Phase I Trial of Combretastatin A-4 Phosphate with Carboplatin

Bilenker, Joshua H.; Flaherty, Keith T.; Rosen, Mark; Davis, Lisa E.; Gallagher, Maryann; Stevenson, James P.; Sun, Weijing; Vaughn, David J.; Giantonio, Bruce J.; Zimmer, Ross; Schnall, Mitchell D.; O’Dwyer, Peter J.

doi:10.1158/1078-0432.ccr-04-1434

Cited by 91 publications

(56 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Because at least additive effects are observed with taxanes, these regimens are highly desirable in ovarian cancer management. However, an early phase trial of CA-4-P and carboplatin documented higher than expected hematologic toxicity, predominantly thrombocytopenia, highlighting the necessity to design trials with careful pharmacokinetic studies to evaluate the potential for drug-drug interactions (43). In the current study, we identified a potential dose threshold for AVE8062 from which additional dose escalation did not improve cytotoxicity.…”

Section: Discussionmentioning

confidence: 75%

Antitumor and Antivascular Effects of AVE8062 in Ovarian Carcinoma

Kim

Ravoori²,

Landen

et al. 2007

Cancer Research

View full text Add to dashboard Cite

The purpose of this study was to examine the therapeutic efficacy and underlying mechanisms of action of a vasculardisrupting agent, AVE8062, and to determine its effects on tumor metabolic activity. The in vitro and in vivo effects of AVE8062 alone and in combination with docetaxel were tested in chemotherapy-sensitive and chemotherapy-resistant ovarian cancer models. Tumors were analyzed for necrosis, microvessel density, endothelial cell apoptosis, and proliferation following treatment. The effect of AVE8062 on tumor regression and metabolic activity was examined by magnetic resonance (MR) or by [18 F]fluorodeoxyglucose ([ 18 F]FDG) uptake by positron emission tomography (PET) with MR imaging, respectively. AVE8062 monotherapy was effective in inhibiting tumor growth in all models (range 43-51% versus control; P < 0.05). Combination therapy was even more effective in inhibiting tumor growth (range 76-90% compared with controls, P < 0.01). AVE8062 in combination with chemotherapy significantly prolonged survival in HeyA8-injected mice (P < 0.001) compared with other groups. AVE8062-based therapy resulted in rapid development of central tumor necrosis, decreased microvessel density, decreased proliferation, and induction of apoptosis of tumor-associated endothelial cells. MR imaging showed regression of established HeyA8 ovarian tumors and [18 F]FDG PET with MR showed rapid decrease in metabolic activity after AVE8062 therapy. Combination of AVE8062 plus docetaxel results in potent inhibition of ovarian cancer growth. These results suggest that AVE8062 may be useful as a clinical therapeutic approach for ovarian cancer patients and that functional [18 F]FDG PET imaging may predict clinical response before an anatomic reduction in tumor size. [Cancer Res 2007;67(19):9337-45]

show abstract

Section: Discussionmentioning

confidence: 75%

Antitumor and Antivascular Effects of AVE8062 in Ovarian Carcinoma

Kim

Ravoori²,

Landen

et al. 2007

Cancer Research

View full text Add to dashboard Cite

show abstract

“…5, 9, 10). This agent has been extensively examined in various preclinical and clinical trials with encouraging results (11,12).Tubulin binding agents like CA4P disorganize the microtubules within endothelial cells; specifically, they bind to the h-tubulin subunits, preventing the formation of microtubules (9, 13). After treatment with CA4P, newly formed daughter endothelial cells have been observed to undergo shape changes (14, 15) as a consequence of cytoskeletal alterations.…”

mentioning

confidence: 99%

“…5,9,10). This agent has been extensively examined in various preclinical and clinical trials with encouraging results (11,12).…”

mentioning

confidence: 99%

Effect of the Second-Generation Vascular Disrupting Agent OXi4503 on Tumor Vascularity

