– Early studies of weekly and twice-weekly
ixazomib plus lenalidomide and dexamethasone demonstrate deep
responses after induction, with deepening responses seen after
single-agent ixazomib maintenance –
– Data to be presented during two oral sessions
at the 2017 European Hematology Association (EHA) Annual Meeting
–
Takeda Pharmaceutical Company Limited (TSE: 4502) today
announced that data from two Phase 1/2 clinical trials evaluating
NINLARO™ (ixazomib) in patients with newly diagnosed multiple
myeloma will be presented during oral sessions at the 2017 European
Hematology Association (EHA) annual meeting on Saturday, June 24,
11:45 a.m. – 12 p.m. CEST and Sunday, June 25, 8:15 a.m. – 8:30
a.m. CEST. Both studies evaluated NINLARO plus lenalidomide and
dexamethasone in newly diagnosed patients with multiple myeloma who
did not undergo stem cell transplant (SCT), followed by maintenance
with single-agent ixazomib. NINLARO is currently not approved for
the treatment of newly diagnosed multiple myeloma or in the
maintenance setting.
“Despite recent progress, multiple myeloma remains a rare,
devastating and incurable hematologic cancer. Data being presented
at EHA demonstrate Takeda’s ongoing commitment to exploring new
ways to provide effective and sustainable treatment for patients
with multiple myeloma, both at the time of diagnosis and for
long-term use,” said Jesus Gomez Navarro, M.D., Vice President,
Head of Oncology Clinical Research and Development, Takeda. “These
Phase 1/2 data demonstrate the potential use of ixazomib in
combination with lenalidomide-dexamethasone in newly diagnosed
multiple myeloma and as a single-agent maintenance therapy, which
resulted in patients achieving deepening responses with continual
use of the treatment. Ixazomib’s efficacy and safety profile –
coupled with its administration as a completely oral regimen –
potentially can reduce some logistical burdens, and help patients
be able to sustain a multiple myeloma therapy.”
Deep and Durable Responses with Weekly Ixazomib, Lenalidomide
and Dexamethasone in Patients with Newly Diagnosed Multiple
Myeloma: Long-Term Follow-up of Patients who did not Undergo SCT
(Abstract S408, oral presentation at 11:45 a.m. CEST on June 24,
2017 at IFEMA Madrid, Hall A)
In this Phase 1/2 study, patients with newly diagnosed multiple
myeloma received weekly oral ixazomib (1.68 - 3.95 mg/m2 in Phase 1
and 4.0 mg in Phase 2) plus lenalidomide and dexamethasone for up
to twelve, 28-day induction cycles. Of the 65 enrolled patients, 42
continued on study treatment without withdrawing early for SCT.
After initial therapy, 25 patients went on to receive weekly,
single-agent ixazomib at the last tolerated dose given during
induction until disease progression or unacceptable toxicity.
Key findings, which will be presented by Dr. Shaji Kumar of the
Mayo Clinic, Rochester, Minnesota, include:
- Patients who did not undergo SCT and
were treated with ixazomib plus lenalidomide and dexamethasone at
induction achieved high response rates, demonstrate the activity of
this regimen
- At a median follow-up of 55.2 months,
the confirmed overall response rate (ORR) was 80%, complete plus
very good partial response (CR+VGPR) rate was 63% and CR rate was
32%
- Of the patients who achieved sCR/CR and
were evaluated for minimal residual disease (MRD), 6 of 7 (86%)
were MRD-negative.
- Median progression-free survival (PFS)
was 29.4 months
- Median overall survival (OS) was not
reached at a median follow-up of 55.2 months; four-year landmark OS
estimate was 82%
- A total of 86% of patients had grade ≥
3 adverse events (AEs) and 52% of patients had serious AEs. The
most common grade ≥ 3 AEs were neutropenia, thrombocytopenia,
diarrhea, back pain, vomiting, rashes, eruptions and exanthems,
peripheral neuropathy and nausea. Of the two patients who died on
study, one was considered to be treatment-related and was due to
respiratory syncytial viral pneumonia
- After completing 12 cycles of induction
therapy with lenalidomide and dexamethasone, 25 patients went on to
receive maintenance single-agent ixazomib
- Increased depth of response occurred in
a number of patients who received maintenance therapy with
single-agent ixazomib; 32% of patients improved their response
during maintenance
- The occurrence of the most common grade
≥ 3 AEs and adverse drug reactions (ADRs), which included
neutropenia, thrombocytopenia, back pain and rashes, eruptions and
exanthems, was confined almost exclusively to the induction period
- Less toxicity was reported during the
maintenance versus induction periods
“Based on an increasing body of evidence that long-term therapy
may improve clinical outcomes, this Phase 1/2 trial focused on
continuous treatment of patients with newly diagnosed multiple
myeloma,” said lead investigator Shaji Kumar, M.D., Mayo Clinic,
Rochester, Minn. “The trial evaluated patients who received weekly
ixazomib plus lenalidomide and dexamethasone as an induction
regimen followed by maintenance with single-agent ixazomib. Data
showed that patients had deep responses on single-agent therapy and
median progression-free survival of more than two years. We remain
committed to gathering additional data of ixazomib in this
investigational, maintenance setting.”
