Abstract CT052: Phase I study of the anti-heparin binding-EGF antibody U3-1565 with cetuximab in patients with cetuximab- or panitumumab-resistant metastatic colorectal cancer
Authors: Nakajima Takako E. , Boku Narikazu , Arai Hiroyuki , Mizukami Takuro , Horie Yoshiki , Izawa Naoki , Hirakawa Mami , Ogura Takashi , Tsuda Takashi , Sunakawa Yu 
Published: August 2018

Abstract
BACKGROUND KRAS-wild type colorectal cancers initially responsive to anti-EGFR (endothelial growth factor receptor) antibodies (cetuximab [Cmab]/panitumumab [Pmab]) develop acquired resistance in most patients. It is reported that overexpression of EGFR ligands such as heparin binding EGF (HB-EGF) may be one of the mechanisms of resistance. On the other hand, re-challenge with anti-EGFR antibodies may have some clinical benefits.
PATIENTS AND METHODS This phase I study of combination therapy of U3-1565 (a fully human anti-HB-EGF antibody) and Cmab enrolled patients with KRAS-wild type metastatic colorectal cancer who had received 2≤ regimens with fluoropyrimidine, oxaliplatin, irinotecan and Cmab/Pmab and had disease progression on Cmab/Pmab. In the 1st-stage of this study determined recommended dose (RD), followed by the 2nd-stage evaluating safety and efficacy of this regimen at the RD level. Cmab was given at a loading dose of 400mg/m2 followed by weekly infusions of 250mg/ m2 in level 1 and level 0. U3-1565 was administered at a loading dose of 24mg/m2 followed by biweekly infusions of 16mg/ m2 in level 1 and 16mg/m2-12mg/m2 respectively in level 0. Treatment was repeated until disease progression or unacceptable toxicity occurred. Serum HB-EGF was measured on day1 (pre-treatment), 8, 15 and 29.
RESULTS 22 patients were enrolled between Jul 2014 and Jul 2016. No DLTs were observed among 3 patients in level 1 of the 1st-stage, and the RD was determined at level 1. All patients were treated at the RD included in the 2nd-stage. Grade 3≤ adverse events occurred in 59.1%, and those observed in 5%≤ patients were anemia, Γ-GTP elevation, and rash acneiform. Partial response and disease control were obtained in one (4.5%) and 17 patients (77.3%), respectively. The median progression- free survival time was 85.0 days (95% CI: 54.0-91.0), and the median survival time was 196 days (95% CI: 113-306). No correlation was observed between pre-treatment serum HB-EGF level and the efficacy, while serum HB-EGF level on day 8 in the first cycle decreased lower than the measurement sensitivity in all patients.
CONCLUSIONS The RD of this combination therapy was determined to be biweekly infusion of U3-1565 at a loading dose of 24mg/m2 followed by 16mg/ m2 and Cmab at a loading dose of 400mg/m2 followed by 250mg/ m2. The efficacy of this combination therapy after progression on Cmab/Pmab was modest. &lt;!–EndFragment–&gt;
Citation Format: Takako E. Nakajima, Narikazu Boku, Hiroyuki Arai, Takuro Mizukami, Yoshiki Horie, Naoki Izawa, Mami Hirakawa, Takashi Ogura, Takashi Tsuda, Yu Sunakawa. Phase I study of the anti-heparin binding-EGF antibody U3-1565 with cetuximab in patients with cetuximab- or panitumumab-resistant metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT052.