ac-7700 and Neoplasms

Vascular Disrupting Agents (VDA) are a potential new class of oncology drugs that have garnered attention recently as a number of these agents have entered into Phase 2-3 studies. Currently available data suggest how the subsequent evolution of these agents into clinical practice may proceed, with new therapeutic paradigms based on similarities, differences and interactions with current standard of care agents. In particular, the broadly successful group of agents targeting angiogenesis through the Vascular Endothelial Growth Factor (VEGF) pathway, can be contrasted to the VDAs that principally disrupt established tumor vasculature through a different set of molecular targets. Although the angiogenesis inhibitors may benchmark where other vascularly targeted agents such as VDAs may be successful, the differences in terms of efficacy and safety profiles lead to important differentiation in how VDAs are likely to be used. Although the majority of VDAs bind tubulin, significant differences also exist between VDAs and cytotoxic agents, including tubulin targeted agents such as taxanes and vinca alkyloids. Clinical trial data is now available for several VDAs allowing such assessment. Data of yet has been the strongest in NSCLC, with indications of how these drugs may be developed beneficially in subsets of patients such as those with squamous cell histology or at risk of bleeding events. Other indications being aggressively pursued include prostate carcinoma, ovarian carcinoma, sarcomas and astrocytomas. The field also continues to advance with investigation into how to optimally schedule administration of VDAs and what effects might be class effects and/or markers of efficacy.

Topics: Angiogenesis Inhibitors; Blood Vessels; Clinical Trials as Topic; Diketopiperazines; Humans; Neoplasms; Neovascularization, Pathologic; Serine; Tubulin

Vascular disrupting agents (VDAs) have presented a new kind of anti-cancer drug in recent years. VDAs take advantage of the weakness of established tumor endothelial cells and their supporting structures. In contrast to anti-angiogenic therapy, which inhibits the outgrowth of new blood vessels, vascular targeting treatments selectively attack the existing tumor vasculature. Here we summarized the anti-tumor activities, mechanisms and clinical applications of small molecule VDAs.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Bibenzyls; Diphosphates; Endothelial Cells; Humans; Molecular Structure; Neoplasms; Neovascularization, Pathologic; Oligopeptides; Organophosphorus Compounds; Serine; Stilbenes; Tubulin Modulators; Xanthones

Angiogenesis has an essential role in promoting and supporting tumor growth and it is an important therapeutic target. The tumor vascular network is the result of pro-angiogenic and inhibitory factors as well as of the interaction between endothelial cells and extracellular matrix. Different antiangiogenic therapeutics have been developed to improve tumor control through vascular-targeting agents (VTA). VTAs can be divided into two groups: antiangiogenic agents and vascular-disrupting agents (VDAs). VTAs inhibit specific factors required to induce and direct the angiogenic process, with major activity against small tumor masses and at the tumor periphery, encompassing monoclonal antibodies and small molecules inhibitors of the tyrosine kinase domain of the VEGF receptor. VDAs specifically target and destroy well-established tumor vessels with ischemia and destruction of large masses with central hemorrhagic necrosis and survival of a thin peripheral tumor layer. VDAs can be divided into biologics, such as ligand-based, and small-molecule agents; this second group includes small-molecule VDAs like flavonoids, such as 5,6-dimethylxanthenone-4-acetic acid (DMXAA), and microtubule-destabilizing agents. In this review we will discuss the mechanism of action, as well as the preclinical and clinical results, of one of the most promising antitubulin agents: the combretastatin A4-phosphate derivative, AVE8062A.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Clinical Trials as Topic; Drug Evaluation, Preclinical; Humans; Neoplasms; Neovascularization, Pathologic; Serine; Stilbenes; Tubulin

Despite extensive research efforts, effective therapies for refractive cancers have not yet been established, and development of successful treatment strategies remains the most important task in the field of oncology. We recently showed that AVE8062 (formerly AC7700), a derivative of combretastatin A-4, achieved irreversible stasis of tumor blood flow (TBF), thereby causing necrosis of tumor tissue by halting the supply of nutrients. Such effects were unrelated to cancer type. In this review, we summarize our experiments on antivascular and antitumor effects by AVE8062. We maintain that such starvation tactics against solid tumors constitute a new therapeutic strategy for all solid tumors, including refractory cancers.

