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Background The safety, pharmacokinetics (PK) and pharmacodynamics of CEP-18770, a new peptide boronic acid proteasome inhibitor, have been investigated after intravenous administration on days 1, 4, 8 and 11 of every 21 d cycle in patients with solid tumours and multiple myeloma (MM). Patients and methods Thirty-eight patients were treated with CEP-18770 at escalating doses from 0.1 to 1.8 mg/m 2 where 2 out of 5 patients showed dose limiting toxicities. The maximum tolerated/recommended dose (MTD/RD) of 1.5 mg/m 2 was tested in 12 additional patients. Skin rash was dose-limiting and occurred in 53% of patients; other frequent toxicities were asthenia (29%), stomatitis (21%) and pyrexia (16%). No significant peripheral neuropathy was observed. PK in plasma was linear with a half-life of the elimination phase of 62.0 ± 43.5 h. Proteasome inhibition in peripheral blood mononuclear cells was dose related in MM patients; it was of 45.4 ± 11.5% at the RD. Conclusions CEP-18770 showed a favourable safety profile with lack of neurotoxicity and linear plasma PK. The definition of the optimal biological dose and schedule of treatment is actively pursued because of the high incidence of skin toxicity of the twice a week schedule.

Background Lucitanib is a potent, oral inhibitor fibroblast growth factor receptor types 1 and 2 (FGFR), vascular endothelial growth factor receptor types 1, 2, and 3 (VEGFR), platelet-derived growth factor receptor types α and β (PGFRα/β), which are essential kinases for tumor growth, survival, migration, and angiogenesis. Several tumor types, including breast carcinoma, demonstrate amplification of fibroblast growth factor (FGF)-related genes. There are no approved drugs for molecularly defined FGF-aberrant (FGFR1- or FGF3/4/19-amplified) tumors. Methods This open-label phase I/IIa study involved a dose-escalation phase to determine maximum tolerated dose (MTD), recommended dose (RD), and pharmacokinetics of lucitanib in patients with advanced solid tumors, followed by a dose-expansion phase to obtain preliminary evidence of efficacy in patients who could potentially benefit from treatment (i.e. with tumors harboring FGF-aberrant pathway or considered angiogenesis-sensitive). Results Doses from 5 to 30 mg were evaluated with dose-limiting toxic effects dominated by vascular endothelial growth factor (VEGF) inhibition-related toxic effects at the 30 mg dose level (one case of grade 4 depressed level of consciousness and two cases of grade 3 thrombotic microangiopathy). The most common adverse events (all grades, all cohorts) were hypertension (91%), asthenia (42%), and proteinuria (57%). Exposure increased with dose and t½ was 31–40 h, suitable for once daily administration. Seventy-six patients were included. All but one had stage IV; 42% had >3 lines of previous chemotherapy. Sixty-four patients were assessable for response; 58 had measurable disease. Clinical activity was observed at all doses tested with durable Response Evaluation Criteria In Solid Tumors (RECIST) partial responses in a variety of tumor types. In the angiogenesis-sensitive group, objective RECIST response rate (complete response + partial response) was 26% (7 of 27) and progression-free survival (PFS) was 25 weeks. In assessable FGF-aberrant breast cancer patients, 50% (6 of 12) achieved RECIST partial response with a median PFS of 40.4 weeks for all treated patients. Conclusion Lucitanib has promising efficacy and a manageable side-effect profile. The spectrum of activity observed demonstrates clinical benefit in both FGF-aberrant and angiogenesis-sensitive populations. A comprehensive phase II program is planned.

