First-in-Human Phase I Study of Aprutumab Ixadotin, a Fibroblast Growth Factor Receptor 2 Antibody-Drug Conjugate (BAY 1187982) in Patients with Advanced Cancer.

Abstract

BACKGROUND:

Fibroblast growth factor receptor (FGFR) 2 is overexpressed in several tumor types, including triple-negative breast cancer and gastric cancer, both of which have a high unmet medical need. Aprutumab ixadotin (BAY 1187982) is the first antibody-drug conjugate (ADC) to target FGFR2 and the first to use a novel auristatin-based payload.

OBJECTIVE:

This first-in-human trial was conducted to determine the safety, tolerability, and maximum tolerated dose (MTD) of aprutumab ixadotin in patients with advanced solid tumors from cancer indications known to be FGFR2-positive.

PATIENTS AND METHODS:

In this open-label, multicenter, phase I dose-escalation trial (NCT02368951), patients with advanced solid tumors received escalating doses of aprutumab ixadotin (starting at 0.1 mg/kg body weight), administered intravenously on day 1 of every 21-day cycle. Primary endpoints included safety, tolerability, and the MTD of aprutumab ixadotin; secondary endpoints were pharmacokinetic evaluation and tumor response to aprutumab ixadotin.

RESULTS:

Twenty patients received aprutumab ixadotin across five cohorts, at doses of 0.1-1.3 mg/kg. The most common grade ≥ 3 drug-related adverse events were anemia, aspartate aminotransferase increase, proteinuria, and thrombocytopenia. Dose-limiting toxicities were thrombocytopenia, proteinuria, and corneal epithelial microcysts, and were only seen in the two highest dosing cohorts. The MTD was determined to be 0.2 mg/kg due to lack of quantitative data following discontinuations at 0.4 and 0.8 mg/kg doses. One patient had stable disease; no responses were reported.

CONCLUSIONS:

Aprutumab ixadotin was poorly tolerated, with an MTD found to be below the therapeutic threshold estimated preclinically; therefore, the trial was terminated early. CLINICALTRIALS.

GOV IDENTIFIER:

NCT02368951.

• Authors: Sung-Bae Kim, Funda Meric-Bernstam, Aparna Kalyan, Aleksei Babich, Rong Liu, Takahiko Tanigawa, Anette Sommer, Motonobu Osada, Frank Reetz, Dirk Laurent, Sabine Wittemer-Rump, Jordan Berlin
• Journal: Targeted oncology (Target Oncol) Vol. 14 Issue 5 Pg. 591-601 (10 2019) ISSN: 1776-260X [Electronic] France
• PMID: 31502117 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents, Immunological
• Immunoconjugates
• Oligopeptides
• aprutumab ixadotin
• FGFR2 protein, human
• Receptor, Fibroblast Growth Factor, Type 2

Topics

• Adult
• Aged
• Antibodies, Monoclonal, Humanized (therapeutic use)
• Antineoplastic Agents, Immunological (therapeutic use)
• Cholangiocarcinoma (drug therapy)
• Colorectal Neoplasms (drug therapy)
• Early Termination of Clinical Trials
• Female
• Humans
• Immunoconjugates (therapeutic use)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasm Staging
• Oligopeptides (therapeutic use)
• Receptor, Fibroblast Growth Factor, Type 2 (immunology)
• Treatment Failure
• Young Adult