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Phase I and Biomarker Study of the Wnt Pathway Modulator DKN-01 In Published OnlineFirst September 2, 2020; DOI: 10.1158/1078-0432.CCR-20-1310 CLINICAL CANCER RESEARCH | CLINICAL TRIALS: TARGETED THERAPY Phase I and Biomarker Study of the Wnt Pathway Modulator DKN-01 in Combination with Gemcitabine/ Cisplatin in Advanced Biliary Tract Cancer A C Lipika Goyal1, Cynthia Sirard2, Michael Schrag3, Michael H. Kagey2, Jennifer R. Eads4, Stacey Stein5, Anthony B. El-Khoueiry6, Gulam A. Manji7, Thomas A. Abrams8, Alok A. Khorana9, Rebecca Miksad10, Devalingam Mahalingam11, Andrew X. Zhu1,12, and Dan G. Duda13 ABSTRACT ◥ Purpose: Dickkopf-1 (DKK1) modulates Wnt signaling, pro- were seen, and the expansion phase proceeded with DKN-01 moting tumor growth, metastasis, and immunosuppression. High 300 mg (N ¼ 47).Themostfrequentgrade3/4treatment- DKK1 expression has been detected in various tumor types— emergent adverse events included neutropenia (60%), thrombo- including biliary tract cancer (BTC)—and is associated with poor cytopenia (34%), and anemia (23%). The objective response rate prognosis. DKN-01—a humanized mAb targeting DKK1—was was 21.3% and median progression-free survival was 8.7 months evaluated in a phase I multicenter study in combination with (95% confidence interval, 5.4–10.3 months). Better outcomes gemcitabine and cisplatin in patients with unresectable or meta- were associated with biomarkers of angiogenesis inhibition static BTC with no prior systemic therapy for advanced disease. (increased sVEGFR1 and lower VEGF-C) and reduced inflam- Patients and Methods: This study included a dose-escalation mation (lower IL6 and decreased TNFa). phase assessing DKN-01 at two dose levels (150 mg and 300 mg) Conclusions: DKN-01 300 mg was well tolerated in this com- combined with gemcitabine (1,000 mg/m2) and cisplatin (25 mg/m2) bination but did not appear to have additional activity beyond followed by dose expansion. Primary endpoints evaluated safety and historically reported efficacy with gemcitabine/cisplatin alone. tolerability; secondary endpoints evaluated efficacy, pharmacokinet- Exploratory pharmacokinetic and biomarker data indicate potential ics, and circulating biomarkers. antiangiogenic and immunomodulatory activity of DKN-01/ Results: Fifty-one patients with intrahepatic cholangiocarci- chemotherapy and the need for increased dose/intensity. A study noma (63%), extrahepatic cholangiocarcinoma (8%), and gall- with DKN-01 600 mg in combination with a PD-1 inhibitor in BTC bladder cancer (29%) were enrolled. No dose-limiting toxicities is ongoing. Introduction rare but aggressive malignancies with a poor prognosis (1). Surgery remains the mainstay of cure for early-stage BTC, but the majority of Biliary tract cancer (BTC)—which includes intrahepatic and extra- patients recur (2–5). Up to 80% of patients present with unresectable/ hepatic cholangiocarcinoma and gallbladder carcinoma—is a group of metastatic disease (5). The combination of gemcitabine and cisplatin fi 1 has been the global rst-line standard of care in advanced BTC since Hematology/Oncology, Massachusetts General Hospital Cancer Center, Boston, – 2 3 2009 (6, 7), after showing objective response rates (ORR) of 20% 26%, Massachusetts. Leap Therapeutics, Cambridge, Massachusetts. ProPharma – Services LLC, Superior, Louisville, Colorado. 4Abramson Cancer Center, Univer- median progression-free survival (PFS) of 6 8 months, and overall sity of Pennsylvania, Philadelphia, Pennsylvania. 5Yale School of Medicine, New survival (OS) of 11–12 months (7, 8). More effective regimens are Haven, Connecticut. 6Keck School of Medicine of USC, Los Angeles, California. needed to improve clinical outcomes in BTC. 7Columbia University Irving Medical Center, New York, New York. 8Dana-Farber Wnt signaling is a key pathway regulating stem cell maintenance, 9 Cancer Institute, Boston, Massachusetts. Cleveland Clinic, Cleveland, Ohio. cell proliferation, and migration during development and adult tissue 10Boston Medical Center, Boston, Massachusetts, and Flatiron Health, New York, homeostasis (9–13). This pathway is frequently dysregulated in cancer, New York. 11Northwestern Medical Group, Robert H Lurie Cancer Center, Chicago, Illinois. 12Jiahui International Cancer Center, Shanghai, China. 