On December 3, 2018 Takeda Pharmaceutical Company Limited (TSE: 4502) reported the presentation of results from the randomized Phase 3 study TOURMALINE-MM3 to evaluate the efficacy of oral monotherapy with NINLARO (Ixazomib) as a maintenance treatment in adult multiple myeloma patients previously responding to high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) at the 60th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper), Sunday, December 2, 2018 in San Diego, California (Press release, Takeda, DEC 3, 2018, View Source [SID1234531834]).
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The study reached its primary endpoint with NINLARO leading to a statistically significant improvement in progression-free survival (PFS) compared to placebo in adult patients with multiple myeloma who responded to HDT and ASCT, with assessment by an independent review panel (Independent Review Panel) Review Committee, IRC) (HR 0.72, p-value = 0.002). This equates to a 28 percent reduction in the risk of disease progression or death and a 39 percent improvement in NINLARO PFS compared to placebo. The safety profile of NINLARO maintenance therapy is in line with the already published results on the use of NINLARO as monotherapy.
"The evidence that multiple myeloma maintenance therapy may extend the duration of disease control is increasing," said Meletios Dimopoulos, MD, professor and chair of the Department of Clinical Therapeutics at the Faculty of Medicine, University of Athens, Athens, Greece. "Because there are currently limited treatment options and no proteasome inhibitor among them, there is a need for additional maintenance therapies that can prolong remission and have an acceptable safety profile. Data from the TOURMALINE-MM3 clinical trial suggest monotherapy with NINLARO as a potential oral treatment option for maintenance therapy with an ASCT proteasome inhibitor. "
"The positive results of this pivotal trial, which is the first and only placebo-controlled Phase 3 trial to test a proteasome inhibitor in this setting, support the use of NINLARO as a potential maintenance therapy in patients undergoing stem cell transplantation," said Jesús Gómez Navarro, MD, Vice President, Head of Oncology Clinical Research and Development, Takeda. "It is imperative that we continue to assist patients with the development of treatment options that support and deepen remission and delay disease progression. NINLARO-treated patients showed an improvement in progression-free survival compared to the control arm,
"Continuing research efforts are constantly evolving treatment options for multiple myeloma. This message is encouraging for anyone dealing with multiple myeloma, but further efforts are needed to bring us closer to our goal of meeting patients’ unmet medical needs, "said Brian Durie, MD, Chairman of the Board Board, International Myeloma Foundation. "This requires the development of additional safe and effective maintenance therapies."
Maintenance therapy with oral proteasome inhibitor (PI) Ixazomib causes significant progression-free survival (PFS) after autologous stem cell transplantation (ASC) in patients with newly diagnosed multiple myeloma (NDMM): the TOURMALINE-MM3 phase 3 study Sunday, 2. December 2018, 7:30 am – 9:00 am, Marriott Marquis San Diego Marina, Grand Ballroom 7
Among the main results, by Dr. med. Meletios Dimopoulos are presented include:
The study reached its primary endpoint with NINLARO leading to a statistically significant improvement in PFS compared to placebo in adult patients with multiple myeloma who responded to HDT and ASCT, assessed by an independent review panel (IRC) (HR 0.72, 95% CI: 0.582, 0.890, p-value = 0.002). This equates to a 28 percent reduction in the risk of disease progression or death and 39 percent improvement in PFS under NINLARO.
According to the IRC assessment, median PFS for patients in the NINLARO arm was 26.5 months compared to 21.3 months for the placebo arm.
The conversion of documented positive finding for minimal residual disease (MRD) at study to MRD negativity was more common in NINLARO-treated patients compared to placebo (12 percent versus 7 percent).
Maintenance therapy with NINLARO resulted in higher rates of deep remission compared to placebo (relative risk 1.41, 95 percent CI: 1.10, 1.80, p = 0.0042).
PFS benefits were broadly distributed across subgroups, including ISS III (HR 0.661), PI pretreated (HR 0.750), PI naive (HR 0.497), and patients with high-risk cytogenetic signs (HR 0.625).
