Requisitos que deberán cumplir los licitantes e instrucciones para elaborar las propuestas y desarrollo del procedimiento

or gefitinib are being treated with continuous XL647 [92].

2.1.2.15 XL999

XL999 (Exelixis, Inc., South San Francisco, CA, USA) is an oral multikinase inhibitor. A Phase II study determined the efficacy, safety, and tolerability of XL999 [93]. Eligible patients had previously treated, stage IIIb/IV NSCLC (Table 2). Two tumor responses and one SD were reported.

2.1.2.16 CP-547,632

CP-547,632 (Pfizer, New York, USA) is an inhibitor of VEGFR-2 and PDGFR. The combination of CP-547,632 and paclitaxel and carboplatin was assessed in a Phase I/ randomized Phase II study (Table 2) [94]. Patients with stage IIIb/IV or recurrent NSCLC receiving first-line chemotherapy were treated with oral daily CP-547,632 in combination with paclitaxel and carboplatin. Sixty-eight patients were treated, 37 in Phase I and 31 in Phase II. Dose-limiting toxicity at 250 mg was grade 3 rash and grade 3 diarrhea. In Phase I, seven subjects (22.6%) had a confirmed PR. In Phase II, four subjects in each arm (chemotherapy + CP-547,632: 28.6%; chemotherapy alone: 25%) had a confirmed PR.

2.1.2.17 AV-951

AV-951 (Aveo Pharmaceuticals, Cambridge, MA, USA) is a new, highly potent and specific inhibitor of VEGF receptors 1, 2 and 3. Strong activity was observed in a Phase I study consisting of 40 patients with advanced solid tumors; AV-951 was also found to be well tolerated [95]. A Phase Ib and a Phase IIa trial will examine the safety, tolerability and MTD of AV-951 with a once-daily oral dosing schedule, as well as overall RR of AV-951 administration in NSCLC [96].

2.1.3 Thalidomide and its analogs 2.1.3.1 Thalidomide

Thalidomide (Celgene, Summit, NJ, USA) is thought to exert antiangiogenesis activity partially by antagonizing basic fibroblast growth factor (bFGF)-induced angiogenesis [97]. Phase II studies of thalidomide in patients with advanced NSCLC have shown promising activity (Table 2) [98,99]. Several ongoing trials are examining the potential role of thalido- mide in the treatment of advanced NSCLC. A Phase II trial will determine the RR of 37 patients with stage III or IV NSCLC treated with second-line docetaxel and thali- domide [100]; another Phase II trial will determine the RR of 21 patients with stage II or IIIa NSCLC receiving neoad- juvant carboplatin, gemcitabine and thalidomide [101]. Recruitment has stopped for both studies; final data collection is in progress.

A Phase III study to evaluate the survival and TTP of patients with stage III NSCLC when treated with carboplatin- paclitaxel and radiotherapy with or without thalidomide is ongoing (ECOG3598) [102].

2.1.3.2 Lenalidomide

Lenalidomide (Revlimid, CC-5013, Celgene; Summit, NJ, USA) is a thalidomide analog. A Phase I study that investi- gated lenalidomide monotherapy in 55 pretreated patients with advanced solid tumors demonstrated three radiologic responses. The drug was well tolerated, although grade 3 or 4 neutropenia was observed in four patients [103]. A Phase II study to evaluate lenalidomide monotherapy in 40 patients with recurrent NSCLC has been completed [104]. The final results have not yet been published.

2.1.4 Matrix metalloproteinase inhibitors 2.1.4.1 BMS-275291

BMS-275291 (Bristol Myers Squibb, New York, USA) is a new broad-spectrum sulfhydryl-based second-generation matrix metalloproteinase (MMP) inhibitor rationally designed to spare a class of closely related metalloproteinases known as sheddases. The interim analysis of a large, randomized, Phase III study of the MMP inhibitor, BMS-275291 con- ducted in advanced lung cancer in 774 patients demonstrated no survival benefit from addition of this MMP inhibitor to chemotherapy with carboplatin and paclitaxel (Table 2) [105]. Moreover, the combination of the MMPI with chemotherapy caused an increased toxicity in the experimental arm, and study treatment was stopped.

2.1.5 Other antiangiogenic agents 2.1.5.1 Cilengitide

Cilengitide (EMD 121974, Merck, Darmstadt, Germany) binds to and inhibits the activities of the αvβ3 and αvβ5 integrins, thereby inhibiting endothelial cell–cell interactions, endothelial cell-matrix interactions and angiogenesis. After Phase I studies proved the tolerability of cilengitide [106,107], a randomized Phase II study with a safety run-in part was started to investigate cilengitide in combination with cetuximab and platinum-based chemotherapy compared with cetuximab and platinum-based chemotherapy alone as first-line treatment for patients with advanced NSCLC (CERTO) [108].

2.1.5.2 Volociximab (M200)

Volociximab (M200, PDL Biopharma, Incline Village, NV, USA) is a chimeric monoclonal antibody jointly developed by PDL BioPharma and Biogen Idec for treatment of a variety of advanced solid tumors. It binds to and inhibits the func- tional activity of α5β1 integrin. The results of a Phase I, pharmacokinetic, and biological correlative study of volocix- imab have recently been published [109]. Twenty-one patients with advanced solid malignancies, including one NSCLC patient, were treated with escalating doses of volociximab. Treatment was well tolerated, and dose-limiting toxicity was not identified over the range examined. One minor response (renal, 7 months) and one durable SD (melanoma, 14 months) were reported.

