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FDA Approves New Melphalan Formulation in Myeloma

Jason M. Broderick @jasoncology
Published: Tuesday, Mar 15, 2016

The FDA has approved Captisol-enabled (CE) melphalan (Evomela) as a high-dose conditioning treatment for use in patients with multiple myeloma prior to autologous stem cell transplantation (ASCT), as well as for the palliative treatment of patients with myeloma for whom oral therapy is not appropriate, according to a statement from the developer of the drug, Spectrum Pharmaceuticals.

The approval was based on results from a multicenter, open-label phase IIb study in which the overall response rate (ORR) to CE melphalan was 95% among 61 patients, with all patients having successful myeloablation (median 5 days post-ASCT) and subsequent neutrophil and platelet engraftment (median, 12-13 days post-ASCT) with no mortality at day 100.

“The approval of Evomela marks the first new formulation of melphalan approved by the FDA, since its initial approval in 1964,” lead author Parameswaran Hari, MD, Armand J. Quick/William F. Stapp Professor of Hematology at the Medical College of Wisconsin, director of the Adult Blood and Marrow Transplant Program at Froedtert Hospital and the section head of Hematologic Malignancies and Transplantation, in the Division of Hematology and Oncology in the Department of Medicine, said in statement.

“Melphalan is extensively used in the treatment of multiple myeloma and is the main drug in conditioning therapy pretransplant. Evomela’s new formulation does not contain propylene glycol and is stable for 4 hours at room temperature in addition to the 1 hour following reconstitution.”

The phase II trial included 56 newly diagnosed multiple myeloma patients and 5 patients who had relapsed following ASCT. Patients had received a median of 3 prior lines of therapy (range, 2-16). The trial’s primary endpoint was safety, with secondary endpoints focused on efficacy and rates of myeloablation and engraftment.

Patients received 200 mg/m2 of CE-melphalan followed by ASCT. The treatments were administered in 100 mg/m2 doses 3 and 2 days prior to transplantation. Investigator-assessed ORR was 95%, with a complete response (CR) rate of 31% (16% stringent CRs). ORR and CR rates were 100% and 21%, respectively, by independent pathology review. According to Spectrum, the lower CR rate by independent review could be attributed to missing data.

The most common grade 3/4 adverse events were hematologic in nature, including neutropenia, leukopenia, lymphopenia, thrombocytopenia, and anemia.

The most frequently reported grade 3/4 nonhematologic adverse events were hypophosphatemia (48%), hypokalemia (28%), febrile neutropenia (28%), mucosal inflammation (10%), and stomatitis (5%). The most common all-grade nonhematologic toxicities were diarrhea (93%), nausea (90%), fatigue (77%), hypokalemia (74%), and vomiting (64%).

Spectrum gained development and commercialization rights to CE-melphalan from Ligand Pharmaceuticals Incorporated in March 2013.

“I am very proud to announce that Spectrum has been able to bring another new cancer drug to the market,” Rajesh C. Shrotriya, MD, chairman and CEO of Spectrum Pharmaceuticals said in a statement. “This represents the commercialization of our sixth Hematology/Oncology product in the United States. Our Evomela formulation does not contain propylene glycol and is reconstituted and admixed with normal saline. This new formulation also uses Captisol technology, which allows the admixture solution to be stable for 4 hours at room temperature in addition to the 1 hour following reconstitution and has been used in several other FDA-approved products.”

Hari PN, Ajitawi O, Arce-Lara C, et al. Results of a phase ii study of propylene glycol (PG)-free, captisol-enabled melphalan conditioning for autologous hematopoietic stem cell transplantation (AHCT) in patients with multiple myeloma (MM). BBMT. 2015;21(2)(suppl):S138.

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