The US FDA has granted accelerated approval to Allos Therapeutics' folate analogue metabolic inhibitor Folotyn (pralatrexate), making it the first drug approved for the orphan indication of relapsed or refractory peripheral T-cell lymphoma (PTCL). Folotyn is expected to be available in October.

Approval was based on a 27% overall response rate (29 of 109 evaluable patients) in the pivotal Phase II PROPEL trial, the largest prospective study ever conducted in the relapsed/refractory PTCL population.

The open-label, single-arm trial enrolled 115 patients with relapsed or refractory PTCL who had progressive disease after at least one prior therapy. The median number of prior therapies was three. The median duration of response was 9.4 months, and response duration ranged from one to 500 days.

In early September, the FDA's oncologic drugs advisory panel recommended pralatrexate's approval, concluding that the 27% response rate and durability of responses were reasonably likely to predict clinical benefit. The endorsement, by a vote of 10 to four, came despite FDA reviewers' concerns about the duration of overall response, uncertainty about response determination and clinical meaningfulness of the results, which were driven by partial responses (scripnews.com, September 3rd, 2009).

confirmatory studies

The labelled indication states that clinical benefit, such as improvement in progression-free survival and overall survival, has not been shown. In conjunction with the accelerated approval, Allos will conduct two randomised, Phase III trials to confirm clinical benefit in patients with T-cell lymphomas, company officials said during an analysts call.

The first study will examine the efficacy of sequential pralatrexate versus observation in patients with newly diagnosed PTCL who have responded following initial treatment with CHOP therapy (cyclophosphamide, doxorubicin, vincristine and prednisone) or similar regimens. The primary endpoint will be progression-free survival. Patients will be enrolled prior to initiation of CHOP therapy, and those who achieve a complete response or partial response will then be randomised 2:1 to pralatrexate or observation.

The company will also conduct a study of pralatrexate in combination with bexarotene (Eisai's Targretin) versus bexarotene alone in patients with cutaneous T-cell lymphoma who are refractory to at least one prior systemic therapy. The primary endpoint will be progression-free survival, with response rate as a secondary endpoint. Prior to initiation of the Phase III study, the company will conduct a Phase I study to determine the maximum tolerated dose of the combination.

Company officials said the two studies are part of pralatrexate's lifecycle development plan and could extend the drug's use to the broader T-cell population. The compound is also being studied in non-small cell lung cancer, and refractory and relapsed Hodgkin's and non-Hodgkin's lymphomas.

PTCL represents about 10-15% of all non-Hodgkin's lymphomas diagnosed in the US, with about 9,500 cases each year. There previously were no medicines specifically approved for the condition, which is usually treated with CHOP or similar regimens in the first-line setting. There is no accepted standard of care in the relapsed or refractory settings.

Pralatrexate labelling includes warnings and precautions on the risks of thrombocytopenia; neutropenia; anaemia; mucositis; fetal harm when used by pregnant women; and liver function test abnormalities. Caution should be used in patients with moderate to severe renal impairment. The company said it has agreed, as a postmarketing commitment, to conduct a Phase I pharmacokinetics study of pralatrexate in relapsed and refractory lymphoma patients with mild to severe renal impairment.