MIDOSTAURIN for FLT3-mutated acute myeloid leukemia | Acute myeloid leukemia

Inclusion criteria

• {"criterion_text":"- Documented diagnosis of previously untreated de novo AML according to WHO 2016 criteria except acute promyelocytic leukemia. Participants 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). Participants may begin the first local induction chemotherapy as part of Block 1 while the results of their FLT3 analysis are pending.\n- Presence of a FLT3 mutation, as measured/confirmed by a Novartis designated central laboratory or a local laboratory that has successfully passed the Novartis laboratory qualification procedure with results available prior to first dose of midostaurin: ●\tjuxtamembrane internal tandem duplication (ITD), as determined by PCR based on a mutant/wild type signal ratio cutoff of ≥ 0.05 ●\tand/or mutation in the tyrosine kinase domain (TKD) as determined by PCR (mutant/wild type signal ratio cutoff of ≥ 0.05) or NGS\n- Participants from 3 months of age to less than 18 years of age with expected survival of greater than 12 weeks.\n- Participants with Lansky or Karnofsky performance status ≥ 60. The Lansky performance status will be used for participants from 1 year to 16 years old, and the Karnofsky performance status will be used for participants ≥16 years old.\n- Participants with the following laboratory values that indicate adequate organ function: ●\tAspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 times upper limit of normal (ULN) ●\tSerum total bilirubin ≤ 1.5 times ULN, unless in case of hyperbilirubinemia due to an isolated Gilbert’s syndrome ●\tEstimated creatinine clearance ≥ 30 mL/min based on “bedside formula” by Schwartz and Work 2009. ●\tThese values should be collected at baseline/before the start of the local chemotherapy and also prior to midostaurin intake\n- The parent or legal guardian and/or the participant will have provided written informed consent according to local laws and regulations prior to any study related screening procedures being performed."}

Exclusion criteria

• {"criterion_text":"- Patients with any of the following oncologic diagnoses are not eligible: a)\tAny 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)\tPatients with symptomatic leukemic CNS involvement. c)\tPatients with isolated extramedullary leukemia, secondary AML and MDS. d)\tPatients with Acute Promyelocytic Leukemia (APL).\n- Known impairment of gastrointestinal (GI) function or GI disease that might alter significantly the absorption of midostaurin.\n- Known confirmed diagnosis of human immunodeficiency virus (HIV) infection or active viral hepatitis.\n- Left ventricular shortening fraction of < 27%, as determined by MUGA scan or echocardiogram.\n- Patients who are under 2.5 kg of body weight.\n- Abnormal electrocardiogram (ECG) finding, including: ●\tQTcF ≥ 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. ●\tAny clinically relevant cardiac conduction abnormality. ●\tAny clinically relevant morphologic abnormality. ●\tAny clinically relevant ST/T wave abnormality. ●\tAny clinically relevant atrial or ventricular arrhythmia.\n- Pregnant or nursing (lactating) females\n- Female patients of child-bearing potential (e.g., are menstruating), who do not agree to abstinence or, if sexually active, do not agree to the use of effective contraception during dosing and for at least 4 months after stopping midostaurin (or as per their respective local labels of the chemotherapeutic drugs, whichever is longer) (as defined in Section 7.2.2.7.6). Highly effective contraception methods include: ●\tTotal abstinence (when this is in line with the preferred and usual lifestyle of the participant). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. ●\tFemale sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), or total hysterectomy, at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment. ●\tMale sterilization (at least 6 months prior to screening). The vasectomized male partner should be the sole partner for that participant. ●\tUse of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception\n- If they don’t agree to abstinence, sexually active males must use condom during intercourse while taking the drug and for at least 4 months after stopping midostaurin (or as per their respective local labels of the chemotherapeutic drugs, whichever is longer) and should not father a child in this period.\n- Patients/parents unwilling or unable to comply with the protocol.\n- Hypersensitivity to midostaurin, cytarabine, daunorubicin/idarubicin, fludarabine, etoposide or mitoxantrone or to any of the excipients\n- 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)\n- 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.\n- Patients who have received prior treatment with a FLT3 inhibitor (including sorafenib, lestaurtinib, or quizartinib). However, up to 1 week of FLT3 inhibitor (except midostaurin) exposure prior to study enrollment is permissible.\n- Patients who take strong CYP3A4/5 enzyme inducing drugs or strong CYP3A4/5 enzyme inducing herbal supplements (see Appendix 2) unless they can be discontinued or replaced prior to enrollment.\n- 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.\n- 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.\n- 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.\n- Patients with Fanconi anemia, Schwachman syndrome, any other known bone marrow failure syndrome, or constitutional trisomy 21 or with constitutional mosaicism of trisomy 21."}

