Abstract C45: Phase I study of WNT974, a first-in-class Porcupine inhibitor, in advanced solid tumors (2015)

Abstract Background: Aberrant Wnt pathway activation is critical for initiation and maintenance of multiple tumor types, yet therapeutic inhibition of Wnt/β-catenin signaling has been challenged by the lack of tractable targets. WNT974 is an oral investigational agent that potently and selectively inhibits Porcupine, a membrane-bound O-acyltransferase enzyme required for Wnt secretion. Based on preclinical studies, cancers that are Wnt ligand-dependent due to upstream aberrations in the Wnt pathway (e.g. mutations in RNF43 or its homolog ZNRF3, and fusions in R-spondin [RSPO]) are predicted to be sensitive to WNT974. RNF43 is frequently mutated in microsatellite unstable colorectal, gastric, and endometrial cancers (80%, 55%, and 51% respectively), pancreatic ductal adenocarcinoma (10%), and liver fluke-associated cholangiocarcinoma (9%). ZNRF3 is mutated in adrenocortical carcinoma (21%). RSPO2 and RSPO3 fusions occur in 10% of colorectal cancers. Methods: A Phase I clinical trial is being conducted in patients (pts) with advanced cancer to evaluate the safety and tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) properties, and antitumor activity of WNT974 (NCT01351103). Dose escalation was completed in a molecularly unselected population and guided by an adaptive Bayesian logistic regression model based on dose limiting toxicities and adverse events (AEs). Pre- and on-treatment specimens (blood, skin, and tumor) were collected for PK/PD evaluation. Expansion cohort enrollment is restricted to pts with tumors harboring molecular alterations that portend Wnt ligand dependence (e.g. RNF43 mutation, RSPO fusion). Results: As of data cut-off, March 2, 2015, 68 pts have enrolled. Sixty-six pts were treated in the dose escalation at dose ranges and schedules of 5-30 mg QD; 30-45 mg QD 4 days on, 3 days off; and 5 mg BID. WNT974 showed rapid absorption (median Tmax 1-3 h) and a mean elimination half-life of 5-8 h. Accumulation on Cycle 1 Day 15 was small (ratio &lt;2). PK exposure was dose proportional and inter-patient variability was generally moderate. Reported AEs (&gt;10%) suspected to be related to WNT974 included: dysgeusia (49%), decreased appetite (28%), nausea (27%), fatigue (19%), diarrhea (18%), vomiting (16%), hypercalcemia (13%), alopecia (10%), asthenia (10%), and hypomagnesemia (10%). Grade 3/4 related AEs (&gt;2%) included: asthenia (4%), fatigue (4%), decreased appetite (3%), and enteritis (3%). Measurement of AXIN2, a ß-catenin target gene, in matched skin specimens, showed Wnt pathway inhibition at a wide range of doses. A recommended dose for expansion of 10 mg QD was chosen based on PK, PD, and tolerability data; maximum tolerated dose was not determined. There was no evidence of WNT974 antitumor activity in the dose escalation. As of data cut-off, two pts had initiated study treatment in the dose expansion and one, a pt with appendiceal cancer with an RNF43 mutation, had completed the first response assessment. This pt had stable disease with tumor shrinkage of -27%. Updated clinical data will be reported. Conclusion: WNT974 is a first-in-class Porcupine inhibitor. Preliminary clinical data suggest WNT974 has a manageable safety profile and potential for antitumor activity in a molecularly selected population. Studies to further evaluate the safety, tolerability, and antitumor activity of WNT974 as a single agent and in combination are ongoing. Citation Format: Filip Janku, Roisin Connolly, Patricia LoRusso, Maya de Jonge, Ulka Vaishampayan, Jordi Rodon, Guillem Argilés, Andrea Myers, Shu-Fang Hsu Schmitz, Yan Ji, Margaret McLaughlin, Michael R. Palmer, Jennifer Morawiak. Phase I study of WNT974, a first-in-class Porcupine inhibitor, in advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C45.