Phase 1/1b open-label, dose-escalation study of fruquintinib in patients with advanced solid tumors in the United States

• Published in: Investigational new drugs Vol. 41; no. 6; pp. 851 - 860
• Main Authors: Wang-Gillam, Andrea, Schelman, William, Ukrainskyj, Stacey, Chien, Caly, Gonzalez, Martha, Yang, Zhao, Kania, Marek, Yeckes-Rodin, Heather
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-12-2023; Springer Nature B.V
• Subjects: Anticancer properties; Antitumor activity; Cancer therapies; Dosage; Drug dosages; Hypertension; International organizations; Labels; Medicine; Medicine & Public Health; Metastasis; Neutropenia; Oncology; Patients; Pharmacokinetics; Pharmacology/Toxicology; Safety; Solid tumors; Toxicity; Tumors; Vascular endothelial growth factor; United States > US; China; Angiogenesis; Fruquintinib; Solid tumors; Tyrosine kinase inhibitor; Vascular endothelial growth factor receptors
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-023-01395-y

Summary
This open-label, phase 1/1b study was conducted to evaluate the safety, tolerability, and pharmacokinetics (PK) of fruquintinib in United States (U.S.) patients to confirm the recommended phase 2 dose (RP2D) established in China. Patients with advanced solid tumors who had progressed on approved systemic therapy, were enrolled into 2 successive dose escalation cohorts, fruquintinib 3 mg (n = 7) or 5 mg (n = 7), orally, once daily (QD), 3 weeks on and 1 week off (3/1) with a 3 + 3 design followed by a dose expansion cohort at the RP2D 5 mg dose (n = 6). PK samples were collected on Days 1, 14, and 21 (Cycle 1). One of 6 dose-limiting toxicity (DLT)-evaluable patients in the 3 mg cohort had a DLT of grade 4 hypertension; there were no DLTs in the 5 mg cohort. The RP2D was confirmed to be 5 mg QD 3/1. All 20 patients experienced a treatment-emergent adverse event; grade ≥ 3 in 5 (71.4%; 3 mg dose) and 12 (92.3%; 5 mg dose) patients. Two patients had a confirmed partial response. After single and multiple doses, median peak plasma concentrations occurred at 2 h post-dose. Steady-state was achieved after 14 days of QD dosing with systemic exposure four-fold higher than that after a single dose. Fruquintinib was well tolerated, and the safety and PK profile at the 5 mg RP2D in U.S. patients with advanced solid tumors was consistent with dose-finding studies in China. Preliminary anticancer activity was observed. This study is registered at
Clinicaltrials.gov NCT03251378
.