A phase I trial of AUC-directed carboplatin with infusional doxorubicin and ifosfamide plus G-CSF in patients with advanced gynecologic malignancies

The effect of the addition of G-CSF to carboplatin, ifosfamide and doxorubi cin (CIA) at the maximally tolerated dose (MTD) was studied in a phase I cl inical trial. Nine patients with incurable solid tumors were treated: six e ndometrial and epithelial ovarian cancers, one colon cancer with pelvic mas ses and two unknown primary cancers. The carboplatin dose was calculated us ing the Calvert formula and administered in a standard 30-min intravenous i nfusion. The initial carboplatin dose was AUC 4.0 mg/ml per min. Fixed dose s of ifosfamide (1.25 g/m(2) per day) mesna (1.0 g/m(2) per day, and doxoru bicin (15 mg/m(2) per day) were combined and given as a 4-day continuous in travenous infusion in an attempt to decrease nonhematologic toxicity. The d ose-limiting toxicity of CIA was myelosuppression, mainly neutropenia and t hrombocytopenia. Nonhematologic toxicities were hemorrhagic cystitis, weakn ess, fatigue, and nausea and vomiting. The MTD for CIA was established at t he first dose level of carboplatin (4.0 mg/ml per min). Following this, G-C SF was added to the regimen in an unsuccessful effort to escalate the carbo platin dose. Free and total carboplatin pharmacokinetics were determined us ing flameless atomic absorption spectroscopy. There was one complete respon se and one partial response among eight evaluable patients. Both responding patients had advanced ovarian cancer. We conclude that carboplatin dose in tensification beyond an AUC of 4.0 mg/ ml per min is not made feasible by t he addition of G-CSF to infusional doxorubicin and ifosfamide in patients w ith advanced gynecologic cancer.