Phase I study of BNC105P, carboplatin and gemcitabine in partially platinum-sensitive ovarian cancer patients in first or second relapse (ANZGOG-1103).

PURPOSE: The primary objective of this study was to determine the recommended dose of the vascular disrupting agent, BNC105P, in combination with gemcitabine and carboplatin in patients with ovarian cancer in first or second relapse with a minimum 4 month progression-free interval after last platinum. METHODS: Patients received carboplatin AUC4 on day 1 in combination with escalating doses of 800 or 1000 mg/m2 gemcitabine on days 1 and 8 and escalating doses of 12 or 16 mg/m2 BNC105P on days 2 and 9 every 21 days for a maximum for six cycles. Maintenance treatment with 16 mg/m2 BNC105P treatment continued for a maximum of six additional cycles. Patients were followed for safety and anti-tumor activity. RESULTS: Fifteen patients were enrolled in the study. Adverse events were most commonly of hematological origin. Dose-limiting toxicities (thrombocytopenia and neutropenia) occurred in two patients at the dose level of 800 mg/m2 gemcitabine, carboplatin AUC4 and 16 mg/m2 BNC105P. No dose-limiting toxicities were observed at a dose level of gemcitabine 1000 mg/m2, carboplatin AUC4 and BNC105P 12 mg/m2. BNC105P as a single agent was well tolerated at a dose of 16 mg/m2 in maintenance treatment. Ten patients (67%) achieved a complete or partial response according to CA125 and/or RECIST response criteria, four of 13 (31%) responded by RECIST alone. The median progression-free survival was 5.9 months. CONCLUSIONS: We have established that BNC105P 12 mg/m2 with gemcitabine 1000 mg/m2 and carboplatin AUC4 is the recommended dose level and has an acceptable toxicity profile. Further exploration of BNC105P in the ovarian cancer setting is planned.

A Phase I/II Trial of BNC105P with Everolimus in Metastatic Renal Cell Carcinoma.

PURPOSE: BNC105P inhibits tubulin polymerization, and preclinical studies suggest possible synergy with everolimus. In this phase I/II study, efficacy and safety of the combination were explored in patients with metastatic renal cell carcinoma (mRCC). EXPERIMENTAL DESIGN: A phase I study in patients with clear cell mRCC and any prior number of therapies was conducted using a classical 3 + 3 design to evaluate standard doses of everolimus with increasing doses of BNC105P. At the recommended phase II dose (RP2D), patients with clear cell mRCC and one to two prior therapies (including ≥ 1 VEGF-TKI) were randomized to BNC105P with everolimus (arm A) or everolimus alone (arm B). The primary endpoint of the study was 6-month progression-free survival (6MPFS). Secondary endpoints included response rate, PFS, overall survival, and exploratory biomarker analyses. RESULTS: In the phase I study (N = 15), a dose of BNC105P at 16 mg/m(2) with everolimus at 10 mg daily was identified as the RP2D. In the phase II study, 139 patients were randomized, with 69 and 67 evaluable patients in arms A and B, respectively. 6MPFS was similar in the treatment arms (arm A: 33.82% vs. arm B: 30.30%, P = 0.66) and no difference in median PFS was observed (arm A: 4.7 mos vs. arm B: 4.1 mos; P = 0.49). Changes in matrix metalloproteinase-9, stem cell factor, sex hormone-binding globulin, and serum amyloid A protein were associated with clinical outcome with BNC105P. CONCLUSIONS: Although the primary endpoint was not met in an unselected population, correlative studies suggest several biomarkers that warrant further prospective evaluation.

The vascular disrupting agent BNC105 potentiates the efficacy of VEGF and mTOR inhibitors in renal and breast cancer.