Background Amplification of the FGFR1 gene occurs in subsets of tumors, notably breast cancer (BC), where the altered FGF pathway may be clinically relevant. Methods E-3810 is a kinase inhibitor targeting FGFR1 and VEGFR1, 2, 3. Its safety and activity, at the daily oral dose of 20 or 15 mg on a continuous schedule, are being assessed in patients with solid tumors and FGFR1 amplification or potentially sensitive to antiangiogenic agents. The study is an open label non comparative extension of the first in man dose-escalation trial; the efficacy threshold, set for the FGFR1+ cohort only, requires 3/14 confirmed objective RECIST responses or non-progressive disease ≥ 6 cycles (one-stage Fleming design: H0 5%, H1 30%, power 80%). Results 46 patients with various tumor types (including 13 FGFR1+) were recruited. 8 patients (4/13 and 4/33 treated respectively at 20 and 15 mg; none in the FGFR1+ cohort) were withdrawn for toxicity including: G3 proteinuria (5), headache and vomiting (2), pancreatic enzymes increase (1), recovered in all cases. Hypertension G2-3, proteinuria G2, GI intolerance, asthenia and weight loss led to dose reduction in 20 patients; frequent TSH increase required supplementation. Tolerability was better in the FGFR1+ cohort, in line with a limited prior exposure to antiangiogenic treatments. Antitumor activity is shown in the table: Antiangiogenic Sensitive FGF-amplified (1) Evaluable PR SD PD Evaluable PR SD PD Breast cancer 1 1 9 4** 3 2 Other 23 3*** 13 7 2 1* 1 Total 24 3 14 7 11 4 4 3 (1) incl. the two BC patients with 11q amplification; * SD ≥ 24 weeks; ** 1 PET response (bone lesions); ***2 thyroid; 1 thymic carcinoma. 12 women with BC were recruited (9 HR + , 1 HER2 + /HR + , 2 TN); 8 were FGFR1 + , 2 more had 11q amplification (CGH). They were treated with a median of 5 prior chemotherapy lines; 9, 10 and 5 patients also received ≥ 1 endocrine, antiangiogenic and experimental therapies, respectively. There were 4 PRs sustained over 4-6 courses (3 FGFR1 and one FGF4 amplification), with 3 responders still on treatment. Conclusions E-3810 has shown significant activity in heavily pretreated BC, with durable responses in patients with altered FGF pathway. Further studies are planned in this population. Disclosure R. Cereda: Currently an employee and stock holder at EOS SpA. M.G. Camboni: Currently an employee and stock holder at EOS SpA. All other authors have declared no conflicts of interest.

Aim: Lucitanib is a potent, oral inhibitor of the tyrosine kinase activity of FGFR1/2, VEGFR1-3 and PDGFRa/b. These well-described signaling pathways are essential for tumor growth, survival, migration, and angiogenesis. Considering the highly vascular nature and the expression of FGFR in thyroid cancer, targeting these pathways is particularly relevant in metastatic setting. Methods: The first in human phase I/II study is currently evaluating oral lucitanib as monotherapy. The escalation phase used a 3 + 3 design in pts with advanced solid tumors to establish a recommended dose for further study. Safety and efficacy were further evaluated in pts with FGF aberrant or angiogenesis sensitive tumors, using continuous or intermittent dosing schedules. Results: Among 32 pts treated in Vall d'Hebron Institute of Oncology (VHIO), 3 had medullary thyroid cancer and 6 differentiated thyroid cancer. Median age was 56 yrs [range 38-68]. All pts were treated at 15mg, 5 on continuous and 4 on intermittent schedules (21 days on / 7 days off). 4 pts (45%) received lucitanib after progression on at least one previous multikinase inhibitor (MKI). In this population, the most common adverse events related to lucitanib (all grades, continuous and intermittent dosing schedules) were hypertension, asthenia and proteinuria. For all these AEs, the highest grade observed was G2. All pts on continuous schedule had a dose decrease to 10mg due to drug-related toxicities. 2/4 pts on intermittent schedule maintained on their initial 15mg dosing. The anti-tumor activity was recorded in 8 of the 9 pts evaluable according to RECISTv1.1. One pt achieved CR (12%), 2 pts had PR (25%) including 1 MKI pretreated, and 4 pts had SD (50%) lasting at least 6 months, including 2 pts MKI pretreated. Moreover, 1 pt had a prolonged CR (30 months), evaluable on non-target lesions only. Median PFS was 15.0 months, and 3 pts are still ongoing for more than 28 cycles. Conclusions: Lucitanib demonstrated promising clinical activity and a torelable side-effect profile in pts with metastatic thyroid cancer even in those already pretreated with multikinase inhibitors. Disclosure: R. Cereda: Full employment at EOS Spa; J. Litten: Full employment at Clovis; J. Collin, F. Legrand, R. Robert and C. Saba: full employment at Servier. All other authors have declared no conflicts of interest.

