Pralatrexate Approved by FDA as the First Drug for Treatment of Peripheral T-cell Lymphoma

The U.S. Food and Drug Administration (FDA) approved pralatrexate (Folotyn®, Allos Therapeutics), the first treatment for a form of cancer known as Peripheral T-cell Lymphoma (PTCL), an often aggressive type of non-Hodgkins lymphoma.

Pralatrexate, also known as 10-propargyl-10-deazaaminopterin, is a folate analog inhibitor of dihydrofolate reductase studied for the treatment of cancer. The drug candidate was approved under the FDA's accelerated approval process, which allows earlier approval of drugs that meet unmet medical needs. It is approved for patients who have relapsed, or have not responded well to other forms of chemotherapy.

Lymphoma is a cancer of the lymphatic system, which is part of the immune system. There are many types of lymphoma: one type is called Hodgkin's disease, and the rest are called non-Hodgkin's lymphomas. PTCL involves a type of white blood cell called T-cells. It is a relatively rare disease, occurring in less than 9,500 patients each year in the United States.

“Folotyn's approval demonstrates FDA's commitment to the rapid approval of drugs for rare and uncommon diseases,” said Richard Pazdur, M.D., director of the Office of Oncology Drug Products in the FDA's Center for Drug Evaluation and Research.

When studying a new drug, it can take time to learn whether a drug actually provides real improvement for patients – such as living longer or feeling better. This real improvement is known as a “clinical outcome.” In 1992 FDA instituted accelerated approvals which allow earlier approval of drugs based on a surrogate endpoint, a laboratory measurement or physical sign that can serve as an indirect or substitute measurement for clinical outcomes.

In the case of pralatrexate, this meant the FDA approved the drug based on evidence that it reduces tumor size, because tumor shrinkage is considered reasonably likely to predict a clinical benefit such as extending the survival of cancer patients. Tumor shrinkage was seen on imaging scans in one study. Of 109 patients with PTCL in the trial, 27% had reduction in tumor size.
To speed the drug's availability, pralatrexate was granted priority review, ensuring a review within six months rather than 10 months for a standard review. The drug was also designated as an orphan drug, which provides a variety of financial incentives to manufacturers that develop drugs for a small number of patients with a rare disorder.

The most common adverse reactions seen with pralatrexate were irritation or sores of the mucous membranes such as the lips, the mouth, and the digestive tract, low platelet cell counts, low white blood cell counts, fever, nausea, and fatigue.

Pralatrexate can harm a fetus. Therefore, women should avoid becoming pregnant while being treated with this drug and pregnant women should be informed of the potential risk.
Patients treated with pralatrexate should take folate and vitamin B12 supplements to reduce mucous membrane irritation.

Pralatrexate is manufactured by Allos Therapeutics Inc. of Westminster, Colorado (USA). As a condition of accelerated approval, Allos will conduct studies to confirm that tumor shrinkage actually does predict that patients will live longer.

For more information:

• EMEA - Public Summary of Positive Opinion for Orphan Designation of
  pralatrexate for the treatment of peripheral T-cell lymphoma
  (nodal, other extranodal and leukaemic/disseminated)

Also read these PubMed abstracts:

• O'Connor OA, Horwitz S, Hamlin P, Portlock C, Moskowitz CH, et al. 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.
• Mould DR, Sweeney K, Duffull SB, Neylon E, et al. 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.
• Marneros AG, Grossman ME, Silvers DN, Husain S, et al. 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.
• 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.

New Drug Shows Promise in the Treatment of Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma

One of the largest prospective clinical trials in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL), the PROPEL trial (Pralatrexate in patients with Relapsed Or refractory PEripheral T-cell Lymphoma), found that the investigational chemotherapy agent pralatrexate produces CR (complete responses or disappearance of all signs of cancer) in patients who had previously failed an average of three treatment regimens, including an autologous stem cell transplant for some patients.

