A Phase I trial of Cis-diammine-1,1-cyclobutane dicarboxylate platinum II (Carboplatin, CBDCA, JM-8) with a single dose every five week-schedule

Abstract

Carboplatin, a new platinum analogue, was administered intravenously on a schedule of a single dose every five weeks to 23 patients with advanced malignant solid tumors. Patients were treated at six dosage levels ranging from 200-550 mg/m2 every five weeks. Thrombocytopenia was dose-limiting. At 550 mg/m2 Carboplatin, the median platelet nadir was 65 000/mm3. Leukopenia was common, but usually of mild to moderate degree. Gastrointestinal upset was commonly seen at all dose levels, but 35% of the patients experienced no vomiting. No significant increase of the serum creatinine following Carboplatin was seen. In 16 patients serial determinations of the creatinine clearance were performed. The median base line creatinine clearance was 87 (50-155) ml/min and dropped to a median lowest creatinine clearance of 69 (23-171) ml/min on day four (p less than 0.05). The median creatinine clearance before the next Carboplatin treatment was 89 (42-155) ml/min. No significant proteinuria or electrolyte disturbances were noted. Carboplatin exhibited antitumor activity in ovarian, endometrial, thyroid and gastric carcinomas. The maximally tolerated dose appears to be 550 mg/m2 every five weeks. A starting dose of 450 mg/m2 seems to be appropriate for Phase II studies. In patients with impaired renal function and/or prior cis-Platin chemotherapy, Carboplatin at doses of 200-500 mg/m2 induced renal and severe hematological toxicity.

Long-term follow-up and salvage surgery in patients with T2N0M0 squamous cell carcinoma of the glottic larynx who received concurrent chemoradiation therapy with carboplatin (CBDCA) – AUC 1.5 vs AUC 2.0

“…In preclinical studies, CDBCA was associated with markedly improved nephrotoxicity and reduced gastrointestinal toxicity, but more severe hematotoxicity, compared with CDDP. Phase I studies of CBDCA were primarily conducted in Europe and America [5][6][7], and showed that the dose-limiting factor (DLF) was hematotoxicity, as expected. In a Japanese phase I study, the DLFs were thrombocytopenia and leukopenia, and nephrotoxicity was mild and reversible, with a primary clinical toxicity of gastrointestinal disorder [8,9].…”

Exosomes as mediators of platinum resistance in ovarian cancer

“…The clinical introduction and use of platinum–based chemotherapeutics, specifically cis -diamminedichloroplatinum(II) (cisplatin), significantly improved overall survival (OS) by ~6 months in 29% of patients with ovarian cancer, leading the way to its adoption as the backbone of most chemotherapeutic regimens [1, 2]. In the mid-1980’s, a cisplatin analog, Carboplatin [cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II)], with an improved toxicity profile and equivalent therapeutic efficacy, replaced cisplatin as standard of care [3–5]. The last major advance occurred in the early 1990's with the introduction of the mitotic inhibitor, paclitaxel, that further improved OS 3-15 months (depending on the study) when used in combination with platinum [6–8].…”

Pharmacokinetics of ethylenediaminemalonatoplatinum(II) (JM-40) during phase I trial

“…These facts may explain the higher reactivity of JM-40 compared to carboplatin, and also why, from a pharmacokinetic point of view, JM-40 seems to be more related to cis-platin than to carboplatin (Vermorken et al, 1984bElferink et al, submitted;Harland et al, 1984). Besides, the dose-limiting toxicities of JM-40 (nephro and gastro-intestinal toxicity, (Winograd et al, 1986)) are similar to that of cis-platin, whereas the dose limiting toxicity of carboplatin is myelotoxicity (Joss et al, 1984). Vermorken et al (1985) indicated a relationship between the nephrotoxic properties of 6 platinum complexes and their stability in aqueous solution.…”