Michael Vasconcelles, MD
The European Medicines Agency (EMA) has accepted a marketing authorization application (MAA) for ixazomib in combination with lenalidomide and dexamethasone for patients with relapsed/refractory multiple myeloma, according to a statement from the oral proteasome inhibitor's developer, Takeda.
Prior to the acceptance of the application, the Committee for Medicinal Products for Human Use (CHMP) of the EMA granted ixazomib an accelerated assessment. Under this program, the EMA will assess the MAA within 150 days, as compared with 210 days under a standard review.
In mid-July, a new drug application was also submitted to the FDA. This application is scheduled for review by mid-September, at which point the agency will assign a decision deadline under the Prescription Drug User Fee Act. If a priority review is granted, a decision will be made within 6 months.
“The ixazomib applications in Europe and the United States are the first of several that we anticipate submitting by the end of this fiscal year,” said Melody Brown, vice president of Regulatory Affairs, Takeda. “By filing in many regions in rapid succession, we hope to bring ixazomib to as many people living with relapsed/refractory multiple myeloma as soon as possible.”
Both applications for ixazomib included data from the phase III TOURMALINE-MM1 trial, which showed that ixazomib, lenalidomide, and dexamethasone significantly extended progression-free survival (PFS) compared with lenalidomide and dexamethasone alone. Outside of an announcement that the study met its primary endpoint of extension in PFS, Takeda has not yet made data from the TOURMALINE-MM1 trial available.
In the phase III study, 722 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.
Secondary endpoints of the study included overall survival, objective response rate (ORR), and safety, along with several other outcome measures.
Patients enrolled in the TOURMALINE-MM1 study continue to receive treatment, according to the original blinded clinical trial protocol. PFS data were assessed at a prespecified interim analysis by an Independent Data Monitoring Committee (IDMC). Following the demonstration of benefit in February 2015, enrollment in the trial was stopped.
Takeda plans to keep the study blinded until advised otherwise by the IDMC, Michael Vasconcelles, MD, head, Oncology Therapeutic Area Unit, Takeda, told OncLive
"The TOURMALINE-MM1 study remains blinded at the recommendation of the Independent Data Monitoring Committee. Keeping the trial blinded protects the integrity of the trial’s secondary endpoint, that is, survival," he said. "Unique among multiple myeloma trials, the study continues as an active, double-blind, placebo controlled clinical trial as patients continue to be treated as randomized and followed for a future planned final analysis. The study, therefore, continues in accordance with the protocol."
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.