Evaluation of Midostaurin with Chemotherapy in Pediatric Patients with Newly Diagnosed FLT3-Mutated Acute Myeloid Leukemia
- Trial ID
- 2023-509834-20-00
- Protocol
- CPKC412A2218
- Sponsor
- Novartis Pharma AG
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **safety** and tolerability of midostaurin in combination with chemotherapy, followed by 12 cycles of midostaurin post-consolidation therapy in pediatric participants with newly diagnosed FLT3-mutated Acute Myeloid Leukemia (AML). This is clinically relevant as it aims to establish a safe and effective treatment regimen for this specific pediatric population, potentially improving outcomes and reducing treatment-related adverse effects.
Secondary objectives include:
- Characterizing the pharmacokinetics of midostaurin and its active metabolites in the pediatric population to support dose selection.
- Determining the rates of response after two cycles of induction therapy using morphologic assessment.
- Assessing the time to response and response duration.
- Evaluating efficacy as measured by the event-free survival rate at 18 months.
- Determining the median overall survival and probability of survival at yearly intervals.
- Determining the median disease-free survival and its probability at yearly intervals.
- Determining the percentage of participants who reached MRD-negative status by study treatment phase and those who remained MRD-negative post-consolidation.
- Evaluating the acceptability of the oral midostaurin solution.
- Evaluating the bone marrow and peripheral blood blast response rate at the end of induction cycles.
Participants
The clinical trial involves a total of **9 participants** diagnosed with **untreated FLT3-mutated Acute Myeloid Leukemia**. The study population includes both male and female pediatric participants ranging from 3 months to less than 18 years of age. Participants are required to have a documented diagnosis of previously untreated de novo Acute Myeloid Leukemia, excluding acute promyelocytic leukemia, and must exhibit a FLT3 mutation confirmed by a designated laboratory. The trial population was selected based on specific inclusion criteria, including a performance status of at least 60 on the Lansky or Karnofsky scale, and adequate organ function as indicated by laboratory values. Participants are expected to have a survival prognosis of greater than 12 weeks. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The study includes a vulnerable population, as it involves pediatric subjects. The sponsor has not provided additional information regarding the selection process or lifestyle factors.
Plans and Procedures
The clinical trial is designed as a **phase II**, open-label, single-arm study to evaluate the safety, efficacy, and pharmacokinetics of twice-daily **midostaurin** combined with standard chemotherapy and as a single agent post-consolidation therapy in pediatric patients with untreated **FLT3-mutated Acute Myeloid Leukemia (AML)**. The trial will involve a sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, including a documented diagnosis of de novo AML, presence of a **FLT3 mutation**, and adequate organ function. Participants will be children aged 3 months to less than 18 years with an expected survival of more than 12 weeks.
The trial will proceed with follow-up visits to monitor safety and tolerability, focusing on the frequency and severity of adverse events, electrocardiograms, and laboratory abnormalities. The primary endpoint is to assess safety and tolerability, while secondary endpoints include response rate, event-free survival, overall survival, and disease-free survival. The trial will also evaluate the pharmacokinetics of midostaurin and its metabolites. The overall trial duration is estimated to end by December 30, 2029, with recruitment having started on March 13, 2019.
Participants will be involved in the study for a maximum treatment period of 476 days, with conditions for early termination including significant adverse events or withdrawal of consent. The end-of-study visit will conclude the trial, assessing the final outcomes and any long-term effects of the treatment. The study will utilize a combination of intravenous and oral administration of the investigational products, with midostaurin being administered as an oral solution. The trial aims to provide comprehensive data on the safety and efficacy of midostaurin in combination with chemotherapy for this specific pediatric population.
Treatment
The clinical trial involves the administration of several **experimental medications** and standard chemotherapy agents. **IDARUBICIN** is provided as a solution for injection, with a maximum daily dose of 12 mg/m². It is administered intravenously, and the treatment period can extend up to 476 days. **DAUNORUBICIN** is supplied as a powder for solution for infusion, with a maximum total dose of 300 mg/m². This medication is also administered intravenously over a treatment period of up to 476 days.
**PKC412**, containing the active substance **MIDOSTAURIN**, is an oral solution used in this trial. It is administered orally with a maximum daily dose of 60 mg/m². The treatment period for PKC412 is also up to 476 days. This formulation is specifically designed for pediatric use and is classified as an orphan drug.
