Updated phase I results of a phase I/II trial of BNC105P with everolimus in patients with metastatic renal cell carcinoma (mRCC).

Abstract

397 Background: BNC105P is an inhibitor of tubulin polymerization. In vivo exposure to BNC105P leads to selective damage of tumor vasculature in both primary and metastatic lesions, causing disruption of blood flow to tumors, 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 cellular response to hypoxic stress. The combined use of BNC105P with an agent active against mTOR may improve clinical outcome in patients with progressive mRCC who are refractory to VEGFR-directed tyrosine kinase inhibitors (TKI). Methods: A phase I/II study in mRCC patients who have received 1-2 prior TKIs was undertaken. The phase I component enrolled 12 subjects at 4 dose levels of BNC105P (4.2, 8.4, 12.6, 16 mg/m2; IV infusion Days 1 and 8, 21-day repeating cycle). Everolimus was administered concurrently (10 mg p.o.). PK analysis was performed during cycle 1. Results: Updated results from the completed phase I component confirm the BNC105P/everolimus combination was well tolerated. No DLTs (drug-related, during cycle 1) were observed in any of the phase I subjects. Toxicities on study deemed to be drug-related (either single agent or combination) included single grade 3 events of anemia and pericardial effusion. Grade 2 events (more than 1 occurrence) of fatigue, anemia, and oral mucositis were also observed. 8 of the 12 phase I subjects achieved disease stabilization (7 of these subjects had a minimum time on therapy of 18 weeks, 6 cycles). Across all subjects a median of 6 cycles (range: 1-21) was administered, with removal from study predominantly due to disease progression. PK analysis confirmed no drug-drug interaction. The randomized phase II component of the study continues and will compare everolimus given concomitantly with BNC105P to a sequential approach (everolimus followed by BNC105P). Conclusions: BNC105P (16 mg/m2) can be combined with full dose everolimus and is being evaluated in a randomized phase II study. Clinical trial information: NCT01034631.