Now Available: Final Rule for FDAAA 801 and NIH Policy on Clinical Trial Reporting

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
  Purpose
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.

Condition Intervention Phase
Acute Myeloid Leukemia
Acute Lymphoblastic Leukemia
Drug: midostaurin
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • 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).


Secondary Outcome Measures:
  • 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.


Enrollment: 22
Study Start Date: September 2009
Study Completion Date: September 2014
Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
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: 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.
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

  Eligibility

Ages Eligible for Study:   3 Months to 18 Years   (Child, Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00866281

Locations
United States, Washington
Seattle Children's Hospital CPKC412A2114
Seattle, Washington, United States, 98105
France
Novartis Investigative Site
Paris Cedex 19, France, 75935
Italy
Novartis Investigative Site
Genova, GE, Italy, 16147
Novartis Investigative Site
Monza, MB, Italy, 20900
Novartis Investigative Site
Roma, RM, Italy, 00165
Novartis Investigative Site
Torino, TO, Italy, 10126
Netherlands
Novartis Investigative Site
Rotterdam, Netherlands, 3015 GJ
Sweden
Novartis Investigative Site
Stockholm, Sweden, SE-171 76
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT00866281     History of Changes
Other Study ID Numbers: CPKC412A2114  2008-006931-11 
Study First Received: March 19, 2009
Results First Received: September 8, 2015
Last Updated: November 18, 2015
Health Authority: United States: Food and Drug Administration
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Italy: Ministry of Health
Netherlands: Ministry of Health, Welfare and Sport
Sweden: Medical Products Agency

Keywords provided by Novartis:
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

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
4'-N-benzoylstaurosporine
Staurosporine
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 26, 2016