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A Phase 1 Study of Pralatrexate in Combination with Paclitaxel or Docetaxel in Patients with Advanced Solid Tumors

Authors' Affiliations: ¹ Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine; ² Department of Radiology, ³ Sloan-Kettering Institute, ⁴ Department of Nursing, ⁵ Clinical Trials Office, and ⁶ Biostatistics, Memorial Sloan-Kettering Cancer Center, Weill Medical College of Cornell University, New York, New York; and ⁷ Allos Therapeutics, Inc., Westminster, Colorado

Requests for reprints: Christopher G. Azzoli, Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Phone: 212-832-2834; Fax: 1-212-794-4357; E-mail: azzolic{at}mskcc.org.

Purpose: Pralatrexate is a rationally designed antifolate with greater preclinical antitumor activity than methotrexate. Pralatrexate was synergistic with paclitaxel and with docetaxel in mouse xenograft experiments. This phase 1 study was designed to determine the maximum tolerated dose and toxicity of pralatrexate plus paclitaxel or docetaxel in patients with advanced cancer.

Experimental Design: Pralatrexate was administered i.v. every 2 weeks (days 1 and 15) in a 4-week cycle. Depending on the taxane used and dose being tested, the taxane was administered on days 1 and 15; days 2 and 16; or days 1, 8, and 15. In the latter part of the study, patients in the docetaxel arm were treated with vitamin B₁₂ and folic acid supplementation to mitigate toxicity and allow pralatrexate dose escalation.

Results: For the combination of pralatrexate plus paclitaxel without vitamin supplementation, dose-limiting stomatitis and peripheral neuropathy were encountered at the lowest dose levels tested. For pralatrexate plus docetaxel plus vitamin supplementation, pralatrexate 120 mg/m² plus docetaxel 35 mg/m² administered on the same day every other week was defined as the maximum tolerated dose and schedule, with dose-limiting toxicities at higher dose combinations including stomatitis and asthenia. Significant antitumor activity was observed for this combination in patients with non–small-cell lung cancer.

Conclusions: Pralatrexate (120 mg/m²) plus docetaxel (35 mg/m²) plus vitamin supplementation is well tolerated with signs of efficacy against non–small-cell lung cancer that merit phase 2 testing.

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