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

This study has been terminated.
(Despite considerable efforts to boost recruitment during the final year of the study, no new patients were enrolled.)
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00866281
First received: March 19, 2009
Last updated: November 18, 2015
Last verified: November 2015

March 19, 2009
November 18, 2015
September 2009
September 2014   (final data collection date for primary outcome measure)
Maximum Tolerated Dose (MTD) of Midostaurin- Posterior Probability of DLT [ Time Frame: Baseline, End of dose escalation phase (6 months) ] [ Designated as safety issue: No ]
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).
to determine the maximum tolerated dose for two age groups (3 months to 2 years; and >2 years to <18 years) based on the rate of dose-limiting toxicity (DLT) within the equivalent dose ranges studied in adults [ Time Frame: primarily the first 7 days of treatment ] [ Designated as safety issue: Yes ]
Complete list of historical versions of study NCT00866281 on ClinicalTrials.gov Archive Site
  • Percentage of Participants With Best Overall Response by Indication [ 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) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, End of treatment (up to 24 months after last dose or until death whichever occurred first) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, End of treatment (up to 24 months after last dose or until death whichever occurred first) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Day 1, Day 5, Day 7, Day 15 (Day 1 of Cycle 2), Day 29 (Day 1 of Cycle 3) ] [ Designated as safety issue: No ]
    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 [ 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) ] [ Designated as safety issue: Yes ]
    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.
  • to characterize acute and chronic safety and tolerability [ Time Frame: Continuous ] [ Designated as safety issue: Yes ]
  • to characterize the pharmacokinetics of single and repeated doses in the pediatric population [ Time Frame: Continous ] [ Designated as safety issue: No ]
  • to determine the preliminary efficacy, including response rates, time to relapse and overall survival [ Time Frame: Continuous ] [ Designated as safety issue: No ]
  • to determine the presence and correlate baseline levels of activating mutations or WT-overexpression of the FLT3 gene in AMl and MLL rearranged ALL samples [ Time Frame: Predose, Day 3, and end of treatment ] [ Designated as safety issue: No ]
  • to evaluate changes in FLT3 phosphorylation following treatment, and correlate with changes in clinical outcome and pharmacokinetics [ Time Frame: Predose, Day 3, and end of treatment ] [ Designated as safety issue: No ]
Not Provided
Not Provided
 
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
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.
Not Provided
Interventional
Phase 1
Phase 2
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Acute Myeloid Leukemia
  • Acute Lymphoblastic Leukemia
Drug: midostaurin
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.
Other Name: PKC412
  • Experimental: 30 mg/m^2 bid
    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.
    Intervention: Drug: midostaurin
  • Experimental: 60 mg/m^2 bid
    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.
    Intervention: Drug: midostaurin
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Terminated
22
September 2014
September 2014   (final data collection date for primary outcome measure)

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
Both
3 Months to 18 Years   (Child, Adult)
No
Contact information is only displayed when the study is recruiting subjects
United States,   France,   Italy,   Netherlands,   Sweden
 
NCT00866281
CPKC412A2114, 2008-006931-11
Not Provided
Not Provided
Not Provided
Novartis Pharmaceuticals
Novartis Pharmaceuticals
Not Provided
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
Novartis
November 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP