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Drug description of pralatrexate:  Pralatrexate is a 1:1 racemic mixture of S- and R- diastereomers at the C10 position (indicated with *). The molecular formula is C23H23N7O5 and the molecular weight is 477.48 g/mol.  Pralatrexate is an off-white to yellow solid. It is soluble in aqueous solutions at pH 6.5 or higher. Pralatrexate is practically insoluble in chloroform and ethanol. The pKa values are 3.25, 4.76, and 6.17.  FOLOTYN (pralatrexate solution for intravenous injection) is supplied as a preservative-free, sterile, isotonic, non-pyrogenic clear yellow aqueous parenteral solution contained in a single-use clear glass vial (Type I) for intravenous administration. Each 1 mL of solution contains 20 mg of pralatrexate, sufficient sodium chloride to achieve an isotonic (280-300 mOsm) solution, and sufficient sodium hydroxide, and hydrochloric acid if needed, to adjust and maintain the pH at 7.5-8.5. FOLOTYN (pralatrexate solution for intravenous injection) is supplied as either 20 mg (1 mL) or 40 mg (2 mL) single-use vials at a concentration of 20 mg/mL.

Indications of pralatrexate: FOLOTYN (pralatrexate solution for intravenous injection) is indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). This indication is based on overall response rate. Clinical benefit such as improvement in progression-free survival or overall survival has not been demonstrated.

Mechanism of Action: Pralatrexate is a folate analog metabolic inhibitor that competitively inhibits dihydrofolate reductase. It is also a competitive inhibitor for polyglutamylation by the enzyme folylpolyglutamyl synthetase. This inhibition results in the depletion of thymidine and other biological molecules the synthesis of which depends on single carbon transfer.

Discovery history of pralatrexate:  Research on this class of drugs began in the 1950s at SRI International, where scientists were focused on developing new chemotherapies and antifolates that would be effective against tumor cells. In the late 1970s, researchers at Memorial Sloan Kettering Cancer Center discovered that cancerous cells take in natural folate through a protein identified as plasma membrane transporter (now referred to as “reduced folate carrier type 1” or “RFC-1”). Further research showed that when normal cells evolve into cancerous cells they often overproduce RFC-1 to ensure they get enough folate.  A subsequent scientific collaboration was ultimately formed among SRI International, Memorial Sloan Kettering Cancer Center, and the Southern Research Institute with the intention of developing an antifolate with greater therapeutic selectivity – an agent that could be more effectively internalized into tumors (transported into the cells through RFC-1) and would be more toxic to cancer cells than normal cells. This collaboration, supported by the National Cancer Institute, led to the identification of pralatrexate in the mid-1990s. Pralatrexate was later licensed to Allos Therapeutics in 2002 for further development. (source: http://en.wikipedia.org/wiki/Pralatrexate).

Highlight on recent results using pralatrexate

Data published in 2011:

Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: results from the pivotal PROPEL study. PURPOSE: Peripheral T-cell lymphoma (PTCL) is a poor prognosis subtype of non-Hodgkin's lymphoma with no accepted standard of care. This study evaluated the efficacy and tolerability of pralatrexate, a novel antifolate with promising activity. CONCLUSION:  To our knowledge, PROPEL (Pralatrexate in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma) is the largest prospective study conducted in patients with relapsed or refractory PTCL. Pralatrexate induced durable responses in relapsed or refractory PTCL irrespective of age, histologic subtypes, amount of prior therapy, prior methotrexate, and prior autologous stem-cell transplant. These data formed the basis for the US Food and Drug Administration approval of pralatrexate, the first drug approved for this disease. (source: J Clin Oncol. 2011 Mar 20;29(9):1182-9. Epub 2011 Jan 18. O'Connor OA, Pro B, Pinter-Brown L, Bartlett N, Popplewell L, Coiffier B, Lechowicz MJ, Savage KJ, Shustov AR, Gisselbrecht C, Jacobsen E, Zinzani PL, Furman R, Goy A, Haioun C, Crump M, Zain JM, Hsi E, Boyd A, Horwitz S.)

Data published in 2011:

Single agent and combination studies of pralatrexate and molecular correlates of sensitivity. BACKGROUND: Pralatrexate is a dihydrofolate reductase (DHFR) inhibitor with high affinity for reduced folate carrier 1 (RFC-1) and folylpolyglutamate synthetase (FPGS), resulting in extensive internalization and accumulation in tumour cells. Pralatrexate is approved in the US for the treatment of relapsed or refractory peripheral T-cell lymphoma and is being investigated in various malignancies. Here, we evaluated molecular correlates of sensitivity to pralatrexate and explored combinations with a variety of anticancer agents. CONCLUSION: Pralatrexate was more potent than methotrexate in a panel of solid tumour lines. Our findings support the further clinical development of pralatrexate in combination with certain cytotoxics and targeted therapies, and suggest that RFC-1, FPGS and DHFR may be potential biomarkers of outcome. [source: Br J Cancer. 2011 Jan 18;104(2):272-80. Epub 2010 Dec 21. Single agent and combination studies of pralatrexate and molecular correlates of sensitivity. Serova M, Bieche I, Sablin MP, Pronk GJ, Vidaud M, Cvitkovic E, Faivre S, Raymond E. Source INSERM U728, RayLab, and Departments of Medical Oncology, Beaujon University Hospital, Assistance Publique - Hôpitaux de Paris, Paris 7 Diderot, 100 boulevard du Général Leclerc, Clichy 92110, France.).

Data  published in 2010:

Folotyn (pralatrexate injection) for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma: U.S. Food and Drug Administration drug approval summary. PURPOSE: On September 24, 2009, the U.S. Food and Drug Administration granted accelerated approval for Folotyn (pralatrexate injection, Allos Therapeutics, Inc.) as a single agent for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL); it is the first drug approved for this indication. CONCLUSION: This accelerated approval was based on a response rate that is reasonably likely to predict clinical benefit in this heavily pretreated patient population with this rare disease. The applicant has committed to conducting postmarketing clinical trials to assess clinical benefit. The recommended starting dose of pralatrexate in patients with relapsed or refractory PTCL is 30 mg/m(2) via intravenous push over 3 to 5 min weekly for 6 weeks followed by a one-week rest (one cycle). Intramuscular injection of 1 mg vitamin B(12) should be administered every 8 to 10 weeks along with 1.0 mg folic acid given orally once a day. (source: Clin Cancer Res. 2010 Oct 15;16(20):4921-7. Epub 2010 Aug 25. Folotyn (pralatrexate injection) for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma: U.S. Food and Drug Administration drug approval summary.
Malik SM, Liu K, Qiang X, Sridhara R, Tang S, McGuinn WD Jr, Verbois SL, Marathe A, Williams GM, Bullock J, Tornoe C, Lin SC, Ocheltree T, Vialpando M, Kacuba A, Justice R, Pazdur R. Source Office of Oncology Drug Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA. shakun.malik@fda.hhs.gov).

Data published in 2009:

Pralatrexate, a new hope for aggressive T-cell lymphomas? Aggressive T-cell lymphomas represent a particularly poor-prognosis subgroup of lymphomas. This is especially true for patients with recurrent or refractory disease who typically have a limited response to salvage therapy and an extremely poor overall survival. There is thus a strong need to develop potentially active drugs for these malignancies. Pralatrexate is a novel antifolate designed to have high affinity for the reduced folate carrier type 1. Preclinical and clinical studies have demonstrated that pralatrexate has significant activity against T-cell lymphomas.The dose-limiting toxicity for pralatrexate is mucositis,which could be abrogated with folic acid and vitamin B12 supplementation. Pralatrexate is now being evaluated in phase II clinical trials for the treatment of peripheral T-cell lymphoma, and in a phase I/II trial in combination with gemcitabine for the treatment of non-Hodgkin's lymphoma. Because of the limited therapies available for aggressive T-cell lymphoma, pralatrexate could secure a niche for the treatment of this condition, provided on going clinical trials and future phase III trials confirm the efficacy of the drug. (source: Clin Transl Oncol. 2009 Apr;11(4):215-20. Pralatrexate, a new hope for aggressive T-cell lymphomas? Rueda A, Casanova M, Quero C, Medina-Pérez A. Source Servicio de Oncohematología, Hospital Costa del Sol, Autovía A-7, Km 187, Marbella, Málaga, Spain. arueda@hcs.es).