BNC105 is a tubulin targeting compound that selectively disrupts vasculature within solid tumors. The severe tumor hypoxia and necrosis that ensues translates to short term tumor growth inhibition. We sought to identify the molecular and cellular events activated following BNC105 treatment that drives tumor recovery. We investigated tumor adaptation to BNC105-induced hypoxia in animal models of breast and renal cancer. HIF-1α and GLUT-1 were found to be strongly upregulated by BNC105 as was the VEGF signaling axis. Phosphorylation of mTOR, 4E-BP-1 and elF2α were upregulated, consistent with increased protein synthesis and increased expression of VEGF-A. We sought to investigate the potential therapeutic utility of combining BNC105 with agents targeting VEGF and mTOR signaling. Bevacizumab and pazopanib target the VEGF axis and have been approved for first line use in renal cancer. Everolimus targets mTOR and is currently approved in second line therapy of renal and particular breast cancers. We combined these agents with BNC105 to explore the effects on tumor vasculature, tumor growth inhibition and animal survival. Bevacizumab hindered tumor vascular recovery following BNC105 treatment leading to greater tumor growth inhibition in a breast cancer model. Consistent with this, addition of BNC105 to pazopanib treatment resulted in a significant increase in survival in an orthotopic renal cancer model. Combination treatment of BNC105 with everolimus also increased tumor growth inhibition. BNC105 is currently being evaluated in a randomized phase II clinical trial in combination with everolimus in renal cancer.

A phase II clinical trial of the vascular disrupting agent BNC105P as second line chemotherapy for advanced Malignant Pleural Mesothelioma.

BNC105P is a tubulin polymerisation inhibitor that selectively disrupts tumour vasculature and suppresses cancer cell proliferation. This agent has exhibited preclinical and phase I activity in Malignant Pleural Mesothelioma (MPM). This phase II, single arm trial investigated the efficacy and safety of BNC105P as second line therapy in MPM. Participants had progressive MPM after first line pemetrexed/platinum chemotherapy, ECOG PS 0-1, adequate organ function, and measurable disease. BNC105P 16 mg/m(2) was administered intravenously on day 1 and 8 every 21 days until progression or undue toxicity. The primary endpoint was centrally reviewed objective response rate (RR). Tumour response was assessed every two cycles using modified RECIST. 30 patients were enrolled in 10 months, predominantly male (90%), ECOG PS 1 (77%), epithelioid histology (67%), and non-metastatic disease (67%). All patients received at least one dose of study drug, with a median of 2 cycles. No significant haematologic, biochemical, or cardiac adverse events (AEs) were observed. Grade 3 or 4 AEs occurred in 10 patients (33%). There were 2 deaths on study: 1 cardiorespiratory, the other to pneumonia. We observed 1 partial response (3%); 13 patients had stable disease (43%). Median progression free survival was 1.5 months (95% CI 1.4-2.4); median overall survival was 8.2 months (95% CI 3.8-11.9). BNC105P was safe and tolerable. The sole response was insufficient to warrant further research as a single agent.

Clinical, pharmacodynamic, and pharmacokinetic evaluation of BNC105P: a phase I trial of a novel vascular disrupting agent and inhibitor of cancer cell proliferation.

PURPOSE: To determine the recommended phase II dose and evaluate the safety and toxicity profile and pharmacokinetic (PK) and pharmacodynamic (PD) effects of BNC105P, an inhibitor of tubulin polymerization that has vascular disrupting and antiproliferative effects. EXPERIMENTAL DESIGN: BNC105P was administered as a 10-minute infusion on days 1 and 8 of a 21-day cycle in a first-in-human phase I study. A dynamic accelerated dose titration method was used for dose escalation. Plasma concentrations of BNC105P (phosphate prodrug) and BNC105 (active agent) were determined. PD assessments were carried out using dynamic contrast enhanced (DCE)-MRI and analysis of a blood-borne biomarker. RESULTS: Twenty-one subjects with advanced solid tumors were enrolled on 6 dose levels (range: 2.1-18.9 mg/m(2)). The recommended dose level was 16 mg/m(2) and was well tolerated. BNC105P (prodrug) rapidly converted to BNC105 with a half-life of 0.13 hours. Plasma concentrations of BNC105 generally increased in proportion to dose with a half-life of 0.57 hours. Pharmacodymanically active plasma levels were obtained with a dose dependant reduction in the levels of polymerized tubulin (on-target action) being observed in PBMCs. DCE-MRI also indicated blood flow changes in the tumor lesions of a number of subjects. CONCLUSIONS: BNC105P has a favorable toxicity profile at the recommended dose of 16 mg/m(2) and is associated with PD changes consistent with its known mechanism of action. Phase II studies in renal cancer and mesothelioma have commenced.

