DKK1 is an inhibitor of the canonical Wnt/ß-catenin pathway and a modulator of non-canonical signaling. High tissue DKK1 expression in intrahepatic cholangiocarcinoma (CCA) is associated with advanced stage and shorter survival. DKK1 may enhance the invasive properties of CCA, promoting lymph node metastasis by induction of MMP9 and VEGF-C. D has previously demonstrated activity in lung and esophageal cancers. This study evaluated the maximum tolerated dose (MTD), safety and efficacy of D in combination with GC in pts with ABC.
Patients with histologically confirmed, advanced ABC were eligible. In Part A (3 + 3 design), pts received D at either 150 or 300 mg with G 1000 mg/m2 and C 25 mg/m2 on days 1 and 8 of each 21 day cycle. Part B (300 mg D expansion) has completed enrollment. Response was assessed every 2 cycles using RECISTv1.1.
24 pts were enrolled; 22 pts evaluable for safety; 4 dosed at 150 mg and 18 dosed at 300 mg; 86% screened ABC (21 pts) had DKK1+ tumor tissue. Median age: 65; Female: 68%; White: 86%. Gallbladder cancer 36%, intrahepatic CCA 59%. 3 pts had prior adjuvant G. Median number of cycles: 2 (range 1, 10+); 15 pts still on therapy. No dose limiting toxicities, related serious AEs or treatment emergent adverse events (TEAEs) which lead to discontinuation or dose reduction of D. 13 pts (59%) had grade 3/4 TEAEs; events in ≥ 2 pts include: neutropenia (n = 10), leukopenia, thrombocytopenia (n = 3 each), anemia and AST elevation (n = 2 each). 8 pts (36%) had D-related grade 3/4 TEAEs; events in ≥ 2 pts include: neutropenia (n = 5), thrombocytopenia and AST elevation (n = 2 each). The MTD of D + GC was 300 mg. At the MTD, 9 of 18 patients are evaluable for response; 3 pts had a partial response (PR), 5 pts had stable disease (SD), and 1 pt had progressive disease (PD). Among 4 pts dosed at 150 mg D, 3 pts had SD, 1 pt had PD. Responses and SD have been durable.
Study enrollment is complete. D + GC is well tolerated; safety profile of this regimen appears similar to GC alone. Preliminary data with D (300 mg) + GC demonstrate a response rate of 33% in pts with advanced ABC. Further investigation is ongoing.
Clinical trial identification
Legal entity responsible for the study
Leap Therapeutics, Inc.
J. Eads: Research: BMS. Consulting: ClearView Healthcare Partners. A. El-Khoueiry: Honoraria: BMS, Bayer, Astra Zeneca, Genentech, GSK. Consulting/Advisory Role: BMS, Astra Zeneca, Genentech/Roche. Speakers Bureau: Merimak. Research Funding: Astex. G. Manji: Merck. Research Funding: Conquer Cancer Foundation. Research Funding Ardelyx – Consultant Celgene – Consultant
A.A. Khorana: Janssen, Sanofi, Pfizer, Roche and Halozyme. R. Miksad: corporate sponsored research (to the institution): Bayer, Exelixis, Novartis, Macrogenics. D. Mahalingam: Consulting or Advisory Role - Azaya Therapeutics; Baxalta; Bayer; Dendreon; Genspera; Oncolytics Speakers' Bureau - Bayer; Dendreon.
C. Sirard: Employment - Leap Therapeutics, Inc. Stock and Other Ownership Interests - Leap Therapeutics, Inc. Patents, Royalties, Other Intellectual Property - Leap Therapeutics, Inc.
All other authors have declared no conflicts of interest.