Phase I/II Trial of Imatinib and Bevacizumab in Patients With Advanced Melanoma and Other Advanced Cancers

Background.

Vascular endothelial growth factor and platelet-derived growth factor signaling in the tumor microenvironment appear to cooperate in promoting tumor angiogenesis.

Patients and Methods.

We conducted a phase I trial combining bevacizumab (i.v. every 2 weeks) and imatinib (oral daily). Once a recommended phase II dose combination was established, a phase II trial was initiated in patients with metastatic melanoma. A Simon 2-stage design was used with 23 patients required in the first stage and 41 patients in total should the criteria to proceed be met. We required that 50% of the patients be progression-free at 16 weeks. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and power Doppler ultrasonography were performed in patients with metastatic tumors amenable to imaging with these methods at baseline and after 4 weeks.

Results.

A total of 17 patients were accrued to 4 dose and combination levels. Bevacizumab 10 mg/kg every 2 weeks could be safely combined with imatinib 800 mg daily. Common toxicities included fatigue, nausea, vomiting, edema, proteinuria, and anemia, but were not commonly severe. A total of 23 patients with metastatic melanoma (48% with American Joint Commission on Cancer stage M1c; median age, 63 years) were enrolled in the first stage of phase II. The 16-week progression-free survival rate was 35%, leading to termination of phase II after the first stage. In the small subset of patients who remained on study with lesions evaluable by DCE-MRI, significant decreases in tumor vascular permeability were noted, despite early disease progression using the Response Evaluation Criteria In Solid Tumors.

Conclusion.

Bevacizumab and imatinib can be safely combined at the maximum doses used for each agent. We did not observe significant clinical activity with this regimen in melanoma patients.

Implications for Practice:

Vascular endothelial growth factor (VEGF)-targeted antiangiogenic therapy has proven clinical efficacy as a standalone therapy in renal cell carcinoma and glioblastoma multiforme. Also, enhancement of conventional cytotoxic chemotherapy efficacy has been observed in colorectal, non-small-cell lung, breast, and ovarian cancers. Optimal strategies to cotarget angiogenic cytokines combined with VEGF have not been defined. It was found that bevacizumab could be safely combined with imatinib, which was used as a platelet-derived growth factor receptor inhibitor in our study. High-dose imatinib-related edema was not observed when paired with bevacizumab. This regimen might be suitable for further investigation in other cancers but apparently not in melanoma.