FDA Accepts NDA for New Formulation of Melphalan for Myeloma

Rajesh C. Shrotriya, MD

The FDA has accepted a New Drug Application (NDA) for Captisol-enabled (CE) melphalan for the treatment of patients with multiple myeloma prior to autologous hematopoietic stem cell transplantation (AHCT), according to Spectrum Pharmaceuticals, the company developing the chemotherapy. The NDA is also for the palliative treatment of patients with myeloma for whom oral therapy is not appropriate.

The NDA was submitted based on results from a phase II study that demonstrated a 95% response rate among 61 patients and no deaths by day 100. A Prescription Drug User Free Act (PDUFA) date of October 23, 2015, has been set for CE-melphalan.

“The drug's improved solubility and stability should make it an attractive treatment option for both transplant conditioning and the palliative treatment of patients with [multiple myeloma],” Rajesh C. Shrotriya, MD, chairman and CEO of Spectrum, said in a statement. “Eliminating the need for propylene glycol in the preparation of CE-melphalan eliminates the risk of the toxicities associated with this excipient.”

This new, 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 new formula of melphalan itself eases the process, Shrotriya said, and could allow for a quick uptake in practice.

“CE-melphalan's increased stability simplifies the logistics for pharmacies and nursing staff, and is anticipated to allow for longer infusion times which may permit the administration of higher dose intensities,” Shrotriya said. “We anticipate these characteristics of CE-melphalan will facilitate rapid adoption.”

In the trial, 61 patients were enrolled who received a median of 3 prior lines of therapy (range 2-16). Prior to CE-melphalan treatment, 32% of patients achieved partial response (PR), 44% achieved very good partial response (VGPR), 5% achieved complete response (CR), and no patients had a stringent complete response (sCR), according to the data presented at the 2015 BMT Tandem Meetings.

The trial’s primary endpoint was safety, with secondary endpoints focused on efficacy and rates of myeloablation and engraftment. Patients received 200 mg/m2 (100 mg/m2 administered on consecutive days) of CE-melphalan followed by AHCT.

Overall, 95% of patients responded to CE-melphalan, according to the Spectrum press release, and 67% of high-risk patients achieved VGPR or better.

According to data presented at the 2015 BMT Tandem Meetings, overall, 18% of patients had PR, 61% achieved VGPR, 8% had CR, and 13% achieved sCR.

Most common grade 3/4 adverse events were hematologic in nature (neutropenia, leukopenia, lymphopenia, thrombocytopenia, and anemia). The most common grade 3/4 non-hematologic adverse events were hypophosphatemia (48%), hypokalemia (28%), febrile neutropenia (28%), mucosal inflammation (10%), and stomatitis (5%). The most common all-grade non-hematologic toxicities were diarrhea (93%), nausea (90%), fatigue (77%), hypokalemia (74%), and vomiting (64%).

“Intravenous melphalan has become the standard of care conditioning agent used for high-dose treatment of [multiple myeloma] patients undergoing AHCT, and the substitution of Captisol in CE-melphalan addresses some of the limitations of the currently approved formulations," Parameswaran Hari, MD, MRCP, MS, from the Medical College of Wisconsin and lead author on the study, said in a statement following the BMT Tandem meeting in February 2015.

“The improved stability of the CE-melphalan formulation may potentially ensure that cancer patients receive the full, intended therapeutic dose of IV melphalan by increasing the use time and infusion time of IV melphalan, and simplifying clinical administration logistics.”

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.