10-propargyl-10-deazaaminopterin: an antifolate with activity in patients with previously treated non-small cell lung cancer.
OBJECTIVE
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/m(2) 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.


METHODS
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/m(2) every 2 weeks. However, to decrease the frequency of stomatitis, the last 10 patients were treated at a dose of 135 mg/m(2). 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.
Krug
Lee M
LM
Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Weill Medical College of Cornell University New York, New York 10021, USA. krugl@mskcc.org
Azzoli
Christopher G
CG
Kris
Mark G
MG
Miller
Vincent A
VA
Khokhar
Nushmia Z
NZ
Tong
William
W
Ginsberg
Michelle S
MS
Venkatraman
Ennapadam
E
Tyson
Leslie
L
Pizzo
Barbara
B
Baez
Valerie
V
Ng
Kenneth K
KK
Sirotnak
F M
FM
D000328:Adult; D000368:Aged; D000630:Aminopterin / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D002352:Carrier Proteins / Q000235:genetics; D005260:Female; D005493:Folic Acid Antagonists / Q000627:therapeutic use*; D006710:Homocysteine / Q000097:blood; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D026901:Membrane Transport Proteins; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis
C418863:10-propargyl-10-deazaaminopterin; D002352:Carrier Proteins; D005493:Folic Acid Antagonists; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D012333:RNA, Messenger; C120043:SLC19A2 protein, human; C492292:Slc19a2 protein, mouse; D006710:Homocysteine; D000630:Aminopterin