The FDA has granted a priority review designation to the oral proteasome inhibitor ixazomib (MLN9708) in combination with lenalidomide and dexamethasone as a treatment for patients with relapsed and/or refractory multiple myeloma, according to a statement from the drug's developer, Takeda.
The application for ixazomib was based on findings from the 722-patient phase III TOURMALINE-MM1 trial, which demonstrated an extension in progression-free survival (PFS) with the oral triplet therapy compared with lenalidomide and dexamethasone alone. With these findings, ixazomib became the first oral proteasome inhibitor to demonstrate efficacy in a phase III trial.
The FDA will make a decision on the application for ixazomib within 6 months, placing a decision deadline on March 10, 2016. An application for ixazomib was also granted an accelerated assessment from the European Medicines Agency in August 2015. Under this program, the European regulatory agency is scheduled to make a decision in early 2016.
“We are encouraged that both the US and European regulatory bodies have determined that the ixazomib applications qualify for an expedited review, underscoring the importance of new treatment options for patients with relapsed/refractory multiple myeloma,” Melody Brown, vice president of Regulatory Affairs, Takeda, said in a statement.
In the phase III study, patients were treated with 25 mg of oral lenalidomide on days 1-21 and 40 mg of oral dexamethasone on days 1, 8, 15, and 22 in combination with ixazomib at 4 mg on days 1, 8, and 15 or placebo. Treatment was administered until disease progression. The study enrolled patients who had received 1 to 3 prior therapies with an ECOG PS of 0, 1, or 2. Patients who were refractory to lenalidomide or a proteasome inhibitor were excluded from the study.
An Independent Data Monitoring Committee assessed PFS data at a prespecified interim analysis. Following the demonstration of benefit in February 2015, enrollment in the trial was stopped. Secondary endpoints of the study included overall survival, objective response rate (ORR), and safety along with several other outcome measures.
Outside of an announcement that the study had met its primary endpoint of extension in PFS, Takeda has not yet made data from the TOURMALINE-MM1 trial available. Patients enrolled in the study continue to receive treatment, according to the original blinded clinical trial protocol.
“Our ixazomib program is designed to evaluate whether sustained therapy with an oral proteasome inhibitor improves the outcomes of patients living with multiple myeloma," said Brown. "There is a significant unmet medical need in multiple myeloma and we look forward to working with the regulatory bodies to bring ixazomib to patients.”
Continuous or sustained treatment has traditionally been labeled as maintenance therapy for patients with multiple myeloma. In this treatment paradigm, following a response to initial therapy, treatment is continued in order to prolong progress-free and overall survival.
In a preceding phase II study presented at the 2014 ASH Annual Meeting, induction therapy with the triplet of ixazomib, lenalidomide, and dexamethasone was followed by maintenance therapy with ixazomib in previously untreated patients with multiple myeloma. Following induction therapy, 29 patients received continuous treatment with ixazomib.
After a median treatment duration of 26.6 months, the ORR among 49 evaluable patients was 90%, including a 59% very good partial response (VGPR) or better. In the maintenance arm, 11 patients experienced a complete response (CR) with continuous ixazomib (52%), 4 of which were stringent CRs (19%). Overall, 33% of patients had an improvement in their response during maintenance treatment.
At this time of this analysis, all enrolled patients remained alive. Follow-up for the full trial ranged from 24.6 to 30.3 months. In the maintenance portion of the study, median follow-up was 16.9 months (range, 12.9-18.9).
In the maintenance portion of the study, 71% of patients experienced a drug-related adverse (AE) event with ixazomib. Grade 3 AEs occurred in just 2 patients and none experienced a grade 4 AE. The most frequently reported grade 1/2 ixazomib-related adverse events were diarrhea (38%), nausea (14%), extremity pain (14%), anemia (10%), and headache (10%). Peripheral neuropathy was not reported.
“These findings suggest that treatment with single-agent ixazomib, an investigational oral proteasome inhibitor, in the maintenance setting has the potential to extend depth of response for patients following induction therapy,” lead investigator of the phase II study Shaji K. Kumar, MD, from the Mayo Clinic, said when the data were presented. “The future availability of such an agent in the maintenance setting could represent an important addition to the treatment of patients with multiple myeloma.”
The TOURMALINE clinical trial program contains 4 other phase III studies in addition to MM1. In the MM2 study, the combination of ixazomib, lenalidomide, and dexamethasone is being explored in newly diagnosed patients with multiple myeloma. In earlier settings, the MM3 and MM4 studies are investigating maintenance therapy with ixazomib in patients who have and have not undergone an autologous stem cell transplant.
In addition to multiple myeloma, ixazomib is being evaluated in combination with dexamethasone for patients with relapsed/refractory systemic light-chain (AL) amyloidosis in the phase III TOURMALINE-AL1 trial. In early December 2014, ixazomib was granted a breakthrough therapy designation as a treatment for patients with AL amyloidosis.
Kumar S, Berdeja JG, Niesvizky R, et al. Long-Term Ixazomib Maintenance Is Tolerable and Improves Depth of Response Following Ixazomib-Lenalidomide-Dexamethasone Induction in Patients (Pts) with Previously Untreated Multiple Myeloma (MM): Phase 2 Study Results. Presented at: the 56th Annual Meeting of the American Society of Hematology; December 6-9, 2014; San Francisco, California. Abstract 82.