Topics: Animals; Antineoplastic Agents; Microcirculation; Neoplasms; Rats; Regional Blood Flow; Serine; Stilbenes

To determine ombrabulin's maximum tolerated dose and dose recommended for Japanese patients with advanced solid tumors and to assess its antitumor activity and overall safety and pharmacokinetic profiles.. This was a multi-center, open-label, sequential-cohort, dose-escalation phase I study of ombrabulin, a vascular disrupting agent, administered once every 3 weeks. Patients were treated with 15.5, 25, 35, or 50 mg/m(2) ombrabulin over a 30-min intravenous infusion. The recommended dose was the highest dose at which <33 % of all evaluable patients experienced dose-limiting toxicities (DLTs) during the first treatment cycle or 50 mg/m(2) (recommended in Caucasian patients) if the previous definition was not met.. Fifteen patients were treated. No DLT occurred with 15.5, 25, or 35 mg/m(2) ombrabulin. In the 50 mg/m(2) group, one patient had Grade 3 lymphopenia, and another experienced Grade 2 hypertension and Grade 3 diarrhea judged as DLTs. The most frequent related adverse events in this group were diarrhea, nausea, and hypertension. Two patients had Grade 3 anemia, one at the 15.5 mg/m(2) and the other at the 50 mg/m(2). No AEs necessitating dose reduction or Grade 4 AEs were observed. Overall, five patients had stable disease. Pharmacokinetic parameters were comparable to those in non-Japanese patients.. Ombrabulin treatment once every 3 weeks was well tolerated in Japanese patients with advanced solid tumors. The dose recommended is 50 mg/m(2), as in Caucasian patients. The safety and pharmacokinetic profiles were comparable between Japanese and Caucasian patients (funded by Sanofi; ClinicalTrials.gov number, NCT00968916).

Topics: Asian People; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Neovascularization, Pathologic; Serine

The vascular disrupting agent ombrabulin shows synergy with docetaxel in vivo. Recommended phase II doses were determined in a dose escalation study in advanced solid tumours.. Ombrabulin (30-min infusion, day 1) followed by docetaxel (1-h infusion, day 2) every 3 weeks was explored. Ombrabulin was escalated from 11.5 to 42 mg m(-2) with 75 mg m(-2) docetaxel, then from 30 to 35 mg m(-2) with 100 mg m(-2) docetaxel. Recommended phase II dose cohorts were expanded.. Fifty-eight patients were treated. Recommended phase II doses were 35 mg m(-2) ombrabulin with 75 mg m(-2) docetaxel (35/75 mg m(-2); 13 patients) and 30 mg m(-2) ombrabulin with 100 mg m(-2) docetaxel (30/100 mg m(-2); 16 patients). Dose-limiting toxicities were grade 3 fatigue (two patients; 42/75, 35/100), grade 3 neutropaenic infection (25/75), grade 3 headache (42/75), grade 4 febrile neutropaenia (30/100), and grade 3 thrombosis (35/100). Toxicities were consistent with each agent; mild nausea/vomiting, asthaenia/fatigue, alopecia, and anaemia were common, as were neutropaenia and leukopaenia. Diarrhoea, nail disorders and neurological symptoms were frequent at 100 mg m(-2) docetaxel. Pharmacokinetic analyses did not show any relevant drug interactions. Ten patients had partial responses (seven at 30 mg m(-2) ombrabulin), eight lasting >3 months.. Sequential administration of ombrabulin with 75 or 100 mg m(-2) docetaxel every 3 weeks is feasible.

Topics: Adolescent; Adult; Aged; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Drug Interactions; Female; Humans; Male; Middle Aged; Neoplasms; Serine; Taxoids; Treatment Outcome; Young Adult

Preclinical evidence supports synergy between the vascular disrupting agent ombrabulin and various chemotherapy agents. Ombrabulin was combined with two standard taxane/platinum doublets in a phase I study to determine the recommended combination doses.. Ombrabulin (30-min infusion, day 1 every 3 weeks) was escalated from 15.5 to 35 mg/m(2) with two chemotherapy doublets; OCD, 75 mg/m(2) cisplatin (C), day 1 (cohort 1) or day 2 (cohort 2) with 60/75 mg/m(2) docetaxel (D), day 2; and OCP, AUC5/6 carboplatin (C) and paclitaxel (P) 175 mg/m(2) (cohort 3) or 200 mg/m(2) (cohort 4), day 2. Safety, pharmacokinetics, and tumor response were evaluated.. Sixty-nine patients were treated (32 OCD, 37 OCP). Four had DLTs in cycle 1, two in cohort 1 (grade 4 febrile neutropenia, grade 4 pulmonary embolism) and one each in cohorts 2 (grade 3 ALT elevation) and 4 (grade 3 peripheral ischemia). Ombrabulin escalation in cohorts 2, 3 and 4 was halted at the highest planned dose (35 mg/m(2)). Asthenia, nausea, paresthesia, alopecia, vomiting, and stomatitis were common, as was grade 3-4 neutropenia. Ombrabulin clearance was high with a short terminal half-life and a medium volume of distribution. Pharmacokinetic analysis showed no clinically relevant drug interactions between the taxane-platinum doublet and ombrabulin or its active metabolite RPR258063, however docetaxel and carboplatin pharmacokinetics were slightly altered. One complete and 15 partial responses (10 OCD, 5 OCP; median duration 5.5 and 4.4 months, respectively) were reported.. The addition of ombrabulin to standard doses of cisplatin/docetaxel or carboplatin/paclitaxel proved feasible with manageable overlapping toxicities but appears to have limited impact on the efficacy of these doublets. Recommended combination doses are 35 mg/m(2) ombrabulin with 75 mg/m(2) cisplatin/75 mg/m(2) docetaxel or 200 mg/m(2) paclitaxel/AUC6 carboplatin, every 3 weeks.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cisplatin; Docetaxel; Drug Interactions; Female; Humans; Male; Middle Aged; Neoplasms; Paclitaxel; Response Evaluation Criteria in Solid Tumors; Serine; Taxoids; Young Adult

