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Bone metastasis remains a major cause of mortality and morbidity in breast cancer. Therefore, there is an urgent need to better select high-risk patients in order to adapt patient’s treatment and prevent bone recurrence. Here, we found that integrin alpha5 (ITGA5) was highly expressed in bone metastases, compared to lung, liver, or brain metastases. High ITGA5 expression in primary tumors correlated with the presence of disseminated tumor cells in bone marrow aspirates from early stage breast cancer patients (n = 268; p = 0.039). ITGA5 was also predictive of poor bone metastasis-free survival in two separate clinical data sets (n = 855, HR = 1.36, p = 0.018 and n = 427, HR = 1.62, p = 0.024). This prognostic value remained significant in multivariate analysis (p = 0.028). Experimentally, ITGA5 silencing impaired tumor cell adhesion to fibronectin, migration, and survival. ITGA5 silencing also reduced tumor cell colonization of the bone marrow and formation of osteolytic lesions in vivo. Conversely, ITGA5 overexpression promoted bone metastasis. Pharmacological inhibition of ITGA5 with humanized monoclonal antibody M200 (volociximab) recapitulated inhibitory effects of ITGA5 silencing on tumor cell functions in vitro and tumor cell colonization of the bone marrow in vivo. M200 also markedly reduced tumor outgrowth in experimental models of bone metastasis or tumorigenesis, and blunted cancer-associated bone destruction. ITGA5 was not only expressed by tumor cells but also osteoclasts. In this respect, M200 decreased human osteoclast-mediated bone resorption in vitro. Overall, this study identifies ITGA5 as a mediator of breast-to-bone metastasis and raises the possibility that volociximab/M200 could be repurposed for the treatment of ITGA5-positive breast cancer patients with bone metastases.

We propose a new plausible mechanism by mean of which SARS-CoV-2 produces extrapulmonary damages in severe COVID-19 patients. The mechanism consist on the existence of vulnerable proteins (VPs), which are (i) mainly expressed outside the lungs; (ii) their perturbations is known to produce human diseases; and (iii) can be perturbed directly or indirectly by SARS-CoV-2 proteins. These VPs are perturbed by other proteins, which are: (i) mainly expressed in the lungs, (ii) are targeted directly by SARS-CoV-2 proteins, (iii) can navigate outside the lungs as cargo of extracellular vesicles (EVs); and (iv) can activate VPs via subdiffusive processes inside the target organ. Using bioinformatic tools and mathematical modeling we identifies 26 VPs and their 38 perturbators, which predict extracellular damages in the immunologic endocrine, cardiovascular, circulatory, lymphatic, musculoskeletal, neurologic, dermatologic, hepatic, gastrointestinal, and metabolic systems, as well as in the eyes. The identification of these VPs and their perturbators allow us to identify 27 existing drugs which are candidates to be repurposed for treating extrapulmonary damage in severe COVID-19 patients. After removal of drugs having undesirable drug-drug interactions we select 7 drugs and one natural product: apabetalone, romidepsin, silmitasertib, ozanezumab, procaine, azacitidine, amlexanox, volociximab, and ellagic acid, whose combinations can palliate the organs and systems found to be damaged by COVID-19. We found that at least 4 drugs are needed to treat all the multiorgan damages, for instance: the combination of romidepsin, silmitasertib, apabetalone and azacitidine., Highlights • A new mechanism for multiorgan damage in COVID-19 based on extracellular vesicle transport of proteins from the lungs and intracellular subdiffusive movement of the proteins at target organs is proposed and validated. • The new mechanism explains the main damages observed in most of organs reported in patients with severe COVID-19. • Several repurposable drugs for targeting extracellular damages in COVID-19 severe patients are identified.

