10-Propargyl-10-deazaaminopterin: An antifolate with activity in patients with previously treated non-small cell lung cancer Journal Article

Authors: Krug, L. M.; Azzoli, C. G.; Kris, M. G.; Miller, V. A.; Khokhar, N. Z.; Tong, W.; Ginsberg, M. S.; Venkatraman, E.; Tyson, L.; Pizzo, B.; Baez, V.; Ng, K. K.; Sirotnak, F. M.
Article Title: 10-Propargyl-10-deazaaminopterin: An antifolate with activity in patients with previously treated non-small cell lung cancer
Abstract: Purpose: 10-propargyl-10-deazaaminopterin (PDX) has superior antitumor efficacy in mouse xenograft models, likely attributable to increased uptake by the RFC-1 folate transporter and greater intracellular polyglutamylation. In a previous Phase I trial, stomatitis was the dose-limiting (and only clinically significant) toxicity of PDX. The recommended Phase II dose was 150 mg/m2 i.v. every 2 weeks. Responses observed in patients with non-small cell lung cancer (NSCLC) in the Phase I trial prompted this Phase II trial. Experimental Design: Patients had stage IIIB or IV NSCLC and either no previous chemotherapy or progression after initial response or stable disease to one previous chemotherapy regimen. Initially, PDX was administered at a dose of 150 mg/m2 every 2 weeks. However, to decrease the frequency of stomatitis, the last 10 patients were treated at a dose of 135 mg/m2. We planned to correlate PDX effects with folate and homocysteine levels and the expression of genes associated with folate transport and polyglutamylation. Results: Thirty-nine patients were enrolled, 38 of whom were evaluable for response. Four patients had confirmed, major objective responses (10% based on intent to treat, 95% confidence interval 3-25) lasting 4, 9, 12, and 15 months. Twelve patients (31%) had stable disease. The median survival was 13.5 months. The predicted 1- and 2-year survival rates were 56 and 36%, respectively. Two patients (5%) suffered grade 4 stomatitis, and 6 (15%) had grade 3. No clinically significant myelosuppression occurred. No correlation between homocysteine or serum folate levels and severity of stomatitis was observed. Area under the curve (calculated using a limited sampling model) correlated with mucositis grade. A trend was noted between folate transporter expression and treatment effect. Conclusions: The broad applicability of this new antifolate with limited toxicity and proven efficacy in NSCLC encourage further development of this compound. Several trials are now underway combining PDX with other chemotherapeutic agents and testing its efficacy in other cancers.
Keywords: adult; cancer survival; clinical article; aged; middle aged; survival rate; unclassified drug; clinical trial; fatigue; neutropenia; area under the curve; drug efficacy; drug eruption; liver toxicity; phase 2 clinical trial; anemia; bone marrow suppression; blood toxicity; leukopenia; lung non small cell cancer; nausea; stomatitis; thrombocytopenia; carcinoma, non-small-cell lung; lung neoplasms; membrane proteins; antineoplastic activity; prediction; alanine aminotransferase blood level; aspartate aminotransferase blood level; dyspnea; lung embolism; alanine aminotransferase; aspartate aminotransferase; chemotherapy induced emesis; drug fatality; correlation analysis; rna, messenger; carrier proteins; folic acid; homocysteine; folic acid antagonist; folic acid antagonists; alopecia; epistaxis; aminopterin; membrane transport proteins; aminopterin derivative; humans; human; male; female; priority journal; article; 10 propargyl 10 deazaminopterin; folic acid blood level
Journal Title: Clinical Cancer Research
Volume: 9
Issue: 6
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2003-06-01
Start Page: 2072
End Page: 2078
Language: English
PUBMED: 12796370
PROVIDER: scopus
Notes: Export Date: 12 September 2014 -- Source: Scopus