Peripheral T-cell lymphoma or PTCL is a biologically diverse group of blood cancers that account for 1 in 100 cases of non-Hodgkin's lymphoma (NHL) in the United States. The disease is more common in adults than in children, and it affects slightly more men than women. The average five-year survival is approximately 25 percent.

Dr. Owen A. O'Connor MD, PhD, the Principal Investigator of the PROPEL trial and the Director of the Lymphoid Development and Malignancy Program and Chief of the Lymphoma Service at the Herbert Irving Comprehensive Cancer Center at New York-Presbyterian Hospital/Columbia University Medical Center, and Associate Professor of Medicine at Columbia University College of Physicians and Surgeons, who presented the results of the trial during the 50th Annual Meeting of the American Society of Hematology (ASH) in San Francisco, explained: ‘Presently, there are no FDA-approved treatments for patients with PTCL, either in the first-line or relapsed or refractory setting. This underscores the need for new therapies to treat this challenging disease. Pralatrexate has the potential to play a clinically meaningful role in the treatment of these patients.’

Pralatrexate, a novel targeted antifolate, is in the same class of drugs as methotrexate, a chemotherapy drug that has been available for several decades, but it is far more potent. The new drug is a designed to accumulate in high concentrations in tumor cells, inhibiting DNA synthesis.

Based on preclinical studies, pralatrexate is thought to selectively enter cells expressing RFC-1, a protein that is over expressed on cancer cells compared to normal cells. Once inside cancer cells, pralatrexate is efficiently polyglutamylated, which leads to high intracellular drug retention. Polyglutamylated pralatrexate essentially becomes ‘trapped’ inside cancer cells, making it less susceptible to efflux-based drug resistance. Acting on the folate pathway by ‘mimicking folic acid,’ pralatrexate interferes with DNA synthesis and triggers cancer cell death. Researchers believe that pralatrexate has the potential to be delivered as a single agent or in combination therapy regimens.

A total of 115 patients were enrolled into this phase II, single-arm, non-randomized, open-label study and received weekly intraveneous infusions of pralatrexate (30 mg/m2) for seven weeks. All patients also received vitamin B12 and folic acid throughout the study in order to prevent potential side effects of the pralatrexate. The primary endpoint of the study was the objective response rate (ORR), including all patients who had some response of their disease to therapy. Secondary endpoints included duration of response, progression-free survival, and overall survival.

Interim data of the first 65 evaluable patients showed that 29 percent of patients responded to treatment, with 11 percent experiencing a complete response and 18 percent experiencing a partial response. The most common severe (grade 3 and 4) side effects associated with pralatrexate were thrombocytopenia (31 percent), mucositis (14 percent), anemia (12 percent), and neutropenia (11 percent).

Orphan drug status and Fast-track approval
This is the first promising treatment to be developed in years and based on the promising results of this and previous studies the US Food and Drug Administration granting orphan drug statusand a fast-track approval process to pralatrexate for T-cell lymphoma.

Commenting on the PROPEL trial, Dr Owen O'Connor concluded: ‘This [ ..] trial demonstrate that pralatrexate produced durable, complete responses in heavily pre-treated patients.’

Allos Therapeutics Inc., the maker of the drug, will submit a NDA for pralatrexate for the treatment of patients with relapsed or refractory PTCL to the FDA once the Phase II data has been fully reviewed. This is expected sometime in the first half of 2009.

Pralatrexate was developed by a team of researchers at Memorial Sloan-Kettering Cancer Center (MSKCC) and the Southern Research Institute, including Dr. O'Connor, while at MSKCC. Dr. O'Connor and his colleagues identified the unique activity of pralatrexate in patients with lymphoma. Dr. O'Connor has continued to study pralatrexate at NewYork-Presbyterian/Columbia, now focusing on determining how the drug works in T-cell lymphoma, and on how best to combine it with other drugs to improve the treatment of patient with hematologic cancers.