**ETOPOSIDE** is provided as a concentrate for solution for infusion, administered intravenously. The treatment period for etoposide is up to 476 days, although specific dosing details are not provided. Similarly, **CYTARABINE** is available as a solution for injection or infusion, administered intravenously, with a treatment period of up to 476 days.
**MITOXANTRONE** is another concentrate for solution for infusion, administered intravenously, with a treatment period of up to 476 days. **FLUDARABINE** is also included in the trial as a concentrate for solution for infusion, administered intravenously, with a maximum daily dose of 25 mg/m² and a total dose of 2125 mg/m² over a treatment period of up to 476 days.
All medications are chemical substances, and participant compliance is monitored throughout the trial. The trial aims to evaluate the safety, efficacy, and pharmacokinetics of these medications, particularly focusing on the combination of midostaurin with standard chemotherapy in pediatric participants with newly diagnosed FLT3-mutated acute myeloid leukemia (AML).
Efficacy
The efficacy of the clinical trial will be assessed through a series of predefined primary and secondary endpoints. The primary endpoints focus on safety and tolerability, including the frequency and severity of adverse events (AEs), electrocardiogram (ECG) results, multiple-gated acquisition (MUGA) scan abnormalities, and laboratory abnormalities. Tolerability will be evaluated by monitoring the number of dose interruptions, dose reductions, and discontinuations due to the study drug.
Secondary endpoints will include the response rate, defined as the proportion of participants achieving a complete response (CR) or complete response with incomplete hematologic recovery (CRi) according to established criteria. Additional secondary endpoints encompass event-free survival (EFS), overall survival (OS), disease-free survival, and the percentage of participants achieving minimal residual disease (MRD) negative status. The duration of MRD negative status will also be compared between the end of the consolidation phase and during the post-consolidation phase. Furthermore, the palatability of the oral solution will be assessed through a questionnaire, and bone marrow, peripheral blood parameters, and extramedullary involvement will be evaluated to assess morphologic remission. Plasma concentrations of **midostaurin** and its major metabolites will be measured to determine pharmacokinetic parameters such as area under the curve (AUC) and maximum concentration (Cmax), if feasible.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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.
- 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: ● 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
- Participants from 3 months of age to less than 18 years of age with expected survival of greater than 12 weeks.
- 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.
- Participants 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’s 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
- 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
- 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).
- 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)
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Patients with Fanconi anemia, Schwachman syndrome, any other known bone marrow failure syndrome, or constitutional trisomy 21 or with constitutional mosaicism of trisomy 21.
- Known impairment of gastrointestinal (GI) function or GI disease that might alter significantly the absorption of midostaurin.
- Known confirmed diagnosis of human immunodeficiency virus (HIV) infection or active viral hepatitis.
- Left ventricular shortening fraction of < 27%, as determined by MUGA scan or echocardiogram.
- Patients who are under 2.5 kg of body weight.
- 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.
- Pregnant or nursing (lactating) females
- 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: ● Total 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. ● Female 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. ● Male sterilization (at least 6 months prior to screening). The vasectomized male partner should be the sole partner for that participant. ● Use 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
- 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.
- Patients/parents unwilling or unable to comply with the protocol.
- Hypersensitivity to midostaurin, cytarabine, daunorubicin/idarubicin, fludarabine, etoposide or mitoxantrone or to any of the excipients
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 13 Mar 2019 | 1 |
 Czechia | Not Recruiting | 13 Mar 2019 | 2 |
 Germany | Not Recruiting | 13 Mar 2019 | 4 |
 Italy | Not Recruiting | 13 Mar 2019 | 4 |
 Poland | Not Recruiting | 13 Mar 2019 | 1 |
 Slovenia | Not Recruiting | 13 Mar 2019 | 1 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
IDARUBICIN | Test | — | INTRAVENOUS USE | 12 | 476 | SUB08111MIG |
FLUDARABINE | Test | — | INTRAVENOUS USE | 25 | 476 | SUB07678MIG |
CYTARABINE | Test | — | INTRAVENOUS USE | 00 | 476 | SUB06880MIG |
DAUNORUBICIN | Test | — | INTRAVENOUS USE | 00 | 476 | SUB06917MIG |
MITOXANTRONE | Test | — | INTRAVENOUS USE | 00 | 476 | SUB09012MIG |
ETOPOSIDE | Test | — | INTRAVENOUS USE | 00 | 476 | SUB07337MIG |
PKC412 | Test | ORAL SOLUTION | ORAL USE | 60 | 476 | PRD855620 |