BOTHELL, Wash. & CAMBRIDGE, Mass.--(BUSINESS WIRE)--Seattle
Genetics, Inc. (Nasdaq: SGEN) and Takeda
Pharmaceutical Company Limited (TSE:4502) today announced completion
of patient enrollment in the ECHELON-2 clinical trial. ECHELON-2 is a
global phase 3 randomized trial evaluating ADCETRIS (brentuximab
vedotin) as part of a frontline combination chemotherapy regimen in
patients with previously untreated CD30-positive mature T-cell lymphoma
(MTCL). ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30,
which is expressed on several types of non-Hodgkin lymphoma, including
subsets of MTCL, as well as Hodgkin lymphoma. ADCETRIS is currently not
approved for the frontline treatment of MTCL.
“Mature T-cell lymphoma is a rare, aggressive type of cancer in which
the standard of care chemotherapy regimen has not changed in decades”
Patients in ECHELON-2 were randomized to receive a novel combination
regimen consisting of ADCETRIS plus cyclophosphamide (C), doxorubicin
(H) and prednisone (P) (referred to as A+CHP) versus cyclophosphamide,
doxorubicin, vincristine (O) and prednisone (referred to as CHOP), the
recognized standard of care treatment regimen for frontline MTCL. The
trial enrolled 452 patients. The ECHELON-2 trial is being conducted
under a Special Protocol Assessment (SPA) agreement from the U.S. Food
and Drug Administration (FDA) and the trial also received European
Medicines Agency (EMA) scientific advice.
“Our goal is to establish ADCETRIS as the foundation of care for
CD30-expressing lymphomas and redefine frontline treatment in Hodgkin
lymphoma and MTCL through our broad, late-stage clinical development
program currently underway. The ECHELON-2 clinical trial represents our
fourth phase 3 study to complete enrollment,” said Naomi Hunder, M.D.,
Vice President, Clinical Development at Seattle Genetics. “We look
forward to the results of the ECHELON-2 frontline MTCL study in the 2017
to 2018 timeframe and expect to refine the timeline in the future. The
ultimate goal of this phase 3 trial is to improve outcomes for frontline
patients with CD30-expressing MTCL and, if the trial results are
positive, to submit data from this trial to regulatory agencies to
expand the label for ADCETRIS use in the frontline setting.”
“Mature T-cell lymphoma is a rare, aggressive type of cancer in which
the standard of care chemotherapy regimen has not changed in decades,”
said Dirk Huebner, M.D., Executive Medical Director, Oncology
Therapeutic Area Unit, Takeda Pharmaceutical Company. “Achieving target
enrollment represents a key milestone for ECHELON-2 as we evaluate the
efficacy and safety of brentuximab vedotin in newly diagnosed mature
T-cell lymphoma patients, and to our ultimate goal of bringing important
new therapies to patients with CD30-positive malignancies.”
Data from a phase 1 trial evaluating ADCETRIS plus CHP in MTCL were
previously presented at the American Society of Hematology (ASH) Annual
Meetings in 2012 and 2015. Data demonstrated that 26 of 26 patients (100
percent) achieved an objective response, including 23 (88 percent) with
a complete remission and three patients (12 percent) with a partial
remission. Long-term follow-up data estimated the three-year overall
survival was 80 percent and three-year progression-free survival was 52
percent, with no patients receiving a consolidative stem cell transplant
in first remission. Three-year overall survival and progression-free
survival rates of less than 40 percent and 30 percent, respectively,
have previously been reported for patients in this setting treated with
CHOP (Reimer et al., J Clin Oncol 27: 106-113; 2009; Fanale et al., J
Clin Oncol 32: 3137-3143; 2014).The most common adverse events of any
grade occurring in more than 30 percent of patients in this phase 1
trial were peripheral sensory neuropathy, diarrhea, fatigue and hair
loss. Additional four-year follow-up data from this trial will be
presented in a poster presentation at the 2016 ASH Annual Meeting.
