A Phase 1 Dose-Escalation Study of the Cladribine Added to CPX-351 in Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML) a Study of the Polish Adult Leukemia Group (AML-1/2018): Preliminary Results of the Dose Escalation Stage

Abstract

Two first authors equally contributed to the study Introduction: CPX-351, a liposomal formula of cytarabine (AraC) and daunorubicine (DNR), was shown as a highly potent drug in newly diagnosed high-risk/secondary acute myeloid leukemia (AML) (Lancet JE, J Clin Oncol 2018). Cladribine is a purine analogue that acts by increasing cellular uptake of AraC in leukemic blasts as well as by direct inhibition of DNA synthesis (Robak T, Leuk Res 2014). Additionally, cladribine compromises DNA methylation in leukemic cells by affecting the cellular S-adenosylmethionine (SAM) level (Libura M, et al. Sci Rep. 2021). Based on the favorable results of cladribine-based salvage regimens (CLAG-M, CLAG) (Wierzbowska A; Eur J Hematol 2008) and induction DAC therapy (Hołowiecki J, J Clin Oncol 2012; Pluta A, Am J Hematology 2017), the phase I/II study was designed to explore safety (MTD), toxicity and efficacy of increasing doses of cladribine in combination with standard dose of CPX-351 in relapsed/refractory AML (R/R AML) patients (pts). (EudraCT number: 2020-002535-29). Here we present the results of the first three three-participant cohorts of patients enrolled. Methods: Pts with R/R AML were eligible if age ≥55 years, ECOG performance status ≤1, HCT-CI ≤3, left ventricular ejection fraction (LVEF) by echocardiogram >50%, adequate hepatic and renal function, and no prior CPX-351 therapy. CPX-351 induction therapy was administered by 90-minute infusion at a dose of 100 U/m2 on days 1, 3, and 5. Cladribine dose escalation started at 1 mg/m2, followed by 3 mg/m2 and 5 mg/m2 in 2 hours intravenous infusion, 2 hours before CPX-351 in 3+3 design. DLTs were assessed in cycle 1. Disease response was assessed by the 2017 ELN criteria. Allogeneic hematopoietic cell transplantation (allo-HCT) was recommended for all eligible pts who had a donor immediately after achieving a complete remission (CR). Patients not eligible for transplant received up to 2 consolidation cycles of CPX-351 + cladribine at the same dose. Results: Nine pts were enrolled with a median age 65.5 (range 62-68) years and 55% of pts were male. Pts were generally heavily pretreated, with a median of 2 prior therapies (range 1-4), importantly 78% (7) pts were primary refractory to the former treatment. Fifty percent of pts were in the poor risk group according to ELN2017. One patient (11%) had previous allo-HCT. No DLTs have been observed to date. No drug-related serious adverse events (SAEs) were reported in cohort 1. Also, in cohort 2 there were no drug-related SAE reports. In cohort 3, till now one death potentially related to treatment was reported. It was due to a septic shock during G4 neutropenia. Two other pts are still in aplasia after the first induction cycle. To date, toxicities of grade ≥ 3 during the induction cycle were: febrile neutropenia (88%), infection (88%), neutropenic enterocolitis (11%), and vulvitis (11%). In cohorts 1 and 2, 50% (3) AML pts achieved a CR/CRi, one partial response (PR), and 2 not responded (NR). In cohort 3, assessment of treatment response is not available yet, however, 2 pts were evaluable for early response evaluation on day 14 and both have the blast clearancein the bone marrow. The third patient died early in aplasia. From cohorts 1 and 2, 3 (50%) of pts were transplanted. Conclusions: Preliminary results suggest that cladribine at doses 1 and 3mg/m2 administered with a standard dose of CPX-351 is well tolerated with no DLTs observed. The dose 5mg/m2 is still under evaluation. Till now the safety profile does not indicate any significant additional myelosuppression. CR was observed in 50% of heavily pretreated R/R AML pts indicating satisfying clinical activity. Further evaluation of the safety and efficacy of this regimen is ongoing.