Twice Weekly Ixazomib Plus Lenalidomide-Dexamethasone in
Patients with Newly Diagnosed Multiple Myeloma: Long-Term Follow-up
Data for Patients who did not Undergo Stem Cell Transplant (SCT)
(Abstract S780, oral presentation at 8:15 a.m. CEST on June 25,
2017 at IFEMA Madrid, Hall D)
This Phase 1/2 study evaluated twice-weekly oral ixazomib (3.0
or 3.7 mg) plus lenalidomide and dexamethasone for up to sixteen,
21-day cycles followed by maintenance therapy with single-agent
twice weekly ixazomib (at last tolerated dose). Of the 64 patients
enrolled, 41 continued on study treatment without early withdrawal
for SCT.
Key findings, which will be presented by Deborah Berg, Senior
Scientific Director, Oncology Clinical Research, Takeda, on behalf
of Dr. Paul Richardson, Dana-Farber Cancer Institute, Boston,
Mass., include:
- In patients who did not undergo SCT,
initial treatment with twice-weekly ixazomib plus lenalidomide and
dexamethasone was associated with deep responses
- At median follow-up of 47 months, the
ORR was 92%, the CR + VGPR rate was 69% and the CR rate was
31%
- Of the patients who achieved sCR/CR and
were evaluated for minimal residual disease (MRD), 8 of 9 (89%)
were MRD-negative
- Median PFS for patients was 24.9 months
and median OS was not estimable; three-year landmark OS estimate
was 86%
- A total of 85% of patients had grade ≥
3 AEs and 54% of patients had serious AEs. The most common grade ≥3
AEs included rash, eruptions and exanthems, hyperglycemia,
peripheral neuropathy, peripheral edema, thrombocytopenia and
neutropenia. There was one on-study treatment-related death due to
cardio respiratory arrest.
- After completing induction therapy, 18
patients went on to receive maintenance with twice-weekly
single-agent ixazomib
- Patients on maintenance therapy
received a median of 31.5 treatment cycles
- 22% patients improved their responses
during maintenance
- 44% of patients who received
maintenance therapy had an onset of a grade ≥ 3 AE and ADRs in
cycle 17 or beyond. The most common grade ≥ 3 AEs and ADRs were
hyperglycemia, rashes, eruptions and exanthems, diarrhea, vomiting,
peripheral neuropathy, nausea and neutropenia.
“The addition of ixazomib – a first in class oral proteasome
inhibitor – to doublet therapy has been shown to substantially
improve efficacy in newly diagnosed multiple myeloma patients,”
said lead investigator Paul Richardson, M.D., Dana-Farber Cancer
Institute. “In this Phase 1/2 trial in newly diagnosed multiple
myeloma, ixazomib plus lenalidomide and dexamethasone resulted not
only in high quality of responses using a twice a week schedule but
also in an encouraging deepening of responses over time in patients
who did not receive a stem cell transplant. In addition, impressive
durable clinical benefit was seen as patients went on to receive
maintenance therapy with single-agent ixazomib after successful
induction/remission therapy using this all oral approach.”
About Multiple Myeloma
Multiple myeloma is a cancer of the plasma cells, which are
found in the bone marrow. In multiple myeloma, a group of
monoclonal plasma cells, or myeloma cells, becomes cancerous and
multiplies. These malignant plasma cells have the potential to
affect many bones in the body, possibly resulting in compression
fractures, lytic bone lesions and related pain. Multiple myeloma
can cause a number of serious health problems affecting the bones,
immune system, kidneys and red blood cell count, with some of the
more common symptoms including bone pain and fatigue, a symptom of
anemia. Multiple myeloma is a rare form of cancer, with
approximately 114,000 new cases globally per year.
About NINLAROTM (ixazomib)
capsules
NINLAROTM (ixazomib) is an oral proteasome inhibitor which
is also being studied across the continuum of multiple myeloma
treatment settings as well as systemic light-chain (AL)
amyloidosis. It was the first oral proteasome inhibitor to enter
Phase 3 clinical trials and to receive approval. NINLARO was
approved by the U.S. Food and Drug Administration (FDA) in November
2015 following a priority review and by the European Commission in
November 2016. In the U.S. and Europe, NINLARO is indicated in
combination with lenalidomide and dexamethasone for the treatment
of patients with multiple myeloma who have received at least one
prior therapy.
