title: Phase I trial of intravenous carboplatin and cyclosporin A in refractory gynecologic cancer patients.
abstract: Our objective was to determine the maximum tolerated dose of cyclosporin A (CsA) delivered as a loading dose (LD) and continuous i.v. infusion (CI) in combination with carboplatin in patients with refractory gynecologic cancers. Twenty-nine heavily pretreated patients (25 ovarian epithelial, 2 cervical, and 2 endometrial carcinomas) received 113 cycles of CsA and carboplatin from September 1989 to September 1991. Twenty-four of these 29 carcinomas were strictly defined to be platinum resistant. CsA was administered as a LD escalated from 6 to 10 mg/kg followed by a 24-h CI from 2.5 to 14.5 mg/kg/day. Carboplatin was targeted to an area under the time versus concentration curve (AUC) of 6 mg/ml x min and was not dose escalated. Whole-blood CsA concentrations (fluorescence polarization immunoassay) at the maximum tolerated dose (10 mg/kg LD, 14.5 mg/kg/day CI) ranged from 2.4 to 3.0 microgram/ml over 12 h. Estimated median carboplatin AUC, based on calculated carboplatin clearance, was 7.9 mg/ml x min. The dose-limiting toxicity of the combination of CsA and carboplatin was grade 4 thrombocytopenia. Grade 3 or 4 thrombocytopenia occurred in 35% of the patients, which could be explained by the effects of carboplatin (AUC of 6 mg/ml x min) alone. Overall, neutropenia occurred in 24% of the patients and anemia in 17% of the patients. Grade 3 or 4 nausea or vomiting was noted in 10 and 14% of the patients, respectively. Grade 3 hypertension during CsA administration occurred in 14% of the patients. No grade 3 or 4 nephrotoxicity was seen in this trial. Three objective responses were noted: one complete response (11 months) and one partial response (5 months), both in potentially platinum-sensitive patients with platinum-free intervals of only 9 months each. One platinum-resistant patient had a partial response for 21 months. Five additional patients experienced >75% reduction of CA-125 or a return to a normal CA-125 titer. We concluded that whole-blood CsA concentrations of >3.0 microgram/ml (as seen when CsA is used as a modulator of multidrug resistance) were not achievable in this combination with carboplatin in this population of heavily pretreated gynecologic cancer patients. However, because CsA is used in this trial as a chemosensitizer in platinum-sensitive tumors and as a chemomodulator of platinum resistance, we targeted a CsA concentration of >1.0 microgram/ml, which was achieved. The CsA dose recommended for a Phase II trial of this combination is 10 mg/kg LD and 11.6 mg/kg/day CI, which results in blood CsA concentrations ranging from 1.2 to 1.3 microgram/ml over 12 h. Responses in this population of refractory gynecologic cancer patients are unusual, and these encouraging results form the basis for a Phase II trial of this combination.
authors.affiliation: Departments of Obstetrics and Gynecology, Surgery, and Pharmacology and Comprehensive Cancer Center Clinical Research Office, Yale University School of Medicine, New Haven, Connecticut 06520-8063, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Chambers
authors.forename: C A
authors.initials: CA
authors.lastname: Davis
authors.forename: J T
authors.initials: JT
authors.lastname: Chambers
authors.forename: P E
authors.initials: PE
authors.lastname: Schwartz
authors.forename: M I
authors.initials: MI
authors.lastname: Lorber
authors.forename: R E
authors.initials: RE
authors.lastname: Hschumacher
mesh_terms: D000740:Anemia / Q000139:chemically induced; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D016190:Carboplatin / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016572:Cyclosporine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D006973:Hypertension / Q000139:chemically induced; D007022:Hypotension / Q000139:chemically induced; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007262:Infusions, Intravenous; D007970:Leukopenia / Q000139:chemically induced; D009325:Nausea / Q000139:chemically induced; D009503:Neutropenia / Q000139:chemically induced; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced
chemical_list: D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D016190:Carboplatin