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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)485-493
Number of pages9
JournalCancer Chemotherapy and Pharmacology
Volume73
Issue number3
DOIs
StatePublished - 2014

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Pharmacodynamics
Renal Cell Carcinoma
Vascular Endothelial Growth Factor A
Cells
Neoplasms
Hemolytic Anemia
sunitinib
Bevacizumab
Ligands
Imaging techniques
Pharmacokinetics
Computerized tomography
Program Evaluation
Therapeutics

Keywords

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

ASJC Scopus subject areas

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

Cite this

A phase I pharmacodynamic trial of sequential sunitinib with bevacizumab in patients with renal cell carcinoma and other advanced solid malignancies. / Bruce, Justine Yang; Kolesar, Jill M.; Hammers, Hans; Stein, Mark N.; Carmichael, Lakeesha; Eickhoff, Jens; Johnston, Susan A.; Binger, Kimberly A.; Heideman, Jennifer L.; Perlman, Scott B.; Jeraj, Robert; Liu, Glenn.

In: Cancer Chemotherapy and Pharmacology, Vol. 73, No. 3, 2014, p. 485-493.

Research output: Contribution to journalArticle

Bruce, JY, Kolesar, JM, Hammers, H, Stein, MN, Carmichael, L, Eickhoff, J, Johnston, SA, Binger, KA, Heideman, JL, Perlman, SB, Jeraj, R & Liu, G 2014, 'A phase I pharmacodynamic trial of sequential sunitinib with bevacizumab in patients with renal cell carcinoma and other advanced solid malignancies', Cancer Chemotherapy and Pharmacology, vol. 73, no. 3, pp. 485-493. https://doi.org/10.1007/s00280-013-2373-9
Bruce, Justine Yang ; Kolesar, Jill M. ; Hammers, Hans ; Stein, Mark N. ; Carmichael, Lakeesha ; Eickhoff, Jens ; Johnston, Susan A. ; Binger, Kimberly A. ; Heideman, Jennifer L. ; Perlman, Scott B. ; Jeraj, Robert ; Liu, Glenn. / A phase I pharmacodynamic trial of sequential sunitinib with bevacizumab in patients with renal cell carcinoma and other advanced solid malignancies. In: Cancer Chemotherapy and Pharmacology. 2014 ; Vol. 73, No. 3. pp. 485-493.
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AU - Bruce, Justine Yang

AU - Kolesar, Jill M.

AU - Hammers, Hans

AU - Stein, Mark N.

AU - Carmichael, Lakeesha

AU - Eickhoff, Jens

AU - Johnston, Susan A.

AU - Binger, Kimberly A.

AU - Heideman, Jennifer L.

AU - Perlman, Scott B.

AU - Jeraj, Robert

AU - Liu, Glenn

PY - 2014

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N2 - 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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