Abstract CT177: A phase I, first in human study of CBA-1205, glycoengineered humanized anti-DLK-1 monoclonal antibody in patients with advanced solid tumors
Authors: Ikeda Masafumi , Matsubara Nobuaki , Kondoh Chihiro , taoka shose , Katsuya Yuki , Koyama Takafumi , Yamamoto Noboru 
Published: April 2023

Abstract
Background: CBA-1205 is a novel humanized anti-delta-like 1 homolog (DLK-1) antibody. It is a glycoengineered antibody by GlymaxX® technology to potentiate antibody-dependent cellular cytotoxicity activity. DLK-1 is a membrane protein with 6 tandem EGF-like motifs in extracellular region. Overexpression of DLK-1 has been reported in variety of cancer types including hepatocellular carcinoma (HCC), suggesting that DLK-1 could be an ideal target for cancer therapy.
Methods: This is a first in human, multicenter, open-label Phase I study. The purpose of part 1 is to evaluate the safety and tolerability in patients with advanced solid tumors who had no standard therapy or were refractory or intolerant to standard therapies and to determine the starting dose for part 2 in HCC patients. The standard 3+3 dose escalation design was utilized in seven cohorts (0.1, 0.3, 1, 3, 10, 20, 30 mg/kg). CBA-1205 was administered at 2-week intervals in a 28-day cycle. If the patient had no Dose Limiting Toxicity (DLT) during 28 days after the first two doses, CBA-1205 administration will be continued for further cycles unless any of the criteria for discontinuation. Serum DLK-1 concentration before the start of CBA-1205 administration was analyzed using the Human Pref-1/DLK1/FA1 DuoSet ELISA (R&D Systems, Inc.). Immunohistochemical analysis of DLK-1 expression in the archival tumor specimen was determined in FFPE tissue sections using mouse anti-hDLK-1 antibody (clone DI-2-20, Chiome Bioscience).
Results: 22 patients with advanced solid tumors were enrolled. CBA-1205 was well tolerated in these patients and no DLT was observed even at the highest dose tested. No ≥ Grade 3 treatment related adverse events was observed throughout the study periods. The serum concentration of CBA-1205 increased dose-proportionally. The exposure to CBA-1205 exceeded the effective concentrations observed in a mouse xenograft model. No serum anti-CBA-1205 antibody was detected. The disease control was seen in 8 patients (38.1%, all with SD). Especially, long SD was observed in 3 patients with invasive thymoma, malignant melanoma, and pancreatic carcinoma, where progression free survival (PFS) was 39, 72(ongoing, at data cutoff), and 41 weeks, respectively. The serum concentration of soluble DLK-1 was detected in 6 out of 22 patients. Patients with SD by the best overall response had a higher rate of detectable serum DLK-1 concentration and a higher mean concentration than patients with PD. No DLK-1 expression in tumor was detected by IHC method, in 14 patients who consented to use the archival tumor specimens.
Conclusions: CBA-1205 was well tolerated without any severe toxicity in patients with advanced solid tumors.Part 2 of this Phase I study with two cohorts (20, 30 mg/kg) in patients with unresectable advanced/recurrent HCC refractory or intolerable to the standard therapy has been initiated.
Citation Format: Masafumi Ikeda, Nobuaki Matsubara, Chihiro Kondoh, shose taoka, Yuki Katsuya, Takafumi Koyama, Noboru Yamamoto. A phase I, first in human study of CBA-1205, glycoengineered humanized anti-DLK-1 monoclonal antibody in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT177.