Phase I Study of a Liposomal Carrier (CPX-351) Containing an Optimized, Synergistic, Fixed Molar Ratio of Cytarabine (Ara-C) and Daunorubicin (DNR) in Advanced Leukemias and Myelodysplastic Syndromes (MDS).

Background: The molar ratio of Ara-C and DNR profoundly affects the antitumor activity of this doublet in vitro. CPX-351 is a liposomal formulation of Ara-C and DNR which fixes the 5:1 molar ratio found to produce optimal synergy and efficacy in both in vitro and in vivo preclinical leukemia models, superior to that observed with conventionally dosed, non-encapsulated drugs. CPX-351 overcomes the individual pharmacokinetics of each drug maintaining the 5:1 molar ratio for extended periods of time after IV administration and delivers this ratio to bone marrow. We initiated an escalating-dose phase 1 trial of CPX-351 in patients with advanced acute leukemias or MDS.

Objectives: 1) to determine safety, tolerability, and pharmacokinetics of a 3 day schedule (day 1, 3, 5) of CPX-351 in advanced leukemia and MDS, and 2) to seek preliminary evidence of antitumor activity.

Methods: Patients with relapsed or refractory AML, ALL, or high-risk MDS were eligible for the study. 90 min. IV infusions of CPX-351 were administered on Days 1, 3, and 5 of each induction course. A second induction course was permitted if there was evidence of antileukemic effect and persistent leukemia in a day 14 bone marrow. Dose escalation began at 3 units/m² (1 u = 1 mg Ara-C and 0.44 mg DNR) with single patient cohorts and doubling of doses with each cohort until evidence of antileukemic activity was observed. Thereafter, 3 patient cohorts and 33% dose increments were to be continued until DLTs signaled the end of further dose escalation. PK samples were collected after each dose.

Results: Twenty-two subjects have received 31 courses of CPX-351: M/F = 15/7, median age = 62.5 years (range 24–78); 19 patients had AML and 3 patients had ALL; median number of prior regimens = 2 (1–7). At 24 u/m² antileukemic effects were observed and future cohort size and escalation rate were adjusted (3 subjects/cohort, 33% dose increments). Non-hematologic toxicities observed to date have included transient grade 1–2 mucositis (5 patients), grade 2 skin rash (2 patients), grade 3 GI bleed (1 patient), and RSV pneumonia which resulted in death (1 patient). In addition, 6 subjects recovered from neutropenic fevers (5 grade 3) that were not considered study drug related. Except for a single patient treated at 24 u/m², hair loss has not been observed. No DLT has been observed at doses up to 57 u/m² (57 mg/m² Ara-C/25 mg/m² DNR). Clinical responses were observed beginning at 32 u/m². At 32 u/m² bone marrow aplasia occurred in 2 of 3 subjects with AML resulting in 1 CRp and 1 PR. At 43 u/m² 2 of 3 subjects achieved CR (1 AML, 1 ALL).

Conclusions: CPX-351 administered on a 3x/week schedule in advanced leukemia appears to be well-tolerated, with preliminary and promising signs of clinical activity as measured by CR and decreases in bone marrow blasts. Accrual to this trial is ongoing, and updated clinical data will be presented.