Epithelial ovarian cancer is a fatal disease, with a cure rate of only 30%. Several recent studies have targeted integrins for cancer treatment. Preclinical studies have shown the effectiveness of several integrin inhibitors for blocking cancer progression, especially by blocking angiogenesis. Because the initial critical step in ovarian cancer metastasis is the attachment of cancer cells to the peritoneum or omentum and because clinical trials have provided positive results for anti-angiogenic therapy, therapies targeting integrins may be the most feasible approach for treating cancer. This review summarizes the current understanding of integrin biology in ovarian cancer metastasis and various therapeutic approaches involving integrin inhibitors. However, no integrin inhibitor has shown favorable results thus far. However, conjugates of cytotoxic agents with the triplet sequence arginine-glycine-aspartate (RGD) peptides targeting α5β1-, αvβ3-, and αvβ6-integrins may be promising integrin-targeting therapies for further clinical investigation.

Primary cancer treatment, involving both local and often systemic adjuvant therapy, is often successful, especially if the cancer is detected at an early stage of progression. However, for some patients, the cancer may recur either locally or as distant metastases, in some cases many years after apparently successful primary treatment. Significant tumor dormancy has been documented in several cancers, such as breast, melanoma, and renal cancer. Tumor dormancy has long been recognized as an important problem in management of cancer patients. Recent work has clarified biologic aspects of tumor dormancy and has shown that dormant tumor cells may be resistant to cytotoxic chemotherapy and radiation. This work has led to recognition of a key role for β1-integrin in regulating the switch from a dormant state to active proliferation and metastasis. Here we discuss the role of β1-integrin and its signaling partners in regulating the dormant phenotype. We also consider possible therapeutic approaches, such as small molecules or antibodies (ATN-161, volociximab, and JSM6427), directed against β1-integrin signaling to target dormant cancer cells and to prevent metastatic recurrence. Clin Cancer Res; 17(23); 7219–23. ©2011 AACR.

This phase II, multicenter, single-arm, two-stage study in platinum-resistant, advanced epithelial ovarian or primary peritoneal cancer evaluated the efficacy, safety, and tolerability of weekly single-agent volociximab. Pharmacokinetic/pharmacodynamic (PK/PD) studies were also performed.Sixteen patients were enrolled in Stage 1. Volociximab was administered at 15mg/kg IV qwk until progression of disease or drug intolerability. Tumor response was assessed every 8weeks. Serum samples for PK or whole blood for the evaluation of circulating tumor cells, endothelial cells, and endothelial progenitor cells were obtained on Days 1, 8, 15, 29, and 50. Ascites from one patient was collected for volociximab concentration analysis. Archived tumor tissue was analyzed by immunohistochemistry (IHC) for α5 integrin expression.Safety data are available on all 16 patients; 14 were evaluable for efficacy. One patient had stable disease at 8weeks. The remaining 13 progressed on treatment. Twelve patients (75%) experienced study-related adverse events (AEs); the most common (≥20%) were headache and fatigue. Three patients experienced possible study-related serious AEs (SAEs): reversible posterior leukoencephalopathy syndrome, pulmonary embolism, and hyponatremia. Peak serum concentrations of volociximab increased 2-3 fold from Day 1 to Day 50. Clinically relevant trough levels were achieved (150μg/mL). IHC analysis of archived tumor sections showed low-to-moderate expression of α5 integrin on all ovarian cancer tissue evaluated.Despite insufficient clinical activity in this refractory patient population to continue the study, weekly volociximab was well tolerated, and the gained understanding of the mechanism of action of volociximab will inform future development efforts.