1: Foss FM. Evaluation of the pharmacokinetics, preclinical and clinical efficacy of pralatrexate for the treatment of T-cell lymphoma. Expert Opin Drug Metab Toxicol. 2011 Jul 5. [Epub ahead of print] PubMed PMID: 21726160.

2: O'Connor OA, Pro B, Pinter-Brown L, Bartlett N, Popplewell L, Coiffier B, Lechowicz MJ, Savage KJ, Shustov AR, Gisselbrecht C, Jacobsen E, Zinzani PL, Furman R, Goy A, Haioun C, Crump M, Zain JM, Hsi E, Boyd A, Horwitz S. Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: results from the pivotal PROPEL study. J Clin Oncol. 2011 Mar 20;29(9):1182-9. Epub 2011 Jan 18. PubMed PMID: 21245435; PubMed Central PMCID: PMC3083873.

3: Serova M, Bieche I, Sablin MP, Pronk GJ, Vidaud M, Cvitkovic E, Faivre S, Raymond E. Single agent and combination studies of pralatrexate and molecular correlates of sensitivity. Br J Cancer. 2011 Jan 18;104(2):272-80. Epub 2010 Dec 21. PubMed PMID: 21179031; PubMed Central PMCID: PMC3031902.

4: Malik SM, Liu K, Qiang X, Sridhara R, Tang S, McGuinn WD Jr, Verbois SL, Marathe A, Williams GM, Bullock J, Tornoe C, Lin SC, Ocheltree T, Vialpando M, Kacuba A, Justice R, Pazdur R. Folotyn (pralatrexate injection) for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma: U.S. Food and Drug Administration drug approval summary. Clin Cancer Res. 2010 Oct 15;16(20):4921-7. Epub 2010 Aug 25. Review. PubMed PMID: 20739433.

5: Pralatrexate (Folotyn) for peripheral T-cell lymphoma. Med Lett Drugs Ther. 2010 Jul 12;52(1342):55-6. PubMed PMID: 20622807.

6: Zain J, O'Connor O. Pralatrexate: basic understanding and clinical development. Expert Opin Pharmacother. 2010 Jul;11(10):1705-14. Review. PubMed PMID: 20509772.

7: Marchi E, Paoluzzi L, Scotto L, Seshan VE, Zain JM, Zinzani PL, O'Connor OA. Pralatrexate is synergistic with the proteasome inhibitor bortezomib in in vitro and in vivo models of T-cell lymphoid malignancies. Clin Cancer Res. 2010 Jul 15;16(14):3648-58. Epub 2010 May 25. PubMed PMID: 20501616.

8: Zain JM, Marchi E. Pralatrexate - from bench to bedside. Drugs Today (Barc). 2010 Feb;46(2):91-9. PubMed PMID: 20393637.

9: Thompson CA. FDA approves pralatrexate for treatment of rare lymphoma. Am J Health Syst Pharm. 2009 Nov 1;66(21):1890. PubMed PMID: 19850775.

10: O'Connor OA, Horwitz S, Hamlin P, Portlock C, Moskowitz CH, Sarasohn D, Neylon E, Mastrella J, Hamelers R, Macgregor-Cortelli B, Patterson M, Seshan VE, Sirotnak F, Fleisher M, Mould DR, Saunders M, Zelenetz AD. Phase II-I-II study of two different doses and schedules of pralatrexate, a high-affinity substrate for the reduced folate carrier, in patients with relapsed or refractory lymphoma reveals marked activity in T-cell malignancies. J Clin Oncol. 2009 Sep 10;27(26):4357-64. Epub 2009 Aug 3. PubMed PMID: 19652067.

11: Mould DR, Sweeney K, Duffull SB, Neylon E, Hamlin P, Horwitz S, Sirotnak F, Fleisher M, Saunders ME, O'Connor OA. A population pharmacokinetic and pharmacodynamic evaluation of pralatrexate in patients with relapsed or refractory non-Hodgkin's or Hodgkin's lymphoma. Clin Pharmacol Ther. 2009 Aug;86(2):190-6. Epub 2009 May 27. PubMed PMID: 19474785.

