untreated FLT3-mutated acute myeloid leukemia MedDRA version: 21.0 Level: LLT Classification code 10000886 Term: Acute myeloid leukemia System Organ Class: 100000004864
Conditions
Sponsors
Novartis Pharma AG
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Patients eligible for inclusion in this study have to meet all of the following criteria: 1. Documented diagnosis of previously untreated de novo AML according to WHO 2016 criteria except acute promyelocytic leukemia. 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 syndrome ? Estimated creatinine clearance = 30 mL/min based on “bedside formula” by Schwartz and Work 2009. ? These values should be collected at baseline/before the start of the local chemotherapy and also prior to midostaurin intake. 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. Are the trial subjects under 18? yes Number of subjects for this age range: 23 F.1.2 Adults (18-64 years) no F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 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 (excluding Block 1 local induction 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 (excluding Block 1 local induction chemotherapy) 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 (see protocol Appendix 2) unless they can be discontinued or replaced prior to enrollment. 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. Progression of infection is defined as hemodynamic instability attributable to sepsis, new symptoms, worsening physical signs; worsening radiography finding in the optional chest X-ray attributable to infection or other clinically significant pulmonary conditions. Persisting fever without other signs or symptoms will not be interpreted as progressing infection. 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 ar
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Part 1 - To Determine recommended phase II dose RP2D of midostaurin Part 2 - To evaluate safety and tolerability of 30 mg/m2 (or 1mg/kg BID bid for participants <10 kg body weight) in sequential combination with chemotherapy followed by 12 cycles of midostaurin post-consolidation therapy in pediatric participants with newly diagnosed FLT3-mutated AML.;Secondary Objective: 1. CR and modified CRi after 2cycles of induction 2. TTR and response duration 3. EFS at 18 months of midostaurin in sequential combination with chemo. followed by 12 cycles (28 days in each cycle) of mido. postconsolidation in ped. participants with newly diagnosed FLT3-mutated AML (aftercompletion of 18months follow-up), and non-censored at the time of HSCT. 4. OS and probability of survival at yearly intervals 5. DFS and DFS probability at yearly intervals. 6. % of participants who reached MRD-negative by flow cytometry status by study treatment phase and those who reached and remained MRD-negative in the post-consolidation. 7. acceptability of the oral midostaurin solution 8. bone marrow and peripheral blood blast response rate of treated ped. patients at the end of Induction Block1 and 2 9. PK of mido. and its 2active metabolites in the ped. population. Compare predicted exposure metrics to observed exposure metrics to support dose selection.;Primary end point(s): Part 1: Occurrence of dose-limiting toxicity (DLT) from the start of midostaurin treatment in Block 1 to the end of Block 2 and other safety, tolerability, and laboratory data in the dose-determining set in Block 2 and thereafter. DLT, as per the definition provided in protocol Part 2 Safety run-in: incidence of DLTs Expansion phase: frequency/ severity of AEs, ECG, MUGA and laboratory abnormalities;Timepoint(s) of evaluation of this end point: Part 1: Completed Part 2: until 5 years after LPFV | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. CR and modified CRi rate at the end of Block 2, 2. Time to response (TTR) and response duration, 3. Event-free survival (EFS) is the time from date of start of study 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 study treatment, regardless of HSCT. 4. Overall survival (OS), 5. Disease Free Survival (DFS), 6.Assess palatability of oral solution through questionnaire assessment, 7. Percentage of participants with MRD negative status (by multiparameter flow cytometry), 8. Plasma concentrations of midostaurin and its two major metabolites, CGP52421 and CGP62221, will be evaluated during Parts 1 and 2, and compared to predicted concentrations.;Timepoint(s) of evaluation of this end point: 1. 18 months after LPFV Others secondary endpoints (2-8): until 5 years after LPFV | — |
Countries
Austria, Czechia, Czech Republic, Germany, Greece, Italy, Japan, Jordan, Korea, Republic of, Poland, Russian Federation, Slovenia, United States
Contacts
Public ContactMedical Information Desk
Novartis Pharma Services Inc. Podružnica v Sloveniji
Outcome results
None listed