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

Abstract

CWP232291 (CWP291) is a small-molecule inhibitor of Wnt signaling that causes degradation of β-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 = 64; myelodysplastic syndrome, n = 5) in 15 dose-escalation cohorts of 4 to 334 mg/m2 using a modified 3+3 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 = 44, 64%), vomiting (n = 32, 46%), diarrhea (n = 25, 36%), and infusion-related reactions (n = 20, 29%). Grade ≥3 TEAEs in >3 patients (5%) were pneumonia (n = 8, 12%); hypophosphatemia (n = 6, 8%); leukocytosis, nausea, cellulitis, sepsis, and hypokalemia (n = 5 each, 7% each); and hypertension (n = 4, 6%). Dose-limiting toxicities included nausea (n = 3) and abdominal pain, anaphylactic reaction, myalgia, and rash (n = 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.

Conflict of interest statement

Conflict-of-interest disclosure: S.F. is an employee and stockholder of Jazz Pharmaceuticals. J.M.P. was a consultant for Actinium Pharmaceuticals. S.-S.Y. was on advisory committees at Janssen, Celgene, and Amgen. P.S.B. received research funding form AbbVie, Amgen, Bristol-Myers Squibb, JW Pharmaceutical, Novartis, Pfizer, Glycomimetics, Trovagene, Invivoscribe, Aptose Biosciences, and Trethera; performed consulting for CVS Caremark and McKesson; and received honoraria from Physician Education Resource and The France Foundation. J.C., K.L., and M.K. are employees of JW Pharmaceutical. J.E.C. received research support (to institution) from JW Pharmaceutical, BMS, Novartis, Astellas, Daiichi, Jazz, Pfizer, Amphivena, and Merus; and consulting fees from Novartis, Pfizer, Jazz, and Daiichi. The remaining authors declare no competing financial interests.

© 2020 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Profile of CWP232204 over time in patients. PK of CWP232204 on day 1 (A) and steady state (day 7) (B).

Figure 2.

Biomarker analysis for Wnt signaling pathway inhibition. Survivin protein concentrations in plasma vs time and CWP291 concentrations in plasma vs time. (A) Data pooled for the entire study. (B) Data for each cohort. (Note: A LOESS smoothing line is overlaid for survivin. Concentration-time profiles of CWP232204 were also shown for comparison with survivin. Patient 4015 was excluded.)

Figure 3.

Survivin profile. (A) Minimum survivin protein levels achieved (percentage of baseline levels) for dose administered and cohort. Note: A LOESS smoothing line is overlaid. (B) For the box-and-whisker plot, the line across each box, the top edge, and the bottom edge represent the median, the first quartile, and the third quartile, respectively. The horizontal lines connected with the whiskers extending from the box denote the minimum and the maximum values, respectively. Empty circles (○) indicate an outlier, defined as a value less than the first quartile minus 1.5 times interquartile range or a value greater than the third quartile plus 1.5 times interquartile range.