The secondary endpoints, including median PFS2 and OS, have not been reached in either arm. The median follow-up time was 31 months.
Overall quality of life scores (EORTC QLQ-C30) were similar in NINLARO-treated patients compared to the placebo group.
The safety profile of NINLARO maintenance therapy is in line with the already published results on the use of NINLARO as monotherapy.
The discontinuation of treatment due to adverse events (AEs) was low and was 7 percent in the NINLARO arm compared to 5 percent in the placebo arm.
A third or higher grade of AEs occurred in 42 percent of patients in the NINLARO arm compared with 26 percent in the placebo arm.
In the NINLARO arm, severe AEs were found in 27 percent of the cases compared to 20 percent in the placebo arm.
Common AEs 3 or higher included infections (15 vs. 8 percent) in both the NINLARO and placebo arm, including pneumonia (6 vs. 4 percent), gastrointestinal disorders (6 vs. 1 percent ), Neutropenia (5 vs. 3 percent), and thrombocytopenia (5 vs. <1 percent).
In the NINLARO arm, peripheral neuropathy was observed in 19 percent of patients compared to 15 percent in the placebo arm. In the NINLARO arm, less than 1 percent of the incidence of peripheral neuropathy was Grade 3 AEs compared to 0 percent in the placebo arm.
The second tumor rate was 3 percent in both arms.
One patient in the NINLARO arm died during the study, whereas no death occurred in the placebo arm. The only death in the study was classified as a treatment-related event and was the result of pneumonia.
About the study TOURMALINE-MM3
TOURMALINE-MM3 is a randomized, placebo-controlled, double-blind Phase 3 study in 656 patients to determine the effect of NINLARO (Ixazomib) maintenance therapy on progression-free survival (PFS) versus placebo in patients with multiple myeloma who have a history of disease Remission (complete remission [CR], very good partial remission [VGPR] or partial remission [PR]) on induction therapy followed by high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) The primary endpoint is progression-free survival (PFS) An important secondary endpoint includes overall survival (OS). For more information, seeView Source .
About NINLARO (ixazomib) capsules
NINLARO (Ixazomib) is an oral proteasome inhibitor that is also being studied in the multiple myeloma therapy continuum and in systemic light chain amyloidosis (AL), the first oral proteasome inhibitor tested in Phase 3 clinical trials and approved. NINLARO was approved by the US Food and Drug Administration (FDA) in November 2015 after a Priority Review and by the European Commission in November 2016. In the US and Europe, NINLARO is used in combination with lenalidomide and dexamethasone in the treatment of patients with multiple myeloma NINLARO has received marketing approval from regulators in more than 60 countries.
In 2011, Ixazomib was granted orphan drug status in multiple myeloma in the US and Europe, and AL amyloidosis in the US and Europe in 2012. In 2014, Ixazomib received breakthrough therapy from the FDA for relapsed or refractory systemic light chain amyloidosis (AL), a related extremely rare disease. The Japanese Ministry of Health, Labor and Social Affairs granted Ixazomib orphan drug status in 2016.
TOURMALINE, the comprehensive Ixazomib clinical development program, includes a total of six ongoing regulatory trials – five investigating all major groups of multiple myeloma patients and one dealing with light chain amyloidosis:
TOURMALINE-MM1 for testing ixazomib over placebo in combination with lenalidomide and dexamethasone in relapsed and / or refractory multiple myeloma
TOURMALINE-MM2 for the testing of ixazomib versus placebo in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma
TOURMALINE-MM3 for testing ixazomib versus placebo as a maintenance treatment in patients with newly diagnosed multiple myeloma after induction therapy and autologous stem cell transplantation (ASCT)
TOURMALINE-MM4 for the testing of ixazomib versus placebo as a maintenance treatment in patients with newly diagnosed multiple myeloma who have not undergone autologous stem cell transplantation (ASCT)
TOURMALINE-AL1 for the testing of ixazomib plus dexamethasone for a physician on the basis of a selection of therapies in patients with relapsed or refractory AL amyloidosis. Patients are currently enrolled in this study.