ECHELON-2 Trial Design
The double-blind, placebo-controlled global phase 3 trial is
investigating ADCETRIS plus CHP versus CHOP as frontline therapy in
patients with CD30-positive MTCL. The primary endpoint is
progression-free survival per independent review facility assessment
using the Cheson 2007 Revised Response Criteria for Malignant Lymphoma.
Secondary endpoints include overall survival, complete remission rate
and safety. The multi-center trial is being conducted in North America,
Europe and Asia. The study enrolled 452 patients, with approximately 225
patients per treatment arm. Data from the trial will be available when a
pre-specified number of progression-free survival events have occurred.
For more information about the trial, please visit www.clinicaltrials.gov.
About T-Cell Lymphomas
Lymphoma is a general term for a group of cancers that originate in the
lymphatic system. There are two major categories of lymphoma: Hodgkin
lymphoma and non-Hodgkin lymphoma. Non-Hodgkin lymphomas are broadly
divided into two major groups: B-cell lymphomas, which develop from
abnormal B-lymphocytes, and T-cell lymphomas, which develop from
abnormal T-lymphocytes. The World Health Organization identifies 22
subtypes of mature T- and NK-cell neoplasms, including systemic
anaplastic large cell lymphoma (ALCL) which is an aggressive type of
T-cell non-Hodgkin lymphoma that expresses CD30. Other mature T-cell
lymphomas include peripheral T-cell lymphoma (PTCL), angioimmunoblastic
T-cell lymphoma and adult T-cell lymphoma.
ADCETRIS is being evaluated broadly in more than 70 ongoing clinical
trials, including two phase 3 studies, ECHELON-1 in frontline classical
Hodgkin lymphoma and ECHELON-2 in frontline mature T-cell lymphomas, as
well as trials in many additional types of CD30-expressing malignancies,
including B-cell lymphomas.
ADCETRIS is an ADC comprising an anti-CD30 monoclonal antibody attached
by a protease-cleavable linker to a microtubule disrupting agent,
monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary
technology. The ADC employs a linker system that is designed to be
stable in the bloodstream but to release MMAE upon internalization into
CD30-expressing tumor cells.
ADCETRIS for intravenous injection has received approval from the FDA
for three indications: (1) regular approval for the treatment of
patients with classical Hodgkin lymphoma after failure of autologous
hematopoietic stem cell transplantation (auto-HSCT) or after failure of
at least two prior multi-agent chemotherapy regimens in patients who are
not auto-HSCT candidates, (2) regular approval for the treatment of
classical Hodgkin lymphoma patients at high risk of relapse or
progression as post-auto-HSCT consolidation, and (3) accelerated
approval for the treatment of patients with systemic anaplastic large
cell lymphoma (sALCL) after failure of at least one prior multi-agent
chemotherapy regimen. The sALCL indication is approved under accelerated
approval based on overall response rate. Continued approval for the
sALCL indication may be contingent upon verification and description of
clinical benefit in confirmatory trials. Health Canada granted ADCETRIS
approval with conditions for relapsed or refractory Hodgkin lymphoma and
ADCETRIS was granted conditional marketing authorization by the European
Commission in October 2012 for two indications: (1) for the treatment of
adult patients with relapsed or refractory CD30-positive Hodgkin
lymphoma following autologous stem cell transplant (ASCT), or following
at least two prior therapies when ASCT or multi-agent chemotherapy is
not a treatment option, and (2) the treatment of adult patients with
relapsed or refractory sALCL. ADCETRIS has received marketing
authorization by regulatory authorities in 65 countries.
In June 2016, the European Commission extended the current conditional
approval of ADCETRIS and approved ADCETRIS for the treatment of adult
patients with CD30-positive Hodgkin lymphoma at increased risk of
relapse or progression following ASCT. See important safety information
Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the
terms of the collaboration agreement, Seattle Genetics has U.S. and
Canadian commercialization rights and Takeda has rights to commercialize
ADCETRIS in the rest of the world. Seattle Genetics and Takeda are
funding joint development costs for ADCETRIS on a 50:50 basis, except in
Japan where Takeda is solely responsible for development costs.
