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A phase I study of the VEGFR kinase inhibitor vatalanib in combination with the mTOR inhibitor, everolimus, in patients with advanced solid tumors

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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.

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Data availability

The data generated and/or analyzed during the study were available from the corresponding author on reasonable request.

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Funding

This study was funded by the National Cancer Institute P30CA015083 and U01CA069912 grants.

Author information

Authors and Affiliations

  1. Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA

    Mojun Zhu, Julian R. Molina, Gary A. Croghan, James Glockner, Lorelei J. Hanson, Michelle M. Roos, Angelina D. Tan & Alex A. Adjei

  2. Roswell Park Cancer Institute, Buffalo, NY, 14263, USA

    Grace K. Dy

  3. Dignity Health Medical Foundation, San Francisco, CA, 94107, USA

    Yingwei Qi

Authors
  1. Mojun Zhu
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  2. Julian R. Molina
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  3. Grace K. Dy
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  4. Gary A. Croghan
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  5. Yingwei Qi
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  6. James Glockner
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  7. Lorelei J. Hanson
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  10. Alex A. Adjei
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Contributions

Conception and design: Adjei, Dy, Qi.

Development of methodology: Adjei, Dy, Molina, Glockner.

Acquisition of data (provided animals, acquired and managed patients, provided facility, etc.): Qi, Tan, Roos, Hanson, Croghan, Molina.

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): Tan, Qi, Zhu, Adjei.

Writing, review, and/or revision of the manuscript: All.

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): Roos, Qi, Tan.

Study supervision: Adjei, Molina.

Corresponding author

Correspondence to Alex A. Adjei.

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Conflict of interest

The authors declare no potential conflicts of interest or competing interests.

Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki. The study was approved by the institutional review board of Mayo Clinic.

Informed consent

Written informed consent was obtained from all individual participants included in the study.

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Zhu, M., Molina, J.R., Dy, G.K. et al. A phase I study of the VEGFR kinase inhibitor vatalanib in combination with the mTOR inhibitor, everolimus, in patients with advanced solid tumors. Invest New Drugs 38, 1755–1762 (2020). https://doi.org/10.1007/s10637-020-00936-z

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  • DOI: https://doi.org/10.1007/s10637-020-00936-z

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