Pralatrexate and belinostat are two T-cell lymphoma treatments with accelerated approval from the US Food and Drug Administration (FDA), whose confirmatory trial processes have been delayed for years. In a commentary published in the Journal of Clinical Oncology, a team of authors led by Edward R. Scheffer Cliff, MBBS, MPH, discuss these drugs and make recommendations to improve the development of novel agents in oncology.
Pralatrexate and belinostat are indicated for relapsed or refractory peripheral T-cell lymphoma (PTCL) and received accelerated approval from the FDA in 2009 and 2014, respectively. According to the commentary authors, because management options for PTCL are lacking, both have entered common use for this disease and received preferred status in the National Comprehensive Cancer Network guidelines.
“But clinician endorsement does not suffice as evidence of clinical benefit, even in rare and serious diseases like PTCL. Trials testing clinical endpoints are still needed,” the authors wrote.
However, multiple factors have prevented the implementation of these trials. These include unknowns regarding dosing safety, the use of these agents in polytherapy, and how updates to the standard of care affect trial design. Changes in ownership of the two drugs have also complicated the launch of clinical trials.
In November 2023, the FDA convened the Oncologic Drugs Advisory Committee (ODAC) to discuss solving the delay in confirmatory trials for pralatrexate and belinostat. Acrotech Biopharma, the current owner of both agents, proposed that a five-arm dose-optimization study followed by a three-arm randomized controlled trial could fulfill the need for the trials.
The commentary authors critiqued Acrotech’s proposal as prolonging clinical uncertainty over the utility of the two drugs, leaving questions about their benefits in subtypes of PTCL unresolved, and that soon-upcoming patent expirations for the drugs will diminish sponsor financial incentives. They alternatively suggested that trials for both drugs be performed in the relapsed or refractory setting, and at global sites to accelerate recruitment.
“Using pralatrexate and/or belinostat as a single agent (a clinical context in which a safe dose is already known) or in a previously tested combination would avoid the need for the two sequential confirmatory trials proposed, which would further reduce the time until clinical end point data are available,” the authors elaborated.
The authors also recommended that confirmatory trials already be underway for a drug once it receives accelerated approval, the federal government should offer incentives and penalties for sponsors to adhere to the trial timeline, and new owners of a drug should meet with the FDA to reaffirm the timeline. They stressed that maintaining clinicians’ access to agents such as pralatrexate and belinostat is a priority.
“Keeping these drugs on the market requires a better plan for timely completion of their confirmatory trials,” the authors concluded.
The commentary was supported by Arnold Ventures.
Reference
Cliff ERS, Russler-Germain DA, Daval CJR, Kesselheim AS. US Food and Drug Administration’s directive to deal with delayed confirmatory trials: Lessons from pralatrexate and belinostat for T-cell lymphoma. J Clin Oncol. 2024. doi:10.1200/JCO.24.00100