Phase I and Biomarker Study of the Wnt Pathway Modulator DKN-01 in Combination with Gemcitabine/Cisplatin in Advanced Biliary Tract Cancer.
Adult
Aged
Aged, 80 and over
Antibodies, Monoclonal
/ therapeutic use
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
Biliary Tract Neoplasms
/ drug therapy
Cisplatin
/ administration & dosage
Deoxycytidine
/ administration & dosage
Drug Therapy, Combination
Female
Follow-Up Studies
Humans
Intercellular Signaling Peptides and Proteins
/ chemistry
Male
Middle Aged
Prognosis
Survival Rate
Wnt Signaling Pathway
/ drug effects
Gemcitabine
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
01 12 2020
01 12 2020
Historique:
received:
09
04
2020
revised:
08
06
2020
accepted:
14
08
2020
pubmed:
4
9
2020
medline:
15
12
2021
entrez:
4
9
2020
Statut:
ppublish
Résumé
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. 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/m 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 ( 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.
Identifiants
pubmed: 32878766
pii: 1078-0432.CCR-20-1310
doi: 10.1158/1078-0432.CCR-20-1310
doi:
Substances chimiques
Antibodies, Monoclonal
0
DKK1 protein, human
0
Intercellular Signaling Peptides and Proteins
0
Deoxycytidine
0W860991D6
Cisplatin
Q20Q21Q62J
Gemcitabine
0
Banques de données
ClinicalTrials.gov
['NCT02375880']
Types de publication
Clinical Trial, Phase I
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
6158-6167Informations de copyright
©2020 American Association for Cancer Research.
Références
Rizvi S, Khan SA, Hallemeier CL, Kelley RK, Gores GJ. Cholangiocarcinoma - evolving concepts and therapeutic strategies. Nat Rev Clin Oncol. 2018;15:95–111.
Patel T. Cholangiocarcinoma–controversies and challenges. Nat Rev Gastroenterol Hepatol. 2011;8:189–200.
Ciombor KK, Goff LW. Current therapy and future directions in biliary tract malignancies. Curr Treat Options Oncol. 2013;14:337–49.
Valle JW, Borbath I, Khan SA, Huguet F, Gruenberger T, Arnold D, et al. Biliary cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016;27:v28–37.
Brandi G, Venturi M, Pantaleo MA, Ercolani G. Cholangiocarcinoma: current opinion on clinical practice diagnostic and therapeutic algorithms: a review of the literature and a long-standing experience of a referral center. Dig Liver Dis. 2016;48:231–41.
Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362:1273–81.
Okusaka T, Nakachi K, Fukutomi A, Mizuno N, Ohkawa S, Funakoshi A, et al. Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: a comparative multicentre study in Japan. Br J Cancer. 2010;103:469–74.
Valle JW, Furuse J, Jitlal M, Beare S, Mizuno N, Wasan H, et al. Cisplatin and gemcitabine for advanced biliary tract cancer: a meta-analysis of two randomised trials. Ann Oncol. 2014;25:391–8.
Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 2004;20:781–810.
MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell. 2009;17:9–26.
Clevers H, Nusse R. Wnt/β-catenin signaling and disease. Cell. 2012;149:1192–205.
Clevers H, Loh KM, Nusse R. Stem cell signaling. An integral program for tissue renewal and regeneration: Wnt signaling and stem cell control. Science. 2014;346:1248012.
Sedgwick AE, D'Souza-Schorey C. Wnt signaling in cell motility and invasion: drawing parallels between development and cancer. Cancers. 2016;8:E80.
Lu B, Green BA, Farr JM, Lopes FCM, Van Raay TJ. Wnt drug discovery: weaving through the screens, patents and clinical trials. Cancers. 2016;8:82.
Zimmerli D, Hausmann G, Cantù C, Basler K. Pharmacological interventions in the Wnt pathway: inhibition of Wnt secretion versus disrupting the protein–protein interfaces of nuclear factors Br J Pharmacol. 2017;174:4600–10.
Niehrs C. Function and biological roles of the dickkopf family of wnt modulators. Oncogene. 2006;25:7469–81.
Mukhopadhyay M, Shtrom S, Rodriguez-Esteban C, Chen L, Tsukui T, Gomer L, et al. Dickkopf1 is required for embryonic head induction and limb morphogenesis in the mouse. Dev Cell. 2001;1:423–34.
MacDonald BT, Joiner DM, Oyserman SM, Sharma P, Goldstein SA, He X, et al. Bone mass is inversely proportional to Dkk1 levels in mice. Bone. 2007;41:331–9.
Pinzone JJ, Hall BM, Thudi NK, Vonau M, Qiang YW, Rosol TJ, et al. The role of Dickkopf-1 in bone development, homeostasis, and disease. Blood. 2009;113:517–25.
Kagey MH, He X. Rationale for targeting the Wnt signalling modulator Dickkopf-1 for oncology. Br J Pharmacol. 2017;174:4637–50.