The vascular disrupting agent ombrabulin rapidly reduces tumor blood flow and causes necrosis in vivo. A phase I dose-escalation study was designed to determine the recommended phase II dose (RP2D) of single-agent ombrabulin administered once every three weeks in patients with advanced solid malignancies.. Ombrabulin (30-minute infusion) was escalated from 6 to 60 mg/m2, with RP2D cohort expansion. Safety, tumor response, pharmacokinetics, and pharmacodynamic biomarkers were evaluated.. Eleven dose levels were evaluated in 105 patients. Two patients had dose-limiting toxicities in cycle 1 during escalation: grade 3 abdominal pain at 50 mg/m2, grade 3 tumor pain/grade 3 hypertension at 60 mg/m2, and the RP2D was 50 mg/m2 (39 patients). Common toxicities were headache, asthenia, abdominal pain, nausea, diarrhea, transient hypertension, anemia, and lymphopenia. No clinically significant QTc prolongations or left ventricular ejection fraction (LVEF) decreases occurred. Ombrabulin was rapidly converted to its active metabolite RPR258063 (half-life 17 minutes and 8.7 hours, respectively), both having dose-proportional exposure. Weak inhibition of CYP2C19-mediated metabolism occurred at the clinical doses used and there was no effect on CYP1A2 and CYP3A4. A patient with rectal cancer had a partial response and eight patients had stable disease lasting four months or more. Circulating endothelial cells (CEC), VEGF, and matrix metalloproteinase (MMP)-9 levels increased significantly six to 10 hours postinfusion in a subset of patients.. The recommended schedule for single-agent ombrabulin is 50 mg/m2 every 3 weeks. CECs, VEGF, and MMP-9 are potential biomarkers of ombrabulin activity.

Topics: Adult; Aged; Biomarkers, Tumor; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Neoplasms; Serine; Treatment Outcome

Targeting tumor vasculature represents an intriguing therapeutic strategy in the treatment of cancer. In an effort to discover new vascular disrupting agents with improved water solubility and potentially greater bioavailability, various amino acid prodrug conjugates (AAPCs) of potent amino combretastatin, amino dihydronaphthalene, and amino benzosuberene analogs were synthesized along with their corresponding water-soluble hydrochloride salts. These compounds were evaluated for their ability to inhibit tubulin polymerization and for their cytotoxicity against selected human cancer cell lines. The amino-based parent anticancer agents 7, 8, 32 (also referred to as KGP05) and 33 (also referred to as KGP156) demonstrated potent cytotoxicity (GI50=0.11-40nM) across all evaluated cell lines, and they were strong inhibitors of tubulin polymerization (IC50=0.62-1.5μM). The various prodrug conjugates and their corresponding salts were investigated for cleavage by the enzyme leucine aminopeptidase (LAP). Four of the glycine water-soluble AAPCs (16, 18, 44 and 45) showed quantitative cleavage by LAP, resulting in the release of the highly cytotoxic parent drug, whereas partial cleavage (<10-90%) was observed for other prodrugs (15, 17, 24, 38 and 39). Eight of the nineteen AAPCs (13-16, 42-45) showed significant cytotoxicity against selected human cancer cell lines. The previously reported CA1-diamine analog and its corresponding hydrochloride salt (8 and 10, respectively) caused extensive disruption (at a concentration of 1.0μM) of human umbilical vein endothelial cells growing in a two-dimensional tubular network on matrigel. In addition, compound 10 exhibited pronounced reduction in bioluminescence (greater than 95% compared to saline control) in a tumor bearing (MDA-MB-231-luc) SCID mouse model 2h post treatment (80mg/kg), with similar results observed upon treatment (15mg/kg) with the glycine amino-dihydronaphthalene AAPC (compound 44). Collectively, these results support the further pre-clinical development of the most active members of this structurally diverse collection of water-soluble prodrugs as promising anticancer agents functioning through a mechanism involving vascular disruption.