Primary endpoints

• {"endpoint_text":"- Part 2: Safety: Frequency/severity of AEs, ECG, MUGA and laboratory Abnormalities","definition_or_measurement_approach":"Safety assessed by frequency and severity of adverse events, ECG, MUGA and laboratory abnormalities (as listed)."}
• {"endpoint_text":"- Part 2 : Tolerability: number of dose interruptions, dose reductions and discontinuation due to study drug","definition_or_measurement_approach":"Tolerability measured by counting number of dose interruptions, dose reductions and discontinuations attributable to the study drug."}

Secondary endpoints

• {"endpoint_text":"- Response rate, defined as the proportion of participants with a CR or CRi according to Cheson et al (2003) and Döhner et al (2017) criteria, or modified CRi as defined in Section 4.1 at the end of Block 2.","definition_or_measurement_approach":"Proportion of participants achieving CR or CRi per Cheson 2003 / Döhner 2017 criteria or modified CRi at end of Block 2 (morphologic assessment)."}
• {"endpoint_text":"- TTR criteria.Participants not experiencing CRi or better response will be censored at maximum follow-up.Participants not experiencing induction failure and who did not die will be censored at their last adequate response assessment date which is different from “unknown” or “not done”.Response duration is the time from CR, CRi or modified CRi in induction to relapse or death due to any cause.Only participants who will achieve a CRi or better response in induction will be evaluated","definition_or_measurement_approach":"Time to response (TTR) and response duration measured from CR/CRi/modified CRi to relapse or death; censoring rules defined in the endpoint text."}
• {"endpoint_text":"- 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 CRiwithin induction, relapse after CR/modified CRi, or death due to any cause, whichever occurs first.","definition_or_measurement_approach":"EFS measured from Day 1 of chemotherapy to first EFS event (failure to obtain CR/modified CRi within induction, relapse after CR/modified CRi, or death)."}
• {"endpoint_text":"- Overall survival (OS) is defined as the time from Day 1 of chemotherapy to the date of death due to any cause. If a participant is not known to have died, survival will be censored at the date of last contact.","definition_or_measurement_approach":"OS measured from Day 1 of chemotherapy to date of death; censored at last contact if alive."}
• {"endpoint_text":"- 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 participants who will achieve a CR/modified CRi in induction.","definition_or_measurement_approach":"DFS measured from CR/modified CRi to relapse or death; derived only for participants achieving CR/modified CRi in induction."}
• {"endpoint_text":"- 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 post-consolidation phase (if sufficient number of participants enter post consolidation)","definition_or_measurement_approach":"MRD negativity assessed by multiparameter flow cytometry; percentage achieving MRD-negative and duration of MRD-negative status; comparisons between consolidation end and post-consolidation phases if numbers permit."}
• {"endpoint_text":"- Assess palatability of oral solution through questionnaire assessment","definition_or_measurement_approach":"Palatability assessed via patient/parent questionnaire."}
• {"endpoint_text":"- Bone marrow, peripheral blood parameters and extramedullary involvement to assess morphologic remission.","definition_or_measurement_approach":"Morphologic remission assessed using bone marrow, peripheral blood parameters and assessment of extramedullary disease."}
• {"endpoint_text":"- Plasma concentrations of midostaurin and its two major metabolites, CGP52421 and CGP62221, will be evaluated; PK parameters (AUC, Cmax if feasible, and pre-dose concentrations)","definition_or_measurement_approach":"Pharmacokinetic assessment measuring plasma concentrations of midostaurin and metabolites; PK parameters include AUC, Cmax (if feasible), and pre-dose concentrations."}