About Seattle Genetics
Seattle Genetics is an innovative biotechnology company that develops
and commercializes novel antibody-based therapies for the treatment of
cancer. The company’s industry-leading antibody-drug conjugate (ADC)
technology harnesses the targeting ability of antibodies to deliver
cell-killing agents directly to cancer cells. ADCETRIS®
(brentuximab vedotin), the company’s lead product, in collaboration with
Takeda Pharmaceutical Company Limited, is the first in a new class of
ADCs commercially available globally in 65 countries for relapsed
classical Hodgkin lymphoma and relapsed systemic anaplastic large cell
lymphoma (sALCL). Seattle Genetics is also advancing vadastuximab
talirine (SGN-CD33A; 33A), an ADC in a phase 3 trial for acute myeloid
leukemia. Headquartered in Bothell, Washington, Seattle Genetics has a
robust pipeline of innovative therapies for blood-related cancers and
solid tumors designed to address significant unmet medical needs and
improve treatment outcomes for patients. The company has collaborations
for its proprietary ADC technology with a number of companies including
AbbVie, Astellas, Bayer, Genentech, GlaxoSmithKline and Pfizer. More
information can be found at www.seattlegenetics.com.
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
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.
ADCETRIS (brentuximab vedotin) U.S. Important Safety Information
Progressive multifocal leukoencephalopathy (PML): JC virus infection
resulting in PML and death can occur in patients receiving ADCETRIS.
ADCETRIS is contraindicated with concomitant bleomycin due to pulmonary
toxicity (e.g., interstitial infiltration and/or inflammation).
Warnings and Precautions
Peripheral neuropathy (PN): ADCETRIS treatment causes a PN that is
predominantly sensory. Cases of motor PN have also been reported.
ADCETRIS-induced PN is cumulative. Monitor patients for symptoms of
neuropathy, such as hypoesthesia, hyperesthesia, paresthesia,
discomfort, a burning sensation, neuropathic pain or weakness and
institute dose modifications accordingly.
Anaphylaxis and infusion reactions: Infusion-related reactions,
including anaphylaxis, have occurred with ADCETRIS. Monitor patients
during infusion. If an infusion-related reaction occurs, interrupt the
infusion and institute appropriate medical management. If anaphylaxis
occurs, immediately and permanently discontinue the infusion and
administer appropriate medical therapy. Patients who experienced a
prior infusion-related reaction should be premedicated for subsequent
infusions. Premedication may include acetaminophen, an antihistamine,
and a corticosteroid.
Hematologic toxicities: Prolonged (=1 week) severe neutropenia and
Grade 3 or 4 thrombocytopenia or anemia can occur with ADCETRIS.
Febrile neutropenia has been reported with ADCETRIS. Monitor complete
blood counts prior to each dose of ADCETRIS and consider more frequent
monitoring for patients with Grade 3 or 4 neutropenia. Monitor
patients for fever. If Grade 3 or 4 neutropenia develops, consider
dose delays, reductions, discontinuation, or G-CSF prophylaxis with
Serious infections and opportunistic infections: Infections such as
pneumonia, bacteremia, and sepsis or septic shock (including fatal
outcomes) have been reported in patients treated with ADCETRIS.
Closely monitor patients during treatment for the emergence of
possible bacterial, fungal or viral infections.
Tumor lysis syndrome: Closely monitor patients with rapidly
proliferating tumor and high tumor burden.
Increased toxicity in the presence of severe renal impairment: The
frequency of =Grade 3 adverse reactions and deaths was greater in
patients with severe renal impairment compared to patients with normal
renal function. Avoid the use of ADCETRIS in patients with severe
Increased toxicity in the presence of moderate or severe hepatic
impairment: The frequency of =Grade 3 adverse reactions and deaths was
greater in patients with moderate or severe hepatic impairment
compared to patients with normal hepatic function. Avoid the use of
ADCETRIS in patients with moderate or severe hepatic impairment.
