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Leukemia

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Leukemia, Lymphoid

Leukemia, Myeloid

Leukemia, Myeloid, Acute

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Acute Graft Versus Host Disease

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Pharmaceutical Solutions

All Drugs and Chemicals

Antineoplastic Agents

Midostaurin

Protein Kinase Inhibitors

Enzyme Inhibitors

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.

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.

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.

midostaurin

Novartis Pharmaceuticals

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.

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

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

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).

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 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 (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.

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.

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.

Participants received bodyweight and BSA stratified dose of midostaurin 30 mg/m\^2 bid through oral route. The total daily dose in 30 mg/m\^2 bid cohort was 60 mg/m\^2.

Cohort 1: Midostaurin (30 Milligrams/Meters^2)

Cohort 2: Midostaurin (60 mg/m^2)

Participants received body-weight and BSA stratified dose of midostaurin 30 mg/m\^2 bid through oral route. The total daily dose in 30 mg/m\^2 bid cohort was 60 mg/m\^2.

Participants received body-weight 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.

Total

Age, Continuous

Infants and toddlers (28 days-23 months)

Children (2--11 years)

Adolescents (12--17 years)

Age, Customized

Sex: Female, Male

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

The study was terminated early since despite considerable efforts to boost recruitment, no new participants were enrolled in the final year of this study.

Study Director

Younger stratum (≥ 3months -≤ 2 years): (n=2, 5)

Older stratum (>2 years- <18years): (n=4,6)

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

Maximum Tolerated Dose (MTD) of Midostaurin- Posterior Probability of DLT

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

Stable disease

Progressive disease

Not Done

Participants with response

Subjects with acute myeloid leukemia (AML) and received body-weight stratified dosage midostaurin 30 or 60 mg/m\^2.

AML Subjects

Subjects with mixed lineage leukemia gene- rearranged acute lymphoblastic leukemia (MLLr-ALL) and received body-weight stratified dosage midostaurin 30 or 60 mg/m\^2.

MLLr-ALL Subjects

Percentage of Participants With Best Overall Response by Indication

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

Time to Response With Midostaurin

The analysis was performed in FAS population.

Overall Survival With Midostaurin

PKC412-Cycle 1/Day 1 (1 hour)

PKC412-Cycle 1/Day 1 (2 hour)

PKC412-Cycle 1/Day 1 (3 hour)

PKC412-Cycle 1/Day 1 (12 hour)

PKC412-Cycle 1/Day 5 (0 hour)

PKC412-Cycle 1/Day 7 (0 hour)

PKC412-Cycle 2/Day 1 (0 hour)

PKC412-Cycle 3/Day 1 (0 hour)

CGP62221-Cycle 1/Day 1 (1 hour)

CGP62221-Cycle 1/Day 1 (2 hour)

CGP62221-Cycle 1/Day 1 (3 hour)

CGP62221-Cycle 1/Day 1 (12 hour)

CGP62221-Cycle 1/Day 5 (0 hour)

CGP62221-Cycle 1/Day 7 (0 hour)

CGP62221-Cycle 2/Day 1 (0 hour)

CGP62221-Cycle 3/Day 1 (0 hour)

CGP52421-Cycle 1/Day 1 (1 hour)

CGP52421-Cycle 1/Day 1 (2 hour)

CGP52421-Cycle 1/Day 1 (3 hour)

CGP52421-Cycle 1/Day 1 (12 hour)

CGP52421-Cycle 1/Day 5 (0 hour)

CGP52421-Cycle 1/Day 7 (0 hour)

CGP52421-Cycle 2/Day 1 (0 hour)

CGP52421-Cycle 3/Day 1 (0 hour)

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

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.

Plasma Concentrations of Midostaurin and Its Metabolites CGP52421 and CGP62221

AEs suspected to be drug related

On-treatment death

SAEs

SAEs suspected to be drug related

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

Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment Related AEs or SAEs and Death During the Study

Overall Study

Spots Global Cancer Trial Database for A Study of the Safety and Preliminary Efficacy of Oral Midostaurin (PKC412) in Relapsed or Refractory Pediatric Leukemia

Trial Identification

Conditions

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Study Description

Keywords

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