title: A phase I study of TNP-470 administered to patients with advanced squamous cell cancer of the cervix.
abstract: 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.
authors.affiliation: Departments of Clinical Investigations, Gynecologic Oncology, Clinical Immunology and Biological Therapy, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas 77030-4059, USA.
authors.forename: A P
authors.initials: AP
authors.lastname: Kudelka
authors.forename: T
authors.initials: T
authors.lastname: Levy
authors.forename: C F
authors.initials: CF
authors.lastname: Verschraegen
authors.forename: C L
authors.initials: CL
authors.lastname: Edwards
authors.forename: S
authors.initials: S
authors.lastname: Piamsomboon
authors.forename: W
authors.initials: W
authors.lastname: Termrungruanglert
authors.forename: R S
authors.initials: RS
authors.lastname: Freedman
authors.forename: A L
authors.initials: AL
authors.lastname: Kaplan
authors.forename: D G
authors.initials: DG
authors.lastname: Kieback
authors.forename: C A
authors.initials: CA
authors.lastname: Meyers
authors.forename: K A
authors.initials: KA
authors.lastname: Jaeckle
authors.forename: E
authors.initials: E
authors.lastname: Loyer
authors.forename: M
authors.initials: M
authors.lastname: Steger
authors.forename: R
authors.initials: R
authors.lastname: Mante
authors.forename: G
authors.initials: G
authors.lastname: Mavligit
authors.forename: A
authors.initials: A
authors.lastname: Killian
authors.forename: R A
authors.initials: RA
authors.lastname: Tang
authors.forename: J U
authors.initials: JU
authors.lastname: Gutterman
authors.forename: J J
authors.initials: JJ
authors.lastname: Kavanagh
mesh_terms: D000328:Adult; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology / Q000628:therapy; D003131:Combined Modality Therapy; D003510:Cyclohexanes; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D009422:Nervous System Diseases / Q000139:chemically induced; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D016879:Salvage Therapy; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000628:therapy
chemical_list: D000903:Antibiotics, Antineoplastic; D003510:Cyclohexanes; D012717:Sesquiterpenes; D000077609:O-(Chloroacetylcarbamoyl)fumagillol