ArticleCancer chemotherapy and pharmacology2014
A phase I pharmacodynamic trial of sequential sunitinib with bevacizumab in patients with renal cell carcinoma and other advanced solid malignancies.
Article in Cancer chemotherapy and pharmacology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
8 citing papers in PubMed, 1 synthesis or guideline pooled it, 14 citations in OpenAlex.
- Benefit, Risk, and Outcomes in Drug Development: A Systematic Review of Sunitinib.Journal of the National Cancer Institute · 2016Pooled it
- Phase I dose-escalation study of pazopanib combined with bevacizumab in patients with metastatic renal cell carcinoma or other advanced tumors.BMC cancer · 2017Article
- Maintenance of antiangiogenic and antitumor effects by orally active low-dose capecitabine for long-term cancer therapy.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Time-Based Switching Control of Genetic Regulatory Networks: Toward Sequential Drug Intake for Cancer Therapy.Cancer informatics · 2017Article
- An imaging-based computational model for simulating angiogenesis and tumour oxygenation dynamics.Physics in medicine and biology · 2016Article
- The changing landscape of phase I trials in oncology.Nature reviews. Clinical oncology · 2016Review
- Detecting functional changes with [(18)F]FAZA in a renal cell carcinoma mouse model following sunitinib therapy.EJNMMI research · 2014Article
- Monitoring Dual VEGF Inhibition in Human Pancreatic Tumor Xenografts With Dynamic Contrast-Enhanced Ultrasound.Technology in cancer research & treatmentArticle
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Authors and funding
12 authors at 4 institutions in 1 country.
Funding
Abstract
backgroundSunitinib 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.
methodsPatients 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).
resultsSix 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
conclusionsSubclinical 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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