A Phase 1/2 Study of Quizartinib (Q) in Combination with Re-Induction Chemotherapy and As Single-Agent Continuation Therapy in Pediatric and Young Adult Patients with Relapsed/Refractory (R/R) FLT3-ITD Acute Myeloid Leukemia (AML)
Authors: Zwaan C. Michel , Kolb Edward Anders , Mires Derek E. , Vigliotti Michele , Xie Jingdong , Downs Pamela , DeCillis Arthur P , Rabik Cara A , Cooper Todd M 
Published: November 2019

Background
Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations occur in 10%-15% of pediatric/adolescent patients with AML and are associated with treatment resistance, risk of relapse, and poor survival. Nearly 50% of children with newly diagnosed FLT3-ITD AML fail treatment or relapse as their first event (Levis, et al, Intl J Hematol 2005; Gilliland, Blood 2002). Therefore, targeting FLT3-ITD may improve clinical responses or prevent relapse in younger patients with FLT3-ITD mutations. No FLT3 inhibitors are approved for use in children. Q is an oral, highly potent and selective, type II FLT3 inhibitor. In the phase 3 QuANTUM-R trial, Q monotherapy prolonged overall survival vs salvage chemotherapy in adult patients with R/R FLT3-ITD AML (Cortes, et al, Lancet Oncol 2019). In another study, Q combined with chemotherapy in pediatric patients (age ≤ 21 years) with R/R AML or acute lymphoblastic leukemia, regardless of FLT3-ITD status, resulted in a marked reduction in bone marrow blasts for patients with FLT3-ITD vs other patients (Cooper, et al, Clin Cancer Res 2016). Thus, there is a strong rationale to investigate Q for treatment of R/R FLT3-ITD AML in pediatric/adolescent patients.
Study Design and Methods
This open-label, multicenter, single-arm, phase 1/2 study (NCT03793478) consists of dose-escalation and -expansion phases. Patients will be stratified into 2 age groups: 1 to < 12 months (younger age group) and 1 to ≤ 21 years (older age group). Key inclusion criteria are diagnosis of FLT3-ITD AML, first relapse or refractory to first-line high-dose chemotherapy with adequate organ function. Patients who received prior therapy with other FLT3 inhibitors or prior stem cell transplant (SCT) are eligible. Key exclusion criteria include acute promyelocytic leukemia or juvenile myelomonocytic leukemia, significant cardiovascular disease (including QTc > 450 ms), active systemic infections, liver disease, or HIV infection. Phases 1 and 2 include ≤ 2 reinduction cycles, optional consolidation therapy, and continuation therapy for those having a partial response (PR) or remission. Reinduction therapy will consist of fludarabine and cytarabine (FLA; 30 mg/m2/day and 2000 mg/m2/day, respectively) followed by Q in 28-day cycles. Patients will be treated with intrathecal (IT) triple chemotherapy prophylaxis before reinduction cycles 1 and 2 and after cycle 2. Additional IT triple chemotherapy prophylaxis may be given at investigator discretion for patients with CNS2 disease. Patients achieving at least a PR after reinduction may receive optional consolidation chemotherapy as a bridge to allogeneic hematopoietic SCT (HSCT). Optional consolidation regimens are high-intensity chemotherapy (cytarabine 500 mg/m2/day + etoposide 100 mg/m2/day) followed by Q, or low-intensity consolidation with either Q monotherapy or cytarabine (75 mg/m2/day). Patients who achieve at least a PR after reinduction or continue to be in remission after HSCT may receive continuation therapy with Q monotherapy (for up to twelve 28-day cycles). In phase 1, the starting dose of Q for the reinduction cycle for patients 1 to ≤ 21 years will be 40 mg/m2 once daily with body surface area (BSA) < 1.5 m2 or 60 mg once daily for patients with BSA ≥ 1.5 m2. The starting dose of Q for younger patients in phase 1 will be determined from the recommended phase 2 dose (RP2D) from the older age group and pharmacokinetic (PK) modeling. Up to 9 patients per dose level will be enrolled in the older age group, and younger patients will be enrolled using a rolling 6 design. Patients in phase 2 will receive the RP2D for their respective age group. The planned sample size is 41-65 patients to meet the target of 41 response-evaluable patients at the RP2D. QTc based dose modifications will be instituted for Q. The primary endpoints are safety, composite complete remission rate (CRc; defined as complete remission + complete remission with incomplete recovery), and PK parameters. Secondary endpoints include duration of responses, relapse rates, overall survival, and event-free survival at 1, 2, and 3 years, number of patients proceeding to HSCT, pharmacodynamics, gene mutations in bone marrow blasts, minimal residual disease, and FLT3 allelic ratio. This study is recruiting and being conducted in collaboration with the Children's Oncology Group in North America and the Innovative Therapies for Children with Cancer Consortium in Europe.

Disclosures
Zwaan: Servier: Consultancy; Pfizer: Research Funding; BMS: Research Funding; Janssen: Consultancy; Roche: Consultancy; Celgene: Consultancy, Research Funding; Sanofi: Consultancy; Jazz Pharmaceuticals: Other: Travel support; Incyte: Consultancy; Novartis: Consultancy. Mires:Daiichi Sankyo: Employment. Vigliotti:Daiichi Sankyo, Inc.: Employment. Xie:Daiichi Sankyo, Inc.: Employment. Downs:Daiichi Sankyo, Inc.: Employment. DeCillis:Pyramid: Consultancy; Codiak: Consultancy; Eleven: Consultancy; Arvinas: Consultancy; Exelixis: Consultancy; Novartis: Consultancy; Genocea: Consultancy; Daiichi Sankyo, Inc.: Consultancy; CytomX: Consultancy.