Pralatrexate, a
10-deazaaminopterin derivative, is being developed by Allos
Therapeutics Inc for the potential treatment of
malignancies. The
folate analog inhibits
dihydrofolate reductase and was developed to overcome the limitations of the
folate analog
methotrexate. Compared with
methotrexate in preclinical studies,
pralatrexate demonstrated superior intracellular transport via the
reduced folate carrier, and increased accumulation within cells by enhanced polyglutamylation. Preclinical studies in vitro and in models of
B-cell lymphomas,
T-cell lymphomas and NSCLC indicated that
pralatrexate exhibited antitumor activity that was superior to the activity of other
antifolates. In phase I clinical trials, the DLT for
pralatrexate was
mucositis, which could be abrogated with
folic acid and
vitamin B12 supplementation. The administration of
pralatrexate to patients with
T-cell lymphomas and NSCLC resulted in significant
tumor remissions. At the time of publication,
pralatrexate was in phase II clinical trials for the treatment of
peripheral T-cell lymphoma, a phase I/II trial in combination with
gemcitabine for the treatment of
non-Hodgkin's lymphoma, and a phase IIb trial in comparison with
erlotinib in patients with NSCLC. Because of the limited
therapies available for
peripheral T-cell lymphoma,
pralatrexate could have a secure niche for the treatment of this indication, if ongoing clinical trials and future phase III trials confirm the efficacy of the
drug. In contrast, for
pralatrexate to be incorporated into the accepted treatment options for NSCLC, the
drug will need to prove clear superiority to established agents.