TPS8119^ Background: Lucitanib, a potent, oral inhibitor of the tyrosine kinase activity of Fibroblast Growth Factor Receptors 1/2 (FGFR1/2), Vascular Endothelial Growth Factor Receptors 1-3 (VEGFR...

The effects of ITF 296 on venous tone, estimated as changes in total effective vascular compliance (TEVC), were investigated in the anesthetized, spontaneously breathing dog under autonomic blockade. TEVC was calculated from the correlation between the observed changes in central venous pressure (CVP) and the experimentally induced changes in blood volume during an 11-min cycle of whole blood infusion (2 ml/kg/min), withdrawal, and reinfusion. Stepwise increasing doses (short steady-state infusions) of ITF 296 (3, 10, and 30 micrograms/kg/min) resulted in a dose-dependent increase in TEVC (+27, +54, and +67%), whereas mean blood pressure (MBP) was reduced (-12, -23, and -33%, respectively). SIN-1 (10 micrograms/kg/min), administered at the end of the experiment as the reference NO-releasing compound, induced a rather complete venodilation (TEVC +182%) and a marked reduction in MBP (-47%). When nitroglycerin (NTG) was used as the reference compound at 1.5 micrograms/kg/min, a 67% increase in TEVC was observed. These results suggest that ITF 296 exerts a venodilator action but that this effect, and therefore the reduction in venous return, is less than that in response to nitrovasodilators such as SIN-1 or NTG. Furthermore, the vasodilator spectrum of ITF 296 compared to other nitrovasodilators is shifted somewhat more toward the arteriolar bed, with less pronounced venodilator effects, as indicated by the fall in MBP.

The action of the newly developed organic nitrate ITF 296 on large coronary arteries was investigated during acute and long-term treatment in the conscious dog, chronically instrumented for recording of large coronary artery diameter (CD), mean arterial blood pressure (MBP), and heart rate (HR). Short-term steady-state infusion of ITF 296 at doses of 0.1-30 micrograms/kg/min induced a dose-dependent increase in CD. Maximal coronary artery dilation (+11%) was reached at 10 micrograms/kg/min and no further increase was observed at 30 micrograms/kg/min. At the same doses no significant variations of MBP or HR were observed. Long-term administration (5-day infusion) of ITF 296 at 20 micrograms/kg/min resulted in a 10% increase in CD, and the effect was well maintained over the entire infusion period. MBP did not change significantly, whereas HR rose by 21% by the second day of infusion and remained elevated until the end of the treatment. These results confirm that ITF 296 is an effective dilator of large coronary arteries at doses devoid of peripheral hemodynamic effects. Moreover, the vasodilating effect on coronary arteries is well maintained during long-term administration, suggesting a reduced tolerance development.

The action of low doses of nitrovasodilators on coronary circulation is characterised by a selective dilatation of large conductance coronary arteries1,2,3, which is accompanied by a minimal effect on small coronary resistance vessels4,5,6,7. This ability of nitroderivatives to dilate selectively large coronary arteries, becomes of major importance when the capability of the conduit epicardial coronary arteries to dilate in response to increases in blood flow is impaired, as it happens after removal of coronary endothelium with angioplasty8 or in patients with atherosclerosis9,10. In those conditions, while the flow-dependent endothelium-mediated response is depressed, the endothelium-independent relaxing effect of nitravasodilators on large conduit coronary arteries remains effective. This has been confirmed in clinical studies, where the coronary vasospasm in anginal patients in which endothelium is likely not functional, has been effectively reversed by nitrovasodilators 11,12

TPS149 Background: Co-selective inhibition of VEGFRs and FGFR has the potential benefit of blocking the two most relevant players in tumor angiogenesis and simultaneously targeting proliferation in...

