Dose-finding and pharmacologic study of chronic oral idarubicin therapy inmetastatic breast cancer patients

Oral idarubicin (IDA) is an active drug In metastatic breast cancer, but it s role In the management of this tumor is yet not established completely. T o investigate a new modality of IDA administration, a dose-finding study wa s designed with hyperfractionated doses. The purpose was to determine the m aximum tolerated dose (MTD), the dose-limiting toxicity (DLT), and the phar macokinetics of this schedule. IDA was administered twice daily as outpatie nt therapy in cycles of 3 weeks followed by a 1-week rest. Thirty-one patie nts with progressive metastatic breast cancer and pretreated with chemother apy (including epirubicin and doxorubicin) were enrolled. DLT was defined a s G4 hematological toxicity or any other toxicity G3 or higher (Bloom and R ichardson grading). Inter- and intrapatient dose increases were studied. Ph armacokinetics of IDA and its metabolite idarubicinol(IDOL) were evaluated. IDA dose was increased from 2 mg/day to 10 mg/day, by steps of 1 mg/day, w ith the larger dose given in the evening. MTD was reached at 10 mg/day, Ove rall, the therapy cycles were 69 (median/patient, 2; range, 1-6), DLTs were G4 neutropenia associated with leukopenia and thrombocytopenia in one pati ent and G3 diarrhea in another of the 5 patients in the 10 mg/day cohort. T he two patients developing DLT at the daily dose of 10 mg received a dose n ormalized for body surface of 6.85 and 5.65 mg/m(2)/day, respectively. We c onsidered 5.5 mg/m(2)/day to be the MTD. Other toxicities were nausea, vomi ting, neutropenia, and diarrhea, grades G1 to G2. By univariate analysis, s ignificant correlations were observed between absolute neutrophil count at nadir and IDA area under the curve (P = 0.022; r = -0.33). IDA C-max (P = 0 .0067; r = -0.38). IDOL area under the curve (P = 0.0009; r = -0.43), and I DOL C-max (P = 0.0016; r = -0.41), respectively. By multivariate analysis, IDA C-max was the strongest determinant for neutropenia (R-2 = 0.14; P = 0. 01), Among the 21 patients evaluable for response, 3 (14.3%) had partial re sponse (lasting 3, 6, and 8 months, respectively), and 6 (28.6%) had a comp lete arrest of disease progression (lasting 2-6 months). In conclusion, the MTD of this schedule is 10 mg/day and the DLTs are neutropenia and diarrhe a. Tolerance was good, and the treatment is feasible as home therapy. Some objective measurable responses were documented in this group of anthracycli ne-pretreated patients. IDOL could have a role for the pharmacological effe ct. Further evaluation of this schedule is warranted to assess the activity and toxicity of prolonged oral IDA administration.