Acute Meyloid Leukemia and high risk myelodysplastic syndromes 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) MedDRA version: 21.1 Level: PT Classification code 10028533 Term: Myelodysplastic syndrome System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Trade Name: Rydapt
Product Name: Midostaurin
Pharmaceutical Form: Capsule
INN or Proposed INN: midostaurin
CAS Number: 120685-11-2
Other descriptive name: MIDOSTAURIN
Concentration unit: mg milligram(
Sponsors
HOVON Foundation
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: • Patients with: - a diagnosis of AML and related precursor neoplasms according to WHO 2016 classification (excluding acute promyelocytic leukemia) including secondary AML (after an antecedent hematological disease (e.g. MDS) and therapy-related AML, or - a diagnosis of myelodysplastic syndrome with excess of blasts (MDS) and IPSS-R > 4.5 • Patients 18 years and older. • Patients NOT eligible for standard chemotherapy, defined as HCT-CI = 3. (Appendix G) or Patients NOT eligible for standard chemotherapy for other reasons (wish of patient). • WBC = 30 x109/L (prior hydroxyurea allowed for a maximum of 5 days, stop 2 days before start decitabine treatment) • Adequate renal and hepatic functions unless clearly disease related as indicated by the following laboratory values: - Serum creatinine = 221.7 µmol/L (= 2.5 mg/dL ), unless considered AML-related - Serum bilirubin = 2.5 x upper limit of normal (ULN), unless considered AML-related or due to Gilbert’s syndrome - Alanine transaminase (ALT) = 2.5 x ULN, unless considered AML-related • WHO performance status 0, 1 or 2 (see Appendix D). • Patient is willing and able to use adequate contraception during and until 5 months after the last protocol treatment. • Written informed consent. • Patient is capable of giving informed consent. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 14 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 126
Exclusion criteria
Exclusion criteria: • Acute promyelocytic leukemia. • Acute leukemia's of ambiguous lineage according to WHO 2016 • Patient has symptomatic central nervous system (CNS) leukemia (NO routinely lumbar puncture required to investigate CNS involvement) • Blast crisis of chronic myeloid leukemia. • Diagnosis of any previous or concomitant malignancy is an exclusion criterion: - except when the patient completed successfully treatment (chemotherapy and/or surgery and/or radiotherapy) with curative intent for this malignancy at least 6 months prior to randomization. OR - except for basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix • Patients previously treated for AML (any antileukemic therapy including investigational agents), a short treatment period ( = 5 days) with Hydroxyurea is allowed • Current concomitant chemotherapy, radiation therapy, or immunotherapy; other than hydroxyurea • Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, pulmonary disease etc.) • Cardiac dysfunction as defined by: - Myocardial infarction within the last 3 months of study entry, or - Reduced left ventricular function with an ejection fraction < 40% as measured by MUGA scan or echocardiogram or - Unstable angina or - New York Heart Association (NYHA) grade IV congestive heart failure (see Appendix I) or - Unstable cardiac arrhythmias. • History of stroke or intracranial hemorrhage within 6 months prior to randomization. • Patient has a history of human immunodeficiency virus (HIV) or active infection with Hepatitis C or B. • Patients known to be pregnant • Patients with a history of non-compliance to medical regimens or who are considered unreliable with respect to compliance. • Patients with any serious concomitant medical condition which could, in the opinion of the investigator, compromise participation in the study. • Patients who have senile dementia, mental impairment or any other psychiatric disorder that prohibits the patient from understanding and giving informed consent. • Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess in a randomized comparison the effect of midostaurin added to 10-day decitabine treatment on the cumulative CR/CRi rate during 3 cycles.;Secondary Objective: - To assess the safety and tolerability of midostaurin added to 10-day decitabine treatment for AML (frequency and severity of toxicities and the durations of neutropenia and thrombocytopenia) as regards to the selected dose level of the study. - To determine the efficacy profile: response rate (CRMRD-, CR, CRi, MLFS, PR), event free survival (EFS) and overall survival (OS) associated with the two therapy regimens. - To measure MRD by immunophenotyping and PCR in relation to clinical response parameters. - To identify gene mutations as potential biomarkers predictive of response, EFS and OS by exploratory analysis. - To evaluate the prognostic value of baseline physical and functional conditions using comprehensive geriatric assessment tools (short physical performance battery (SPPB) and activities of daily living (ADL)) on treatment outcome. ;Primary end point(s): Cumulative CR/CRi rate during 3 cycles;Timepoint(s) of evaluation of this end point: The endpoints will be evaluated when relevant data for all patients are available | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secundary endpoints: • Safety and tolerability of midostaurin added to 10-day decitabine treatment for AML (type, frequency, severity and relationship of adverse events to study treatment). • Efficacy profile (response rate after each first three cycles and best response during three cycles and after 9 months (CRMRD-, CR, CRi, MLFS, PR)) • Event free survival (EFS) • Overall survival (OS)). (see Appendix B and 13.4 for definition of the survival endpoints) • Days of staying in hospital and transfusion needs during three cycles. • Prognostic value of MRD (by flowcytometry or PCR). • Gene mutations predictive of response, EFS and OS by exploratory analysis. • Prognostic value of baseline physical and functional conditions using comprehensive geriatric assessment tools (short physical performance battery (SPPB) and activities of daily living (ADL) on treatment outcome. Translational endpoints: To identify potential biomarkers (molecular) that predict for response to decitabine and/or midostaurin. ;Timepoint(s) of evaluation of this end point: These endpoints will be evaluated when relevant data for all patients are available | — |
Countries
Germany, Ireland, Netherlands, Switzerland
Contacts
Public ContactHOVON Data Center
Erasmus MC, HOVON Data Center
Outcome results
None listed