Carboplatin (
CBDCA;
NSC 241240) is a second-generation
platinum coordination compound which in preclinical testing was found to be less nephrotoxic and emetogenic than
cis-diamminedichloroplatinum (CDDP), while retaining a broad spectrum of antitumor activity. We have conducted a Phase I trial of
CBDCA in 38 patients with advanced
carcinoma. The
drug was given without hydration as a 24-hr constant i.v. infusion on Day 1 of a 28-day cycle. Seventy-five cycles of
CBDCA were administered in eight dose levels ranging from 20 to 320 mg/sq m. Dose-limiting toxicity was myelosuppression, primarily
thrombocytopenia, occurring between Days 14 and 28 of the cycle. Myelosuppression was first observed at a dose of 240 mg/sq m and became dose-limiting at 320 mg/sq m, which is the recommended dose for Phase II trial. Other toxicities included
nausea and
vomiting and reversible
renal failure seen in two patients with low normal pretreatment
creatinine clearances. No consistent changes were seen on serial audiograms. Plasma concentrations of total and ultrafilterable
platinum were measured by flameless atomic absorption spectrophotometry. Following cessation of the infusion, a half-life of 170 +/- 34 min (S.D.) was found for
CBDCA-derived ultrafilterable
platinum. In vitro clonogenic assay of a CDDP-sensitive human
ovarian cancer cell line using clinically achievable
drug concentrations suggests that prolonged infusions of
CBDCA may be more cytotoxic than bolus administration. In this study, minimal responses were seen in two patients with ovarian
carcinoma who had failed previous
combination chemotherapy including CDDP. In addition, three patients with refractory metastatic
breast cancer responded to
CBDCA (two minimal responses and one partial response) with remission durations averaging 3 months.
CBDCA behaves as predicted by preclinical studies with different toxicities from CDDP and apparent activity in
breast cancer.