Safety and pharmacokinetics of the antisense oligonucleotide (ASO) LY2181308 as a single-agent or in combination with idarubicin and cytarabine in patients with refractory or relapsed acute myeloid leukemia (AML)

Abstract

Survivin is expressed in tumor cells, including acute myeloid leukemia (AML), regulates mitosis, and prevents tumor cell death. The antisense oligonucleotide sodium LY2181308 (LY2181308) inhibits survivin expression and may cause cell cycle arrest and restore apoptosis in AML. In this study, the safety, pharmacokinetics, and pharmacodynamics/efficacy of LY2181308 was examined in AML patients, first in a cohort with monotherapy (n = 8) and then post-amendment in a cohort with the combination of cytarabine and idarubicin treatment (n = 16). LY2181308 was administered with a loading dosage of three consecutive daily infusions of 750 mg followed by weekly intravenous (IV) maintenance doses of 750 mg. Cytarabine 1.5 g/m(2) was administered as a 4-hour IV infusion on Days 3, 4, and 5 of Cycle 1, and idarubicin 12 mg/m(2) was administered as a 30-minute IV infusion on Days 3, 4, and 5 of Cycle 1. Cytarabine and idarubicin were administered on Days 1, 2, and 3 of each subsequent 28-day cycle. Reduction of survivin was evaluated in peripheral blasts and bone marrow. Single-agent LY2181308 was well tolerated and survivin was reduced only in patients with a high survivin expression. In combination with chemotherapy, 4/16 patients had complete responses, 1/16 patients had incomplete responses, and 4/16 patients had cytoreduction. Nine patients died on study: 6 (monotherapy), 3 (combination). LY2181308 alone is well tolerated in patients with AML. In combination with cytarabine and idarubicin, LY2181308 does not appear to cause additional toxicity, and has shown some clinical benefit needing confirmation in future clinical trials.

Figures

Fig 1

Study Design. Pre amendment- 750 milligrams intravenous bolus dose LY2181308 was administered in loading doses on days 1-3 and day 8. Weekly doses of 750 mg LY2181308 were administered intravenously on days 15, 22, 29, and day 36 thereafter. Post-amendment- 750 milligrams intravenous bolus dose LY2181308 was administered in loading doses on days 1-3 followed by idarubicin 12.0 mg/m2 plus cytarabine 1.5 mg/m2. Weekly doses of 750 mg LY2181308 were administered iv on days 8, 15, and 22 thereafter. Pharmacokinetic and bone marrow sampling are depicted as white and grey boxes, respectively. See methods for details.

Fig 2

LY2181308 plasma pharmacokinetic profile following Day 3 dosing (LY2181308 750 mg 3-hour infusion). Black circles represent observed data-- red lines represent simulated profile from a four compartment PK model (median, 5th, and 95th percentiles) LY2181308 (15). Data were analyzed on the log scale using a mixed effect model in order to account for any incomplete data and repeated measures on each patient

Fig 3

LY2181308 detection in peripheral blood mononuclear cells (PBMCs) after monotherapy. Enzyme-linked immunosorbent assay was used to measure LY2181308 abundance in peripheral blood monocyte lysates before and 10-12 days after initial bolus dose administration (2-4 days after Day 3 dose). The red circle denotes the median concentration value predose on Day 8. The black lines denote the model simulated median, 5th, and 95th percentile concentrations at the end of LY2181308 infusion on Day 3 in combination patients (ie, prior to administration of the first dose of chemotherapy – idarubicin and cytarabine). ID = identification; PK = pharmacokinetic

Fig 4

Survivin expression before and up to 5 days after LY2181308 administration as monotherapy (n=8 pts). The survivin index was calculated as [(blast survivin mean equivalent fluorescence (MEFL) – blast isotypic control MEFL)/blast isotypic control MEFL] using the fluorescence-activated cell sorting (FACS) assay. The results are presented using least-squares geometric means (LSGM) for time categories and 90% confidence intervals for the key variables