Figure 1

Trial design. Patients will be enrolled in cohorts of 5 per dose level. The first 5 patients enrolled will be assigned to dose level 0 in order to assess immune and anti-angiogenic effects of everolimus monotherapy. In subsequent dose levels the cyclophosphamide dose will be increased up to a maximum of 150 mg cyclophosphamide twice daily. The dose level showing the most selective depletion of Tregs will be selected for phase II. Endpoints for the phase I part are safety, immunologic and angiogenesis parameters, response rate and drug levels. In the phase II part of the study patients will receive 10 mg everolimus per day in combination with the optimal Treg depleting dose cyclophosphamide. Endpoints for the phase II part are progression free survival, safety, immunologic and angiogenesis parameters and response rate.