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By Donna Young
Washington Editor
SILVER SPRING, Md. - FDA advisers Wednesday said the response rate and duration of response from Allos Therapeutics Inc.'s single-arm study were reasonably likely to predict the clinical benefit of Folotyn (pralatrexate) in treating patients with relapsed or refractory peripheral T-cell lymphoma (PTCL).
Westminster, Colo.-based Allos is seeking accelerated approval of Folotyn in PTCL, an array of aggressive non-Hodgkin's lymphomas (NHLs).
Richard Pazdur, director of the FDA's Office of Oncology Drug Products, noted that accelerated approval requires a new therapy to demonstrate benefit to patients over available drugs, which is usually done in the context of a randomized trial.
In addition, he said, an accelerated approval is based on a surrogate endpoint deemed reasonably likely to predict clinical benefit, such as response rate. Companies granted accelerated approvals are required to conduct confirmatory postmarketing studies to verify and describe the clinical benefit.
The FDA's Oncologic Drugs Advisory Committee voted 10 to 4 that the 27 percent response rate and the 9.4 months median duration of response in Allos' single-arm study were likely to predict clinical benefit of the drug.
"It is not a home run, it is a base hit," said ODAC panelist Brad Kahl, associate professor of medicine at the University of Wisconsin. But, he said, "this group of patients needs a base hit."
There currently are no approved treatments for PTCL and no accepted standard of care in the relapsed or refractory setting due to the paucity of well-conducted, multicenter clinical trials, said Francine Foss, a professor of medicine at Yale University.
"This is a grim disease in the relapsed setting, and almost all of them are relapsed," said FDA panelist Geraldine Schechter, professor of hematology at George Washington University.
"It really is imperative that novel agents specifically for PTCL are developed," said Foss, who presented data about PTCL on behalf of Allos.
But panelist Thomas Fleming, professor of biostatistics at the University of Washington in Seattle, who voted no, argued that patients needed more assurance of Folotyn's efficacy and safety than the single-arm results.
"They need a great result," he said.
Panelist Michael Link, professor of pediatric medicine at Stanford University, asserted that Folotyn, a structural analogue of the antifolate methotrexate, would provide patients who have no curative option the possibility to "get to a place where they can have that option," meaning well enough to undergo a stem cell transplant.
Earlier Wednesday, the ODAC voted 10 to 0, with one abstention, that Gloucester Pharmaceuticals Inc.'s single-arm studies represented a favorable risk-benefit profile of Istodax (romidepsin) as a therapy for previously treated patients with cutaneous T-cell lymphoma (CTCL), a rare, life-threatening form of NHL, which manifests as skin patches, plaques, tumors and erythroderma and pruritus, or extreme itching.
Unlike products examined by the committee Tuesday - Genzyme Corp.'s Clolar (clofarabine) and Vion Pharmaceuticals Inc. Onrigin (laromustine) - the FDA agreed under special protocol assessments to accept Gloucester's and Allos' single-arm studies, but warned that without data from randomized trials, there may be certain issues raised during the agency's review of the investigational drugs.
During Tuesday's meeting, the ODAC said data from Genzyme's and Vion's single-arm Phase II studies were insufficient to validate the safety and efficacy of the firms' drugs to treat elderly patients with acute myeloid leukemia, and called for randomized trials to be conducted.
While that verdict had only a mild affect on Genzyme's shares Tuesday, Vion's stock (OTC BB:VION) was hit hard, with shares plunging 57 percent Wednesday, to close at $1.12, a loss of $1.48.
Both companies had been urged by the FDA to conduct randomized controlled trials before submitting their applications, but the companies chose not to do so.
Single-arm trials, Pazdur said Wednesday, "are problematic," because they "do not allow time-to-event endpoints, such as time-to-progression or overall survival, from being evaluated."
In addition, he said, single-arm trials do not allow for comparison and prioritization of therapies.
"From a medical practice viewpoint, with the advent of larger number of therapeutic options, health care providers and patients desire this information," Pazdur said.
He acknowledged, however, that randomized trials require larger patient numbers and longer follow-up than single-arm studies.
"This may be problematic in diseases where patient numbers are limited," Pazdur said.
Although the panelists Wednesday backed Gloucester's drug, they recommended in a 7-to-3 vote, with one abstention, that the FDA require randomized studies for future approvals of drugs to treat CTCL, rather than relying on single-arm trials alone.
The FDA has based some approvals of oncology drugs on single-arm trials, Pazdur noted.
Eisai Inc.'s Targretin (bexarotene) was granted approval for CTCL in 1999 based on response rates of 54 percent and 45 percent in single-arm studies, with response durations of 107 days and 159 days, respectively. Merck & Co. Inc.'s Zolinza (vorinostat) also was given full approval in 2006 on the basis of response rate in two single-arm studies of patients with refractory CTCL, Pazdur added.
"The FDA has looked at well-documented responses of adequate duration in clinical trials of CTCL trial to be of direct clinical benefit," he explained. "This is due to the fact that this disease is primarily cutaneous and an improvement in skin lesions would be of face value correlating with improvement in cosmesis and potentially improving symptoms and reduction of supportive care medications, such as antibiotics and antipruritic medications. This viewpoint has led to the approval of drugs by the FDA on single arm trials with a primary endpoint of response rate in CTCL," Pazdur said.
Gloucester's application for Istodax, a histone deacetylase inhibitor, is based on data from the company's 96-patient single-arm Phase II GPI-04-0001 study and NCI study 1312, a 71-patient single-arm study conducted by the National Cancer Institute.
There was a 34 percent objective response rate (ORR) in the Gloucester study and a 35 percent ORR in the NCI study. | 