D'Amico L, Mahajan S, Capietto AH, Yang Z, Zamani A, Ricci B, et al. Dickkopf-related protein 1 (Dkk1) regulates the accumulation and function of myeloid derived suppressor cells in cancer. J Exp Med. 2016;213:827–40.
Malladi S, Macalinao DG, Jin X, He L, Basnet H, Zou Y, et al. Metastatic latency and immune evasion through autocrine inhibition of WNT. Cell. 2016;165:45–60.
Shi RY, Yang XR, Shen QJ, Yang LX, Xu Y, Qiu SJ, et al. High expression of dickkopf-related protein 1 is related to lymphatic metastasis and indicates poor prognosis in intrahepatic cholangiocarcinoma patients after surgery. Cancer. 2013;119:993–1003.
Shi XD, Yu XH, Wu WR, Xu X-L, Wang J-Y, Xu L-B, et al. Dickkopf-1 expression is associated with tumorigenity and lymphatic metastasis in human hilar cholangiocarcinoma. Oncotarget. 2016;7:70378–87.
Bendell JC, Murphy JE, Mahalingam D, Halmos B, Sirard CA, Landau SB, et al. Phase I study of DKN-01, an anti-DKK1 antibody, in combination with paclitaxel (pac) in patients (pts) with DKK1+ relapsed or refractory esophageal cancer (EC) or gastro-esophageal junction tumors (GEJ). J Clin Oncol. 2016;34.
Edenfield WJ, Richards DA, Vukelja SJ, Weiss GJ, Sirard CA, Landau SB, et al. A phase 1 study evaluating the safety and efficacy of DKN-01, an investigational monoclonal antibody (Mab) in patients (pts) with advanced non-small cell lung cancer. J Clin Oncol. 2014;32.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–47.
Wang F, Flanagan J, Su N, Wang LC, Bui S, Nielson A, et al. RNAscope: a novel in situ RNA analysis platform for formalin-fixed, paraffin-embedded tissues. J Mol Diagn. 2012;14:22–9.
Bankhead P, Loughrey MB, Fernández JA, Dombrowski Y, McArt DG, Dunne PD, et al. QuPath: open source software for digital pathology image analysis. Sci Rep. 2017;7:16878.
Gibiansky L, Gibiansky E, Kakkar T, Ma P. Approximations of the target-mediated drug disposition model and identifiability of model parameters. J Pharmacokinet Pharmacodyn. 2008;35:573–91.
Hezel AF, Noel MS, Allen JN, Abrams TA, Yurgelun M, Faris JE, et al. Phase II study of gemcitabine, oxaliplatin in combination with panitumumab in KRAS wild-type unresectable or metastatic biliary tract and gallbladder cancer. Br J Cancer. 2014;111:430–6.
Valle JW, Bai L-Y, Orlova R, Van Cutsem E, Alfonso JA, Chen L-T, et al. Ramucirumab (RAM) or merestinib (MER) or placebo (PL) plus gemcitabine (GEM) and cisplatin (CIS) as first-line treatment for advanced or metastatic biliary tract cancer (BTC): A randomized, double-blind, phase II study. J Clin Oncol. 2020;38.
Valle JW, Wasan H, Lopes A, Backen AC, Palmer DH, Morris K, et al. Cediranib or placebo in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer (ABC-03): a randomised phase 2 trial. Lancet Oncol. 2015;16:967–78.
Malka D, Cervera P, Foulon S, Trarbach T, de la Fouchardière C, Boucher E, et al. Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary-tract cancer (BINGO): a randomised, open-label, non-comparative phase 2 trial. Lancet Oncol. 2014;15:819–28.
Wainburg ZA, Fuchs CS, Taberno J, Sahitara K, Muro K, Van E, et al. Efficacy of pembrolizumab (pembro) monotherapy versus chemotherapy for PD-L1–positive (CPS ≥10) advanced G/GEJ cancer in the phase II KEYNOTE-059 (cohort 1) and phase III KEYNOTE-061 and KEYNOTE-062 studies. J Clin Oncol. 2020;38.
Tsukamoto H, Fujieda K, Miyashita A, Fukushima S, Ikeda T, Kubo Y, et al. Combined blockade of IL6 and PD-1/PD-L1 signaling abrogates mutual regulation of their immunosuppressive effects in the tumor microenvironment. Cancer Res. 2018;78:5011–22.
Ozawa Y, Amano Y, Kanata K, Hasegwa H, Matsui T, Kakutani T, et al. Impact of early inflammatory cytokine elevation after commencement of PD-1 inhibitors to predict efficacy in patients with non-small cell lung cancer. Med Oncol. 2019;36:33.
Backen AC, Lopes A, Wasan H, Palmer DH, Duggan M, Cunningham D, et al. Circulating biomarkers during treatment in patients with advanced biliary tract cancer receiving cediranib in the UK ABC-03 trial. Br J Cancer. 2018;119:27–35.