August 9, 2012 — A liposomal vincristine product has received accelerated approval from the US Food and Drug Administration (FDA) for use in the treatment of some patients with acute lymphoblastic leukemia (ALL).
The product, vincristine sulfate liposome injection (Marqibo, Talon Therapeutics), was developed specifically to reduce the adverse effects, particularly dose-limiting neurotoxicity, associated with standard vincristine.
The accelerated approval is for a narrow indication: the treatment of adult patients with Philadelphia chromosome (Ph)-negative ALL in second or greater relapse that has progressed after 2 or more lines of antileukemia therapy. This is "a very rare patient population with a grave prognosis and no current standard of treatment," according to Talon Therapeutics.
The approval was based on response rates, the company noted. Clinical benefit such as improvement in overall survival has not been verified. The injection is administered intravenously at a dose of 2.25 mg/m² over 1 hour once every 7 days; this dosing is different than that for nonliposomal vincristine sulfate.
The recommendation for accelerated approval for this indication was made by the FDA Oncologic Drugs Advisory Committee in March. However, there was a split among the experts, with 7 members voting in favor of recommending approval, 4 voting against, and 2 abstaining. The conclusion was that the product offers a favorable risk/benefit profile in this particular group of patients.
That voting and the approval were based on 2 small clinical trials that lacked comparators: a phase 2 single-group study and a phase 1/2 single-group dose-finding study.
In a press release, the FDA noted that the accelerated approval program allows the agency to approve a drug to treat a serious disease on the basis of clinical data showing that the drug has an effect on a surrogate end point that is reasonably likely to predict a clinical benefit to patients. This program provides earlier patient access to promising new drugs while additional clinical studies are conducted to confirm clinical benefit and safety.
Approval of this liposomal vincristine product "demonstrates the FDA's commitment to the development and approval of drugs that address serious, unmet medical needs," Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research, said in the statement.
The drug also received orphan-product designation by the FDA because it is intended to treat a rare disease or condition.
The drug's effectiveness was evaluated in a single clinical trial of adults whose leukemia had relapsed at least 2 times despite standard treatment, and who had at least 1 previous treatment response lasting at least 90 days, according to the FDA. The study objective was to determine response rate. Of the 65 patients enrolled, 10 (15.4%) responded with either a complete remission or a complete remission with incomplete blood count recovery. In those 10 patients, the median duration of documented remission was 28 days. The median time to the first event of relapse, death, or next therapy was 56 days.
Confirmatory Trial Underway
The accelerated approval was granted with the proviso that a confirmatory trial be undertaken.
That trial, known as HALLMARQ (Halting Newly Diagnosed Adult Acute Lymphoblastic Leukemia With Marqibo Containing Chemotherapy), recently began; Talon Therapeutics announced that the first patient was treated on June 1. HALLMARQ is a larger phase 3 study comparing the new liposomal product with standard vincristine in the front-line setting in adults with newly diagnosed Ph-negative ALL. The principal investigator is Susan O'Brien, MD, from the University of Texas M.D. Anderson Cancer Center in Houston, and it is enrolling patients at sites across the United States. It aims to enroll 348 patients and has an estimated completion date of December 2015.
The product is also being investigated in other clinical trials. In the United States, the Pediatric Oncology Branch of the National Cancer Institute is conducting a phase 1 trial in children and adolescents with relapsed or refractory cancers, both solid tumors and hematologic malignancies, including ALL. In Europe, a large phase 3 trial in patients with newly diagnosed aggressive non-Hodgkin's lymphoma is planned by the German High-Grade Lymphoma Study Group.
The product is also being studied in metastatic malignant uveal melanoma in a phase 2 trial that is expected to recruit 50 patients.
The new product contains vincristine encapsulated in sphingomyelin-based liposomes, which the manufacturer has named Optisome.
In animal studies, this product achieved better tissue drug penetration and accumulation than standard vincristine, and in clinical trials, the liposomal formulation allowed higher doses of vincristine to be used. The dose-intensification study showed that a larger dose could be administered than with standard vincristine (2.25 vs 1.4 mg/m²), and that the dose capping that is routinely applied to standard vincristine could be eliminated with the liposomal product, Talon Therapeutics reported.
In clinical trials, the most common adverse reactions were constipation (57%), nausea (52%), pyrexia (43%), fatigue (41%), peripheral neuropathy (39%), febrile neutropenia (38%), diarrhea (37%), anemia (34%), decreased appetite (33%), and insomnia (32%).
The most commonly reported severe adverse events were febrile neutropenia (20.5%), pyrexia (13.3%), hypotension (7.2%), respiratory distress (6.0%), and cardiac arrest (6.0%). Twenty-eight percent of patients experienced adverse reactions that led to treatment discontinuation, according to the company.
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Cite this: Liposomal Vincristine Approved for Acute Lymphoblastic Leukemia - Medscape - Aug 09, 2012.