title: A phase I pharmacodynamic trial of sequential sunitinib with bevacizumab in patients with renal cell carcinoma and other advanced solid malignancies.
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.
authors.affiliation: Section of Hematology/Oncology, University of Wisconsin Carbone Cancer Center, 1111 Highland Avenue, Rm 7105, Madison, WI, 53705, USA, jybruce@medicine.wisc.edu.
authors.forename: Justine Yang
authors.initials: JY
authors.lastname: Bruce
authors.forename: Jill M
authors.initials: JM
authors.lastname: Kolesar
authors.forename: Hans
authors.initials: H
authors.lastname: Hammers
authors.forename: Mark N
authors.initials: MN
authors.lastname: Stein
authors.forename: Lakeesha
authors.initials: L
authors.lastname: Carmichael
authors.forename: Jens
authors.initials: J
authors.lastname: Eickhoff
authors.forename: Susan A
authors.initials: SA
authors.lastname: Johnston
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Binger
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Heideman
authors.forename: Scott B
authors.initials: SB
authors.lastname: Perlman
authors.forename: Robert
authors.initials: R
authors.lastname: Jeraj
authors.forename: Glenn
authors.initials: G
authors.lastname: Liu
mesh_terms: D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D000068258:Bevacizumab; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D015331:Cohort Studies; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000077210:Sunitinib
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D007211:Indoles; D011758:Pyrroles; D000068258:Bevacizumab; D000077210:Sunitinib