Hepatotoxicity: Serious cases of hepatotoxicity, including fatal
outcomes, have occurred with ADCETRIS. Cases were consistent with
hepatocellular injury, including elevations of transaminases and/or
bilirubin, and occurred after the first dose of ADCETRIS or
rechallenge. Preexisting liver disease, elevated baseline liver
enzymes, and concomitant medications may also increase the risk.
Monitor liver enzymes and bilirubin. Patients experiencing new,
worsening, or recurrent hepatotoxicity may require a delay, change in
dose, or discontinuation of ADCETRIS.
Progressive multifocal leukoencephalopathy (PML): JC virus infection
resulting in PML and death has been reported in ADCETRIS-treated
patients. First onset of symptoms occurred at various times from
initiation of ADCETRIS therapy, with some cases occurring within 3
months of initial exposure. In addition to ADCETRIS therapy, other
possible contributory factors include prior therapies and underlying
disease that may cause immunosuppression. Consider the diagnosis of
PML in any patient presenting with new-onset signs and symptoms of
central nervous system abnormalities. Hold ADCETRIS if PML is
suspected and discontinue ADCETRIS if PML is confirmed.
Pulmonary toxicity: Events of noninfectious pulmonary toxicity
including pneumonitis, interstitial lung disease, and acute
respiratory distress syndrome, some with fatal outcomes, have been
reported. Monitor patients for signs and symptoms of pulmonary
toxicity, including cough and dyspnea. In the event of new or
worsening pulmonary symptoms, hold ADCETRIS dosing during evaluation
and until symptomatic improvement.
Serious dermatologic reactions: Stevens-Johnson syndrome (SJS) and
toxic epidermal necrolysis (TEN), including fatal outcomes, have been
reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and
administer appropriate medical therapy.
Gastrointestinal (GI) complications: Fatal and serious GI
complications, including perforation, hemorrhage, erosion, ulcer,
intestinal obstruction, enterocolitis, neutropenic colitis, and ileus
have been reported in ADCETRIS-treated patients. Lymphoma with
preexisting GI involvement may increase the risk of perforation. In
the event of new or worsening GI symptoms, perform a prompt diagnostic
evaluation and treat appropriately.
Embryo-fetal toxicity: Based on the mechanism of action and findings
in animals, ADCETRIS can cause fetal harm when administered to a
pregnant woman. Females of reproductive potential should avoid
pregnancy during ADCETRIS treatment and for at least 6 months after
the final dose of ADCETRIS.
In two uncontrolled single-arm trials of ADCETRIS as monotherapy in 160
patients with relapsed classical HL and sALCL, the most common adverse
reactions (=20%), regardless of causality, were: neutropenia, peripheral
sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract
infection, diarrhea, pyrexia, rash, thrombocytopenia, cough and vomiting.
In a placebo-controlled trial of ADCETRIS in 329 patients with classical
HL at high risk of relapse or progression post-auto-HSCT, the most
common adverse reactions (=20%) in the ADCETRIS-treatment arm (167
patients), regardless of causality, were: neutropenia, peripheral
sensory neuropathy, thrombocytopenia, anemia, upper respiratory tract
infection, fatigue, peripheral motor neuropathy, nausea, cough, and
Concomitant use of strong CYP3A4 inhibitors or inducers, or P-gp
inhibitors, has the potential to affect the exposure to monomethyl
auristatin E (MMAE).
Use in Specific Populations
MMAE exposure and adverse reactions are increased in patients with
moderate or severe hepatic impairment or severe renal impairment. Avoid
Advise females of reproductive potential to avoid pregnancy during
ADCETRIS treatment and for at least 6 months after the final dose of
Advise males with female sexual partners of reproductive potential to
use effective contraception during ADCETRIS treatment and for at least 6
months after the final dose of ADCETRIS.
