 
| Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment Related AEs or SAEs and Death During the Study | 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. | Baseline (start of study treatment) up to End of treatment (up to 24 months after last dose or until death whichever occurred first) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Myeloid Leukemia, AML, Acute Lymphoblastic Leukemia, ALL, midostaurin, PKC412, Pediatric relapsed or refractory FLT3 positive Acute Myeloid Leukemia, Pediatric relapsed or refractory Mixed-lineage leukemia gene rearranged Acute Lymphoblastic leukemia