Phase I/II study of a BNC105P/everolimus regimen for progressive metastatic renal cell carcinoma (mRCC) following prior tyrosine kinase inhibitors (Hoosier Oncology Group).

Abstract

373 Background: BNC105P is a Vascular Disruption Agent (VDA) that destabilizes tubulin polymers leading to selective damage of tumor vasculature, hypoxia and associated tumor necrosis. BNC105P also has a direct anti-proliferative action on cancer cells. Up regulation of the mTOR pathway has been identified as a survival response by the tumor to hypoxic insult. Preclinical investigations demonstrated that BNC105P is effective at selectively damaging the vasculature in primary and metastatic lesions. Furthermore, BNC105P monotherapy compared well with sunitinib in mice bearing kidney tumors. It follows that the combined use of this VDA with an agent active against mTOR may improve clinical outcome in patients with progressive mRCC who are refractory to tyrosine kinase inhibitors (TKI). Methods: A phase I/II study in mRCC patients who have received 1-2 prior TKIs was undertaken. Using a classic 3+3 design, the phase I component of this study enrolled 12 subjects at 4 dose levels of BNC105P (4.2, 8.4, 12.6 and 16 mg/m2; IV infusion Days 1 & 8, 21-day repeating cycle). Everolimus was administered concurrently (10 mg p.o.). PK analysis was performed during Cycle 1. Results: In the clinic the BNC105P / everolimus combination was well tolerated and no DLTs were observed in any of the phase I patients. Toxicities deemed to be drug-related included single events of Grade 2 anemia, thrombocytopenia and mucositis. Of the 12 patients enrolled to the phase I, 7 remain on treatment. The medium number of cycles is 3 (range: 1–14) and 3 patients have been administered >6 cycles of treatment. The randomized phase II component of the study continues and will compare everolimus given in combination with BNC105P to a sequential approach (everolimus followed by BNC105P). Conclusions: The MTD of BNC105P (16 mg/m2) can be combined with full dose everolimus and is being evaluated in the randomized phase II study.