A phase I dose-finding study of a combination of pegylated liposomal doxorubicin (Doxil), carboplatin and paclitaxel in ovarian cancer

Abstract

Standard chemotherapy for advanced epithelial ovarian cancer is a combination of platinum-paclitaxel. One strategy to improve the outcome for patients is to add other agents to standard therapy. Doxil is active in relapsed disease and has a response rate of 25% in platinum-resistant relapsed disease. A dose finding study of doxil-carboplatin-paclitaxel was therefore undertaken in women receiving first-line therapy. Thirty-one women with epithelial ovarian cancer or mixed Mullerian tumours of the ovary were enrolled. The doses of carboplatin, paclitaxel and doxil were as follows: carboplatin AUC 5 and 6; paclitaxel, 135 and 175 mg m 72 ; doxil 20, 30, 40 and 50 mg m 72 . Schedules examined included treatment cycles of 21 and 28 days, and an alternating schedule of carboplatin-paclitaxel (q 21) with doxil being administered every other course (q 42). The dose-limiting toxicities were found to be neutropenia, stomatitis and palmar plantar syndrome and the maximum tolerated dose was defined as; carboplatin AUC 5, paclitaxel 175 mg m 72 and doxil 30 mg m 72 q 21. Reducing the paclitaxel dose to 135 mg m 72 did not allow the doxil dose to be increased. Delivering doxil on alternate cycles at doses of 40 and 50 mg m 72 also resulted in dose-limiting toxicities. The recommended doses for phase II/III trials are carboplatin AUC 6, paclitaxel 175 mg m 72 , doxil 30 mg m 72 q 28 or carboplatin AUC 5, paclitaxel 175 mg m 72 , doxil 20 mg m 72 q 21. Grade 3/4 haematologic toxicity was common at the recommended phase II doses but was short lived and not clinically important and non-haematologic toxicities were generally mild and consisted of nausea, paraesthesiae, stomatitis and palmar plantar syndrome.

Pharmacokinetic and Toxicodynamic Characterization of a Novel Doxorubicin Derivative

“…Doxorubicin (Dox) is an effective anti-cancer medication that has been clinically used to treat a variety of cancers including breast, ovarian, and lymphoma [ 1 , 2 , 3 , 4 , 5 ]. Despite the clinical effectiveness of Dox, its use is limited by off-target adverse effects, particularly dose-related cardiotoxicity and renal toxicity, which involve free radical formation and tissue damage.…”

Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity

“…PLD is therefore considered for use in combination with PTX, DCT, or carboplatin-PTX (Sparano et al, 2001;Gibbs et al, 2002;Mavroudis et al, 2002;Campos et al, 2003).…”

Phase II multicenter open-label study of carboplatin and pegylated liposomal doxorubicin in uterine and cervical malignancies

“…Further investigation of the combination of carboplatin with PLD ± a taxane is warranted. A phase I study of this particular combination in women with ovarian cancer has already been published (30) and phase three study will start in Summer 2005.…”

“…This is thought to occur due to the small size (∼100 nm diameter) of the liposomes, which allows them to pass through endothelial gaps or leaky membranes more commonly found in tumors (15–17) . PLD has shown clinical activity in Kaposi's sarcoma (18–20) , breast cancer (21–25) , hepatocellular carcinoma (26) , and ovarian cancer (27–30) . Encouraging findings in patients receiving PLD in nonovarian gynecological cancers (27) have been reported.…”