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The Lancet Oncology

Sunday, January 4, 2009

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

Other abstracts:

Also read PubMed Abstracts:

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

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