SILVER SPRING, MD. – A Food and Drug Administration advisory committee voted 7-4 on March 21 to recommend accelerated approval of Marqibo, a liposomal-encapsulated version of vincristine, for adult patients with relapsed or refractory Philadelphia-negative acute lymphoblastic leukemia.
Under accelerated approval regulations, a drug can only be approved if it is superior to what is currently available and eventually is proven superior by a confirmatory trial, said Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Office of New Drugs.
Dr. Richard Pazdur
That sets a high bar for Marqibo, which according to its maker, Talon Therapeutics, is vincristine sulfate "encapsulated in the aqueous core of proprietary, sphingomyelin-based liposomes."
The encapsulated form offers "prolonged plasma circulation, enhanced target tissue delivery, and increased tissue concentration," along with extended release of vincristine, according to Talon. But the advisory panel’s pharmacology experts said the company had not offered enough evidence to support those theoretical advantages.
The panel – the Oncologic Drugs Advisory Committee (ODAC) – was less than enthusiastic in urging approval of Marqibo. Even some of those who voted in favor said they had done so somewhat unwillingly.
Dr. Wyndham H. Wilson, ODAC chairperson and chief of the lymphoma therapeutics section at the National Cancer Institute, said, "I was more voting against the lack of other things than voting for the efficacy of this agent." Dr. Wilson said that although the drug did appear to induce remissions in some patients, there were open questions about toxicity. "I am not at all convinced it is going to be that much more active than vincristine," he added.
Dr. Wyndham H. Wilson
"This was a difficult decision," said Dr. Antoinette J. Wozniak, a panelist from the Karmanos Cancer Institute at Wayne State University, Detroit.
Panelist Dr. Mikkael Sekeres of the Cleveland Clinic Taussig Cancer Institute was more sanguine. "I felt that this drug was able to convert patients who were in a palliative setting into a potentially curative setting," he said.
But Dr. Sekeres and other panelists said they hoped the agency would subsequently remove approval if Marqibo did not pan out in a planned phase III confirmatory study.
Some were openly skeptical that the phase III trial – TTX404 – would prove anything. Talon reached an agreement with the FDA in August 2011 on the conduct of that study, said Dr. Steven R. Deitcher, Talon’s president, CEO, and chief medical officer. The randomized two-arm study has a planned enrollment of 348 newly diagnosed patients, which he said will likely take 48 months. The trial is a superiority study with overall survival as the primary end point, and will compare standard vincristine with Marqibo in a five-course regimen known as the Larson regimen.
So far, not a single patient has been enrolled, but Dr. Deitcher said that three trial sites are open, and an additional 14 sites are "ready to be activated."
If the FDA follows its panel’s advice, Marqibo would be approved this spring for a very small patient population with Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) in second or greater relapse or whose disease has progressed following two or more treatment lines of antileukemia therapy. Talon estimated that out of some 1,400 adult patients with Ph-negative ALL, only about 458 a year would be eligible for Marqibo.
Talon, however, has its sights set on bigger markets. Dr. Deitcher said the company is currently enrolling or already beginning trials in newly diagnosed Ph-negative ALL; as a front-line therapy for aggressive non-Hodgkin’s lymphoma (NHL); in child and adolescent cancers; and in newly diagnosed Ph-positive ALL.
Dr. Mikkael Sekeres
It is not Marqibo’s first time before ODAC. The committee unanimously voted against accelerated approval of the agent for aggressive NHL in 2004. That application had been submitted by Inex Pharmaceuticals, which later sold its rights to Talon.
In seeking approval this time, Talon submitted data from a pivotal, single-arm, 68-patient phase II trial. The median age was 31 years, and 48% of the patients had a prior hematopoietic stem cell transplant. Fifty-one percent had failed three or more prior lines of treatment. The median bone marrow blast percentage was 84%. All had previous vincristine exposure, which made it not surprising that 80% had neuropathy at baseline.
The FDA allowed the company to use a surrogate end point, complete response (CR) plus CRi (defined as a CR with incomplete blood count recovery, as determined by the principal investigator). Talon determined that the response rate was 17% (11 responders) of the 65 patients who underwent treatment. The FDA reviewers, however, said that the response rate was 15%, or 10 of the 65 patients.