‘We are very excited by these results. If approved, the launch of pralatrexate will represent a first to market opportunity for Allos,' said Paul L. Berns, President and Chief Executive Officer of Allos. 'And we would like to extend our appreciation to the patients who participated in the PROPEL trial, as well as to their families, for helping us to identify a potential new treatment option for this disease.’

Other Pralatrexate studies
During the 50th Annual Meeting of the American Society of Hematology results from two other pralatrexate studies were presented as posters. One poster reported interim data from a Phase 1 trial of pralatrexate as a single agent in patients with relapsed or refractory cutaneous T-cell lymphoma (CTCL). The second poster reports interim data from a Phase 1/2a trial of pralatrexate in combination with gemcitabine in patients with relapsed or refractory non-Hodgkin's lymphoma (NHL) or Hodgkin's lymphoma.

The first poster (Pralatrexate is Active in Cutaneous T-Cell Lymphoma: Preliminary Results of a Multi-center Dose-finding Trial; abstract 1569) presented interim data from an ongoing Phase 1 trial of pralatrexate in patients with relapsed or refractory CTCL.

Dr Steven Horwitz, M.D., Assistant Attending Physician, Lymphoma Service, Memorial Sloan-Kettering Cancer Center, the Principal Investigator of the study and his team presented the data which included 24 patients, with 22 evaluable patients who completed at least one cycle of treatment at doses ranging from 10-30 mg/m(2) as part of a weekly schedule for two or three weeks followed by one week of rest. Responses were observed in 12 of 22 evaluable patients (55%), including one complete response and 11 partial responses. Patients received a median of four prior systemic therapies. The most common adverse event was mucosal inflammation, with Grade 1/2 mucosal inflammation observed in 11 of 24 patients and Grade 3 mucosal inflammation observed in 4 of 24 patients. There was no Grade 4 mucosal inflammation and no thrombocytopenia above Grade 1. Up to 56 evaluable patients will be enrolled in the study with the objective of determining the optimal dose and schedule for pralatrexate in this patient population.

The second poster (A Phase 1/2a Open-label Study of Pralatrexate and Gemcitabine in Patients with Relapsed or Refractory Lymphoproliferative Malignancies’; abstract 1570) presented interim data from an ongoing Phase 1/2a open-label, multi-center study of pralatrexate in combination with gemcitabine in patients with relapsed or refractory non-Hodgkin's lymphoma (NHL) or Hodgkin's lymphoma. This data included 27 patients, 22 of whom were evaluable for response. Patients have been enrolled in eight cohorts with different doses and schedules. Partial responses were observed in 6 of 22 evaluable patients, including five patients on a sequential dosing schedule and one patient on a same-day dosing schedule. Patients received a median of three prior systemic regimens. The most common adverse event was thrombocytopenia, with Grade 3 observed in four patients and Grade 4 observed in seven patients. The maximum tolerated dose for the sequential dosing schedule was established as 10 mg/m(2) of pralatrexate followed by 300 mg/m(2) of gemcitabine, once every two weeks. Enrollment in the trial is ongoing to determine the maximum tolerated dose for the same same-day dosing schedule.

For more information, read

• Owen A. O’Connor OA, Pro B, Pinter-Brown L, Popplewell L, et al. PROPEL: A Multi-Center Phase 2 Open-Label Study of Pralatrexate (PDX) with Vitamin B12 and Folic Acid Supplementation in Patients with Replapsed or Refractory Peripheral T-Cell Lymphoma. (Oral Session), Blood (ASH Annual Meeting Abstracts) 2008 112: Abstract #261

Other abstracts:

• Horwitz SM, Duvic M,Kim Y,Zain JM, et al. Pralatrexate (PDX) IS Active in Cutaneous T-Cell Lymphoma: Preliminary Results of a Multi-Center Dose-Finding Trial. (Poster Session) Blood (ASH Annual Meeting Abstracts) 2008 112: Abstract #1569
• Horwitz SM, Vose JM, Advani R, Sankhala K, et el. A Phase 1/2A Open-Label Study of Pralatrexate and Gemcitabine in Patients with Relapsed or Refractory Lymphoproliferative Malignancies. (Poster Session), Blood (ASH Annual Meeting Abstracts) 2008 112: Abstract #1570

