Phase I and biomarker study of the wnt pathway modulator dkn-01 in combination with gemcitabine/ cisplatin in advanced biliary tract cancer

Lipika Goyal*, Cynthia Sirard, Michael Schrag, Michael H. Kagey, Jennifer R. Eads, Stacey Stein, Anthony B. El-Khoueiry, Gulam A. Manji, Thomas A. Abrams, Alok A. Khorana, Rebecca Miksad, Devalingam Mahalingam, Andrew X. Zhu, Dan G. Duda

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


Purpose: Dickkopf-1 (DKK1) modulates Wnt signaling, promoting tumor growth, metastasis, and immunosuppression. High DKK1 expression has been detected in various tumor types-including biliary tract cancer (BTC)-and is associated with poor prognosis. DKN-01-a humanized mAb targeting DKK1-was evaluated in a phase I multicenter study in combination with gemcitabine and cisplatin in patients with unresectable or metastatic BTC with no prior systemic therapy for advanced disease. Patients and Methods: This study included a dose-escalation phase assessing DKN-01 at two dose levels (150 mg and 300 mg) combined with gemcitabine (1,000 mg/m2) and cisplatin (25 mg/m2) followed by dose expansion. Primary endpoints evaluated safety and tolerability; secondary endpoints evaluated efficacy, pharmacokinetics, and circulating biomarkers. Results: Fifty-one patients with intrahepatic cholangiocarcinoma (63%), extrahepatic cholangiocarcinoma (8%), and gallbladder cancer (29%) were enrolled. No dose-limiting toxicities were seen, and the expansion phase proceeded with DKN-01 300 mg (N ¼ 47). The most frequent grade 3/4 treatment-emergent adverse events included neutropenia (60%), thrombocytopenia (34%), and anemia (23%). The objective response rate was 21.3% and median progression-free survival was 8.7 months (95% confidence interval, 5.4-10.3 months). Better outcomes were associated with biomarkers of angiogenesis inhibition (increased sVEGFR1 and lower VEGF-C) and reduced inflammation (lower IL6 and decreased TNFa). Conclusions: DKN-01 300 mg was well tolerated in this combination but did not appear to have additional activity beyond historically reported efficacy with gemcitabine/cisplatin alone. Exploratory pharmacokinetic and biomarker data indicate potential antiangiogenic and immunomodulatory activity of DKN-01/ chemotherapy and the need for increased dose/intensity. A study with DKN-01 600 mg in combination with a PD-1 inhibitor in BTC is ongoing.

Original languageEnglish (US)
Pages (from-to)6158-6167
Number of pages10
JournalClinical Cancer Research
Issue number23
StatePublished - Dec 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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