| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| untreated FLT3-mutated acute myeloid leukemia |
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| E.1.1.1 | Medical condition in easily understood language |
| untreated FLT3-mutated acute myeloid leukemia |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10000886 |
| E.1.2 | Term | Acute myeloid leukemia |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part 1 of the study:
To determine the Recommended Phase 2 Dose (RP2D) of midostaurin.
Part 2 of the Study:
To evaluate efficacy as measured by the event-free survival (EFS) rate at 24 months of midostaurin in sequential combination with chemotherapy followed by 12 cycles of midostaurin post-consolidation therapy in pediatric patients with newly diagnosed FLT3-mutated AML (after all patients have completed at least 24 months of follow-up), and non-censored at the time of HSCT. |
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| E.2.2 | Secondary objectives of the trial |
1: safety and tolerability of midostaurin in combination with chemotherapy
2: EFS rate at 24 months, censored for HSCT
3: median OS and probability of survival at yearly intervals
4: rates of CR and modified CRi after 2 cycles of induction using morphologic assessment
5: TTR and response duration
6: median DFS and DFS probability at yearly intervals
7: CIR
8: percentage of patients who reached MRD negative status by treatment phase and those who reached and maintained MRD-negative status in the post-consolidation phase
9: acceptability of oral midostaurin solution
10: bone marrow and peripheral blood blast response rate of treated ped. patients at the end of Induction Block 1 and Induction Block 2
11: PK of midostaurin and its two active metabolites in the ped. population. Compare predicted exposure metrics to observed exposure metrics to support dose selection.
12: relationships between midostaurin exposure and measures of clinical efficacy, biologic activity, toxicity |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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.
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|
| E.4 | Principal 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 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 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 protocol). Highly effective contraception methods defined in protocol.
17. 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.
18. Patients/parents unwilling or unable to comply with the protocol.
19. Hypersensitivity to midostaurin, cytarabine, daunorubicin/idarubicin, fludarabine, etoposide or mitoxantrone or to any of the excipients. |
|
| E.5 End points |
| E.5.1 | 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: 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. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
1: Frequency/severity of AEs, ECG, MUGA and laboratory abnormalities
2: Event-free survival (EFS) defined as the time from Day 1 of chemotherapy until an EFS event is observed.
3: Overall survival (OS) is defined as the time from Day 1 of chemotherapy to the date of death due to any cause
4: defined as the proportion of patients with a CR according to Cheson 2003 criteria, and modified CRi as defined in Section 4.1 at the end of Block 2
5: is defined as the time between start of treatment to the date of first onset of CRi or better response.
Response duration is defined as the time from CR/ modified CRi in induction to relapse or death due to AML.
6: 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.
7: Cumulative Incidence of Relapse (CIR) is defined for patients with CR or modified CRi and is time from achieving the CR or modified CRi in induction until the onset of relapse from CR or modified CRi. .
8: Percentage of patients with MRD negative status (by multiparameter flow cytometry).
9: Assess palatability of oral solution through questionnaire assessment
10: Bone marrow, peripheral blood parameters and extramedullary involvement to assess morphologic remission.
11: 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)
12: Exposure-response relationship of PK metrics of midostaurin and its major metabolite CGP62221, and focusing on the following response endpoints: EFS, CR/ modified CRi at the end of each block in the induction phase (Block 1 and Block 2), and time to first occurrence of Adverse Events of Special Interest (AESI).
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Austria |
| Czech Republic |
| Germany |
| Greece |
| Italy |
| Japan |
| Korea, Republic of |
| Poland |
| Romania |
| Russian Federation |
| Slovenia |
| Turkey |
| United States |
| Jordan |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 7 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
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