Pralatrexate: basic understanding and clinical development.
BACKGROUND
Pralatrexate (PDX; 10-propargyl 10-deazaaminopterin), is an exciting new chemotherapeutic agent that is approved for the treatment of relapsed and refractory peripheral T-cell lymphomas (PTCL). This is the only approved therapy for patients with PTCL.


METHODS
This review describes the clinical development of PDX from its synthesis to its FDA approval. It details the biochemical basis of the differences between PDX and other antifolates that form the basis of the superiority of its activity. This is followed by a description of the preclinical data that led to early-phase clinical trials in lung cancer and lymphoma and, finally, the definitive trial that led to its approval in PTCL. The review also describes how PDX is being combined with other agents in both the preclinical and clinical arenas.


RESULTS
These trials have been instrumental in defining a safe dose as well as the safety profile of the agent. FDA approval for the use of PDX in PTCL has been granted based on the results of the pivotal Phase II trial of this agent in relapsed and refractory PTCL patients.


CONCLUSIONS
PDX is a unique antifolate that has been rationally designed to have a high affinity for the reduced folate receptor (RFC-1) and the enzyme folylpolyglutamy synthetase. It is active in T-cell lymphomas and non-small-cell lung cancer. It is now being studied in combination with other chemotherapeutic and targeted agents for the treatment of hematological malignancies.
NYU Langone Medical Center-Hematology/Oncology, 160 East 34th Street, New York 10016, USA. jasmine.zain@nyumc.org
Jasmine
J
Zain
Owen
O
O'Connor
D000630:Aminopterin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D002986:Clinical Trials as Topic; D004353:Drug Evaluation, Preclinical; D005493:Folic Acid Antagonists / Q000627:therapeutic use*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D008223:Lymphoma / Q000188:drug therapy; D009369:Neoplasms / Q000188:drug therapy*
C418863:10-propargyl-10-deazaaminopterin; D005493:Folic Acid Antagonists; D000630:Aminopterin