Phase 1 study of CWP232291 in patients with relapsed or refractory acute myeloid leukemia and myelodysplastic syndrome

Je Hwan Lee, Stefan Faderl, John M. Pagel, Chul Won Jung, Sung Soo Yoon, Animesh D. Pardanani, Pamela S. Becker, Howard Lee, Jeongeun Choi, Kyoungjune Lee, Minkyoung Kim, Jorge E. Cortes

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


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 as #NCT01398462.

Original languageEnglish (US)
Pages (from-to)2032-2043
Number of pages12
JournalBlood Advances
Issue number9
StatePublished - May 12 2020

ASJC Scopus subject areas

  • Hematology


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