Purpose: This study aimed to assess the safety and feasibility of administering volociximab, a chimeric monoclonal antibody that specifically binds to α5β1 integrin, and to determine the pharmacokinetics, pharmacodynamics, and preliminary evidence of antitumor activity. Experimental Design: Patients with advanced solid malignancies were treated with escalating doses of volociximab i.v. administered over 60 minutes. Blood samples were assayed to determine plasma pharmacokinetic parameters, detect human antichimeric antibody formation, and determine the saturation of α5β1 sites on peripheral blood monocytes. Results: Twenty-one patients received 223 infusions of volociximab at doses ranging from 0.5 to 15 mg/kg i.v. on days 1, 15, 22, 29, and 36; and weekly thereafter. Treatment was well tolerated, and dose-limiting toxicity was not identified over the range examined. Mild (grade 1 or 2), reversible fatigue was the principal toxicity of volociximab at the highest dose levels of 10 and 15 mg/kg. Nausea, fever, anorexia, headache, vomiting, and myalgias were mild and infrequent, and there was no hematologic toxicity. Volociximab had biexponential distribution; clearance was inversely related to increasing dose, and the half-life at 15 mg/kg was estimated as being 30 days. Three patients tested positive for anti-volociximab antibodies. Saturation of monocyte α5β1 integrin sites was dose-dependent up to 15 mg/kg. There was one minor response (renal, 7 months) and one durable stable disease (melanoma, 14 months). Conclusions: Volociximab can be safely administered at 15 mg/kg i.v. per week. The absence of severe toxicities and preliminary activity at the highest dose level warrants further disease-directed studies.

Background This phase Ib study evaluated volociximab, an anti-α5β1 integrin antibody, in combination with carboplatin (Eli Lilly and Co., Indianapolis, IN) and paclitaxel (Taxol) in advanced, untreated non-small-cell lung cancer (NSCLC). Patients and methods Three cohorts were treated with volociximab (10, 20, or 30 mg/kg) for up to six 3-week cycles in combination with carboplatin–paclitaxel chemotherapy and continued as maintenance therapy for patients with stable disease (SD) or better. Dose-limiting toxic effects, adverse events (AEs), pharmacokinetics, and anti-volociximab antibodies were assessed. Results A maximum tolerated dose was not reached up to the maximum planned dose of 30 mg/kg. In 29 patients who received volociximab, the most common grade ≥3 AEs were neutropenia (24%), hyponatremia (17%), and fatigue (10%). Three patients experienced volociximab-related serious AEs. No hemorrhages were observed. Of 33 patients enrolled, 8 (24%) achieved a partial response and 17 (52%) had SD. The median progression-free survival was 6.3 months (95% confidence interval 5.5–8.1). Levels of potential biomarkers of angiogenesis or metastasis were reduced following six cycles of treatment. Conclusions Volociximab combined with carboplatin and paclitaxel was generally well-tolerated and showed preliminary evidence of efficacy in advanced NSCLC.

Volociximab is a first-in-class chimeric monoclonal antibody that targets α5β1 integrin. Preclinical studies have shown the ability of volociximab to inhibit tumor neoangiogenesis by blocking the interaction between α5β1 and fibronectin. Volociximab's safety profile, pharmacokinetics and pharmacodynamics have been established. Ongoing clinical trials are evaluating its efficacy in the treatment of different types of solid tumors as a single agent or in combination with chemotherapy. In this review we focus on the biological effect of volociximab and results of completed clinical trials.This review summarizes the structures and functions of integrin α5β1 and its ligand fibronectin, provides an overview of the early development of volociximab, a targeted monoclonal antibody that specifically binds and inhibits activation of integrin α5β1, and discusses the relevant data from pre-clinical and clinical studies.Volociximab has been well tolerated as monotherapy or in combination with chemotherapy. It has shown promising activity in different types of cancer. Randomized trials are required to validate those early results.

