A Phase 1 Study of CPX-351 Plus Gilteritinib in Relapsed or Refractory FLT3-Mutated Acute Myeloid Leukemia
Authors: Chan Onyee , Sweet Kendra L. , Hunter Jhada-Kai , Ball Somedeb , Mo Qianxing , Xie Zhuoer , Yun Seongseok , Kuykendall Andrew T. , Padron Eric , Walker Alison R. , Komrokji Rami S. , Lancet Jeffrey E , Sallman David 
Published: December 2024

Introduction: Outcomes of relapse/refractory (R/R) acute myeloid leukemia (AML) are poor especially for certain subsets such as those with FMS-related tyrosine kinase 3 (FLT3) mutations. Gilteritinib is a potent FLT3 inhibitor that is effective against both FLT3-internal tandem duplications (ITD) and FLT3-tyrosine kinase domain (TKD) mutations. The Food and Drug Administration (FDA) approved gilteritinib for R/R FLT3-mutated AML based on the ADMIRAL trial where gilteritinib was superior to salvage chemotherapy with a CR/CRi rate of 34% vs. 15.3% and median overall survival (OS) 9.3 vs. 5.6 months (Perl et al. NEJM. 2019). CPX-351, a dual-drug liposomal formulation of daunorubicin and cytarabine at the synergistic 1:5 molar ratio, is approved for newly diagnosed therapy-related or myelodysplasia-related AML (Lancet et al. JCO. 2018). Subset analysis showed a potential outcome benefit in FLT3-ITD mutated patients who were treated with CPX-351. In this study, we hypothesize the combination of gilteritinib and CPX-351 will be safe and would synergistically result in higher response rates than gilteritinib alone.

Methods: This is a phase 1 clinical trial (NCT05024552) using CPX-351 combined with gilteritinib (Dose Level [DL] 1: 120 mg; DL -1: 80 mg) for adult patients with FLT3-ITD/TKD positive R/R AML. The primary objective is to determine the safety and recommended phase 2 dose for this combination. Patients start with DL 1, and in the event of DLT(s) according to 3+3 design, de-escalation to DL -1 is possible. Induction consists of CPX-351 (daunorubicin 44 mg/m2 and cytarabine 100 mg/m2) (Day 1, 3, 5) plus gilteritinib Days 6-19. Reinduction is allowed using CPX-351 (Day 1, 3) plus gilteritinib Days 4-17. If CR/CRi is achieved, patients may receive up to 2 cycles of consolidations using CPX-351 (daunorubicin 29 mg/m2 and cytarabine 65 mg/m2) (Day 1, 3) with gilteritinib Days 4-17. For patients who do not proceed with allogeneic hematopoietic cell transplant (alloHCT), maintenance using gilteritinib daily at the same dose as induction will continue for up to 12 months. Serial samples are obtained from patients for correlative studies including RNA sequencing. A total of 22 patients is planned for the study.

Results: At the time of data cut-off, there were 15 patients (7M/8F) with a median age of 60 (range: 46-73) years, enrolled between 2/2022 and 7/2024. By European LeukemiaNet (ELN) 2022 classification, 5/15 (33.3%) had adverse risk disease and the rest had intermediate risk disease. Most common mutations include FLT3-ITD (80%), DNMT3A (73.3%), NPM1 (53.3%), TET2 (26.7%), and FLT3-TKD (20%). There were no patients with TP53 mutation. Median lines of therapy prior to treatment was 1 (range: 1-3). Nine patients (60%) had a prior exposure to FLT3 inhibitor (midostaurin in all cases). No patients had alloHCT prior to study.

The median follow-up was 8 months (range: 0.3-17). At data cut-off, 13 patients were evaluable for response. DL1 (gilteritinib at 120mg) was cleared after treating 3 patients with no dose-limiting toxicities (DLTs), and thus all subsequent patients were treated at DL1. The CR/CRi rate was 46.2% (6/13) with 2 CR and 4 CRi. Median OS was 11.9 months (95% CI: 6.9-17). Among responding cases (5 ITD and 1 TKD) with available MRD by flow cytometry, 4/5 (80%) were MRD negative. Currently, 1 patient is in consolidation, 2 are on maintenance, and 3 have relapsed. One patient relapsed soon after induction and 2 patients relapsed after 1 cycle of consolidation. No patients proceeded to alloHCT.

All patient experienced grade ≥ 3 cytopenias. The median time to neutrophil and platelet recovery to meet the best response (CR: ANC ≥ 1k/µL and platelets ≥ 100k/µL; CRi: ANC ≥ 1k/µL or platelets ≥ 100k/µL) was 41 days (range: 35-45). No DLTs or serious adverse events were observed. The only non-hematologic grade 3/4 adverse events (AEs) ≥ 20% was febrile neutropenia (33.3%). Other AEs were GI related (53.3%), fatigue/weakness (33.3%), and elevated LFTs (13.3%).

Conclusions: The combination of CPX-351 and gilteritinib had a similar safety profile as the individual agents and gilteritinib 120 mg days 6-19 was the recommended expansion dose. The combination achieves a higher response rate than gilteritinib alone in patients with R/R FLT3 mutated AML with a high MRD negativity rate. Updated results will be presented at the meeting.