untreated FLT3-mutated acute myeloid leukemia MedDRA version: 21.0 Level: LLT Classification code 10000886 Term: Acute myeloid leukemia System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Part 1 of the study: To determine the Recommended Phase 2 Dose (RP2D) of midostaurin. Part 2 of the Study: To evaluate safety and tolerability of midostaurin (30mg/m2 bid or 1mg/kg 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: rates of CR and modified CRi after 2 cycles of induction using morphologic assessment 2: TTR and response duration 3: EFS rate at 18 months of mido. in sequential combination with chemo followed by 12cycles of mido. postconsolidation therapy (after all participants have completed=18 months of follow-up), and non-censored at HSCT 4: median OS and probability of survival at yearly intervals 5: median DFS and DFS probability at yearly intervals 6: percentage of participants who reached MRD negative status by treatment phase by flow cytometry and those who reached and remained MRD-negative in the post-consolidation phase 7: acceptability of oral midostaurin solution 8: bone marrow and peripheral blood blast response rate of treated ped. participants at the end of Induction Block 1 and Induction Block 2 9: PK of midostaurin and its two active 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: Frequency/severity of AEs, ECG, MUGA and laboratory abnormalities. Tolerability: number of dose interruptions, dose reductions and discontinuation due to study drug;Timepoint(s) of evaluation of this end point: as defined per protocol | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1: CR, defined as the proportion of participants with a CR according to Cheson 2003 criteria, and modified CRi as defined in Section 4.1 at the end of Block 2. 2: TTR is defined as the time between start of study treatment to the date of first onset of CRi or better response. Participants not experiencing CRi or better response (induction failure) will be censored at maximum follow-up (i.e. date of FPFV to date of LPLV used for the analysis). Participants not experiencing induction failure and who did not die (any cause) will be censored at their last adequate response assessment date which is different from "unknown" or "not done". Response duration is defined as the time from CR/ modified CRi in induction to relapse or death due to AML. This will be derived only for participants who will achieve a CR/ modified CRi in induction. 3: Event-free survival (EFS) defined as the time from Day 1 of chemotherapy until an EFS event is observed. An EFS event is defined as a failure to obtain a CR/modified CRi within induction, relapse after CR/modified CRi, or death due to any cause, whichever occurs first. 4: Overall survival (OS) is defined as the time from Day 1 of chemotherapy to the date of death due to any cause. 5: Disease Free Survival is defined as the time from CR/ modified CRi in induction to relapse or death due to any cause. This will be derived only for patients who will achieve a CR/ modified CRi in induction. 6: Percentage of participants with MRD negative status (by multiparameter flow cytometry) and duration of MRD negative status. Comparisons of percentage of participants who achieved MRD negative between the end of the consolidation phase and during the postconsolidation phase. 7: Assess palatability of oral solution through questionnaire assessment 8: Bone marrow, peripheral blood parameters and extramedullary involvement to assess morphologic remission. 9: Plasma concentrations of midostaurin and its | — |
Countries
Austria, Czechia, Czech Republic, Germany, Greece, Italy, Japan, Jordan, Korea, Republic of, Poland, Russian Federation, Slovenia, United States
Contacts
Public ContactDrug Regulatory Affairs
Novartis Pharma GmbH
Outcome results
None listed