PHASE-I TRIAL OF INTRAVENOUS CARBOPLATIN AND CYCLOSPORINE-A IN REFRACTORY GYNECOLOGIC CANCER-PATIENTS

Our objective was to determine the maximum tolerated dose of cyclospor in A (CsA) delivered as a loading dose (LD) and continuous i.v. infusi on (CI) in combination with carboplatin in patients with refractory gy necologic cancers, Twenty-nine heavily pretreated patients (25 ovarian epithelial, 2 cervical, and 2 endometrial carcinomas) received 113 cy cles of CsA and carboplatin from September 1989 to September 1991, Twe nty-four of these 29 carcinomas were strictly defined to be platinum r esistant, CsA was administered as a LD escalated from 6 to 10 mg/kg fo llowed by a 24-h CI from 2.5 to 14.5 mg/kg/day, Carboplatin was target ed 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 (f luorescence polarization immunoassay) at the maximum tolerated dose (1 0 mg/kg LD, 14.5 mg/kg/day CI) ranged from 2.4 to 3.0 mu g/ml over 12 h, Estimated median carboplatin AUC, based on calculated carboplatin c learance, was 7.9 mg/ml x min, The dose-limiting toxicity of the combi nation of CsA and carboplatin was grade 4 thrombocytopenia. Grade 3 or 3 thrombocytopenia occurred in 35% of the patients, which could be ex plained by the effects of carboplatin (AUC of 6 mg/ml x min) alone, Ov erall, neutropenia occurred in 24% of the patients and anemia in 17% o f the patients, Grade 3 or 4 nausea or vomiting was noted in 10 and 14 % of the patients, respectively, Grade 3 hypertension during CsA admin istration occurred in 14% of the patients, No grade 3 or 4 nephrotoxic ity was seen in this trial, Three objective responses were noted: one complete response (11 months) and one partial response (5 months), bot h in potentially platinum-sensitive patients with platinum-free interv als of only 9 months each, One platinum-resistant patient had a partia l response for 21 months, Five additional patients experienced >75% re duction of CA-125 or a return to a normal CA-125 titer, We concluded t hat whole-blood CsA concentrations of >3.0 mu g/ml (as seen when CsA i s used as a modulator of multidrug resistance) were not achievable in this combination with carboplatin in this population of heavily pretre ated gynecologic cancer patients, However, because CsA is used in this trial as a chemosensitizer in platinum-sensitive tumors and as a chem omodulator of platinum resistance, we targeted a CsA concentration of >1.0 mu g/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, wh ich results in blood CsA concentrations ranging from 1.2 to 1.3 mu g/m l over 12 h, Responses in this population of refractory gynecologic ca ncer patients are unusual, and these encouraging results form the basi s for a Phase II trial of this combination.