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

Back to results

Primary Purpose

Status

Terminated

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

midostaurin

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia focused on measuring 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

Eligibility Criteria

3 Months - 18 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

30 mg/m^2 bid

60 mg/m^2 bid

Arm Description

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.

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

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,

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.

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.

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.

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.

Full Information

NCT ID

NCT00866281

First Posted

March 19, 2009

Last Updated

November 18, 2015

Sponsor

Novartis Pharmaceuticals

1. Study Identification

Unique Protocol Identification Number

NCT00866281

Brief Title

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

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

Study Type

Interventional

2. Study Status

Record Verification Date

November 2015

Overall Recruitment Status

Terminated

Why Stopped

Despite considerable efforts to boost recruitment during the final year of the study, no new patients were enrolled.

Study Start Date

September 2009 (undefined)

Primary Completion Date

September 2014 (Actual)

Study Completion Date

September 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Novartis Pharmaceuticals

4. Oversight

5. Study Description

Brief Summary

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia

Keywords

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

22 (Actual)

8. Arms, Groups, and Interventions

Arm Title

30 mg/m^2 bid

Arm Type

Experimental

Arm Description

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.

Arm Title

60 mg/m^2 bid

Arm Type

Experimental

Arm Description

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 Type

Drug

Intervention Name(s)

midostaurin

Other Intervention Name(s)

PKC412

Intervention Description

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.

Primary Outcome Measure Information:

Title

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

Description

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)

Secondary Outcome Measure Information:

Title

Percentage of Participants With Best Overall Response by Indication

Description

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)

Title

Time to Response With Midostaurin

Description

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)

Title

Overall Survival With Midostaurin

Description

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)

Title

Plasma Concentrations of Midostaurin and Its Metabolites CGP52421 and CGP62221

Description

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)

Title

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

Description

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)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

3 Months

Maximum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

No

Eligibility 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Novartis Pharmaceuticals

Organizational Affiliation

Novartis Pharmaceuticals

Official's Role

Study Director

Facility Information:

Facility Name

Seattle Children's Hospital CPKC412A2114

City

Seattle

State/Province

Washington

ZIP/Postal Code

98105

Country

United States

Facility Name

Novartis Investigative Site

City

Paris Cedex 19

ZIP/Postal Code

75935

Country

France

Facility Name

Novartis Investigative Site

City

Genova

State/Province

GE

ZIP/Postal Code

16147

Country

Italy

Facility Name

Novartis Investigative Site

City

Monza

State/Province

MB

ZIP/Postal Code

20900

Country

Italy

Facility Name

Novartis Investigative Site

City

Roma

State/Province

RM

ZIP/Postal Code

00165

Country

Italy

Facility Name

Novartis Investigative Site

City

Torino

State/Province

TO

ZIP/Postal Code

10126

Country

Italy

Facility Name

Novartis Investigative Site

City

Rotterdam

ZIP/Postal Code

3015 GJ

Country

Netherlands

Facility Name

Novartis Investigative Site

City

Stockholm

ZIP/Postal Code

SE-171 76

Country

Sweden

Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial