Phase I study of CT-2103, a polymer-conjugated paclitaxel, and carboplatin in patients with advanced solid tumors

The primary objective of this study was to determine the maximum tolerated dose (MTD) of CT-2103 (poly L-glutamic acid-paclitaxel) in combination with carboplatin in patients with histologically proven solid tumors that were either refractory to conventional treatment or for which no conventional therapy was available.

Twenty-two adult patients with advanced solid tumors were treated in this dose escalation study. Patients were treated every 21 days with CT-2103 at 175, 210, 225, or 250 mg/m2 (doses expressed as units of conjugated-paclitaxel) via 10-20 minute intravenous (IV) infusion, followed one hour later with carboplatin administered at AUC 5 or 6 via 30 minute IV infusion. No prophylaxis for hypersensitivity was administered with initial treatment. Doses were administered every 21 days until progressive disease or dose-limiting toxicity (DLT) was observed. Toxicity was evaluated using NCI Common Toxicity Criteria for Adverse Events v2.0 (CTCAE v2.0); response to treatment was evaluated using Response Criteria in Solid Tumors (RECIST).

The MTD was determined to be 225 mg/m2. DLTs observed at 250 mg/m2 were neutropenia and thrombocytopenia. No hypersensitivity reactions were observed. Three patients achieved partial responses (PR). Fifteen patients received at least 3 cycles of treatment without observation of progressive disease. Median survival time was 5.9 months. Patients that demonstrated partial responses were all ovarian cancer patients that had previously failed paclitaxel therapy. The only Grade 4, nonhematologic treatment-related toxicity was febrile neutropenia. Grade 4 neutropenia (9 patients) was observed across all dose groups. Twelve patients developed thrombocytopenia (Grade 3/4) while receiving combination therapy. All had resolution of thrombocytopenia with discontinuation of carboplatin, suggesting that carboplatin, and not CT-2103, contributed mainly to platelet toxicity.

CT-2103 administered at 225 mg/m2 every 21 days in combination with carboplatin administered at AUC 6 has a manageable safety profile in patients with solid tumors; further clinical investigation is recommended, especially in patients with ovarian or non-small cell lung cancer.