Phase II study of EL625, a p53 antisense oligonucleotide, and chemotherapy in refractory and relapsed acute myelogenous leukemia (AML)

Abstract

6617 EL625, an antisense phosphorothioate, induces RNase H dependent cleavage of p53 transcripts resulting in loss of p53 production. In vitro, EL625 combined with low doses of p53-inducing genome damaging agents, e.g. idarubicin, eliminates self-renewal of AML blast stem cells without adversely affecting normal cells. To determine the safety & efficacy of EL625 in combination with chemotherapy we are conducting a phase II study in patients (pts) with AML who were refractory to induction chemotherapy or had a 1st remission duration of <12 months, & were receiving their first salvage. As previously published, the expected complete remission rate with salvage chemotherapy for pts with these characteristics is 10–20% (Estey et al. Blood 1996; 88: 756). Pts were randomized to 1 of 3 groups. All pts received EL625 (0.1 mg/kg/hr continuous infusion over 4 days [d]) & Idarubicin (12 mg/m2/d x 3 d) starting 24 hrs after the start of EL625. Ara-C was administered starting 24 hrs after the start of EL625 infusion as follows: Arm 1, no Ara-C; Arm 2, 100 mg/m2/d over 7d; Arm 3, 1 g/m2/d x4d (3d if 60 yrs or older). Pts could receive up to 2 courses of induction therapy. We have treated 11 pts (4 in arm 1; 3 in arm 2; 4 in arm 3). Median age is 56 yrs (range, 25–73 yrs). 7 were refractory to induction & 6 had relapsed after median 1st complete remission (CR) duration of 30 wks (range, 4–46). 4 pts had diploid karyotype & 7 had cytogenetic abnormalities (complex -5/-7 in 2, misc 5). 9 pts are evaluable for efficacy & toxicity (2 too early). 5 pts have received 2 courses of therapy. 4 pts (44%) achieved CR (1 arm 1, 2 arm 2, 1 arm 3). CR occurred in 2 pts with refractory disease & 2 with relapse (1st CR 32 & 46 wks, respectively). All 4 pts continue in CR after 6, 5, 4 & 1 month, respectively; 1 received stem cell transplant in CR. 2 other pts had a morphologic leukemia free state as per the International Working Group (Cheson et al, JCO 2003; 21:4642). 1 pt died on course 1, day 15 of pneumonia. Toxicity was as expected with myelosuppression as the most common adverse event and no grade 3–4 toxicity related to EL625. Although preliminary, these results suggest that EL625 in combination with chemotherapy is well tolerated. The early efficacy data is encouraging. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eleos Eleos