Anti-angiogenics have shown efficacy in the treatment of renal cancer. Most current therapies target the VEGF pathway. In this chapter, we discuss the role of integrins, specifically α5β1, in angiogenesis. The integrin α5β1 is up-regulated on proliferating endothelial cells. The monoclonal antibody volocixi-mab is a potent, high-affinity inhibitor of α5β1. Inhibition of α5β1 function by volociximab results in the apoptosis of proliferating, but not resting, endothelial cells in vitro. Inhibitory activity of volociximab appears to be independent of the growth factor milieu, suggesting a potential role for this agent under pathological conditions where multiple growth factors are present. Additionally, in pre-clinical models of angiogenesis such as the cynomolgus choroidal neovascularization model, volociximab is effective at inhibiting lesion development. An assessment of the expression of α5β1 by immunohistochemistry in annotated samples of renal cancer suggest a relationship between α5β1 expression and clinical grade of the tumour. The analysis shows that the expression of this integrin was very high in the tumour vasculature in all the clinical grades of renal cancer tested. However, we found an increase in target expression on the tumour cells that correlated with worsening clinical grade. These results suggest an additional mechanism by which volociximab may provide clinical benefit. Volociximab may not only exert an anti-angiogenic effect but may also have a direct inhibitory effect on the tumour cells. A phase 1 clinical trial with volociximab has been completed in patients having a variety of tumour types. The results show that the antibody is well tolerated at doses up to 15 mg/kg weekly. No drug-related adverse events were noted, and the best clinical response seen so far is stable disease. Volociximab is currently undergoing further clinical testing, and is being assessed in pilot open label trials, in indications including renal cancer.

Volociximab is a chimeric IgG(4) that is being developed as a novel first-in-class anti-angiogenic, α(5)β(1) integrin inhibitor for the treatment of solid tumors. A mechanism-based pharmacokinetic (PK)/pharmacodynamic (PD) model was developed to investigate the dynamic interaction between volociximab concentrations and free monocyte α(5)β(1) integrin levels in cancer patients.Twenty-one cancer patients from six dose cohorts (0.5, 1.0, 2.5, 5.0, 10, and 15 mg/kg) were included in the analysis. The fully integrated receptor-binding PK/PD model was developed and fit simultaneously to the PK/PD data. A Monte-Carlo parametric expectation-maximization method implement in S-ADAPT program was used to obtain estimates of population parameters and inter- and intra-subject variability.The PK/PD time profiles were well described by the model and the parameters were estimated with good precision. The model was used to simulate PK/PD time profiles for multiple dose regimens at various dose levels, and the results suggested that the monocyte α(5)β(1) integrin binding was saturated (≤5% free) at week 16 in the majority of patients treated with volociximab doses ≥10 mg/kg IV every 2 weeks.The developed model is useful for anticipating the drug exposures and extent of volociximab binding to peripheral monocyte α(5)β(1) integrin in untested regimens and for optimizing the design of future clinical trials.

Angiogenesis, the process by which new blood vessels form from existing vasculature, is critical for tumor growth and invasion. Growth factors, such as VEGF, initiate signaling cascades resulting in the proliferation of resting endothelial cells. Blockade of growth factor pathways has proven effective in inhibiting angiogenesis and tumor growth in vivo. Integrins, including the integrin alpha5beta1, are also important mediators of angiogenesis and these adhesion molecules also regulate cancer cell growth and migration in vitro. Volociximab is a high affinity, function-blocking antibody against integrin alpha5beta1 that is currently in multiple Phase II oncology clinical trials. Volociximab displays potent anti-angiogenic activity in a monkey model of choroidal neovascularization. In this study, we explored the consequences of integrin alpha5beta1 blockade on tumorigenesis. Because volociximab does not cross-react with rodent alpha5beta1, the syngeneic rabbit VX2 carcinoma model was utilized as an alternative to standard mouse xenograft models for the assessment of anti-tumor activity of volociximab. Volociximab administered intravenously to rabbits bearing VX2 tumors is detectable on tumor cells and vasculature 45 min post-administration. Volociximab was found to significantly inhibit the growth of tumors growing subcutaneously or intramuscularly, despite a 20-fold lower affinity for rabbit integrin, relative to human. This effect was found to correlate with decreased blood vessel density within these tumors. These results support the use of volociximab in the intervention of malignant disease.