Salmon

Siemann

2006

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: As first-generation small-molecule vascular disrupting agents (VDA) have begun to enter clinical trials, second-generation agents are under active development. One such agent is the combretastatin A4 disodium phosphate (CA4P) analogue OXi4503 (CA1P). Experimental Design: C3H/HeJ mice bearing KHT sarcomas were treated with CA4P and OXi4503 and the effect on tumor vasculature was determined by evaluating the extent of vascular shutdown (Hoechst-33342 vessel staining) and tumor perfusion inhibition (dynamic contrastenhanced magnetic resonance imaging). Dynamic contrast-enhanced magnetic resonance imaging and tumor necrosis end points also were used to examine the pathophysiologic tumor effects following repeated exposures to these agents. Results: Single doses of either agent (CA4P, 100 mg/kg; OXi4503, 25 mg/kg) resulted in an 80% to 90% reduction in tumor perfusion 4 hours after treatment. Whereas recovery in tumor perfusion was observed 48 hours posttreatment, this recovery was significantly slower in mice treated with OXi4503. Tumors re-treated with either VDA 72 hours after the first drug exposure showed a similar reduction and recovery in tumor perfusion. Histologic evidence showed the presence of a smaller viable rim after exposure to OXi4503 than that observed after CA4P treatment. Furthermore, the extent of recovery of tumor necrosis 72 hours after drug treatment was less for OXi4053. Conclusions:The present studies show that the second-generation VDA OXi4503 possesses significant antivascular effects in solid tumors. Importantly, the vasculature of tumors of mice that had received an initial dose this agent was as responsive to a subsequent treatment.It has been well established that if a tumor is to grow to a clinically relevant size, it must induce a supporting vasculature (1, 2). It has also been shown that the rapid growth and development of the tumor places tremendous strains on this new vasculature, resulting in major vascular abnormalities (3, 4). These vascular abnormalities consist of temporary occlusions, a rapidly dividing endothelial population, blind ends, leaky vessels, and a reduction in pericytes (5, 6). Importantly, the successful treatment of the cancer by conventional therapies may be affected by these vascular abnormalities (3,4).In recent years, therapies targeted specifically at exploiting these tumor vasculature abnormalities have been under investigation (5 -7). A class of vascular disrupting agents (VDA) that cause a rapid and selective shutdown of the tumor vascular by damaging tumor vessel endothelium have now been identified (8). Treatment with such agents results in the arrest of the blood flow, which in turn acts to starve the tumor of the oxygen and nutrients it needs to survive (6, 9). The lead drug in this class of agents is the tubulin binding agent combretastatin A4 disodium phosphate (CA4P; refs. 5, 9, 10). This agent has been extensively examined in various preclinical and clinical trials with encouraging results (11,12).Tubulin binding agents like CA4...

show abstract

“…Another consideration is that CA4P, in common with other microtubule-binding agents, has independent direct cytotoxic activity (27)(28)(29) that may be additive or synergistic with radiation in inducing marrow toxicity. In a phase I trial in which CA4P was given 60 minutes after carboplatin, dose-limiting thrombocytopenia was reported for carboplatin AUC 5 mg min/mL with CA4P at a relatively low dose of 36 mg/m 2 (30). This was probably due to reduced renal clearance of the carboplatin as CA4P has been shown to cause a temporary reduction in renal blood flow (31), although a pharmacodynamic affect on the bone marrow could not be excluded.…”

Section: Discussionmentioning

confidence: 99%

A Phase I Trial of Radioimmunotherapy with 131I-A5B7 Anti-CEA Antibody in Combination with Combretastatin-A4-Phosphate in Advanced Gastrointestinal Carcinomas

Meyer

Gaya²,

Dancey

et al. 2009

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: In preclinical models, radioimmunotherapy with 131 I-A5B7 anti^carcinoembryonic antigen (CEA) antibody ( 131 I-A5B7) combined with the vascular disruptive agent combretastatin-A4-phosphate (CA4P) produced cures unlike either agent alone. We conducted a phase I trial determining the dose-limiting toxicity (DLT), maximum tolerated dose, efficacy, and mechanism of this combination in patients with gastrointestinal adenocarcinomas. Experimental Design: Patients had CEA of 10 to 1,000 Ag/L, QTc V450 ms, no cardiac arrhythmia/ischaemia, and adequate hematology/biochemistry.Tumor was suitable for blood flow analysis by dynamic contrast enhanced-magnetic resonance imaging (MRI).

show abstract

Phase I Trial of Combretastatin A-4 Phosphate with Carboplatin

Cited by 91 publications

References 21 publications

Antitumor and Antivascular Effects of AVE8062 in Ovarian Carcinoma

Antitumor and Antivascular Effects of AVE8062 in Ovarian Carcinoma

Effect of the Second-Generation Vascular Disrupting Agent OXi4503 on Tumor Vascularity

A Phase I Trial of Radioimmunotherapy with 131I-A5B7 Anti-CEA Antibody in Combination with Combretastatin-A4-Phosphate in Advanced Gastrointestinal Carcinomas

Contact Info

Product

Resources

About