Abstract
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 language | English (US) |
|---|---|
| Pages (from-to) | 6158-6167 |
| Number of pages | 10 |
| Journal | Clinical Cancer Research |
| Volume | 26 |
| Issue number | 23 |
| DOIs | |
| State | Published - Dec 2020 |
Funding
L. Goyal reports personal fees from Agios Pharmaceuticals (scientific advisory board), Alentis Therapeutics (scientific advisory board), QED Therapeutics (scientific advisory board and consulting), H3 Biomedicine (scientific advisory board and consulting), Taiho Pharmaceuticals (scientific advisory board and consulting), Debiopharm (scientific advisory board and consulting), Incyte Corporation (scientific advisory board and consulting), SIRTEX (scientific advisory board and consulting), Pieris Pharmaceuticals (scientific advisory board), Klus Pharmaceuticals (scientific advisory board), and AstraZeneca (IDMC member) outside the submitted work. C. Sirard reports other from Leap Therapeutics (CMO of Leap therapeutics salaried employee) during the conduct of the study; other from Leap Therapeutics (stockholder) outside the submitted work; and is listed as a coinventor on 3 patents regarding the use of certain biomarkers for treatment with DKK1 inhibitor therapy which will be owned by Leap Therapeutics. M. Schrag reports personal fees from Leap Therapeutics during the conduct of the study. M.H. Kagey reports personal fees from Leap Therapeutics (full-time employee) during the conduct of the study and outside the submitted work. J.R. Eads reports other from Leap Therapeutics (funding for study conduct) during the conduct of the study, and personal fees from Novartis, Pfizer, Lexicon, Advanced Accelerator Applications, Ipsen, and Bristol-Myers Squibb (husband is an employee) as well as other from Incyte (research support) outside the submitted work. S. Stein is a member of the advisory boards of Eisai, Exelixis, QED, and Genentech. A.B. El-Khoueiry reports personal fees from Bayer, Bristol-Myers Squibb, Merck, Eisai, Roche/Genentech, Exelixis, AstraZeneca, Zyme-works, Agenus, Cytomx, EMD Serono, Gilead, and Pieris, as well as grants from Astex and AstraZeneca outside the submitted work. G.A. Manji reports grants from Merck, BioLineRx, and Regeneron; grants and other from Roche/Genentech (advisory board); and other from Ipsen (advisory board) outside the submitted work. T.A. Abrams reports personal fees from Bristol-Myers Squibb, Agios, and Merck outside the submitted work. A.A. Khorana reports grants from Leap [to institution (Cleveland Clinic)] during the conduct of the study; nonfinancial support from Janssen, Bayer, Sanofi, Halozyme, Bristol-Myers Squibb, Pfizer, Seattle Genetics, Pharmacyclics, Pharmacyte, and Medscape; as well as grants from Merck (to institution), Array (to institution), and Bristol-Myers Squibb (nonfinancial support) outside the submitted work. R. Miksad reports other from Leap Therapeutics during the conduct of the study, as well as other from Flatiron Health [employment, equity ownership in Flatiron Health Inc. (initiated before acquisition by Roche in April 2018) and Roche (stock)] outside the submitted work. D. Mahalingam reports personal fees from Amgen, Exelixis, Eisai, EMD Serono, Bayer, Genentech; grants and personal fees from Merck; and grants from Oncolytics outside the submitted work. A.X. Zhu reports other from Bayer, Lilly, Eisai, Roche-Genentech, Sanofi Aventis, Merck, Exelexis, and Gilead (consulting/ advisory) outside the submitted work. D.G. Duda reports grants and personal fees from Bayer and Bristol-Myers Squibb; grants from Exelixis; and personal fees from Simcere outside the submitted work. No other potential conflicts of interest were disclosed. This study was supported by Leap Pharmaceuticals, which also provided the study drug. DGD's research is supported by DoD Awards #W81XWH-19-1-0284 and W81XWH-19-1-0482.
ASJC Scopus subject areas
- Oncology
- Cancer Research