TOURMALINE-MM5 for the testing of ixazomib plus dexamethasone versus pomalidomide plus dexamethasone in patients with relapsed and / or refractory multiple myeloma who have become resistant to lenalidomide. Patients are currently enrolled in this study.
For more information on actively recruiting Phase 3 studies, visit View Source
In addition to the TOURMALINE study program, Ixazomib is currently being evaluated in several therapeutic combinations in various patient populations worldwide through investigator-initiated studies (IIT).
NINLARO Ixazomib) Capsules: Important Safety Information Worldwide
SPECIAL WARNINGS AND PRECAUTIONS
Thrombocytopenia has been reported with the use of NINLARO (28% vs. 14% with the NINLARO or placebo regimen). Platelets reached their lowest point between the 14th and 21st day of the 28-day treatment cycle and recovered to baseline by the start of the next cycle. This did not lead to increased bleeding events or platelet transfusions. During treatment with NINLARO, the platelet count should be monitored at least monthly and more frequent monitoring should be considered during the first three cycles. Thrombocytopenia should be treated with dose adjustment and platelet transfusions according to the recommendations of the standard guidelines.
Gastrointestinal toxicities have been reported in the NINLARO and placebo regimens, for example, diarrhea (42% vs. 36%), constipation (34% vs. 25%), nausea (26% vs. 21%), and vomiting (22% vs 11%). These occasionally required the use of medication for vomiting and diarrhea, as well as supportive therapy.
Peripheral neuropathy has been reported in NINLARO (28% vs. 21% with the NINLARO or placebo regimen). The most commonly reported adverse reaction was peripheral sensory neuropathy (19% and 14% in the NINLARO or placebo regimen). Peripheral motor neuropathy has not been reported in any of the two regimens (<1%). Patients should be monitored for signs of peripheral neuropathy and dosing adjusted if necessary.
Peripheral edema has been reported in NINLARO (25% vs. 18% with the NINLARO or placebo regimen). The underlying causes should be clarified. If necessary, patients should receive supportive care. Dose adjustment should be made with dexamethasone according to the SPC or with NINLARO if severe symptoms occur.
Skin reactions occurred in 19 percent of patients with the NINLARO regimen compared to 11 percent of patients on the placebo regimen. The most common form of rash on both schemes was a maculopapular and macular rash. Rashes should be treated with supportive therapy, dose adjustment or discontinuation of the drug.
Hepatotoxicity, drug-induced liver damage, hepatocellular damage, fatty liver, and cholestatic hepatitis have not been reported commonly in NINLARO-treated patients. Liver values should be monitored regularly and dose adjustments should be made for symptoms of Grade 3 and 4.
Pregnancy – NINLARO can lead to harm to unborn life. For fertile men and women of childbearing potential, contraceptive methods should be used during treatment and for a further 90 days after the last dose of NINLARO. Due to the possible risk to the unborn child, women of childbearing age should be prevented from taking pregnancy while being treated with NINLARO. Women who use hormonal contraceptives should also use a barrier method for contraception.
Breastfeeding – It is not known whether NINLARO or its breakdown products are excreted in breast milk. Due to possible adverse events in breast-fed infants, NINLARO-treated patients should abstain.
SPECIAL PATIENT POPULATIONS
Hepatic impairment: The starting dose of NINLARO should be reduced to 3 mg in patients with moderate or severe hepatic impairment.
Renal impairment: In patients with severe renal impairment or dialysis-dependent patients with end stage renal disease (ESRD), the starting dose of NINLARO should be reduced to 3 mg. NINLARO is not dialyzable and can therefore be administered independently of the dialysis schedule.
INTERACTIONS WITH OTHER MEDICINAL PRODUCTS
Simultaneous use of NINLARO and strong CYP3A inducers is foreseeable.
SIDE EFFECTS
The most common adverse reactions reported in at least 20% of NINLARO regimens or more frequently than placebo 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 side effects that occurred in at least 2 percent of patients included thrombocytopenia (2%) and diarrhea (2%). For each adverse reaction, one or more of the three drugs was discontinued in ≤ 1 percent of patients on NINLARO regimen.