Antiangiogenic therapy with sunitinib and sorafenib has become the standard of care for patients with advanced renal cell carcinoma. However, the clinical benefit of these agents after prior antiangiogenic therapy has not been defined. Currently, several agents with a putative antiangiogenic mechanism exist and they are often being used in sequence with little to no data regarding activity in a second line or later setting.Patients with advanced renal cell carcinoma currently being treated with either sunitinib or sorafenib after receiving 1 or more prior antiangiogenic agent(s) were investigated in a retrospective analysis. Time to progression and the overall response rate by Response Evaluation Criteria in Solid Tumors were evaluated.Thirty patients receiving current sunitinib (16 patients) or sorafenib (14 patients) were identified. Patients received 1 or more prior antiangiogenic therapies: thalidomide, lenalidomide, bevacizumab, volociximab, AG13736, sorafenib or sunitinib. Of 16 patients treated with sunitinib 13 had some degree of tumor shrinkage, including 9 with a partial response by Response Evaluation Criteria in Solid Tumors. Of 14 patients treated with sorafenib 10 had some degree of tumor shrinkage, including 1 with a partial response. The median time to progression for the entire cohort was 10.4 months.Significant antitumor activity is observed when sorafenib or sunitinib are used in patients who have failed prior therapy with an antiangiogenic agent. Prior response to an antiangiogenic agent does not appear to predict subsequent clinical benefit to either sunitinib or sorafenib.

5560 Background: Volociximab (V), a chimeric monoclonal antibody with direct antitumor effects, blocks α5β1 binding to fibronectin and induces apoptosis in proliferating endothelial cells. A Phase I/II study was performed to evaluate PLD with/without V in patients (pts) with recurrent ovarian or primary peritoneal cancer that relapsed after platinum/taxane-based chemotherapy (maximum 2 prior lines). Methods: A 3-arm adaptive randomization design compared efficacy and safety of PLD (40 mg/m2 q4wk) + V (15 mg/kg q2wk or qwk) vs. PLD alone. Pts were stratified by platinum sensitivity and received treatment until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Pharmacokinetic (PK) and pharmacodynamic effects were also evaluated. Results: There were 6 iterations of adaptive randomization based on accumulating PFS data. 127 pts were randomized: 66 in Group A (PLD), 34 in Group B (PLD+V [q2wk]), and 27 in Group C (PLD+V [qwk]). The incidence of AEs was balanced across treatment groups. The most common Grade 3/4 AEs (≥5% in any group) were abdominal pain, intestinal obstruction, ascites, fatigue, hypoalbuminemia, and cytopenias. Based on preclinical data, therapeutic levels of V were maintained during treatment, and V did not appear to alter the PK of PLD. Response rates were comparable across groups. There were no CRs; PRs were 16%, 18%, and 19%. The median PFS estimates were 193, 164, and 221 days. Conclusions: The safety profile of V+PLD appeared similar to PLD alone. Preliminary analysis of PFS suggested that there was a low probability of detecting a statistically significant difference in favor of V+PLD, so the study was closed to enrollment. Analyses correlating PFS with platinum sensitivity and α5β1 tumor expression are ongoing. [Table: see text]

16527 Background: Preclinical studies demonstrate that the chimeric α5β1 integrin antibody volociximab inhibits tumor angiogenesis by blocking binding of activated vascular endothelial cells to fib...

9051 Background: Preclinical studies demonstrate that the α5β1 integrin antibody volociximab inhibits tumor angiogenesis by blocking binding of activated endothelial cells to fibronectin present in...

