7 June 2019 - - Japanese pharmaceutical company Takeda Pharmaceutical Company Ltd. (TSX: 4502) (NYSE: TAK) said the Phase 3 TOURMALINE-AL1 clinical trial in patients with relapsed or refractory systemic light-chain amyloidosis did not meet the first of two primary endpoints.
Treatment with Ninlaro (ixazomib) in combination with dexamethasone did not demonstrate a significant improvement in overall hematologic response compared to physician's choice of standard of care regimens.
As a result of this analysis, Takeda has decided to discontinue the trial.
An Independent Data Monitoring Committee did not raise any concerns about the safety profile of Ninlaro NINLARO in this setting. Patients are encouraged to consult their study investigators to address any questions.
TOURMALINE-AL1 (NCT01659658) is an international, randomised, controlled, open-label, multicenter, Phase 3 study, designed to determine whether Ninlaro (ixazomib) in combination with dexamethasone improves hematologic response, two-year vital organ (heart or kidney) deterioration and mortality rate versus a physician's choice of a chemotherapy regimen in participants diagnosed with relapsed or refractory systemic light chain amyloidosis.
Patients were randomly selected to receive either NINLARO plus dexamethasone, or physician's choice of dexamethasone plus melphalan; dexamethasone plus cyclophosphamide; dexamethasone plus thalidomide; dexamethasone plus lenalidomide; or dexamethasone alone.
Primary AL amyloidosis is a condition that falls under the umbrella of plasma cell dyscrasias. AL amyloidosis arises from a clonal plasma cell that produces abnormal immunoglobulin light-chain fragments.
These misfolded light-chains form insoluble fibrils that aggregate as amyloid deposits in organs and tissues throughout the body, ultimately leading to organ dysfunction and death. The most common organs affected are the kidneys, heart, liver, and autonomic or peripheral nerves. There are currently no treatments approved for the treatment of AL amyloidosis.
Ninlaro (ixazomib) is an oral proteasome inhibitor which is being studied across the continuum of multiple myeloma treatment settings. Ninlaro was first approved by the US Food and Drug Administration in November 2015 and is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy.
Ninlaro is currently approved in more than 60 countries, including the United States, Japan and in the European Union, with more than 10 regulatory filings currently under review.
It was the first oral proteasome inhibitor to enter Phase 3 clinical trials and to receive approval.
The comprehensive ixazomib clinical development program, TOURMALINE, includes four ongoing pivotal trials, which together are investigating major multiple myeloma patient populations.
TOURMALINE-MM1 is investigating ixazomib vs. placebo in combination with lenalidomide and dexamethasone in relapsed and/or refractory multiple myeloma
TOURMALINE-MM2 is investigating ixazomib vs. placebo in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma
TOURMALINE-MM3 is investigating ixazomib vs. placebo as maintenance therapy in patients with newly diagnosed multiple myeloma following induction therapy and autologous stem cell transplant
TOURMALINE-MM4 is investigating ixazomib vs. placebo as maintenance therapy in patients with newly diagnosed multiple myeloma who have not undergone ASCT; this study is currently enrolling
In addition to the TOURMALINE programme, ixazomib is being evaluated in multiple therapeutic combinations for various patient populations in investigator initiated studies globally.
Thrombocytopenia has been reported with Ninlaro (28% vs. 14% in the Ninlaro and placebo regimens, respectively) with platelet nadirs typically occurring between Days 14-21 of each 28-day cycle and recovery to baseline by the start of the next cycle. It did not result in an increase in hemorrhagic events or platelet transfusions.
Monitor platelet counts at least monthly during treatment with Ninlaro and consider more frequent monitoring during the first three cycles.
Manage with dose modifications and platelet transfusions as per standard medical guidelines.
Gastrointestinal toxicities have been reported in the Ninlaro and placebo regimens respectively, such as diarrhea (42% vs. 36%), constipation (34% vs. 25%), nausea (26% vs. 21%), and vomiting (22% vs. 11%), occasionally requiring use of antiemetic and anti-diarrheal medications, and supportive care.
Peripheral neuropathy was reported with Ninlaro (28% vs. 21% in the Ninlaro and placebo regimens, respectively). The most commonly reported reaction was peripheral sensory neuropathy (19% and 14% in the Ninlaro and placebo regimens, respectively).
Peripheral motor neuropathy was not commonly reported in either regimen.
Monitor patients for symptoms of peripheral neuropathy and adjust dosing as needed.
Peripheral edema was reported with Ninlaro (25% vs. 18% in the Ninlaro and placebo regimens, respectively).
Evaluate patients for underlying causes and provide supportive care, as necessary. Adjust the dose of dexamethasone per its prescribing information or the dose of Ninlaro for severe symptoms.
Cutaneous reactions occurred in 19% of patients in the Ninlaro regimen compared to 11% of patients in the placebo regimen. The most common type of rash reported in both regimens was maculo-papular and macular rash. Manage rash with supportive care, dose modification or discontinuation.
Hepatotoxicity, drug-induced liver injury, hepatocellular injury, hepatic steatosis, and hepatitis cholestatic have been uncommonly reported with Ninlaro.
Monitor hepatic enzymes regularly and adjust dose for Grade 3 or 4 symptoms.
Pregnancy- Ninlaro can cause fetal harm.
Advise male and female patients of reproductive potential to use contraceptive measures during treatment and for an additional 90 days after the final dose of Ninlaro.
Women of childbearing potential should avoid becoming pregnant while taking Ninlaro due to potential hazard to the fetus. Women using hormonal contraceptives should use an additional barrier method of contraception.
Lactation- It is not known whether Ninlaro or its metabolites are excreted in human milk. There could be potential adverse events in nursing infants and therefore breastfeeding should be discontinued.
The most frequently reported adverse reactions (≥ 20%) in the Ninlaro regimen, and greater than in the placebo regimen, were diarrhea (42% vs. 36%), constipation (34% vs. 25%), thrombocytopenia (28% vs. 14%), peripheral neuropathy (28% vs. 21%), nausea (26% vs. 21%), peripheral edema (25% vs. 18%), vomiting (22% vs. 11%), and back pain (21% vs. 16%).
Serious adverse reactions reported in ≥ 2% of patients included thrombocytopenia and diarrhea. For each adverse reaction, one or more of the three drugs was discontinued in ≤ 1% of patients in the Ninlaro regimen.
Takeda Pharmaceutical Company Ltd. (TSX: 4502) (NYSE: TAK) is a global, values-based, R and D-driven biopharmaceutical leader headquartered in Japan, committed to bringing Better Health and a Brighter Future to patients by translating science into highly-innovative medicines.
Takeda focuses its R and D efforts on four therapeutic areas: Oncology, Gastroenterology, Neuroscience and Rare Diseases. We also make targeted R and D investments in Plasma-Derived Therapies and Vaccines.