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TPS5612 Background: BNC105P is a tubulin polymerization inhibitor and a vascular disrupting agent (VDA). 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, including ovarian cancer cell lines. Pre-clinical data has demonstrated synergistic activity of BNC105P when combined with platinum or with gemcitabine, supporting the proposed study design. This study will determine the safety and efficacy of BNC105P in ovarian cancer when used in combination with gemcitabine-carboplatin. The target population is women with ovarian or primary peritoneal cancers who progressed 4 to 9 months after first-line platinum based chemotherapy, or 4 to 12 months after second line platinum based chemotherapy. Methods: A single arm phase I will be used to determine the phase II dose for the triplet combination (3-6 subjects per dose level, maximum of 24 subjects). Four dose levels of BNC105P (12-16 mg/m2) and gemcitabine (800-1000 mg/m2) will be assessed. The dose of carboplatin will be set at AUC 4. Enrolment to cohort 2 started in January 2013. The phase II component will consist of a 2-arm, randomized (1:1) study of BNC105P, gemcitabine and carboplatin versus gemcitabine and carboplatin alone. The primary endpoint for the phase II trial is objective response rate (ORR, according to RECIST 1.1 and/or GCIG CA125 criteria. An ORR of 40% or more with the experimental regimen would be considered worthy of further investigation, assuming an ORR of 20% with the control regimen. 110 phase II participants are planned (N = 55/arm). Treatment allocation will be balanced using minimization for the study site, target lesions according to RECIST (present vs. absent), progression free interval from last platinum based chemotherapy regimen (

7079^ Background: BNC105P is a tubulin polymerization inhibitor that acts as a Vascular Disrupting Agent (VDA), has direct cytotoxic effects, and had preclinical and phase I activity in MPM. This aim of this study was to determine activity and safety of BNC105P as second-line therapy after pemetrexed and a platin in MPM. Methods: Eligible patients had progressive MPM, prior pemetrexed and platinum, measurable disease by modified RECIST, ECOG 0-1, and adequate organ and cardiovascular function. Important exclusions included recent thromboembolic, cardiovascular or cerebrovascular disease, or therapeutic anticoagulation. Pts received BNC105P (16 mg/m2 IV) Day 1 + 8 q21d until progression or toxicity. The primary endpoint was centrally reviewed objective tumour response rate (RR); the Simon 2-stage design assumed a RR of interest of 20% and a RR of no interest of 5%, with α = β = 0.05. Continuation past first stage accrual required >1 objective response in 24 patients. Results: 30 subjects were accrued over 10 months (90% male; median age 65 (range 41-83); 77% ECOG PS 1; histology epithelioid (67%), biphasic (10%), sarcomatoid (7%), other/unspecified (17%)). All pts received at least one dose of study drug; pts received a median of 2 cycles and median dose intensity was 100%. No significant haematologic, biochemical, peripheral neurotoxic or cardiac adverse events (AEs) including hypertension were observed. Grade 3 or 4 AEs occurred in 10 pts (33%). There were 2 deaths on study: 1 due to stroke, the other due to pneumonia and respiratory failure. We observed 1 partial response (3%) and 13 pts with SD as their best response (43%). Median progression free survival was 1.5 mo (95% CI 1.4-2.4); median overall survival was 8.7 mo (95% CI 3.8-NR). Lung function and QOL data was collected. Biomarker analyses correlating to pharmacological changes induced by BNC105P are ongoing and will be presented. Conclusions: BNC105P was safe and tolerable but its single agent response rate failed to meet the pre-specified primary endpoint of interest.

TPS194 Background: Treatment options remain limited in progressive metastatic renal cell carcinoma (mRCC) for patients who are refractory to tyrosine kinase inhibitors (TKI). Treatment with everoli...

3054 Background: BNC105P is a novel agent which inhibits tubulin polymerization and acts as a VDA. BNC105P is a phosphorylated parent compound which rapidly converts to the active agent BNC105. BNC...

e14512 Background: BNC105P is a novel anticancer agent that inhibits tubulin polymerization and acts as a VDA. BNC105P is a phosphorylated parent compound which rapidly becomes the active agent BNC105. BNC105 exhibits 100-fold specificity for activated endothelial cells compared to quiescent endothelial cells. Methods: BNC105P (2.1 to 18.9 mg/m2) was given IV over 10 min on day 1 and 8 every 21 days to patients (pts) with advanced solid tumors (ECOG 0–2) and adequate organ function. The objectives were to determine safety, tolerability, MTD and pharmacokinetics (PK). A pharmacodynamic response was evaluated using DCE-MRI with two baseline and two post dose assessments (3–6, 24 h). DLTs were determined during the first 21 days. Results: 9 pts (7 M; 2 F), median age 60 years have been enrolled with one pt each at 2.1 and 4.2 mg/m2. At 8.4 mg/m2, one pt experienced Grade 2 (Gr 2) mucositis and a switch to a ‘3+3’ design occurred. No DLTs have been observed in 3 pts at 12.6 mg/m2 and 1 pt at 18.9 mg/m2. Notable toxicity includes one episode of Gr 1 febrile episode possibly related to infusion, two episodes of Gr 1 fatigue and one Gr 1 rash. PK data of BNC105 indicates a linear increase in plasma AUC levels (Table) and plasma half life of < 0.5 h. Best observed responses were SD in 2/9 pts including one pt with mesothelioma (progression at entry) with SD up to week 22 (8.4 mg/m2). At doses ≥ 8.4 mg/m2, DCE-MRI images indicate changes in tumor perfusion post-dose. Two pts at 12.6 mg/m2 had a decrease in Ktrans values of 6 and 15 % compared to baseline. Conclusions: Pharmacodynamically active doses have been achieved with plasma drug levels correlating with active preclinical plasma exposure. To date, no excess toxicity has been observed at doses up to 18.9 mg/m2. [Table: see text] [Table: see text]