Also read PubMed Abstracts:

• Toner LE, Vrhovac R, Smith EA, et al. The schedule-dependent effects of the novel antifolatepralatrexate and gemcitabine are superior to methotrexate and cytarabine in models of human non-Hodgkin's lymphoma. Clin Cancer Res 2006;12(3):924-932.
• O'Connor OA, Hamlin PA, Gerecitano J, et al. Pralatrexate (PDX) produces durable complete remissions in patients with chemotherapy resistant precursor and peripheral T-cell lymphomas: results of the MSKCC Phase I/II experience. (Abstract 400). Presented at The American Society of Hematology's 48th Annual Meeting. Blood 2006;108(11):122a-3a.
• O'Connor O, Hamlin P, Neylon E, et al. Early phase experience with pralatrexate (10-propargyl-10-deazaaminopterin [PDX]), a novel antifolate with high affinity for the reduced folate carrier, in patients with chemotherapy refractory lymphoproliferative malignancies. (Abstract 461). Eur J Cancer 2006;4(Suppl 12):141.
• O'Connor OA. Pralatrexate: an emerging new agent with activity in T-cell lymphomas. Curr Opin Oncol 2006;18(6):591-597.
• Krug LM, Heelan RT, Kris MG, et al. Phase II Trial of Pralatrexate (10-Propargyl-10-deazaaminopterin, PDX) in Patients with Unresectable Malignant Pleural Mesothelioma. J Thorac Oncol 2007;2(4):317-320.
• Azzoli CG, Krug LM, Gomez J, et al. A phase 1 study of pralatrexate in combination withPaclitaxel or docetaxel in patients with advanced solid tumors. Clin Cancer Res2007;13(9):2692-8.
• O'Connor OA, Hamlin PA, Portlock C, et al. Pralatrexate, a novel class of antifol with highaffinity for the reduced folate carrier-type 1, produces marked complete and durableremissions in a diversity of chemotherapy refractory cases of T-cell lymphoma. British Journal of Haematology 2007;139(3):425-428.
• Izbicka E, Diaz A, Campos D, et al. Differential activity and potential mechanism of action of pralatrexate (PDX) methotrexate, and pemetrexed (Alimta) in human cancer models in vivo and in vitro (abstract A135). Proceedings of AACR-NCI-EORTC International Conference Molecular Targets and Cancer Therapeutics: Discovery, Biology, and Clinical Applications October 22-26, 2007:108.
• James LP, Azzoli CG, Krug LM, et al. Phase I study of the antifolate pralatrexate given with vitamin B12 and folic acid supplementation in patients with advanced non-small cell lung cancer (NSCLC) (abstract A143). Proceedings of AACR-NCI-EORTC International Conference Molecular Targets and Cancer Therapeutics: Discovery, Biology, and Clinical Applications October 22-26, 2007:111.
• O'Connor OA, Hamlin PA, Portlock C, et al. A Phase '2-1-2' study of two different doses and schedules of pralatrexate, a high affinity substrate for the reduced folate carrier (RFC-1), in patients with relapsed or refractory lymphoma reveals marked activity in T-cell malignancies (abstract C85). Proceedings of AACR-NCI-EORTC International Conference Molecular Targets and Cancer Therapeutics: Discovery, Biology, and Clinical Applications October 22- 26, 2007:283.
• Leitenberger JJ, Berthelot CN, Polder KD, et al. CD4+ CD56+ hematodermic/plasmacytoid dendritic cell tumor with response to pralatrexate. J Am Acad Dermatol 2008;58(3):480-4.
• Damaj BB. In vitro and in vivo effects of pralatrexate (PDX) on the survival and growth of the A549 non-small cell lung cancer cell line. (Abstract 2298). American Association for Cancer Research (AACR) 2008 Annual Meeting; 2008 14-18 Apr 2008 San Diego, CA; 2008.
• O'Connor OA-, Hamlin P, Moskowitz C, et al. Pralatrexate (PDX) produces a high and durable complete response rate in patients with chemotherapy resistant T-cell lymphomas. (Abstract 138). Ann Oncol (ESMO Conference Proceedings) 2008;19(4):iv128.
• Horwitz S, Duvic M, Kim Y, et al. Low dose pralatrexate (PDX) is active in cutaneous T-celllymphoma: Preliminary results of a multi-center dosse finding trial. (abstract 261). Ann Oncol (ESMO Conference Proceedings) 2008;19(4):iv162.
  O'Connor OA. New drugs for the treatment of T-cell lymphoma. (abstract 134). Ann Oncol (ESMO Conference Proceedings) 2008;19(4):iv127.
• Molina JR. Pralatrexate, a dihydrofolate reductase inhibitor for the potential treatment ofseveral malignancies. IDrugs 2008;11(7):508-21
  