Background Integrins are important adhesion molecules that regulate tumor and endothelial cell survival, proliferation and migration. The integrin α5β1 has been shown to play a critical role during angiogenesis. An inhibitor of this integrin, volociximab (M200), inhibits endothelial cell growth and movement in vitro, independent of the growth factor milieu, and inhibits tumor growth in vivo in the rabbit VX2 carcinoma model. Although volociximab has already been tested in open label, pilot phase II clinical trials in melanoma, pancreatic and renal cell cancer, evaluation of the mechanism of action of volociximab has been limited because this antibody does not cross-react with murine α5β1, precluding its use in standard mouse xenograft models. Methods We generated a panel of rat-anti-mouse α5β1 antibodies, with the intent of identifying an antibody that recapitulated the properties of volociximab. Hybridoma clones were screened for analogous function to volociximab, including specificity for α5β1 heterodimer and blocking of integrin binding to fibronectin. A subset of antibodies that met these criteria were further characterized for their capacities to bind to mouse endothelial cells, inhibit cell migration and block angiogenesis in vitro. One antibody that encompassed all of these attributes, 339.1, was selected from this panel and tested in xenograft models. Results A panel of antibodies was characterized for specificity and potency. The affinity of antibody 339.1 for mouse integrin α5β1 was determined to be 0.59 nM, as measured by BIAcore. This antibody does not significantly cross-react with human integrin, however 339.1 inhibits murine endothelial cell migration and tube formation and elicits cell death in these cells (EC50 = 5.3 nM). In multiple xenograft models, 339.1 inhibited the growth of established tumors by 40–60% (p < 0.05) and this inhibition correlates with a concomitant decrease in vessel density. Conclusion The results herein demonstrate that 339.1, like volociximab, exhibits potent anti-α5β1 activity and confirms that inhibition of integrin α5β1 impedes angiogenesis and slows tumor growth in vivo.

5094 Background: A critical survival step for proliferating endothelial cells is the ligation of fibronectin in the extracellular matrix to integrin a5β1. Voloxicimab, a chimeric monoclonal antibody, blocks fibronectin binding to a5β1, and induces apoptosis of proliferating endothelial cells. Voloxicimab activity is independent of growth factor stimulus, suggesting that a5β1 signalling occurs downstream of growth factor signalling, and is possibly a final common pathway for the development of neovasculature. Methods: This is a multicenter, open label, phase II study in mCCRCC. Patients (pts) received volociximab 10 mg/kg IV every 2 weeks until disease progression. Pts were evaluated for efficacy every 8 weeks using RECIST criteria. Results: A total of 40 pts were enrolled. All pts were evaluable for safety and efficacy. Median time since first diagnosis was 2.5 years. ECOG score was 0–1 in all pts. Prior nephrectomy occurred in 38 (95%) pts. Nineteen (47.5%) pts had ≥ 2 prior therapy. Twenty one (52.5 %) pts had prior anti agiogenic therapy. Other prior treatment included IL-2 in 15 (37.5%), interferon alpha in 7 (17.5 %), IL-2 + interferon in 2 (5%) pts. Most frequent side effects were fatigue in 27 (67.5%) pts, nausea 14 (35%) pts, dyspnoea 8 (20%) pts and arthralgia 7 (17.5%) pts, of which none were grade 3 or 4. Seven (17.5%) pts had SAEs. Stable disease (SD) was observed in 32 (80 %) pts including 1 confirmed PR. Duration of SD ranged from 2–22 months (mo). Fourteen (35%) pts had time to progression (TTP) between 5.8 to 22 mo: Four (10%) pts had TTP ≥ 14 mo (range 14- 22 mo), 8 (20%) pts had TTP ≥ 6 mo (range 6- 12 mo) and 2 (5%) pts had TTP = 5.8 mo. Median TTP was 4 mo. Median overall survival (OS) has not been reached after 22 mo. OS at 6 mo was 79% and 68% at 22 mo. Six (15%) pts died in the study, 5 (12.5%) pts due to progressive disease and 1 with arrhythmia (unrelated to volociximab). Conclusions: Volociximab is well tolerated at 10 mg/kg q2w. Stable disease is noted in 80 % of pts. Based on clinical activity, a randomized controlled trial is being planned. No significant financial relationships to disclose.

