A phase I pharmacodynamic trial of sequential sunitinib with bevacizumab in patients with renal cell carcinoma and other advanced solid malignancies

Justine Yang Bruce, Jill M. Kolesar, Hans Hammers, Mark N. Stein, Lakeesha Carmichael, Jens Eickhoff, Susan A. Johnston, Kimberly A. Binger, Jennifer L. Heideman, Scott B. Perlman, Robert Jeraj, Glenn Liu

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15 Citations (SciVal)


Background: Sunitinib treatment results in a compensatory increase in plasma VEGF levels. Acute withdrawal of sunitinib results in a proliferative withdrawal flare, primarily due to elevated VEGF levels. Concurrent sunitinib plus bevacizumab is poorly tolerated with high (37 %) incidence of microangiopathic hemolytic anemia (MAHA). We evaluated a sequential design administering bevacizumab during the sunitinib treatment break to suppress the sunitinib withdrawal flare. Methods: Patients with no prior VEGF treatment were enrolled in this study. All patients had target lesions amenable to serial FLT PET/CT imaging. Sunitinib 37.5 mg was given on days 1-28 every 6 weeks with bevacizumab 5 mg/kg on day 29. If safe and tolerable, sunitinib increased to 50 mg. FLT PET/CT scans would be obtained at baseline (D1), week 4, and week 6 to evaluate pharmacodynamics of the sequential combination. Sunitinib pharmacokinetics and total, free, and bound VEGF levels were obtained on each cycle at D1, pre-bevacizumab (D29), 4 h post-bevacizumab (D29H4), and day 42 (D42). Results: Six patients enrolled in the safety cohort of sunitinib 37.5 mg plus bevacizumab (see Table). One patient experienced grade 1 MAHA, and after discussion with the Cancer Therapy Evaluation Program (CTEP), the trial was closed to further accrual. No imaging scans were obtained due to early closure. Total and free VEGF levels during cycle 1 Cycle 1 Total VEGF (pg/mL) Mean ± SD Free VEGF (pg/mL) Mean ± SD D1 80 ± 70 51 ± 47 D29 150 ± 62 103 ± 35 D29H4 10 ± 12 2 ± 5 D42 177 ± 34 97 ± 18 Conclusions: Subclinical MAHA was seen despite using sequential sunitinib with low-dose bevacizumab, and this combination was not feasible for further development. As predicted, VEGF levels increased during sunitinib exposure followed by a rapid decline after bevacizumab. Due to the long half-life of bevacizumab, we expected VEGF ligand suppression through D42, but instead observed a complete rebound in total/free VEGF levels by D42. The increase in VEGF at D42 was unexpected based on sunitinib alone and contrary to the hypothesis that we would block VEGF flare with low-dose bevacizumab. VEGF ligand production may increase as a result of bevacizumab, implying a robust host compensatory mechanism to VEGF signaling pathway inhibition. A greater understanding of the compensatory mechanism would aid future sequencing strategies of new agents.

Original languageEnglish
Pages (from-to)485-493
Number of pages9
JournalCancer Chemotherapy and Pharmacology
Issue number3
StatePublished - Mar 2014

Bibliographical note

Funding Information:
Acknowledgments The authors would like to thank the University of Wisconsin Carbone Cancer Center (UWCCC) for use of its Shared Services to complete this research. This work was supported in part by NIH/NCI P30 CA014520—UW Comprehensive Cancer Center Support, NIH/NCI U01 CA062491, Early Clinical Trials of New AntiCancer Agents with Phase I Emphasis [PI: Glenn Liu], and the Pfizer Investigator-Initiated Research Award GA4061YX. The UWCCC is a center of research and hope inspired by our patients and their families whose time and effort made this research possible. The authors would also like to thank the nurses and research specialists of the UWCCC Cancer Therapy Discovery and Development program for their efforts in conducting and managing this trial.


  • Bevacizumab
  • Pharmacodynamic
  • Phase I clinical trial
  • Sequential combination
  • Sunitinib

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)


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