Clinical trials:

Study of Pralatrexate With Vitamin B12 and Folic Acid in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma. Allos Therapeutics, ClinicalTrials.gov Identifier: NCT00364923

Novel Treatments Demonstrate Improvements in Overall Survival (OS) and Response Rates (RR) in Difficult to Treat forms of Leukaemia and Lymphoma

The use of dexamethasone early in the treatment of children with acute lymphoblastic leukemia (ALL), the most common type of childhood cancer, may help reduce the risk of relapse. This is the conclusion from study results presented during the 50th Annual Meeting of the American Society of Hematology (ASH) in San Francisco, CA (December 6 – 9)

Additional research featured during the annual meeting included: the potential role of a combination therapy regimen that includes rituximab as the new standard first-line therapy for the treatment of advanced chronic lymphocytic leukemia, the examination of pralatrexate or 10-propargyl-10-deazaaminopterin (PDX), for the treatment of peripheral T-cell lymphoma in the largest prospective study of this subset of patients, and the results of the first study examining a promising new molecular target for the treatment of B-cell non-Hodgkin lymphoma.

'By conducting ongoing research with new, investigational treatments as well as with different combinations of existing treatment options that have been used for years, we are working to improve the survival of our patients with leukemia and lymphoma,' explained Dr. Linda Burns, MD, Professor of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN. 'The research presented today showcases the great advances we are continuously making in treating various blood cancers.'

Leukemia and lymphoma are two of the most common blood cancers. Leukemias are categorized based on the speed at which the cancer grows – acute leukemias grow quickly while chronic leukemias develop at a slower rate. Leukemias also are categorized as lymphocytic or myelogenous depending on whether they affect lymphocytes (a type of white blood cell) or stem cells found in the bone marrow. According to the National Cancer Institute, each year there are approximately 44,000 new cases and 22,000 deaths associated with leukemia in the United States.

Lymphoma is cancer of the lymphatic system that begins with a change in the lymphocytes, impairing the ability of the body’s immune system to fight infection. Lymphomas are divided into two categories: Hodgkin lymphoma and non-Hodgkin lymphoma. Most non-Hodgkin lymphomas are B-cell lymphomas, which are further classified into 14 different sub-types based on the stage of cell development during which the B cell has been affected. The rest are T-cell lymphomas, which affect another type of white blood cell. There are approximately 66,000 new cases of lymphoma and nearly 20,000 deaths each year in the United States according to the National Cancer Institute.

Also read blog entry:

• Fostamatinib Disodium shows promise in the treatment of Diffuse Large B-Cell Lymphoma and Chronic Lymphocytic Leukemia
• Dexamethasone can Eliminate One-Third of All Relapses in Childhood Acute Lymphoblastic Leukemia
• New Drug Shows Promise in the Treatment of Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma
• Immunochemotherapy with Fludarabine, Cyclophosphamide, and Rituximab Improves Response Rates and Progression-Free Survival of Previously Untreated Patients with Advanced Chronic Lymphocytic Leukemia.