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.

Maintenance of antiangiogenic and antitumor effects by orally active low-dose capecitabine for long-term cancer therapy

“…Combination of AAD with chemotherapy demonstrates improvement of survival benefits and is the most commonly used regimen for treatment of most cancer types (18)(19)(20). To maximize AAD clinical benefits, one of the key unresolved issues is to achieve nonstop lifetime therapy in cancer patients because discontinuation of AAD treatment can cause a rebound effect of tumor neovascularization (21)(22)(23)(24). Additionally, withdrawal of AADs might promote cancer metastasis through a vascular recovery mechanism in remote tissues and organs (13).…”

Time-Based Switching Control of Genetic Regulatory Networks: Toward Sequential Drug Intake for Cancer Therapy

“…This suggests that the drugs are effective when taken simultaneously or sequentially based on the reduction in the expression levels of the proteins and complexes. However, toxicity becomes a concern in the simultaneous intake case as already investigated in the previous studies 3–8. This suggests that the proposed sequential or switched drug inputs approach is a promising solution.…”

“…The state-space trajectory depicts that both the simultaneous drug intake and sequential drug intake significantly reduced the expression levels of the diseased genes. Although they are both effective against the diseased genes, toxicity is a concern with the simultaneous drug intake 3–8. Therefore, this study is focused on time-based switching control and stability analysis for the sequential drug intake approach due to the reduced toxicity associated with such drug intake methods.…”

An imaging-based computational model for simulating angiogenesis and tumour oxygenation dynamics

“…Normalization of vasculature leading to efficient vascular network and better blood flow has been postulated as a consequence of anti-angiogenic drug treatment (Jain 2005). However, evidence of normalization has been controversial, its efficacy moderate and our understanding shallow (Bruce et al 2014). The time scales of normalization are still under investigation.…”