The FDA issued a complete response letter to Spectrum Pharmaceuticals, informing the company that its new drug application (NDA) for the use of Captisol-enabled melphalan in multiple myeloma will not be approved in its current form.
Rajesh C. Shrotriya, MD
The FDA issued a complete response letter to Spectrum Pharmaceuticals, informing the company that its new drug application (NDA) for the use of Captisol-enabled (CE) melphalan (Evomela) in multiple myeloma will not be approved in its current form.
Today is the PDUFA action date assigned to CE-melphalan when the FDA accepted Spectrum’s NDA for the drug. Spectrum was seeking marketing approval for CE- melphalan for the treatment of patients with multiple myeloma prior to autologous hematopoietic stem cell transplantation (AHCT), as well as for the palliative treatment of patients with myeloma for whom oral therapy is not appropriate.
“We will work swiftly with the FDA to address the Complete Response Letter," said Rajesh C. Shrotriya, MD, Chairman and Chief Executive Officer of Spectrum Pharmaceuticals. “We remain committed to bringing Evomela to the market for patients and plan to work closely with the FDA.”
The NDA 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-AHCT) and subsequent neutrophil and platelet engraftment (median, 12-13 days post-AHCT) with no mortality at day 100.
The Captisol-enabled formulation of melphalan eliminates the need for propylene glycol-containing diluent, which can limit dosing due to renal and cardiac toxicities. The use of Captisol, a chemically modified cyclodextrin, is thought to allow for longer administration durations and slower infusion rates. This could enable physicians to safely administer higher dose intensity pre-AHCT chemotherapy.
The phase II trial included 56 newly diagnosed multiple myeloma patients and 5 patients who had relapsed following autologous stem cell transplant (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 AHCT. 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 Pharmaceuticals, which is developing CE-melphalan, 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%).
“These study data confirm the efficacy and acceptable safety profile of Evomela as a high-dose conditioning regimen for ASCT in patients with multiple myeloma,” Shrotriya said in a statement when the phase II data were published in September.
“Our novel Evomela formulation uses captisol to improve the solubility and stability of Melphalan, and has eliminated the need for a propylene glycol-containing cosolvent. Importantly, this allows for longer use and infusion times with Evomela, which potentially simplifies its clinical use and administration logistics. Instead of propylene glycol, which is associated with toxicities including renal dysfunction and arrhythmias, this new formulation uses a standard aqueous diluent for reconstitution.”
In March 2013, Spectrum gained development and commercialization rights to CE-melphalan from Ligand Pharmaceuticals Incorporated. Ligand is eligible to receive milestone payments and royalties if the drug is approved.
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.