Advise patients to report pregnancy immediately and avoid breastfeeding
while receiving ADCETRIS.
For additional Important Safety Information, including Boxed WARNING,
please see the full Prescribing Information for ADCETRIS at www.seattlegenetics.com
ADCETRIS (brentuximab vedotin) Global Important Safety Information
Active Ingredient: brentuximab vedotin
Please refer to Summary of Product Characteristics (SmPC) before
ADCETRIS® is indicated for the treatment of adult patients with relapsed
or refractory CD30+ Hodgkin lymphoma (HL):
1. following autologous stem cell transplant (ASCT) or
2. following at least two prior therapies when ASCT or multi-agent
chemotherapy is not a treatment option.
ADCETRIS is indicated for the treatment of adult patients with CD30+ HL
at increased risk of relapse or progression following ASCT.
ADCETRIS is indicated for the treatment of adult patients with relapsed
or refractory systemic anaplastic large cell lymphoma (sALCL).
IMPORTANT SAFETY INFORMATION
ADCETRIS is contraindicated for patients with hypersensitivity to
brentuximab vedotin and its excipients. In addition, combined use of
ADCETRIS with bleomycin is contraindicated as it causes pulmonary
SPECIAL WARNINGS & PRECAUTIONS
Progressive multifocal leukoencephalopathy (PML): John Cunningham virus
(JCV) reactivation resulting in PML and death can occur in patients
treated with ADCETRIS. PML has been reported in patients who received
ADCETRIS after receiving multiple prior chemotherapy regimens.
Patients should be closely monitored for new or worsening neurological,
cognitive, or behavioral signs or symptoms, which may be suggestive of
PML. Suggested evaluation of PML includes neurology consultation,
gadolinium-enhanced magnetic resonance imaging of the brain, and
cerebrospinal fluid analysis for JCV DNA by polymerase chain reaction or
a brain biopsy with evidence of JCV. ADCETRIS dosing should be held for
any suspected case of PML and should be permanently discontinued if a
diagnosis of PML is confirmed.
Pancreatitis: Acute pancreatitis has been observed in patients
treated with ADCETRIS. Fatal outcomes have been reported. Patients
should be closely monitored for new or worsening abdominal pain, which
may be suggestive of acute pancreatitis. Patient evaluation may include
physical examination, laboratory evaluation for serum amylase and serum
lipase, and abdominal imaging, such as ultrasound and other appropriate
diagnostic measures. ADCETRIS should be held for any suspected case of
acute pancreatitis. ADCETRIS should be discontinued if a diagnosis of
acute pancreatitis is confirmed.
Pulmonary Toxicity: Cases of pulmonary toxicity, some with fatal
outcomes, have been reported in patients receiving ADCETRIS. Although a
causal association with ADCETRIS has not been established, the risk of
pulmonary toxicity cannot be ruled out. New or worsening pulmonary
symptoms should be promptly evaluated and treated appropriately.
Serious infections and opportunistic infections: Serious
infections such as pneumonia, staphylococcal bacteremia, sepsis/septic
shock (including fatal outcomes), and herpes zoster, and opportunistic
infections such as Pneumocystis jiroveci pneumonia and oral candidiasis
have been reported in patients treated with ADCETRIS. Patients should be
carefully monitored during treatment for emergence of possible serious
and opportunistic infections.
Infusion-related reactions (IRR): Immediate and delayed IRR, as
well as anaphylaxis, have occurred with ADCETRIS. Patients should be
carefully monitored during and after an infusion. If anaphylaxis occurs,
administration of ADCETRIS should be immediately and permanently
discontinued and appropriate medical therapy should be administered. If
an IRR occurs, the infusion should be interrupted and appropriate
medical management instituted. The infusion may be restarted at a slower
rate after symptom resolution. Patients who have experienced a prior IRR
should be premedicated for subsequent infusions. IRRs are more frequent
and more severe in patients with antibodies to ADCETRIS.
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