Phase I study of the anti-heparin-binding epidermal growth factor-like growth factor antibody U3-1565 with cetuximab in patients with cetuximab- or panitumumab-resistant metastatic colorectal cancer

• Published in: Investigational new drugs 2020-04, Vol.38 (2), p.410-418
• Main Authors: Nakajima, Takako Eguchi, Boku, Narikazu, Doi, Ayako, Arai, Hiroyuki, Mizukami, Takuro, Horie, Yoshiki, Izawa, Naoki, Hirakawa, Mami, Ogura, Takashi, Tsuda, Takashi, Sunakawa, Yu
• Format: Article
• Language: English
• Subjects: Adult; Aged; Anemia; Antibodies; Antibodies, Monoclonal, Humanized - adverse effects; Antibodies, Monoclonal, Humanized - pharmacokinetics; Antibodies, Monoclonal, Humanized - pharmacology; Antibodies, Monoclonal, Humanized - therapeutic use; Anticoagulants; Antineoplastic Agents, Immunological - adverse effects; Antineoplastic Agents, Immunological - pharmacokinetics; Antineoplastic Agents, Immunological - pharmacology; Antineoplastic Agents, Immunological - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Binding; Cancer; Cetuximab - adverse effects; Cetuximab - pharmacology; Cetuximab - therapeutic use; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - mortality; Combination therapy; Confidence intervals; Disease control; Drug Resistance, Neoplasm; Drug therapy; Epidermal growth factor; Epidermal growth factor receptors; Female; Growth factors; Guanosine triphosphate; Heparin; Heparin-binding EGF-like Growth Factor - blood; Heparin-binding EGF-like Growth Factor - immunology; Heparin-binding EGF-like Growth Factor - metabolism; Heparin-binding epidermal growth factor-like growth factor; Humans; Immunotherapy; Irinotecan; Kaplan-Meier Estimate; Male; Medicine; Medicine & Public Health; Metastases; Metastasis; Middle Aged; Monoclonal antibodies; Oncology; Oxaliplatin; Panitumumab; Pharmacology/Toxicology; Phase I Studies; Proto-Oncogene Proteins p21(ras); Studies; Survival; Targeted cancer therapy; Therapy; Toxicity; Treatment Outcome
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-019-00782-8

Summary KRAS wild-type colorectal cancers initially responsive to anti-endothelial growth factor receptor (EGFR) antibodies [cetuximab (Cetu)/panitumumab (Pani)] develop acquired resistance. Overexpression of EGFR ligands such as heparin-binding EGF-like growth factor (HB-EGF) may be one resistance mechanism. This phase I study of U3-1565, anti-HB-EGF antibody, and Cetu combination therapy enrolled patients with KRAS wild-type metastatic colorectal cancer who had received two ≤ regimens with fluoropyrimidine, oxaliplatin, irinotecan, and Cetu/Pani and had disease progression on Cetu/Pani. Recommended dose (RD) was determined in the 1st stage, followed by evaluation of efficacy at the RD level in the 2nd-stage. Cetu was given at a loading dose of 400 mg/m 2 followed by weekly infusions of 250 mg/m 2 in levels 1 and 0. U3-1565 was administered at a loading dose of 24 mg/m 2 followed by biweekly infusions of 16 mg/m 2 in level 1 and 16–12 mg/m 2 in level 0. Twenty-two patients were enrolled. No dose-limiting toxicities were observed among three patients in level 1 in the first stage, which was determined as RD. Grade 3 or higher adverse events occurred in 59.1%; those in ≥5% of patients were anemia, γ-GTP elevation, and acneiform rash. Overall response rate was 0.0% [95% confidence interval (CI): 0.0%–15.4%] and disease control was achieved in 17 patients (77.3%, 95% CI: 54.6%–92.2%). Median progression-free survival time was 85.0 days (95% CI: 54.0–91.0) and median survival time was 196 days (95% CI: 113.0–306.0). RD was determined as level 1. The efficacy of this combination therapy after progression on Cetu/Pani was negligible. Trial Registration: UMIN000013006.