Ixazomib Phase III Trial Discontinued in AL Amyloidosis

Phil Rowlands, PhD

Ixazomib (Ninlaro) in combination with dexamethasone did not demonstrate a significant improvement in overall hematologic response compared with standard therapy in patients with relapsed/refractory systemic light-chain (AL) amyloidosis, missing one of two primary endpoints in the phase III TOURMALINE-AL1 trial and leading to discontinuation of the study.¹

“While we are disappointed with this outcome, we aim to maximize our learnings from this trial and share findings with the community in hopes of helping to improve care for patients living with this devastating disease,” Phil Rowlands, PhD, head, Oncology Therapeutic Area Unit, of Takeda, the developer of ixazomib, stated in a press release. “This has been one of the largest studies ever conducted in systemic light-chain AL amyloidosis and we are proud to have led it.”

Regarding safety, an Independent Data Monitoring Committee did not raise any concerns with ixazomib’s safety profile in this patient population. Takeda stated in the press release that patients enrolled on this trial are encouraged to consult with study investigators to address any questions.

Primary AL amyloidosis arises from a clonal plasma cell that creates atypical immunoglobulin light-chain fragments that aggregate as amyloid deposits in organs and tissues, leading to organ dysfunction and death. The kidneys, heart, liver, and autonomic or peripheral nerves are the most commonly affected nerves. Moreover, there are no FDA-approved therapies for the treatment of patients with AL amyloidosis.

In the international, randomized, open-label, multicenter phase III TOURMALINE-AL1 trial (NCT01659658), investigators evaluated the combination of 4 mg of ixazomib and 20 mg of dexamethasone compared with physician’s choice of chemotherapy in approximately 248 patients with relapsed/refractory systemic AL amyloidosis. The chemotherapy regimens patients could be randomized to were dexamethasone/melphalan, dexamethasone/cyclophosphamide, dexamethasone/thalidomide (Thalomid), dexamethasone/lenalidomide (Revlimid), or dexamethasone alone.

The primary endpoints were hematologic response and 2-year vital organ deterioration and mortality rates. Secondary endpoints included compete hematologic response rate, overall survival (OS), progression-free survival (PFS), hematologic disease PFS, time to vital organ deterioration and mortality rate, best vital organ response rate, vital organ PFS, duration of hematologic response, adverse events (AEs), time to treatment failure, time to subsequent anticancer treatment, and change from baseline in SF-36 General Health Survey score.

Prior phase I/II data demonstrated activity with ixazomib in patients with relapsed/refractory AL amyloidosis who received ≥1 prior lines of therapy.² First, patients received ixazomib on days 1, 8, and 15 of 28-day cycles for up to 12 cycles. Patients with less than a partial response after 3 cycles were given oral dexamethasone (40 mg, days 1-4) starting with cycle 4.

Then, a 3+3 dose-escalation phase of the study was followed by 2 expansion cohorts for proteasome inhibitor—naïve and –exposed patients at the maximum-tolerated dose (MTD), which was 4.0 mg. A total of 27 patients were enrolled, which comprised 11 during the dose-escalation phase and 16 during the dose-expansion phase.

Results showed that the hematologic response rate was 52% in the 21 patients treated at the MTD, and the organ response rate was 56%—5 of which were cardiac and 5 that were renal. At a median follow-up of 16.9 months, the median hematologic PFS was 14.8 months, and the 1-year PFS and OS rates were 60% and 85%, respectively.

Regarding safety, 3 patients experienced dose-limiting toxicities; 1 occurred at 4.0 mg and 2 occurred at 5.5 mg. The most common AEs included nausea, skin and subcutaneous tissue disorders (SSTD), diarrhea, and fatigue. Grade ≥3 AEs included dyspnea, fatigue, and SSTD.

“This study demonstrated our dedication to this rare and traditionally difficult-to-enroll patient population and we thank the patients and investigators for their engagement and participation,” Rowlands continued in the press release. “We remain optimistic about Ninlaro and continue to investigate Ninlaro in patient populations across the continuum of multiple myeloma care.”

Ixazomib is currently approved by the FDA in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received ≥1 prior therapy.

References

1. Takeda Provides Update on TOURMALINE-AL1 Phase 3 Trial in AL Amyloidosis. Takeda Pharmaceutical Company. Published June 5, 2019. https://bit.ly/2Xu2CIX. Accessed June 5, 2019.
2. Sanchorawala V, Palladini G, Kukreti V, et al. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017;130(5):597-605. doi: 10.1182/blood-2017-03-771220.