Ixazomib was granted orphan drug designation in multiple myeloma
in both the U.S. and Europe in 2011 and for AL amyloidosis in both
the U.S. and Europe in 2012. Ixazomib received Breakthrough Therapy
status by the U.S. FDA for relapsed or refractory systemic
light-chain (AL) amyloidosis in 2014.
The comprehensive ixazomib clinical development program,
TOURMALINE, further reinforces Takeda's ongoing commitment to
developing innovative therapies for people living with multiple
myeloma worldwide and the healthcare professionals who treat them.
TOURMALINE includes a total of five ongoing pivotal trials – four,
which together are investigating every major multiple myeloma
patient population, and one in light-chain amyloidosis:
- TOURMALINE-MM1, investigating ixazomib
vs. placebo, in combination with lenalidomide and dexamethasone in
relapsed and/or refractory multiple myeloma
- TOURMALINE-MM2, investigating ixazomib
vs. placebo, in combination with lenalidomide and dexamethasone in
patients with newly diagnosed multiple myeloma
- TOURMALINE-MM3, investigating ixazomib
vs. placebo as maintenance therapy in patients with newly diagnosed
multiple myeloma following induction therapy and autologous stem
cell transplant (ASCT)
- TOURMALINE-MM4, investigating ixazomib
vs. placebo as maintenance therapy in patients with newly diagnosed
multiple myeloma who have not undergone ASCT; this study is
currently enrolling
- TOURMALINE-AL1, investigating ixazomib
plus dexamethasone vs. physician choice of selected regimens in
patients with relapsed or refractory AL amyloidosis; this study is
currently enrolling
- TOURMALINE-MM5, investigating ixazomib
plus dexamethasone vs. pomalidomide plus dexamethasone in patients
with relapsed and/or refractory multiple myeloma who have become
resistant to lenalidomide
- TOURMALINE-MM6, investigating ixazomib
vs. placebo, in combination with lenalidomide and dexamethasone in
patients with multiple myeloma transitioning from a
bortezomib-based triplet induction regimen
In addition to the TOURMALINE program, ixazomib is being
evaluated in multiple therapeutic combinations for various patient
populations in investigator initiated studies globally.
NINLAROTM (ixazomib): Global Important
Safety Information
SPECIAL WARNINGS AND PRECAUTIONS
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 (< 1%). 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
females 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.
SPECIAL PATIENT POPULATIONS
Hepatic Impairment: Reduce the NINLARO starting dose to 3
mg in patients with moderate or severe hepatic impairment.
Renal Impairment: Reduce the NINLARO starting dose
to 3 mg in patients with severe renal impairment or end-stage renal
disease (ESRD) requiring dialysis. NINLARO is not dialyzable and,
therefore, can be administered without regard to the timing of
dialysis.
DRUG INTERACTIONS
Co-administration of strong CYP3A inducers with NINLARO is not
recommended.
ADVERSE REACTIONS
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 (2%) and diarrhea (2%). For each adverse reaction,
one or more of the three drugs was discontinued in ≤ 1% of patients
in the NINLARO regimen.
For European Union Summary of Product Characteristics:
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003844/WC500217620.pdfFor
US Prescribing
Information: https://www.ninlarohcp.com/pdf/prescribing-information.pdfFor
Canada Product
Monograph: http://www.takedacanada.com/ninlaropm
About Takeda
Takeda Pharmaceutical Company Limited is a global, research and
development-driven pharmaceutical company committed to bringing
better health and a brighter future to patients by translating
science into life-changing medicines. Takeda focuses its R&D
efforts on oncology, gastroenterology and central nervous system
therapeutic areas plus vaccines. Takeda conducts R&D both
internally and with partners to stay at the leading edge of
innovation. New innovative products, especially in oncology and
gastroenterology, as well as our presence in Emerging Markets, fuel
the growth of Takeda. More than 30,000 Takeda employees are
committed to improving quality of life for patients, working with
our partners in health care in more than 70 countries. For more
information, visit http://www.takeda.com/news.
Additional information about Takeda is available through its
corporate website, www.takeda.com, and additional information about
Takeda Oncology, the brand for the global oncology business unit of
Takeda Pharmaceutical Company Limited, is available through its
website, www.takedaoncology.com.
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Takeda Pharmaceutical Company LimitedJapanese
MediaTsuyoshi Tada, +81 (0)
3-3278-2417tsuyoshi.tada@takeda.comorEuropean MediaKate
Burd, +44 7974 151510kate.burd@takeda.comorMedia outside
Japan/EUSara Noonan, +1-508-566-2408sara.noonan@takeda.com