Slovenia

Earliest CTIS Part Ii Submission Date

09-05-2024

Latest Decision Or Authorization Date

10-06-2025

Processing Time Days

397

Number Of Sites

1

Number Of Participants

1

Germany

Earliest CTIS Part Ii Submission Date

09-05-2024

Latest Decision Or Authorization Date

06-06-2025

Processing Time Days

393

Number Of Sites

5

Number Of Participants

4

Poland

Earliest CTIS Part Ii Submission Date

17-05-2024

Latest Decision Or Authorization Date

10-06-2025

Processing Time Days

389

Number Of Sites

2

Number Of Participants

1

Austria

Earliest CTIS Part Ii Submission Date

09-05-2024

Latest Decision Or Authorization Date

11-06-2025

Processing Time Days

398

Number Of Sites

1

Number Of Participants

1

Czechia

Earliest CTIS Part Ii Submission Date

26-07-2024

Latest Decision Or Authorization Date

11-07-2025

Processing Time Days

350

Number Of Sites

2

Number Of Participants

2

Italy

Earliest CTIS Part Ii Submission Date

26-07-2024

Latest Decision Or Authorization Date

09-09-2025

Processing Time Days

410

Number Of Sites

8

Number Of Participants

4

Primary sponsor

Full Name

Novartis Pharma AG

Organisation Type

Pharmaceutical company

Country Of Registered Address

Switzerland

Contract research organisations

Name

IQVIA Limited

Responsibilities

code:3

Name

Iqvia Biotech LLC

Responsibilities

code:3

Name

Parexel International (IRL) Limited

Responsibilities

code:12

Name

Icon Clinical Research Limited

Responsibilities

code:1

Name

Opis S.r.l.

Responsibilities

TMF archive, Activation sites activities

Third parties

• {"country":"France","full_name":"SGS France","duties_or_roles":"code:4","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"IQVIA Limited","duties_or_roles":"code:3","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Iqvia Biotech LLC","duties_or_roles":"code:3","organisation_type":"Pharmaceutical company"}
• {"country":"Italy","full_name":"Opis S.r.l.","duties_or_roles":"code:15; TMF archive, Activation sites activities","organisation_type":"Pharmaceutical company"}
• {"country":"Ireland","full_name":"Parexel International (IRL) Limited","duties_or_roles":"code:12","organisation_type":"Pharmaceutical company"}
• {"country":"Ireland","full_name":"Icon Clinical Research Limited","duties_or_roles":"code:1","organisation_type":"Pharmaceutical company"}
• {"country":"Netherlands","full_name":"VUmc Stichting","duties_or_roles":"code:4","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Poland","full_name":"Centrala Farmaceutyczna Cefarm S.A.","duties_or_roles":"code:15; Drug (IMP/ non-IMP) labeling/relabeling P)","organisation_type":"Pharmaceutical company"}
• {"country":"Slovenia","full_name":"SALUS Veletrgovina druzba za promet s farmacevtskimi medicinskimi in drugimi proizvodi d.o.o.","duties_or_roles":"code:15; Collection and destruction of the investigational medicinal products","organisation_type":"Pharmaceutical company"}
• {"country":"Poland","full_name":"Statmed Sp. z o.o.","duties_or_roles":"code:15; Compensation for patients travel to the clinical site","organisation_type":"Pharmaceutical company"}
• {"country":"Poland","full_name":"Eco-Abc Sp. z o. o.","duties_or_roles":"code:15; Destruction of the investigational medicinal products","organisation_type":"Pharmaceutical company"}
• {"country":"Austria","full_name":"Abf Pharmaceutical Services GmbH","duties_or_roles":"code:15; Local depot for storage and distribution of AxMP to sites/ final Rec. + Destructionof used/unused IMP and AxMP, at EoT","organisation_type":"Pharmaceutical company"}
• {"country":"Poland","full_name":"Komtur Polska Sp. z o.o.","duties_or_roles":"code:15; Local purchase of medicinal products (IMP & non-IMP)","organisation_type":"Pharmaceutical company"}
• {"country":"France","full_name":"Kayentis","duties_or_roles":"code:6; code:7","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Austria","full_name":"Mag. Andreas Raffeiner GmbH","duties_or_roles":"code:8","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"RWS Life Sciences Inc.","duties_or_roles":"code:15; PRO Licensing and translations","organisation_type":"Pharmaceutical company"}
• {"country":"Italy","full_name":"Phardis S.r.l.","duties_or_roles":"code:15; Local equipment storage","organisation_type":"Pharmaceutical company"}