4549 Background: A critical survival step for proliferating endothelial cells is the ligation of fibronectin in the extracellular matrix to integrin a5β1. Volociximab, a chimeric monoclonal antibody, blocks fibronectin binding to a5β1, and induces apoptosis of proliferating endothelial cells. Volociximab activity is independent of growth factor stimuli, suggesting that a5β1 signalling occurs downstream of growth factor signalling, and is possibly a final common pathway for the development of neovasculature. The efficacy and safety of volociximab in combination with GEM was determined in pts with MPC. Methods: This is a multi-center, open-label, 2-cohort, single-arm Phase II study. Eligible pts had confirmed MPC, no prior chemotherapy for MPC, adequate hematologic, renal and hepatic function, and had measurable disease. Pts received volociximab 10mg/kg iv every 2 weeks (days 1 and 15) with GEM (1,000 mg/m2 iv) on days 1, 8, 15 of a 4- week cycle until disease progression (PD). Radiologic assessments of measurable disease were performed every 8 weeks. The primary endpoint was objective tumor response (RECIST criteria). Sample size was 20 pts per cohort. At least 1 confirmed response at 4 months (mo) or SD ≥ 4 mo was necessary in cohort 1 (n=20) before expansion to the second cohort. Results: 20 pts (male=11, female=9), median age = 59.8 years (range 34–74), were treated in cohort 1 and were evaluable for safety and efficacy. PS (ECOG) was 0–1 (n=19; 95%) or 2 (n=1; 5%). Pts received a median of 8 weeks’ (range 2–58) treatment. Most frequent toxicities included nausea in 14 (70%) pts, vomiting (12; 60%) and constipation (10; 50%). Overall response included 1 confirmed PR (5%), and stable disease in 10 (50%) pts. Median time to progression was 4.3 mo; 41% had not progressed at 6 mo. Overall survival was 5.4 mo, and at 6 and 8 mo was 45%, and 37% at 12 mo. 12 pts died in the study due to PD (10 pts), GI perforation (1), pulmonary embolism (1). Conclusions: Volociximab is well tolerated at 10mg/kg 2-weekly with GEM. Cohort 2 is currently recruiting at a higher dose of volociximab (15 mg/kg) administered weekly. [Table: see text]

4111 Background: Tumor angiogenesis occurs when pro-angiogenic growth factors are released, stimulating endothelial cell proliferation and migration to form neovessels. A critical survival step for angiogenesis is the ligation of fibronectin in the extracellular matrix to α5β1 on endothelial cells. M200 is an IgG4 chimeric monoclonal antibody targeting α5β1, thereby inducing apoptosis of proliferating endothelial cells. M200 activity is independent of growth factor stimulus, suggesting that binding of fibronectin to α5β1 occurs downstream of growth factor signalling, and is possibly a final common pathway for the development of neovasculature. Methods: This is a multicenter, open label, single cohort pilot Phase II study of 40 patients (pts) in MPC. Pts received M200 10 mg/kg IV every 2 weeks with Gemcitabine (Gem) 3 weeks on 1 week off for up to 13 cycles or disease progression. Pts were evaluated for efficacy every 8 weeks by objective response using RECIST criteria. An independent data safety monitoring board was utilized to review safety data. Results: A total of 20 pts have been enrolled. All pts were evaluable for safety and 16 pts for objective response (to date) using ITT population. Median age was 59.8 years. ECOG score was 0–1 in 19 (95%) and 2 in 1 (5%) pts. The most frequent side effects for M200 were vomiting in 7 (35%) pts and nausea in 8 (40%) pts and for (Gem) were nausea in 8 (40%) pts and vomiting in 8 (40%) pts. Eight pts died in the study, seven with progressive disease and 1 with GI perforation (possibly related to M200). One partial response was noted to date. Best overall response was (PR) 1/16 and stable disease in 8/16 pts. Median time to progression was 112+ days. Conclusions: M200 appears to be well tolerated at 10 mg/kg Q2W in combination with (Gem). Based on preliminary data from this trial and safety data from other trials, a higher dose level of M200 will be explored. [Table: see text]