Topics: Amino Acids; Animals; Antineoplastic Agents; Bibenzyls; Breast; Breast Neoplasms; Cell Line, Tumor; Coumarins; Drug Design; Female; Humans; Mice; Mice, SCID; Naphthalenes; Neoplasms; Optical Imaging; Prodrugs; Solubility; Structure-Activity Relationship; Tubulin; Water

Vascular-disrupting agents (VDAs) represent a new class of chemotherapeutic agent that targets the existing vasculature in solid tumors. Preclinical and early-phase trials have demonstrated the promising therapeutic benefits of VDAs but have also uncovered a distinctive toxicity profile highlighted by cardiovascular events.. We reviewed all preclinical and prospective phase I-III clinical trials published up to August 2010 in MEDLINE and the American Association of Cancer Research and American Society of Clinical Oncology meeting abstracts of small-molecule VDAs, including combretastatin A4 phosphate (CA4P), combretastatin A1 phosphate (CA1P), MPC-6827, ZD6126, AVE8062, and ASA404.. Phase I and II studies of CA1P, ASA404, MPC-6827, and CA4P all reported cardiovascular toxicities, with the most common cardiac events being National Cancer Institute Common Toxicity Criteria (version 3) grade 1-3 hypertension, tachyarrhythmias and bradyarrhythmias, atrial fibrillation, and myocardial infarction. Cardiac events were dose-limiting toxicities in phase I trials with VDA monotherapy and combination therapy.. Early-phase trials of VDAs have revealed a cardiovascular toxicity profile similar to that of their vascular-targeting counterparts, the angiogenesis inhibitors. As these agents are added to the mainstream chemotherapeutic arsenal, careful identification of baseline cardiovascular risk factors would seem to be a prudent strategy. Close collaboration with cardiology colleagues for early indicators of serious cardiac adverse events will likely minimize toxicity while optimizing the therapeutic potential of VDAs and ultimately enhancing patient outcomes.

Topics: Angiogenesis Inhibitors; Bibenzyls; Cardiovascular System; Clinical Trials as Topic; Humans; Neoplasms; Neovascularization, Pathologic; Organophosphorus Compounds; Quinazolines; Serine; Xanthones

This study is intended to compare the value of uncompressed ultrasonic data, obtained after linear power detection of the ultrasonic radiofrequencies that we call linear data, with usual compressed video data for the quantification of tumor perfusion, particularly for monitoring antivascular therapy.. To form a clinically useful ultrasonic image, the detected power of the received signals (linear data) is compressed in a quasi-logarithmic fashion in order to match the limited dynamic range of the video monitor. The resulting reduced range of signals from an injected contrast agent may limit the sensitivity to changes in the time-intensity curves. Following a theoretical evaluation of the effects of compression on time-intensity curves and as an in vivo example, we measured at different times the effects of an antivascular drug administered to mice bearing melanoma tumors. The mean time-intensity curves within the tumors after bolus injection of a contrast agent were determined using both linear and video data. Linearized data was recovered using the inverse of the true scanner's compression law, which was experimentally determined. Three features were extracted from the time-intensity curves: peak intensity (PI), time to peak intensity (TPI) and area under the curve in the wash-in phase (AUC (wash-in)). When contrast reached its maximum value, the coefficient of variation reflecting the heterogeneity of the intensity of contrast uptake within the tumor, was computed using both data sets.. TPI was found to be similar with either data set (r = 0.98, p < 0.05, factor of 1.09). Linear PI and AUC (wash-in) had significantly earlier decreases after drug administration than video data (p = 0.015 and p = 0.03, respectively). The coefficient of variation was significantly lower when using video rather than linear data (p < 10 (-4)).. In conclusion, the use of linear data is the only mathematically valid methodology for determining a tumor's time-intensity curve and, in practice, it allows earlier demonstration of responses to antivascular drugs.

Topics: Angiogenesis Inhibitors; Animals; Blood Flow Velocity; Contrast Media; Female; Image Enhancement; Image Processing, Computer-Assisted; Linear Models; Melanoma, Experimental; Mice; Mice, Nude; Microcirculation; Neoplasm Transplantation; Neoplasms; Neovascularization, Pathologic; Phantoms, Imaging; Phospholipids; Regional Blood Flow; Serine; Sulfur Hexafluoride; Ultrasonography, Doppler; Videotape Recording