A Phase 1 Study of a CDH6-Targeting Antibody-Drug Conjugate in Patients with Advanced Solid Tumors with Evaluation of Inflammatory and Neurological Adverse Events
| Autor: | Joel Wagner, Cristina Suarez, Keith Mansfield, Vivek Subbiah, Jason E. Faris, Shiling Ruan, Patrick Schöffski, Sarah DiDominick, Yuichi Ando, Shizuka Origuchi, Nicole Concin, Carl Uli Bialucha, Xu Zhu, Ben Tran |
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| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
medicine.medical_specialty Immunoconjugates Encephalopathy Antineoplastic Agents Gastroenterology Pharmacokinetics Neoplasms Internal medicine Humans Medicine Adverse effect Carcinoma Renal Cell Ovarian Neoplasms business.industry Hematology medicine.disease Kidney Neoplasms Oncology Tolerability Toxicity Cohort Vomiting Female medicine.symptom business Progressive disease |
| Zdroj: | Oncology Research and Treatment. 44:547-556 |
| ISSN: | 2296-5262 2296-5270 |
| DOI: | 10.1159/000518549 |
| Popis: | Purpose: This first-in-human study (NCT02947152) evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of HKT288, a first-in-class CDH6-targeting antibody-drug conjugate (ADC). Experimental Design: HKT288 was administered intravenously (IV) every 3 weeks until patients experienced unacceptable toxicity or progressive disease (PD). The starting dose of 0.3 mg/kg was determined based on the highest nonseverely toxic dose in monkeys, which was 2 mg/kg IV weekly. Based on preclinical toxicology, skin, eyes, bone marrow, and liver were expected targets of toxicity. Results: Nine patients were enrolled: 5 with renal cell carcinoma and 4 with epithelial ovarian cancer. The best overall response on the 0.3 mg/kg cohort in patients with measurable disease was RECIST v1.1 stable disease in 3 patients and PD in 2 patients. The most frequent adverse events (AEs) regardless of causality were pyrexia (44.4%), constipation (44.4%), fatigue (33.3%), and vomiting (33.3%). Three suspected-related neurologic AEs (Grade 2) were reported on the 0.75 mg/kg cohort: seizure in 1 patient and another patient with aphasia and encephalopathy. Further studies were unable to identify the underlying mechanism of the neurologic AEs, and the study was terminated early. Conclusions: Preclinical toxicology did not predict the neurotoxicity observed with HKT288, and a comprehensive assessment performed post hoc did not identify the mechanism of toxicity. The development of further CDH6-targeting ADCs should be pursued with caution. |
| Databáze: | OpenAIRE |
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