CWP232291 (CWP291) is a small-molecule inhibitor of Wnt signaling that causes degradation of b-catenin via apoptosis induction through endoplasmic reticulum stress activation. This first-in-human, open-label, dose-escalation study to evaluate the safety, maximum tolerated dose (MTD), and preliminary efficacy of CWP291 enrolled 69 patients with hematologic malignancies (acute myeloid leukemia [AML], n 5 64; myelodysplastic syndrome, n 5 5) in 15 dose-escalation cohorts of 4 to 334 mg/m2 using a modified 313 design and 1 dose-expansion cohort. CWP291 was administered IV daily for 7 days every 21 days. The most common treatment-emergent adverse events (TEAEs) were nausea (n 5 44, 64%), vomiting (n 5 32, 46%), diarrhea (n 5 25, 36%), and infusion-related reactions (n 5 20, 29%). Grade $3 TEAEs in .3 patients (5%) were pneumonia (n 5 8, 12%); hypophosphatemia (n 5 6, 8%); leukocytosis, nausea, cellulitis, sepsis, and hypokalemia (n 5 5 each, 7% each); and hypertension (n 5 4, 6%). Dose-limiting toxicities included nausea (n 5 3) and abdominal pain, anaphylactic reaction, myalgia, and rash (n 5 1, each); the MTD was defined at 257 mg/m2. CWP232204, the active metabolite of CWP291, showed pharmacokinetic linearity on both days 1 and 7, and a terminal half-life of;12 hours. Among 54 response-evaluable AML patients, there was one complete response at a dose of 153 mg/m2 and one partial response at 198 mg/m2; bone marrow blast percentage reduced from a median of 58.3% to 3.5% and 15.0% to 4.2%, respectively. Future studies will explore CWP291, with a mechanism of action aimed at eradication of earlier progenitors via Wnt pathway blockade, as combination therapy. This trial was registered at www.clinicaltrials.gov as #NCT01398462.
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