Phase I and Biomarker Study of the Wnt Pathway Modulator DKN-01 in Combination with Gemcitabine/Cisplatin in Advanced Biliary Tract Cancer

Abstract

This study provides new insights on the effects of blocking Dickkopf-1 (DKK1), a modulator of Wnt signaling, using DKN-01. The phase I multicenter study tested the feasibility, efficacy and biological effects of DKN-01, a humanized monoclonal antibody targeting DKK1, in combination with gemcitabine and cisplatin in patients with unresectable or metastatic biliary tract cancers. The regimen was well tolerated but did not appear to have additional activity beyond historically reported efficacy with gemcitabine/cisplatin alone. Exploratory pharmacokinetic and biomarker data indicated potential antiangiogenic and immunomodulatory activity of DKN-01 and the need for increased dose intensity. Based on the above data and rationale, a phase II trial of DKN-01 combined with nivolumab has been initiated in patients with advanced refractory BTC (NCT04057365). Research.

High Serum Levels of Wnt Signaling Antagonist Dickkopf-Related Protein 1 Are Associated with Impaired Overall Survival and Recurrence in Esophageal Cancer Patients

“…DKK1 has not only been evaluated as a prognostic marker in a wide variety of cancers [ 9 ] but may also serve as a potential novel treatment target [ 18 ]. Recently, Goyal et al reported that DKN-01, an inhibitor of DKK-1, was well tolerable in a phase I clinical trial in combination with gemcitabine or cisplatin in patients with advanced cancer of the biliary tract [ 19 ].…”

Prognostic value of dickkopf-1 and ß-catenin expression according to the antitumor immunity of CD8-positive tumor-infiltrating lymphocytes in biliary tract cancer.

“…DKK1 is known to inhibit Wnt signaling by interacting with the Wnt receptors of the Frizzled family 14,38 . In addition, DKK1 is associated with a so-called immune-desert microenvironment by activating myeloidderived suppressor cells and downregulating natural killer cells in cancer 17,18 .…”

“…DKK1 can inhibit Wnt signaling by interacting with the Wnt receptors of the Frizzled family 14 . DKK1 plays a role in cancer proliferation, invasion, and growth via the modulation of Wnt signaling 14,15 . DKK1 is expressed in multiple tumor types, including BTC, but its impact and the clinical role of this pathway's components are not completely understood 9,16 .…”

Safety, Efficacy, and Biomarker Results from a Phase Ib Study of the Anti-DKK1 Antibody DKN-01 in Combination with Pembrolizumab in Advanced Esophagogastric Cancers

“…This starting dose and accelerated dose escalation were informed by a phase I monotherapy study that established safety up to DKN-01 600 mg intravenously (IV) (NCT01457417) 22 and a study confirming the safety of 150 mg and 300 mg in combination with cytotoxic chemotherapy (NCT02375880). 23…”