Discovery of 7-hydroxy-6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)benzo[b]furan (BNC105), a tubulin polymerization inhibitor with potent antiproliferative and tumor vascular disrupting properties.

A structure-activity relationship (SAR) guided design of novel tubulin polymerization inhibitors has resulted in a series of benzo[b]furans with exceptional potency toward cancer cells and activated endothelial cells. The potency of early lead compounds has been substantially improved through the synergistic effect of introducing a conformational bias and additional hydrogen bond donor to the pharmacophore. Screening of a focused library of potent tubulin polymerization inhibitors for selectivity against cancer cells and activated endothelial cells over quiescent endothelial cells has afforded 7-hydroxy-6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)benzo[b]furan (BNC105, 8) as a potent and selective antiproliferative. Because of poor solubility, 8 is administered as its disodium phosphate ester prodrug 9 (BNC105P), which is rapidly cleaved in vivo to return the active 8. 9 exhibits both superior vascular disrupting and tumor growth inhibitory properties compared with the benchmark agent combretastatin A-4 disodium phosphate 5 (CA4P).

BNC105: a novel tubulin polymerization inhibitor that selectively disrupts tumor vasculature and displays single-agent antitumor efficacy.

Vascular disruption agents (VDA) cause occlusion of tumor vasculature, resulting in hypoxia-driven tumor cell necrosis. Tumor vascular disruption is a therapeutic strategy of great potential; however, VDAs currently under development display a narrow therapeutic margin, with cardiovascular toxicity posing a dose-limiting obstacle. Discovery of new VDAs, which display a wider therapeutic margin, may allow attainment of improved clinical outcomes. To identify such compounds, we used an in vitro selectivity screening approach that exploits the fact that tumor endothelial cells are in a constant state of activation and angiogenesis and do not undergo senescence. Our effort yielded the compound BNC105. This compound acts as a tubulin polymerization inhibitor and displays 80-fold higher potency against endothelial cells that are actively proliferating or are engaged in the formation of in vitro capillaries compared with nonproliferating endothelial cells or endothelium found in stable capillaries. This selectivity was not observed with CA4, a VDA currently under evaluation in phase III clinical trials. BNC105 is more potent and offers a wider therapeutic window. CA4 produces 90% vascular disruption at its no observed adverse event level (NOAEL), whereas BNC105 causes 95% vascular disruption at 1/8th of its NOAEL. Tissue distribution analysis of BNC105 in tumor-bearing mice showed that while the drug is cleared from all tissues 24 hours after administration, it is still present at high concentrations within the solid tumor mass. Furthermore, BNC105 treatment causes tumor regressions with complete tumor clearance in 20% of treated animals.

A vascular cell-restricted RhoGAP, p73RhoGAP, is a key regulator of angiogenesis.

Angiogenesis is a major therapeutic target. Ideal drug targets are genes expressed only in endothelial cells (ECs) or only during the angiogenic process. Here, we describe a gene, p73RhoGAP (p73), that has both of these properties. By using a PCR-based subtraction-hybridization approach to clone cDNAs from ECs undergoing capillary-tube formation, we identified a RhoGAP member, p73. p73 displays GTPase activity to Rho but not to Rac or Cdc42. Knockdown of p73 protein, achieved by adenovirus delivery of p73 antisense and by small interfering RNA into ECs, demonstrated the importance of this protein in EC function. Under such conditions, EC migration, proliferation, and capillary-tube formation were inhibited. Furthermore, angiogenesis in vivo was also inhibited by antisense p73. A mutant R82A alteration achieved a similar phenotype in vitro to the antisense, demonstrating the importance of the GTPase-activating protein activity to p73 function. Expression profiling of p73 shows that it is vascular cell-selective, being highly expressed in ECs and smooth-muscle cells but not in other cell types. Finally, we show that the mRNA of p73 is up-regulated in an angiogenic milieu with little or no regulation seen under nonangiogenic conditions. p73, a vascular cell-specific GTPase-activating protein, is an important modulator of angiogenesis and displays many of features that make it worthy of being a drug target.