4535 Background: Blocking angiogenesis has been shown to be an effective strategy for controlling tumor growth in RCC. Tumor angiogenesis occurs when pro-angiogenic growth factors are released, stimulating endothelial cell proliferation and migration to form neovessels. M200 is an IgG4 chimeric monoclonal antibody that targets α5β1, thereby inducing apoptosis of proliferating endothelial cells. M200 activity is independent of growth factor stimulus, suggesting that binding of fibronectin to α5β1 occurs downstream of growth factor signalling, and is possibly a final common pathway for the development of neovasculature. Methods: This is a multicenter, open label, single cohort pilot phase II study of 40 patients (pts) with RCC. Pts received no more than 2 prior regimens. Pts received M200 10 mg/kg IV every 2 weeks until disease progression. Pts were evaluated for efficacy every 8 weeks by objective response using RECIST criteria. An independent data safety monitoring board was utilized to review safety data. Results: A total of 40 pts were enrolled. All pts were evaluable for safety and 37 pts for objective response (to date). Median age was 62.8 years. ECOG score was 0 in 27 (67.5%) and 1 in 13 (32.5%) pts. Prior nephrectomy occured in 39 (97%) pts. Other prior treatment included IL-2 in 15 (37.5%), interferon alpha in 6 (15%), IL-2 + interferon in 2 (5%) pts. Most frequent side effects were fatigue 37.5%, nausea 15% and hypertension 7.5%. Five pts died in the study, four with progressive disease (PD) and 1 with arrhythmia (unrelated to M200). SD was observed in 32/37 (87%) of pts. No changes in hematological, renal and hepatic parameters were noted. Median time to progression was 113+ days. The average peak and trough concentrations of circulating M200 following 6 weeks of treatment were 390 μg/mL and 140 μg/mL, respectively. There were no detectable immune responses to M200. Conclusions: M200 is well tolerated at 10 mg/kg Q2W. Stable disease is noted in 87% of pts. Follow-up continues. A higher dose level is being evaluated. [Table: see text]

8011 Background: Integrin α5β1 has been reported to be unregulated in metastatic melanoma and in tumor angiogenesis. A critical survival step in angiogenesis is the ligation of fibronectin in the extracellular matrix to α5β1 on endothelial cells. M200 is an IgG4 chimeric monoclonal antibody targeting α5β1, inducing apoptosis of proliferating endothelial cells. M200 activity is independent of growth factor stimulus, suggesting that binding of fibronectin to α5β1 occurs downstream of growth factor signalling, and is possibly a final common pathway for the development of neovasculature. Methods: This is a multicenter, open label, single cohort, pilot phase II study of 40 patients (pts) in metastatic melanoma. Pts received M200 10 mg/kg IV every 2 weeks with DTIC 1g/m2 monthly until disease progression. Pts were evaluated for efficacy every 8 weeks by objective response using RECIST criteria. Additional evaluations included pharmacokinetics and immunogenicity profile. An independent data safety monitoring board was utilized to review safety data. Results: A total of 40 pts have been enrolled to date. All pts were evaluable for safety and 30 pts for objective response using ITT population. Median age was 58.8 years, with 26 (65%) male. ECOG score was 0–1 in 37 (92%) pts. Up to 14 doses of M200 (median 4 doses) and 7 doses of DTIC (median 2) have currently been administered, with dosing continuing. Thirty-one (77.5%) pts have had at least 1 AE with 8 (20%) pts at least 1 SAE. The most frequent adverse events for M200 were nausea 17.5%, constipation 10% and vomiting 10% and for DTIC were nausea 35%, vomiting 20% and pyrexia 15%. Fifteen SAE’s with 2 possibly related to M200 including hypertension and deep vein thrombosis. Four pts died in the study, all with progressive disease (PD). Best overall response at 8 weeks was stable disease (SD) in 16/30 pts and PD in 14/30 pts. Median time to progression was 72 days. Conclusions: M200 appears to be well tolerated at 10 mg/kg Q2W in combination with DTIC. [Table: see text]