A phase I study of the WT2725 dosing emulsion in patients with advanced malignancies

Abstract

WT2725 is a Wilms' tumor gene 1 (WT1)-derived-oligopeptide vaccine designed to induce WT1-specific cytotoxic T-lymphocytes against WT1+ tumors in human leukocyte antigen (HLA)-A*0201+ and/or HLA-A*0206+ patients. Here, we report the results of a phase I study of WT2725. In this phase I, open-label, dose-escalation and expansion two-part study, the WT2725 dosing emulsion was administered as a monotherapy to patients with advanced malignancies known to overexpress WT1, including glioblastoma. In part 1, 44 patients were sequentially allocated to four doses: 0.3 mg (n = 5), 0.9 mg (n = 5), 3 mg (n = 6), and 9 mg (n = 28). In part 2, 18 patients were allocated to two doses: 18 mg (n = 9) and 27 mg (n = 9). No dose-limiting toxicities were observed, so the maximum tolerated dose was not reached. Median progression-free survival was 58 (95% confidence interval [CI] 56-81) days (~ 2 months) across all patients with solid tumors; median overall survival was 394 days (13.0 months) (95% CI 309-648). Overall immune-related response rate in solid tumor patients was 7.5% (95% CI 2.6-19.9); response was most prominent in the glioblastoma subgroup. Overall, 62.3% of patients were considered cytotoxic T-lymphocyte responders; the proportion increased with increasing WT2725 dosing emulsion dose. WT2725 dosing emulsion was well tolerated. Preliminary tumor response and biological marker data suggest that WT2725 dosing emulsion may exert antitumor activity in malignancies known to overexpress the WT1 protein, particularly glioblastoma, and provide a rationale for future clinical development.Trial registration: NCT01621542.

Conflict of interest statement

S.F. and D.A. have nothing to disclose. D.P. is part of the advisory council/committee for AbbVie and Tocagen. H.L. received honoraria from Agios and grants/funds from BMS and Karyopharm. R.L. served on a scientific advisory board for Novocure, Monteris and AbbVie; served on the speakers bureau for Novocure; received consulting fees from AbbVie, American Physician Institute, Medlink Neurology, EBSCO Publishing, Eisai, and New Link Genetics; received a BrainUp grant for Translational Approaches to Brain Tumors; and received research support (drug only) from Bristol Myers Squibb. S.K. is an employee of Pacific Neuroscience Institute, Providence Saint John’s Health Center, John Wayne Cancer Institute; owns stock/shares in Curtana and Nascent; received grants/funds from Aivita, Diffusion, Boston Biomedical, Medicenna, Aadi, BI, Sanofi, Spectrum, Novocure, Northwestern, Orbus Stellar, Prevlar (epicentrx), Stemedica, EORTC-CTCG, EIP Pharma, Caris, Amgen (Omniseq, Guardant, Biocept, LJIAI). D.H. owns stock/shares in OncoResponse Molecular Match (Advisor), OncoResponse (Founder), and Presagia Inc (Advisor); is part of the advisory council/committee and received consulting fees from Alpha Insights, Amgen, Axiom, Adaptimmune, Baxter, Bayer, Genentech, GLG, Group H, Guidepoint, Infinity, Janssen, Merrimack, Medscape, Numab, Pfizer, Prime Oncology, Seattle Genetics, Takeda, Trieza Therapeutics, WebMD; received honoraria from LOXO, miRNA, Genmab, AACR, ASCO, and SITC; received grants/funds from AbbVie, Adaptimmune, Aldi-Norte, Amgen, Astra-Zeneca, Bayer, BMS, Daiichi-Sankyo, Eisai, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa, Lilly, LOXO, Merck, Medimmune, Mirati, miRNA, Molecular Templates, Mologen, NCI-CTEP, Novartis, Pfizer, Seattle Genetics, Takeda, Turning Point Therapeutics. K.Y. is an employee of Sumitomo Dainippon Pharma Co., Ltd. K.W., Y.Z., and Y.L.C. are employees of Sunovion Pharmaceuticals Inc. N.P., J.E., and D.B. are former employees of Sunovion Pharmaceuticals Inc. D.B. is a paid consultant of Sunovion Pharmaceuticals Inc.

© 2021. The Author(s).

Figures

Figure 1

OS (efficacy population). All malignancy types combined. The shaded area represents the 95% CI of the survival probability at that day. CI confidence interval, OS overall survival.

Figure 2

Patient survival in the glioblastoma subgroup. (A) OS. The shaded area represents the 95% CI of the survival probability at that day. (b) Individual patient survival. CI confidence interval, CR complete response, Dx diagnosis, IDH isocitrate dehydrogenase, m months, NMD no measurable disease, OS overall survival, PR partial response, unk unknown, y years.

Figure 3

Change in tumor size over time and imaging for the two glioblastoma patients who achieved an immune-related complete response. CR complete response, D day, m month, NMD no measurable disease, tx treatment.

Figure 4

Baseline and post-baselinea CTL induction activity. All malignancy types combined. The CTLs in blood samples were measured by tetramer assay using flow cytometry; the evaluation of CTL induction is defined in the Efficacy assessments section of the Online Resource. P-values were calculated using the Wilcoxon signed-rank test (comparing post-baseline with baseline assessments). aBased on the mean of all post-baseline assessments of each patient. BL baseline, CTL cytotoxic T-lymphocyte, MPB mean of post-baseline.