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

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Abstract

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.

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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 Anti-Cancer 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.

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Authors and Affiliations

  1. Section of Hematology/Oncology, University of Wisconsin Carbone Cancer Center, 1111 Highland Avenue, Rm 7105, Madison, WI, 53705, USA

    Justine Yang Bruce & Glenn Liu

  2. School of Pharmacy, University of Wisconsin, K4/554 Clinical Science Center, 600 Highland Avenue, Madison, WI, 53792, USA

    Jill M. Kolesar

  3. Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, 1650 Orleans St, CRB I, 1M46, Baltimore, MD, 21231, USA

    Hans Hammers

  4. Section of Hematology/Oncology, Cancer Institute of New Jersey, 195 Little Albany St, New Brunswick, NJ, 08903, USA

    Mark N. Stein

  5. Department of Biostatistics and Medical Informatics, University of Wisconsin, Box 4675, Clinical Science Center K6/422, 600 Highland Avenue, Madison, WI, 53792, USA

    Lakeesha Carmichael

  6. Department of Biostatistics and Medical Informatics, University of Wisconsin, Box 4675, Clinical Science Center K6/434, 600 Highland Avenue, Madison, WI, 53592, USA

    Jens Eickhoff

  7. Pharmaceutical Research Center, University of Wisconsin, 600 Highland Avenue, Madison, WI, 53792, USA

    Susan A. Johnston

  8. University of Wisconsin Carbone Cancer Center, Box 5666, Clinical Science Center, 600 Highland Avenue, Madison, WI, 53792, USA

    Kimberly A. Binger & Jennifer L. Heideman

  9. Department of Radiology, University of Wisconsin, Box 3252, Clinical Science Center, 600 Highland Avenue, Madison, WI, 53792, USA

    Scott B. Perlman

  10. Department of Medical Physics, Wisconsin Institutes for Medical Research, University of Wisconsin, Box 1005, 1111 Highland Avenue, Madison, WI, 53705, USA

    Robert Jeraj

Authors
  1. Justine Yang Bruce
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  2. Jill M. Kolesar
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  3. Hans Hammers
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  4. Mark N. Stein
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  5. Lakeesha Carmichael
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  6. Jens Eickhoff
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  7. Susan A. Johnston
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  8. Kimberly A. Binger
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  9. Jennifer L. Heideman
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  10. Scott B. Perlman
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  11. Robert Jeraj
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  12. Glenn Liu
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Corresponding author

Correspondence to Justine Yang Bruce.

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Bruce, J.Y., Kolesar, J.M., Hammers, H. et al. A phase I pharmacodynamic trial of sequential sunitinib with bevacizumab in patients with renal cell carcinoma and other advanced solid malignancies. Cancer Chemother Pharmacol 73, 485–493 (2014). https://doi.org/10.1007/s00280-013-2373-9

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  • DOI: https://doi.org/10.1007/s00280-013-2373-9

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