Phase 1 study of CWP232291 in relapsed/refractory acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).

Abstract

7044 Background: CWP232291, a novel peptidomimetic small molecule identified via a phenotypic drug discovery screen, shows selective inhibitory activity at submicromolar levels on a Wnt gene reporter and decreases expression of the β-catenin target genes, cyclin D1 and survivin. It has broad anti-cancer efficacy in vitro, with significant preclinical tumor regression outperforming standard cytotoxic AML drugs. Methods: Subjects with relapsed AML or MDS were infused CWP232291 iv over 5 -30 minutes for 7 days in 21-day cycles until disease progression in a first in human, 3+3 dose-escalation, Phase 1 design. Results: Results to January 27, 2015 over a dose range of 4 – 257 mg/m2 in 56 patients (53 AML; 3 MDS) are reported. Common ( ≥ 10% patients) drug-related adverse events (AEs) included nausea (43%), infusion-related reaction (36%), vomiting (29%), diarrhea (16%), and anorexia (11%). Toxicity was mostly ≤ grade 2 (91%), grade 3/4 events comprised 9%, observed similarly across all dose cohorts. Related serious AEs comprised fever, nausea, and anaphylactic reaction, at 19, 54 and 198 mg/m2, respectively. Dose-limiting toxicity included nausea, rash and anaphylactic reaction (54, 153 and 198 mg/m2, respectively). Toxicity was managed effectively with standard-of-care medications and, in the event of recurrence, could be mitigated with prophylaxis in subsequent cycles. Within 30 minutes CWP232291 was completely converted to its active metabolite, CWP232204. CWP232204 maximum plasma concentration (Cmax) and area under the time-concentration curve (AUC) values were dose proportional. At the highest dose with data (153 mg/m2; n = 6), the mean terminal elimination half-life (t½) was 6.3 hrs, mean Cmax was 9922 ng/mL, and AUC was 6797 ng•hr/mL. A complete remission was seen in one AML patient after 2 cycles at 153/118 mg/m2, with normalization of neutrophil and platelet counts; maximum reduction from baseline in β-catenin and survivin expression were > 90% and 77%. No other objective responses were seen but higher doses showed significant reductions in these biomarkers. Conclusions: CWP232291 single agent efficacy was observed in AML. MTD has not been defined; accrual is ongoing. Clinical trial information: NCT01398462.