12: Marneros AG, Grossman ME, Silvers DN, Husain S, Nuovo GJ, MacGregor-Cortelli B, Neylon E, Patterson M, O'Connor OA, Zain JM. Pralatrexate-induced tumor cell apoptosis in the epidermis of a patient with HTLV-1 adult T-cell lymphoma/leukemia causing skin erosions. Blood. 2009 Jun 18;113(25):6338-41. Epub 2009 Apr 23. PubMed PMID: 19389878.

13: Rueda A, Casanova M, Quero C, Medina-Pérez A. Pralatrexate, a new hope for aggressive T-cell lymphomas? Clin Transl Oncol. 2009 Apr;11(4):215-20. Review. PubMed PMID: 19380298.

14: Izbicka E, Diaz A, Streeper R, Wick M, Campos D, Steffen R, Saunders M. Distinct mechanistic activity profile of pralatrexate in comparison to other antifolates in in vitro and in vivo models of human cancers. Cancer Chemother Pharmacol. 2009 Oct;64(5):993-9. Epub 2009 Feb 17. PubMed PMID: 19221750; PubMed Central PMCID: PMC2728224.

15: Molina JR. Pralatrexate, a dihydrofolate reductase inhibitor for the potential treatment of several malignancies. IDrugs. 2008 Jul;11(7):508-21. Review. PubMed PMID: 18600598.

16: Leitenberger JJ, Berthelot CN, Polder KD, Pro B, McLaughlin P, Jones D, Duvic M. CD4+ CD56+ hematodermic/plasmacytoid dendritic cell tumor with response to pralatrexate. J Am Acad Dermatol. 2008 Mar;58(3):480-4. PubMed PMID: 18280345.

17: O'Connor OA, Hamlin PA, Portlock C, Moskowitz CH, Noy A, Straus DJ, Macgregor-Cortelli B, Neylon E, Sarasohn D, Dumetrescu O, Mould DR, Fleischer M, Zelenetz AD, Sirotnak F, Horwitz S. Pralatrexate, a novel class of antifol with high affinity for the reduced folate carrier-type 1, produces marked complete and durable remissions in a diversity of chemotherapy refractory cases of T-cell lymphoma. Br J Haematol. 2007 Nov;139(3):425-8. PubMed PMID: 17910632.

18: Azzoli CG, Krug LM, Gomez J, Miller VA, Kris MG, Ginsberg MS, Henry R, Jones J, Tyson L, Dunne M, Pizzo B, Farmer A, Venkatraman E, Steffen R, Sirotnak FM. A phase 1 study of pralatrexate in combination with paclitaxel or docetaxel in patients with advanced solid tumors. Clin Cancer Res. 2007 May 1;13(9):2692-8. PubMed PMID: 17473201.

19: Krug LM, Heelan RT, Kris MG, Venkatraman E, Sirotnak FM. Phase II trial of pralatrexate (10-propargyl-10-deazaaminopterin, PDX) in patients with unresectable malignant pleural mesothelioma. J Thorac Oncol. 2007 Apr;2(4):317-20. PubMed PMID: 17409804.

20: O'Connor OA. Pralatrexate: an emerging new agent with activity in T-cell lymphomas. Curr Opin Oncol. 2006 Nov;18(6):591-7. Review. PubMed PMID: 16988580.

21: Toner LE, Vrhovac R, Smith EA, Gardner J, Heaney M, Gonen M, Teruya-Feldstein J, Sirotnak F, O'Connor OA. The schedule-dependent effects of the novel antifolate pralatrexate and gemcitabine are superior to methotrexate and cytarabine in models of human non-Hodgkin's lymphoma. Clin Cancer Res. 2006 Feb 1;12(3 Pt 1):924-32. PubMed PMID: 16467107.

22: Fury MG, Krug LM, Azzoli CG, Sharma S, Kemeny N, Wu N, Kris MG, Rizvi NA. A phase I clinical pharmacologic study of pralatrexate in combination with probenecid in adults with advanced solid tumors. Cancer Chemother Pharmacol. 2006 May;57(5):671-7. Epub 2005 Aug 31. PubMed PMID: 16136310.