A NEW FOLATE ANALOGUE

ASH 2008: Pralatrexate Shows Promise in Peripheral T-Cell Lymphoma

December 12, 2008 (San Francisco, California) — The investigational agent pralatrexate (Allos Therapeutics, Inc) shows promise in relapsed and refractory peripheral T-cell lymphoma, according to data presented here at the American Society of Hematology 50th Annual Meeting and Exposition. In this phase 2 trial, 27% of patients experienced either a complete or a partial response.

"Peripheral T-cell lymphomas are a particularly challenging form of non-Hodgkin's lymphoma," said lead author Owen A. O'Connor, MD, PhD, 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 and Columbia University Medical Center, in New York City.

"To date, combination conventional therapy regimens have fallen short and, more importantly, many patients receiving conventional therapy fail to respond," he explained. "So there is a need to develop new T-cell-centered therapy that will achieve remission and hopefully extend the life of these particular patients."

Peripheral T-cell lymphoma is an aggressive and relatively uncommon type of non-Hodgkin's lymphoma, with a generally poor prognosis. Thus far, there are no treatments approved the US Food and Drug Administration (FDA), either in the first-line or relapsed or refractory setting, and no consensus exists on the best therapeutic strategy for newly diagnosed or relapsed/refractory disease.

Pralatrexate, a folate analog inhibitor of dihydrofolate reductase, was granted orphan-drug designation and fast-track designation by the FDA for the treatment of patients with T-cell lymphoma, and was granted similar status in the European Union. It also recently received orphan-drug designation from the FDA for the treatment of diffuse large B cell and follicular lymphomas.

"Based on original work done by myself and colleagues at Memorial Sloan-Kettering Cancer Center and subsequently at Columbia University, we demonstrated in an early phase 1/phase 2 clinical trial that pralatrexate demonstrated efficacy in different types of non-Hodgkin's lymphomas and striking activity in patients with T-cell lymphoma," said Dr. O'Connor.

Responses Seen in Large Phase 2 Trial

Going forward with their preliminary data, an international phase 2 trial was designed to evaluate the safety and efficacy of pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma. PROPEL (Pralatrexate in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma) is the largest prospective study in patients with peripheral T-cell lymphoma, consisting of 115 patients. The single-group non-randomized open-label study was conducted in North America and Europe, and was developed under the FDA Special Protocol Assessment program.

All participants were heavily pretreated and had received a median of 3 previous systemic treatment regimens (range, 1–12); 18 patients (16%) had undergone an autologous stem-cell transplant.

Patients received weekly intravenous infusions of pralatrexate (30 mg/m²) for 6 or 7 weeks, along with vitamin B₁₂ and folic acid supplementation, which has historically been shown to reduce the rate of adverse events associated with pralatrexate. The primary end point of the study was objective response rate, and secondary end points were duration of response, progression-free survival, and overall survival. Information on 109 patients was available for analysis.

Summary of Response Rates to Pralatrexate by Independent Central Review

Best Response	n (%)
Complete response/partial response	29 (27)
Complete response	11 (10)
Partial response	18 (17)
Stable disease	23 (21)
Progressive disease	40 (37)

Of the patients who responded, 69% did so after receiving 1 cycle of therapy. The median duration of treatment in responding patients was 179 days at the time of this analysis, and the duration of response exceeded 3 months in 17 of 29 responders (59%), including 6 of the 17 patients who remain on treatment.

"Toxicities were what we had expected, based on prior clinical experience, and included mucositis and thrombocytopenia," said Dr. O'Connor. "There was very little grade 4 toxicity."

The most common grade 3 or 4 adverse events were thrombocytopenia (in 32% of patients), mucosal inflammation (in 21% of patients), neutropenia (in 20% of patients), and anemia (in 18% of patients).

Dr. O'Connor emphasized that 1 criterion of the study was that there was no limit on previous therapy. "Our results show that the drug has activity, and response was seen irrespective of the number of prior therapies," he said. "This suggests a lack of cross resistance between pralatrexate and other agents."

The patients in this study will continue to be followed and, on the basis of these results, pralatrexate-based combinations might provide a novel platform for future upfront T-cell treatment programs.

Data Early But Promising

"The data are early, as this is only a phase 2 trial, but there was a strong enough response to move it forward," commented Janet Burns, MD, professor of medicine in the Division of Hematology, Oncology, and Transplantation, at the University of Minnesota, in Minneapolis. "But this isn't quite a home run, and Dr. O'Connor knows that he will need to combine pralatrexate with other therapies."

However, it is exciting to see a potential new agent come on the market for peripheral T-cell lymphoma, she told Medscape Oncology. "We are learning more about the genetic signatures of T-cell lymphoma, and hopefully we can begin to develop therapies specific to this lymphoma subtype."