The study to evaluate the safety, efficacy, and pharmacokinetics of twice daily midostaurin (PKC412) combined with standard chemotherapy and as a single agent post-consolidation therapy in children with untreated FLT3-mutated AM
- Conditions
- Diseases of the blood and blood -forming organs and certain disorders involving the immune mechanism
- Registration Number
- KCT0004051
- Lead Sponsor
- ovartis Korea
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Recruiting
- Sex
- All
- Target Recruitment
- 4
1. Documented diagnosis of previously untreated de novo AML according to WHO 2016 criteria. Patients may have received up to 7 days of hydroxyurea or low-dose cytarabine therapy prior to the first chemotherapy dose administered in Block 1, if clinically indicated at the discretion of the investigator. Administration of intrathecal chemotherapy is permitted before receiving study treatment when administered as part of an initial diagnostic lumbar puncture or thereafter according to local Standard of Care (SOC). Patients may begin the first local induction chemotherapy as part of Block 1 while the results of their FLT3 analysis are pending. 2. Presence of a FLT3 mutation, with results available prior to first dose of midostaurin: ? (juxtamembrane internal tandem duplication (ITD), as determined by PCR based on a mutant/wild type signal ratio cutoff of = 0.05 ? and/or mutation in the tyrosine kinase domain (TKD) as determined by PCR (mutant/wild type signal ratio cutoff of = 0.05) or NGS 3. Patients from 3 months of age to less than 18 years of age with expected survival of greater than 12 weeks. 4. Patients with Lansky or Karnofsky performance status = 60. The Lansky performance status will be used for patients from 1 year to 16 years old, and the Karnofsky performance status will be used for patients =16 years old.
5.Patients with the following laboratory values that indicate adequate organ function: ? Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) = 3 times upper limit of normal (ULN) ? Serum total bilirubin = 1.5 times ULN, unless in case of hyperbilirubinemia due to an isolated Gilbert’s syndrome ? Estimated creatinine clearance = 30 mL/min based on bedside formula” by Schwartz and Work 2009. 6. The parent or legal guardian and/or the patient will have provided written informed consent according to local laws and regulations prior to any study related screening procedures being performed.
Patients eligible for this study must not meet any of the following criteria: 1. Patients with any of the following oncologic diagnoses are not eligible: a) Any concurrent malignancy, juvenile myelomonocytic leukemia (JMML), Philadelphia chromosome or bcr-abl1 positive AML, biphenotypic or bilineal acute leukemia, acute myeloid leukemia associated to down syndrome (AML-DS), acute myeloid leukemia arising from myelodysplasia or other preceding hematologic malignancy, or therapy-related myeloid neoplasms. b) Patients with symptomatic leukemic CNS involvement. c) Patients with isolated extramedullary leukemia, secondary AML and MDS. d) Patients with Acute Promyelocytic Leukemia (APL). 2. Any prior chemotherapy, radiation or any other treatment for leukemia, or any prior allogeneic, syngeneic or autologous bone marrow or stem cell transplant; however patients may have received up to 7 days of hydroxyurea or low-dose cytarabine therapy prior to the first dose of chemotherapy administration in Block 1, if clinically indicated at the discretion of the investigator. Administration of intrathecal chemotherapy is permitted before receiving study treatment when administered as part of an initial diagnostic lumbar puncture or thereafter according to local Standard of Care (SOC). 3. Patients who have received any investigational agent within 30 days or 5 half-lives, whichever is greater, prior to the start of study treatment. 4. Patients who have received prior treatment with a FLT3 inhibitor (including sorafenib, lestaurtinib, or quizartinib). 5. Patients who take strong CYP3A4/5 enzyme inducing drugs or strong CYP3A4/5 enzyme inducing herbal supplements while on study drug. 6. Patients who have had any surgical procedure, excluding central venous catheter placement or other minor procedures (e.g., skin or bone marrow biopsy), within 14 days of start of study treatment. 7. Patients with any other known disease or concurrent severe and/or uncontrolled medical condition (e.g., cardiovascular disease including congestive heart failure or active uncontrolled infection) that could compromise participation in the study. 8. Presence of clinically active uncontrolled infection including significant bacterial, fungal, viral or parasitic infection requiring treatment. Infections are considered controlled if appropriate therapy has been instituted and, at the time of screening, no signs of progression are present. 9. Patients with Fanconi anemia, Schwachman syndrome, any other known bone marrow failure syndrome, or constitutional trisomy 21 or with constitutional mosaicism of trisomy 21. 10. Known impairment of gastrointestinal (GI) function or GI disease that might alter significantly the absorption of midostaurin. 11. Known confirmed diagnosis of human immunodeficiency virus (HIV) infection or active viral hepatitis. 12. Left ventricular shortening fraction of < 27%, as determined by MUGA scan or echocardiogram. 13. Patients who are under 2.5 kg of body weight. 14. Abnormal electrocardiogram (ECG) finding, including: ? QTcF = 450 msec (for female children over 12 years: QTcF = 460 msec), PR = 200 msec, or QRS complex = 110 msec at screening or prior to the first dose of study drug. ? Any clinically relevant cardiac conduction abnormality. ? Any clinically relevant morphologic abnormality. ? Any clinically relevant ST/T wave abnormality. ? Any clinically relevant atrial or ventricular arrhythmia. 15. Pregnant or nursing (lactating) females. 16. Female
Study & Design
- Study Type
- Interventional Study
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method For Part 1 of the Study, the primary endpoint will be the incidence of DLTs.;For Part 2 of the Study, the primary endpoint for countries outside of United States will be the event-free survival (EFS).;the primary endpoint for United States will be the frequency/ severity of AEs, ECG, MUGA and laboratory abnormalities.
- Secondary Outcome Measures
Name Time Method Frequency/severity of AEs, ECG, MUGA and laboratory abnormalities (for countries outside of United States) Event-free survival (EFS) is the time from date of start of treatment to the date of death from any cause, induction failure or relapse whatever occurs first. In case of induction failure, the event date will be set to the date of start of treatment, regardless of HSCT (for United States).