A global study of midostaurin in combination with chemotherapy to evaluate safety, efficacy, and pharmacokinetics in newly diagnosed pediatric patients with FLT3-mutated AML

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Novartis Pharma AG

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

13 Mar 2019 → ongoing

Decision date (initial)

2024-05-21

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Novartis Pharma AG

External identifiers

EU CT number

2023-509834-20-00

EudraCT number

2017-004830-28

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacodynamic, Pharmacokinetic, Efficacy

Part 2: To evaluate safety and tolerability of midostaurin (30mg/m2 bid or 1 mg/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 objectives 9

1. Part 2 of the Study: Characterize the pharmacokinetic (PK) of midostaurin and its active metabolites (CGP62221 and CGP52421) in the pediatric population. To compare predicted exposure metrics to observed exposure metrics to support dose selection
2. For Part 2 of the Study: Determine the rates of response (CR, CR/modified CRi and CR/CRi ) after two cycles of induction therapy using morphologic assessment.
3. For Part 2 of the Study: Determine the time to response (TTR) and response duration.
4. For Part 2 of the Study: To evaluate efficacy as measured by the event-free survival (EFS) rate at 18 months of midostaurin in sequential combination with chemotherapy followed by 12 cycles (28 days in each cycle) of midostaurin post-consolidation therapy in pediatric participants with newly diagnosed FLT3-mutated AML (after all participants have completed at least 18 months of follow-up), and non-censored at the time of HSCT.
5. For Part 2 of the Study: Determine the median overall survival (OS) and probability of survival at yearly intervals regardless of HSCT
6. For Part 2 of the Study: Determine the median disease-free survival (DFS) and DFS probability at yearly intervals.
7. For Part 2 of the Study: Determine the percentage of participants who reached MRD (Measurable Residual Disease)-negative status by study treatment phase by multiparameter flow cytometry and those who reached and remained MRD-negative in the post-consolidation phase.
8. For Part 2 of the Study: Evaluate the acceptability of the oral midostaurin solution.
9. For Part 2 of the Study: Evaluate the bone marrow and peripheral blood blast response rate of treated pediatric participants at the end of Induction cycle 1 (Block 1) and Induction cycle 2 (Block 2).

Conditions and MedDRA coding

untreated FLT3-mutated Acute Myeloid Leukemia

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-000780-PIP01-09

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. 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.
2. 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
3. Participants from 3 months of age to less than 18 years of age with expected survival of greater than 12 weeks.
4. 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.
5. 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
6. 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 19

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). However, up to 1 week of FLT3 inhibitor (except midostaurin) exposure prior to study enrollment is permissible.
5. 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.
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 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
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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Part 2: Safety: Frequency/severity of AEs, ECG, MUGA and laboratory Abnormalities
2. Part 2 : Tolerability: number of dose interruptions, dose reductions and discontinuation due to study drug

Secondary endpoints 9

1. 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.
2. 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
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 CRiwithin 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. If a participant is not known to have died, survival will be censored at the date of last contact.
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 participants 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 post-consolidation phase (if sufficient number of participants enter post consolidation)
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 two major metabolites, CGP52421 and CGP62221, will be evaluated; PK parameters (AUC, Cmax if feasible, and pre-dose concentrations)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 7

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Novartis Pharma AG

Sponsor organisation

Novartis Pharma AG

Address

Lichtstrasse 35

City

Basel

Postcode

4056

Country

Switzerland

Scientific contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Public contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Third parties 17

Locations

6 EU/EEA countries · 19 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Corrective measures 1 · Art. 77 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 116 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications