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.

Abstract

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/m2 followed by weekly infusions of 250 mg/m2 in levels 1 and 0. U3-1565 was administered at a loading dose of 24 mg/m2 followed by biweekly infusions of 16 mg/m2 in level 1 and 16-12 mg/m2 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.

• Authors: Takako Eguchi Nakajima, Narikazu Boku, Ayako Doi, Hiroyuki Arai, Takuro Mizukami, Yoshiki Horie, Naoki Izawa, Mami Hirakawa, Takashi Ogura, Takashi Tsuda, Yu Sunakawa
• Journal: Investigational new drugs (Invest New Drugs) Vol. 38 Issue 2 Pg. 410-418 (04 2020) ISSN: 1573-0646 [Electronic] United States
• PMID: 31020609 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents, Immunological
• Heparin-binding EGF-like Growth Factor
• KRAS protein, human
• U3-1565
• Panitumumab
• Proto-Oncogene Proteins p21(ras)
• Cetuximab

Topics

• Adult
• Aged
• Antibodies, Monoclonal, Humanized (adverse effects, pharmacokinetics, pharmacology, therapeutic use)
• Antineoplastic Agents, Immunological (adverse effects, pharmacokinetics, pharmacology, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, pharmacology, therapeutic use)
• Cetuximab (adverse effects, pharmacology, therapeutic use)
• Colorectal Neoplasms (drug therapy, metabolism, mortality)
• Drug Resistance, Neoplasm
• Female
• Heparin-binding EGF-like Growth Factor (blood, immunology, metabolism)
• Humans
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Panitumumab
• Proto-Oncogene Proteins p21(ras)
• Treatment Outcome