Phase II Study of Midostaurin + Chemotherapy in Pediatric Patients with Untreated, Newly Diagnosed, FLT3-Mutated Acute Myeloid Leukemia (AML)
Authors: Reinhardt Dirk , Zwaan Christian Michel , Hoenekopp Albert , Niolat Julie , Ifrah Sophie , Noel-Baron Florence , Locatelli Franco 
Published: November 2019

Background: In pediatric patients with AML, the presence of FLT3-internal tandem duplication (ITD) mutation is indicative of high-risk disease and confers a worse prognosis and a greater chance of relapse. Midostaurin is a multikinase inhibitor with potent activity against both mutated and non-mutated FLT3. In adult patients with FLT3-mutated AML, midostaurin in combination with chemotherapy has demonstrated good safety/tolerability and significantly improved overall survival (OS) and event-free survival (EFS) compared with placebo + chemotherapy. We present here the design of an ongoing phase II study (NCT03591510) evaluating midostaurin combined with standard chemotherapy and as a single-agent post-consolidation therapy in newly diagnosed pediatric patients with FLT3-mutated AML, other than acute promyelocytic leukemia.
Study Design and Methods: This open-label, single-arm study is composed of 2 parts. For Part 1, the primary objective is to determine the recommended phase II dose (RP2D) of midostaurin in combination with chemotherapy, as determined by the occurrence of dose-limiting toxicities. For Part 2, in which patients will receive the RP2D of midostaurin, the primary objective is to evaluate the efficacy of midostaurin + chemotherapy as measured by the EFS rate at 24 mo (for regulatory purposes outside the US) or to assess the safety/tolerability of midostaurin + chemotherapy (for regulatory purposes within the US). Secondary objectives include safety/tolerability (outside US) and EFS at 24 mo (within US), other efficacy parameters (including OS, complete remission [CR], CR with incomplete blood count recovery [CRi], cumulative incidence of relapse, and minimal residual disease-negative status), and characterization of the pharmacokinetics of midostaurin.
Eligible patients are aged 3 mo to < 18 yr with expected survival of > 12 wk, have a Lansky or Karnofsky performance status of ≥ 60, and have previously untreated de novo AML with FLT3 mutation: ITD and/or mutation in the tyrosine kinase domain, with mutant/wild-type signal ratio cutoff of ≥ 0.05. Exclusion criteria include any concurrent malignancy, Philadelphia chromosome or BCR-ABL1-positive AML, AML associated with Down syndrome, secondary AML, symptomatic leukemic central nervous system involvement, bone marrow failure syndrome, or prior treatment with a FLT3 inhibitor.
Patients are to receive 5 treatment blocks: 2 of standard induction (Blocks 1-2) and 3 of consolidation (Blocks 3-5) chemotherapy, each with sequential twice-daily (BID) oral midostaurin. In Part 1 of the study, midostaurin will be given at a starting dose of 30 mg/m2 BID; dose escalation and determination of RP2D will be facilitated by a Bayesian hierarchical logistic regression model guided by escalation with overdose control principle. In Part 2, midostaurin will be administered at the RP2D. Induction therapy will be the local standard chemotherapy regimen with midostaurin starting after 24 hr from identification of FLT3 abnormalities and continuing for 14 d for Block 1, and FLADx (fludarabine + high-dose cytarabine on D1-5, daunorubicin on D2, 4, 6) with sequential midostaurin on D8-21 for Block 2. Patients demonstrating CR or modified CRi will proceed to consolidation with the following chemotherapy regimens, each with sequential midostaurin on D8-21: HAM (high-dose cytarabine on D1-3, mitoxantrone on D3, 4) for Block 3, HA3E (high-dose cytarabine on D1-3, etoposide on D1-5) for Block 4, and HiDAC (high-dose cytarabine on D1-3) for Block 5. Patients must be in continued remission (CR or modified CRi) to receive each block of consolidation therapy. Patients who complete Block 5 and remain in remission will proceed to 12 × 28-d cycles of post-consolidation therapy with single-agent midostaurin. Patients may undergo allogeneic hematopoietic stem cell transplantation at any time at the investigator's discretion.
Overall, the aim is to recruit a minimum of 52 patients, including at least 49 at the RP2D dose. This study is currently enrolling patients at 13 centers in 7 countries (as of July 26, 2019), and a total of 37 centers in 14 countries are planned.

Disclosures
Reinhardt: Novartis: Other: Participation in Advisory Boards; Jazz: Other: Participation in Advisory Boards, Research Funding; CSL Behring: Research Funding; Roche: Research Funding. Zwaan:BMS: Research Funding; Servier: Consultancy; Sanofi: Consultancy; Celgene: Consultancy, Research Funding; Janssen: Consultancy; Pfizer: Research Funding; Novartis: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Other: Travel support; Roche: Consultancy; Incyte: Consultancy. Hoenekopp:Novartis Pharma AG Basel: Employment, Equity Ownership. Niolat:Novartis Pharma: Employment. Ifrah:Novartis: Employment. Noel-Baron:Novartis: Employment, Equity Ownership. Locatelli:Miltenyi: Honoraria; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BluebirdBio: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees.

OffLabel Disclosure:
Midostaurin is a kinase inhibitor approved in combination with chemotherapy for the treatment of FLT3-mutated AML in adults; the study reported here is in pediatric patients with FLT3-mutated AML.