Cancer Chemotherapy and Pharmacology

, Volume 73, Issue 3, pp 485–493

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
Original Article

DOI: 10.1007/s00280-013-2373-9

Cite this article as:
Bruce, J.Y., Kolesar, J.M., Hammers, H. et al. Cancer Chemother Pharmacol (2014) 73: 485. doi:10.1007/s00280-013-2373-9

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.

Keywords

Pharmacodynamic Phase I clinical trial Sequential combination Sunitinib Bevacizumab 

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Justine Yang Bruce
    • 1
  • Jill M. Kolesar
    • 2
  • Hans Hammers
    • 3
  • Mark N. Stein
    • 4
  • Lakeesha Carmichael
    • 5
  • Jens Eickhoff
    • 6
  • Susan A. Johnston
    • 7
  • Kimberly A. Binger
    • 8
  • Jennifer L. Heideman
    • 8
  • Scott B. Perlman
    • 9
  • Robert Jeraj
    • 10
  • Glenn Liu
    • 1
  1. 1.Section of Hematology/OncologyUniversity of Wisconsin Carbone Cancer CenterMadisonUSA
  2. 2.School of PharmacyUniversity of WisconsinMadisonUSA
  3. 3.Johns Hopkins Sidney Kimmel Comprehensive Cancer CenterBaltimoreUSA
  4. 4.Section of Hematology/OncologyCancer Institute of New JerseyNew BrunswickUSA
  5. 5.Department of Biostatistics and Medical InformaticsUniversity of WisconsinMadisonUSA
  6. 6.Department of Biostatistics and Medical InformaticsUniversity of WisconsinMadisonUSA
  7. 7.Pharmaceutical Research CenterUniversity of WisconsinMadisonUSA
  8. 8.University of Wisconsin Carbone Cancer CenterMadisonUSA
  9. 9.Department of RadiologyUniversity of WisconsinMadisonUSA
  10. 10.Department of Medical Physics, Wisconsin Institutes for Medical ResearchUniversity of WisconsinMadisonUSA

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