A phase 1 study of pralatrexate in combination with paclitaxel or docetaxel in patients with advanced solid tumors.
OBJECTIVE
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.


METHODS
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 B(12) 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/m(2) plus docetaxel 35 mg/m(2) 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/m(2)) plus docetaxel (35 mg/m(2)) plus vitamin supplementation is well tolerated with signs of efficacy against non-small-cell lung cancer that merit phase 2 testing.
Azzoli
Christopher G
CG
Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. azzolic@mskcc.org
Krug
Lee M
LM
Gomez
Jorge
J
Miller
Vincent A
VA
Kris
Mark G
MG
Ginsberg
Michelle S
MS
Henry
Roxanne
R
Jones
Jessica
J
Tyson
Leslie
L
Dunne
Megan
M
Pizzo
Barbara
B
Farmer
Amy
A
Venkatraman
Ennapadam
E
Steffen
Robert
R
Sirotnak
F M
FM
D000328:Adult; D000368:Aged; D000630:Aminopterin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects*; D019587:Dietary Supplements; D000077143:Docetaxel; D005260:Female; D005493:Folic Acid Antagonists / Q000008:administration & dosage / Q000009:adverse effects*; D006710:Homocysteine / Q000097:blood; D006801:Humans; D008297:Male; D008764:Methylmalonic Acid / Q000097:blood; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects*; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects*; D014815:Vitamins / Q000008:administration & dosage
C418863:10-propargyl-10-deazaaminopterin; D005493:Folic Acid Antagonists; D043823:Taxoids; D014815:Vitamins; D006710:Homocysteine; D000077143:Docetaxel; D008764:Methylmalonic Acid; D000630:Aminopterin; D017239:Paclitaxel