Background: E-3810 is a potent VEGFR1, 2 and 3 and FGFR 1 kinases inhibitor showing potent anti-angiogenic and antitumor activity in several in vitro and in vivo mouse models (Proceedings AACR-EORTC-NCI Meeting, Boston, November 2009; Abstracts No. 252 and 257). The aim of this study was to investigate, in a rat model, the antitumor activity of E-3810 and its anti-angiogenic effects by using DCE-MRI and to correlate the response with a panel of biological markers. Methods: Nude rats were subcutaneously xenografted with human Calu-6 lung cancer cells and treated orally once daily for 14 consecutive days, either with E-3810 − 10 mpk (dose chosen on the basis of a preliminary study in the same model) or Sorafenib − 100 mpk. Tumor growth and parameters reflecting tumor vascular permeability/perfusion (Ktrans) were evaluated by T2-weighted MRI and by T1-weighted DCE-MRI using Gd-DTPA (Magnevist®) as contrast agent at D-1, D1, D3, D7 and D14. The number, maturity and functionality of tumor vessels were assessed using CD31/α-SMA colocalisation by IHC and injection of Hoechst fluorescent dye on D1, D3, D7 and D14. On the same days, the level of circulating endothelial cells (CEC) and collagen IV were measured by FACS and ELISA assays. Results: In comparison to vehicle-treated animals, a marked tumor growth inhibition was observed in E-3810-treated rats (max T/C 21%) with no remarkable signs of toxicity. In the same animals, Ktrans value in the tumor rim was significantly decreased (up to 49% on D14). This DCE-MRI finding was supported by the significant decrease in the Hoechst stained area observed at D1 (−97%), D7 (−96%) and D14 (−75%). In addition, the number of tumor vessels (both CD31 and colocalized CD31/α-SMA) was significantly decreased at D3 (−72%), D7 (−68%) and D14 (−86%) in E-3810-treated rats. Always in comparison to vehicle group, no significant changes in CEC were observed after treatment with E-3810, whereas collagen IV levels significantly increased at D14 (+38). Similar effects on all the above mentioned parameters were observed in Sorafenib treated animals. Conclusions: E-3810 displayed a marked antitumor activity in the model of Calu-6 tumor bearing nude rats. The antitumor effect is coupled with a strong antiangiogenic activity, as indicated by decrease in vascular permeability/perfusion and decrease of microvessels density that occur early on and are maintained throughout the treatment period. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1367.

The actions of ITF 296 and isosorbide dinitrate (ISDN), 20, 70, and 200 g/kg/min, on myocardial transmural blood flow distribution during acute thrombotic occlusion of the left circumflex coronary artery (LCX) have been evaluated in seven and three anesthetized open-chest dogs, respectively, and compared with four animals receiving vehicle. Occlusion of LCX was achieved in 14 +/- 2 min by the insertion of a copper coil. This caused transmural myocardial ischemia in the LCX area, while leaving blood flow in the left anterior descending coronary artery (control area) unaffected. Infusion of ITF 296 (200 g/kg/min) increased transmural coronary flow in the border zone and in the control area without affecting blood flow in the central ischemic area. ISDN, given in the same dose, reduced systemic blood pressure but did not affect LCX blood flow. In three dogs with residual perfusion in the LCX central area ITF 296 also increased blood flow. These results confirm that ITF 296 promotes an increase of flow to the border zone, thus possibly reducing the area of myocardial infarction.