Pemetrexed combined with paclitaxel: a dose-finding study evaluating three schedules in solid tumors

Area of Science:

• Oncology
• Clinical Pharmacology
• Drug Development

Background:

• Pemetrexed and paclitaxel are established chemotherapy agents.
• Combination chemotherapy can improve efficacy in advanced solid tumors.
• Optimizing dosing and schedules is crucial for safety and effectiveness.

Purpose of the Study:

• Determine the maximum tolerated dose (MTD) and recommended phase II dose (RD) of pemetrexed-paclitaxel combination therapy.
• Evaluate the antitumor activity, safety, and pharmacokinetics of this combination.
• Identify optimal dosing schedules for pemetrexed and paclitaxel.

Main Methods:

• Phase I clinical trial with 95 patients having advanced solid tumors.
• Three different dosing schedules (S1, S2, S3) using pemetrexed and paclitaxel were evaluated over 21-day cycles.
• Dose-limiting toxicities (DLTs) and adverse events were meticulously recorded.

Main Results:

• The MTDs varied across schedules, with notable toxicities including febrile neutropenia, fatigue, and neuromotor issues.
• Grade 3/4 lymphopenia was the most frequent toxicity observed.
• The recommended phase II dose was established as pemetrexed 500 mg/m(2) (d8) and paclitaxel 90 mg/m(2) (d1 and d8), q21d.
• Partial responses were observed in 4 patients, and stable disease in 43 patients.

Conclusions:

• The pemetrexed-paclitaxel combination was found to be well-tolerated at the determined RD.
• The combination demonstrated promising efficacy in patients with thyroid carcinoma and mesothelioma.
• This study provides a foundation for further investigation of this combination in phase II/III trials.