13Edwin and several agents targeting it are in preclinical and clinical develop- L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, ment (14, 15). Dickkopf-1 (DKK1) is a secreted protein characterized Massachusetts General Hospital, Harvard Medical School, Boston, by two cysteine-rich domains, which interacts with the LRP5/LRP6 Massachusetts. coreceptor to inhibit canonical Wnt/b-catenin signaling (16). DKK1 Note: Supplementary data for this article are available at Clinical Cancer plays physiologic roles in embryonic development and bone homeo- Research Online (http://clincancerres.aacrjournals.org/). stasis via modulation of Wnt signaling (17–19). DKK1 also plays a role A.X. Zhu and D.G. Duda contributed equally to this article. in cancer and has been shown to promote proliferation, invasion, and growth in nonclinical models (20). Recent publications have impli- ClinicalTrials.gov Identifier: NCT02375880. cated DKK1 in fostering an immunosuppressive tumor microenvi- Corresponding Author: Lipika Goyal, Massachusetts General Hospital Cancer ronment by activating myeloid-derived suppressor cells, which blunt Center, Harvard Medical School, POB/Lawrence House, 10 North Grove Street T-cell responses, and also by downregulating natural killer (NK)- Boston, MA 02114. Phone: 617-726-2000; Fax: 617-724-3166; E-mail: – [email protected] activating ligands that would otherwise allow for NK cell mediated clearance (21, 22). Therefore, targeting DKK1 has been hypothesized Clin Cancer Res 2020;XX:XX–XX to have anticancer activity through multiple mechanisms, including doi: 10.1158/1078-0432.CCR-20-1310 directly targeting tumor cells and modulating the tumor Ó2020 American Association for Cancer Research. microenvironment (18). AACRJournals.org | OF1 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst September 2, 2020; DOI: 10.1158/1078-0432.CCR-20-1310 Goyal et al. DKK1 suppression. DKN-01 was administered first, followed by Translational Relevance cisplatin and gemcitabine. Gemcitabine/cisplatin and associated pre- This study provides new insights on the effects of blocking medication were administered per standard institutional practice. The Dickkopf-1 (DKK1), a modulator of Wnt signaling, using DKN-01. primary objective was safety and establishing an MTD of DKN-01. For The phase I multicenter study tested the feasibility, efficacy, and each cohort, up to 4 patients may have been screened simultaneously to biological effects of DKN-01, a humanized mAb targeting DKK1, ensure 3 patients would be treated; if all 4 patients were eligible, all 4 in combination with gemcitabine and cisplatin in patients with were permitted to enroll. In the phase Ib dose-expansion portion, up to unresectable or metastatic biliary tract cancers (BTC). The regimen 44 patients were planned to receive DKN-01 at the MTD, or highest was well tolerated but did not appear to have additional activity dose tested if the MTD was not established, to further characterize beyond historically reported efficacy with gemcitabine/cisplatin safety and tolerability within the defined patient population. This alone. Exploratory pharmacokinetic and biomarker data indicated sample size was not based on formal statistical calculations, given the potential antiangiogenic and immunomodulatory activity of DKN- exploratory nature of the phase Ib study. The secondary objectives 01 and the need for increased dose intensity. On the basis of the were efficacy, pharmacokinetics, pharmacodynamics, and tissue and above data and rationale, a phase II trial of DKN-01 combined with circulating biomarkers. Institutional review boards at all participating nivolumab has been initiated in patients with advanced refractory sites approved the study, and all patients provided written informed BTC (NCT04057365). consent before the performance of any study-related procedures. The study was conducted in accordance with International Council for Harmonization Good Clinical Practice (ICH-GCP) guidelines and Declaration of Helsinki. The study was registered at clinicaltrials.gov Elevated DKK1 expression was detected in multiple tumor types, (NCT02375880). including BTC (23), and was associated with poor prognosis (18). For dose escalation, the dose-limiting toxicities (DLT) were defined Analysis of BTC tumor tissue samples from 138 patients revealed that as grade 3 or greater occurring within cycle 1 and considered by the 38% of tumors showed elevated DKK1 expression by IHC, and DKK1 investigator to be possibly related to DKN-01 or gemcitabine/cisplatin. expression was associated with significantly lower 5-year OS and Exceptions were alopecia; grade 3/4 anemia, thrombocytopenia, or higher disease recurrence rate (21). Furthermore, elevated DKK1 neutropenia resolving to ≤grade 2 within 7 days; grade 3 leukopenia expression correlated with increased expression of matrix metallo- or lymphopenia resolving to ≤grade 2 within 14 days or grade 4 proteinase 9 (MMP9) and VEGF-C, proteins with characterized roles leukopenia or lymphopenia resolving to ≤grade 2 within 21 days; grade in tumor cell invasion, angiogenesis, and lymph node metastasis (21). 3/4 asymptomatic laboratory values resolving to ≤grade 2 within Of note, targeted knockdown
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