Two Phase Ib studies investigating the effect of volociximab in combination with carboplatin and paclitaxel [110], and

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carboplatin, paclitaxel and bevacizumab [111] in previously untreated advanced (stage IIIb/IV) NSCLC patients are now recruiting.

The effect of dual inhibition with volociximab and erlotinib in advanced refractory NSCLC is also being evaluated in a Phase II study [112].

2.1.5.3 TNP-470

TNP-470 (Takeda Chemical Industries Ltd, Osaka, Japan) blocks angiogenesis by inhibiting methionine aminopeptidase, an enzyme critical for endothelial cell proliferation. The combination of TNP-470 administered at 60 mg/m2 _three times a week and paclitaxel 225 mg/m2 _{administered every} 3 weeks was defined as both the MTD and the optimal dose in a Phase I study involving 32 patients with solid tumors, including 16 NSCLC [113]. TNP-470, at present, is not going forward in development.

2.1.5.4 AMG 386

AMG-386 (Amgen, Inc.) is an intravenously administered recombinant Fc-peptide fusion protein (peptibody) that inhibits angiogenesis by preventing interaction between angio- poietins and Tie2 receptors. The safety and pharmacokinetics of AMG 386 either in monotherapy [114] or in combination with paclitaxel [115] in advanced solid tumors were examined in two Phase I trials. The treatments were well tolerated. Efficacy data are limited. Phase I and II studies are ongoing with solid tumors other than NSCLC.

2.2 Vascular disrupting agents (VDAs)

Targeting of VEGF has been shown to result in apoptosis only in newly formed, immature tumor vessels and in the developing vasculature of the neonatal mouse, but not in the tumor vessels of adult mice or in quiescent tumor vascular networks [116]. Vascular targeting therapy recognizes that clini- cal diagnosis of cancer commonly occurs when the tumor tissue has already established its vasculature. VDAs specifically target pre-existing tumor capillaries, resulting in rapid cancer tissue ischemia and secondary tumor cell death in the central regions of tumors, although they leave the perfusion in peripheral tumor regions relatively intact. The two major categories of VDA that are in clinical development are the small-molecule VDAs and ligand-directed VDAs [117]. While small-molecule VDAs achieve selective occlusion of tumor vessels by exploiting phenotypic differences between tumor and host tissue ECs (i.e., increased reliance on the tubulin cytoskeleton to maintain cell shape and accelerated prolifera- tion), ligand-directed VDAs use toxins and pro-coagulant agents coupled to peptides or antibodies that selectively bind to the endothelial tube. Although animal studies with ligand- directed VDAs have certainly been elegant, and, furthermore, several potential target molecules exist that are upregulated on tumor versus host tissue capillaries, testing of ligand-based agents are still in the preclinical phase. For that reason, and because they are at a much more advanced stage of clinical

development, only representatives of small molecule VDAs are discussed here.

2.2.1 DMXAA (5,6 dimethylxanthenone-4-acetic acid)

The combination of DMXAA (AS1404 or ASA404, Antisoma, London, UK) with carboplatin and paclitaxel was evaluated in a Phase II trial in previously untreated IIIb or IV NSCLC (Table 2) [118]. Safety profiles were similar and manageable in both groups, with most adverse effects attributed to standard therapy.

Two large Phase III trials are ongoing to investigate ASA404 in the treatment of NSCLC. ATTRACT-1 evaluates ASA404 in combination with paclitaxel and carboplatin as first-line treatment [119], whereas ATTRACT-2 compares ASA404 with placebo in combination with docetaxel in the second-line treatment of patients with stage IIIb/IV NSCLC [120].

2.2.2 Zybrestat

Zybrestat (CA4P, Combretastatin A4 Phosphate, Oxigene, Inc., Waltham, MA, USA) is a phosphate prodrug of the tubulin-binding agent combrestatin A4. Because the CA4P- bevacizumab combination has appeared safe, resulted in significantly decreased tumor blood-flows and shown clinical activity without simultaneous chemotherapy, the developer initiated a controlled Phase II study to assess the safety and efficacy of the combination of carboplatin, paclitaxel and bevacizumab ± CA4P in chemotherapy-naive, stage IIIb/IV non-squamous NSCLC histology. Patients who complete the first six cycles of therapy and have not experienced disease progression will receive maintenance therapy with bevacizumab alone or with bevacizumab plus CA4P [121].

2.2.3 NPI-2358

NPI-2358 is a synthetic analog of diketopiperazine phenyla- histin (halimide), a natural product that was isolated from a marine and a terrestrial fungus Aspergillus sp. Dose escalation of NPI-2358 was conducted in a Phase I trial that enrolled patients with advanced solid tumors and lymphomas [122]. Twenty-five subjects were enrolled. A recommended Phase II dose of 30 mg/m2 _{was selected based on toxicities of nausea,} vomiting, fatigue, fever, tumor pain and transient elevations in blood pressure.

A Phase I/II study of NPI-2358 in combination with docetaxel in patients with advanced NSCLC that has progressed after treatment with at least one chemotherapy regimen is ongoing [123].

2.2.4 ABT-751

ABT-751 (Abbott Laboratories, Abbott Park, IL, USA) is an orally bioavailable antimitotic sulfonamide. ABT-751 binds to the colchicine-binding site on beta-tubulin and inhibits the polymerization of microtubules. There have been three pub- lished Phase I trials of ABT-751 in patients with hematological malignancies and in adult and pediatric solid tumors [124-126]. In advanced NSCLC, a Phase I/II trial is evaluating ABT-751

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Antivascular agents for NSCLC

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