o-(chloroacetylcarbamoyl)fumagillol and Uterine-Cervical-Neoplasms

Treatment options for women with metastatic, persistent, or recurrent cervical cancer are limited and thus the disease portends a poor prognosis. It is critical to understand the pathophysiology of cervical cancer to better delineate therapeutic targets. The development of antiangiogenic therapies and their subsequent analysis in rigorous therapeutic trials have redefined current management strategies and is an exciting area of current exploration.. Translational trials have furthered the understanding of molecular determinants of angiogenesis. Phase II trials have shown promising trends with developing antiangiogenic therapies. A practice-changing phase III trial has recently been published. Given the potential benefits and different toxicity spectrum compared with standard cytotoxic chemotherapy, antiangiogenic options are under active investigation for this vulnerable patient population. Emerging data are promising for other antiangiogenic-directed therapeutics, as well as cervical cancer molecular biomarkers to guide diagnosis and treatment.. Antiangiogenic therapies have evolved during the past 20 years and remain an exciting area of current exploration.. Understanding of the angiogenic microenvironment has furthered understanding of tumor biology and management. Antiangiogenic therapies show promise for women with advanced cervical cancer. A review of the evolution of these biologic agents shows them to be an effective and tolerable management strategy for many patients in this vulnerable population, with exciting future potential.

Topics: Angiogenesis Inhibitors; Bevacizumab; Clinical Trials as Topic; Cyclohexanes; Female; Humans; Neoplasm Metastasis; Neoplasm Recurrence, Local; O-(Chloroacetylcarbamoyl)fumagillol; Prognosis; Sesquiterpenes; Uterine Cervical Neoplasms

A Phase I study of the novel angiogenesis inhibitor TNP-470 was performed. Patients with inoperable recurring or metastatic squamous cell cancer of the cervix with evaluable disease, no coagulopathy, and adequate renal, hepatic, and hematological function were eligible. One course of treatment consisted of an i.v. infusion of TNP-470 over 60 min every other day for 28 days, followed by a 14-day rest period. The starting dose was 9.3 mg/m2. Eighteen evaluable patients were treated, with a median age of 48 years (range 27-55) and performance status Zubrod 1 (range 0-2). Grade 3 neurotoxicities consisting of weakness, nystagmus, diplopia, and ataxia were encountered in two patients receiving the 71.2 mg/m2 dose. An intermediate dose level of 60 mg/m2 was evaluated and found to be well tolerated by three patients. Only one patient experienced grade 3 nausea on the 60 mg/m2 dose level. No myelosuppression, retinal hemorrhage, weight loss, or significant alopecia were observed. One patient had a complete response, which continues for 26 months, and three patients with initially progressive disease stage had stable disease for 5, 7.7, and 19+ months. Other Phase I studies, including over 200 patients, were performed concurrently with this study. Based on this experience, the dose of TNP-470 recommended for further studies is 60 mg/m2 as a 60-min i.v. infusion every Monday, Wednesday, and Friday. Neurotoxicity was dose limiting, but appears to be reversible. Otherwise, the treatment was well tolerated. The drug may be active in squamous cell cancer of the cervix. Further studies of TNP-470 in squamous cell cancer of the cervix are warranted.

Topics: Adult; Antibiotics, Antineoplastic; Carcinoma, Squamous Cell; Combined Modality Therapy; Cyclohexanes; Dose-Response Relationship, Drug; Female; Humans; Infusions, Intravenous; Middle Aged; Nausea; Neovascularization, Pathologic; Nervous System Diseases; O-(Chloroacetylcarbamoyl)fumagillol; Salvage Therapy; Sesquiterpenes; Treatment Outcome; Uterine Cervical Neoplasms

Topics: Angiogenesis Inhibitors; Animals; Antibiotics, Antineoplastic; Clinical Trials as Topic; Cyclohexanes; Female; Glioblastoma; Humans; Melanoma, Experimental; Mice; O-(Chloroacetylcarbamoyl)fumagillol; Rats; Sesquiterpenes; Tumor Stem Cell Assay; Uterine Cervical Neoplasms

Topics: Antibiotics, Antineoplastic; Carcinoma, Squamous Cell; Clinical Trials, Phase I as Topic; Cyclohexanes; Female; Humans; Lung Neoplasms; Middle Aged; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes; Uterine Cervical Neoplasms