A phase I study of the VEGFR kinase inhibitor vatalanib in combination with the mTOR inhibitor, everolimus, in patients
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PHASE I STUDIES
A phase I study of the VEGFR kinase inhibitor vatalanib in combination with the mTOR inhibitor, everolimus, in patients with advanced solid tumors Mojun Zhu 1 & Julian R. Molina 1 & Grace K. Dy 2 & Gary A. Croghan 1 & Yingwei Qi 3 & James Glockner 1 & Lorelei J. Hanson 1 & Michelle M. Roos 1 & Angelina D. Tan 1 & Alex A. Adjei 1 Received: 13 March 2020 / Accepted: 7 April 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Summary Purpose Combining small-molecule inhibitors of different targets was shown to be synergistic in preclinical studies. Testing this concept in clinical trials is, however, daunting due to challenges in toxicity management and efficacy assessment. This study attempted to evaluate the safety and efficacy of vatalanib plus everolimus in patients with advanced solid tumors and explore the utility of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) studies as a predictive biomarker. Patients and Methods This single-center, phase I trial containing 70 evaluable patients consisted of a dose escalation proportion based on the traditional “3 + 3” design (cohort IA and IB) and a dose expansion proportion (cohort IIA and IIB). Toxicity was evaluated using the Common Terminology Criteria of Adverse Events. Antitumor activity was assessed using the Modified Response Evaluation Criteria in Solid Tumors. Results The maximum tolerated doses were determined to be vatalanib 1250 mg once daily or 750 mg twice daily in combination with everolimus 10 mg once daily. No treatment-related death occurred. The most common toxicities were hypertriglyceridemia, hypercholesterolemia, fatigue, vomiting, nausea and diarrhea. There was no complete response. Nine patients (12.9%) had partial response (PR) and 41 (58.6%) had stable disease (SD). Significant antitumor activity was observed in neuroendocrine tumors with a disease-control rate (PR + SD) of 66.7% and other tumor types including renal cancer, melanoma, and non-small-cell lung cancer. Conclusions The combination of vatalanib and everolimus demonstrated reasonable toxicity and clinical activity. Future studies combining targeted therapies and incorporating biomarker analysis are warranted based on this phase I trial. Keywords Phase I . Targeted therapy . Vatalanib . Everolimus
Introduction Signal transduction via vascular endothelial growth factor receptors (VEGFRs) mediates angiogenesis in a broad of range of tumors and is a critical step in tumorigenesis [1]. Over the past decade, numerous VEGFR inhibitors have been Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10637-020-00936-z) contains supplementary material, which is available to authorized users. * Alex A. Adjei [email protected] 1
Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA
2
Roswell Park Cancer Institute, Buffalo, NY 14263, USA
3
Dignity Health Medical Foundation, San Francisco, CA 94107, USA
developed as cancer therapeutic agents with expanding indications. Vatalanib (PTK787/ZK 2225
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