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

NCT00866281 | Terminated Phase 1 Results

• 2 other identifiers: CPKC412A21142008-006931-11
• Study Type: interventional
• Target: 22
• Locations: 5 countries
• Sites: 8

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.

Conditions

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (5)

• Percentage of Participants With Best Overall Response by Indication

  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

  Baseline, End of treatment (up to 24 months after last dose or until death whichever occurred first)

• Overall Survival With Midostaurin

  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

  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

  Baseline (start of study treatment) up to End of treatment (up to 24 months after last dose or until death whichever occurred first)

Study Arms (2)

30 mg/m^2 bid

EXPERIMENTAL

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

60 mg/m^2 bid

EXPERIMENTAL

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

Interventions

midostaurin DRUG

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.

Also known as: PKC412

30 mg/m^2 bid; 60 mg/m^2 bid

Eligibility Criteria

• Age: 3 Months - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (8)

Seattle Children's Hospital CPKC412A2114

Seattle, Washington, 98105, United States

Location

Novartis Investigative Site

Paris, 75935, France

Location

Novartis Investigative Site

Genova, GE, 16147, Italy

Location

Novartis Investigative Site

Monza, MB, 20900, Italy

Location

Novartis Investigative Site

Roma, RM, 00165, Italy

Location

Novartis Investigative Site

Torino, TO, 10126, Italy

Location

Novartis Investigative Site

Rotterdam, 3015 GJ, Netherlands

Location

Novartis Investigative Site

Stockholm, SE-171 76, Sweden

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Interventions

midostaurin

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Lymphoid; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Limitations and Caveats

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

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 19, 2009
• First Posted: March 20, 2009
• Study Start: September 1, 2009
• Primary Completion: September 1, 2014
• Study Completion: September 1, 2014
• Last Updated: December 22, 2015
• Results First Posted: December 22, 2015

Record last verified: 2015-11

Locations

FR (1); SE (1); NL (1); US (1); IT (4)