Docosahexaenoic acid-paclitaxel administered weekly to a maximum dose of 600 mg/m(2) was well-tolerated. The slow release of paclitaxel from DHA-paclitaxel and the weekly schedule approximates continuous infusion paclitaxel which may be more active than every 3 week or weekly taxanes.

Background: We conducted a single-arm, dose-escalation, phase 1 clinical trial in order to define the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of bexarotene in combination with docetaxel. Methods: Patients with solid tumors and no other curative treatment options were eligible. Oral bexarotene was taken daily in combination with docetaxel 25 mg/m² administered intravenously on days 1, 8, and 15 of a 28-day cycle. The dose of bexarotene started at 200 mg/m² and increased by 100 mg/m²/dose level, until either a MTD or the final dose of 400 mg/m² was reached. Results:Fifteen patients were enrolled in the study. Median age was 58 years. The majority had non-small-cell lung cancer. The study went to completion without reaching an MTD. Hematological toxicities were mild. Three patients developed grade 3 hypertriglyceridemia, all occurring during the first cycle of treatment. No objective responses were noted. Four patients had stable disease as a best response, 3 with non-small-cell lung cancer and 1 with angiosarcoma. Conclusions:Treatment was well tolerated and no DLT was seen at docetaxel 25 mg/m² and bexarotene 400 mg/m². Given that stable disease was durable in 4 patients, future studies with this combination may be warranted.

Background: Preclinical studies have shown synergism between topoisomerase I and II inhibitors. Methods: We conducted a phase I study evaluating the combination of pegylated liposomal doxorubicin and irinotecan in patients with previously treated solid tumors. Results: Twelve patients were enrolled. The median age was 62 years (range 19–72). The most common grade 3/4 toxicities were neutropenia (dose-limiting toxicity), diarrhea and nausea/vomiting. The maximal tolerated dose and recommended schedule were pegylated liposomal doxorubicin 20 mg/m² over 60 min on day 1, followed by irinotecan 100 mg/m² over 90 min on days 1 and 8 of a 21-day cycle. There were no objective clinical responses, but 5 patients achieved stable disease lasting a median of 11 weeks duration (range 2–35). Conclusions: This regimen should be further studied in patients with tumors known to have a sensitivity to both topoisomerase I and II inhibitors such as ovarian and small cell carcinoma.

Objectives: Multidrug resistance mediated by P-glycoprotein is a potential obstacle to cancer treatment. This phase 1 trial determined the safety of paclitaxel with valspodar, a P-glycoprotein inhibitor, in patients with advanced solid tumors. Methods: Patients were treated with single-agent paclitaxel Q3W 175 mg/m2 (or 135 mg/m2 if heavily pretreated) as a 3-hour infusion. If their disease was stable (SD) or progressive (PD), paclitaxel at 30% (52.5 mg/m2), 40% (70 mg/m2), or 50% (87.5 mg/m2) of 175 mg/m2 (full dose) was administered with valspodar 5 mg/kg orally 4 times daily for 12 doses. Pharmacokinetic sampling (PK) for paclitaxel and valspodar was performed during single-agent and combination therapy. Results: Sixteen patients had SD/PD after one cycle of paclitaxel and then received paclitaxel at 30% (n=3), 40% (n=3), and 50% (n=10) with valspodar. Hematologic adverse events (AEs) including myelosuppression at paclitaxel 40% were comparable to those of full-dose paclitaxel. Non-hematologic AEs consisted of reversible hepatic (hyperbilirubinemia and transaminitis) and neurologic AEs (ataxia and paresthesias). Eleven patients experienced SD with a median of 12.7 weeks (range, 5.4 to 36.0), 4 patients progressed, and 1 was inevaluable. Reduced dose paclitaxel with valspodar resulted in lower plasma peak concentrations of paclitaxel; otherwise, concentrations were similar to single-agent paclitaxel. Conclusion: Paclitaxel at 70 mg/m2 was administered safely with valspodar. Limited efficacy in hematologic and solid tumors resulted in discontinuation of its clinical development and other transporter inhibitors. Recently, the development of ATP-binding cassette transporter inhibitors has been reconsidered to mitigate resistance to antibody-drug conjugates.