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Seattle Genetics and Takeda Announce Positive Results from Phase 3 ECHELON-2 Clinical Trial Evaluating ADCETRIS® (Brentuximab Vedotin) in Frontline CD30-Expressing Peripheral T-Cell Lymphoma
October 1, 2018 at 6:45 AM EDT
-ADCETRIS in Combination with Chemotherapy Achieved Primary Endpoint, Demonstrating a Statistically Significant Improvement in Progression-Free Survival Compared to a Standard of Care Chemotherapy-
-Statistically Significant Improvement Achieved in All Key Secondary Endpoints, Including Overall Survival-
-First Randomized Phase 3 Trial to Show Improvement in Overall Survival in Frontline Peripheral T-Cell Lymphoma-
-Data to be Presented at the 2018 ASH Annual Meeting; Global Regulatory Submissions Planned-
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Patients in ECHELON-2 were randomized to receive either a combination of
ADCETRIS plus CHP or CHOP, a recognized standard of care for frontline
PTCL. Results from the trial demonstrated that combination treatment
with ADCETRIS plus CHP was superior to the control arm for PFS as
assessed by an Independent Review Facility (IRF; hazard ratio=0.71;
p-value=0.0110). The ADCETRIS plus CHP arm also demonstrated superior
overall survival (OS), a key secondary endpoint, compared to CHOP
(hazard ratio=0.66; p-value=0.0244). All other key secondary endpoints,
including PFS in patients with systemic anaplastic large cell lymphoma
(sALCL), complete remission rate and objective response rate were
statistically significant in favor of the ADCETRIS plus CHP arm. The
safety profile of ADCETRIS plus CHP in the ECHELON-2 trial was
comparable to CHOP and consistent with the established safety profile of
ADCETRIS in combination with chemotherapy. Additional data will be
presented at the
“Peripheral T-cell lymphoma is an aggressive type of non-Hodgkin
lymphoma with approximately 4,000 CD30-expressing patients diagnosed
every year in the United States,” said
“These clinically meaningful results from ECHELON-2 represent a
significant step in the development of a potential frontline treatment
in this disease. This trial is the largest randomized, double-blind,
phase 3 trial in PTCL,” said Jesús Gomez-
ECHELON-2 Phase 3 Clinical Trial Design
The randomized, double-blind, placebo-controlled phase 3 trial is
investigating ADCETRIS plus CHP (cyclophosphamide, doxorubicin,
prednisone) versus CHOP (cyclophosphamide, doxorubicin, vincristine,
prednisone) as frontline therapy in patients with CD30-expressing
peripheral T-cell lymphoma, also known as mature T-cell lymphoma. The
primary endpoint is progression-free survival (PFS) per Independent
Review Facility assessment, with events defined as progression, death,
or receipt of chemotherapy for residual or progressive disease.
Secondary endpoints include PFS in patients with systemic anaplastic
large cell lymphoma (sALCL), complete remission rate, overall survival
and objective response rate, in addition to safety. The multi-center
trial was conducted at sites across
Please see Important Safety Information at the end of this press release.
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. There are more than 60 subtypes of
non-Hodgkin lymphomas which 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. There are many
different forms of T-cell lymphomas, some of which are extremely rare.
T-cell lymphomas can be aggressive (fast-growing) or indolent
(slow-growing). PTCL, also known as MTCL, accounts for approximately 10
percent of non-Hodgkin lymphoma cases in the U.S. and
About ADCETRIS (brentuximab vedotin)
ADCETRIS is being evaluated broadly in more than 70 clinical trials, including the completed phase 3 ECHELON-2 trial in frontline peripheral T-cell lymphomas (also known as mature T-cell lymphoma), the completed phase 3 ALCANZA trial in cutaneous T-cell lymphoma (CTCL) and the completed ECHELON-1 trial in previously untreated Hodgkin lymphoma, as well as trials in many additional types of CD30-expressing malignancies.
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 injection for intravenous infusion has received
ADCETRIS received conditional marketing authorization from the
ADCETRIS has received marketing authorization by regulatory authorities in 71 countries for relapsed or refractory Hodgkin lymphoma and sALCL. See select important safety information, including Boxed Warning, below.
For more information, visit https://www.takeda.com/newsroom/.
Additional information about Takeda is available through its corporate
and additional information about Takeda Oncology, the brand for the
global oncology business unit of
ADCETRIS (brentuximab vedotin) U.S. Select Important Safety Information
BOXED WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML):
JC virus infection resulting in PML and death can occur in ADCETRIS-treated patients.
ADCETRIS concomitant with bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation).
Warnings and Precautions
Most Common (≥20%) Adverse Reactions: Neutropenia, anemia, peripheral sensory neuropathy, nausea, fatigue, constipation, diarrhea, vomiting, and pyrexia.
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
Moderate or severe hepatic impairment or severe renal impairment: MMAE exposure and adverse reactions are increased. Avoid use.
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.
ADCETRIS (brentuximab vedotin) Important Safety Information (
Please refer to Summary of Product Characteristics (SmPC) before prescribing.
ADCETRIS is contraindicated for patients with hypersensitivity to brentuximab vedotin and its excipients. In addition, combined use of ADCETRIS with bleomycin causes pulmonary toxicity.
SPECIAL WARNINGS & PRECAUTIONS
Progressive multifocal leukoencephalopathy (PML): John Cunningham virus (JCV) reactivation resulting in progressive multifocal leukoencephalopathy (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. PML is a rare demyelinating disease of the central nervous system that results from reactivation of latent JCV and is often fatal.
Closely monitor patients 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. A negative JCV PCR does not exclude PML. Additional follow up and evaluation may be warranted if no alternative diagnosis can be established Hold dosing for any suspected case of PML and permanently discontinue ADCETRIS if a diagnosis of PML is confirmed. Be alert to PML symptoms that the patient may not notice (e.g., cognitive, neurological, or psychiatric symptoms).
Pancreatitis: Acute pancreatitis has been observed in patients treated with ADCETRIS. Fatal outcomes have been reported. Closely monitor patients 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. Hold ADCETRIS 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, including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome (ARDS), 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. Promptly evaluate and treat new or worsening pulmonary symptoms appropriately. Consider holding dosing during evaluation and until symptomatic improvement.
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. Carefully monitor patients 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. Carefully monitor patients during and after an infusion. If anaphylaxis occurs, immediately and permanently discontinue administration of ADCETRIS Appropriate medical therapy should be administered. If an IRR occurs, interrupt the infusion and institute appropriate medical management. 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.
Tumor lysis syndrome (TLS): TLS has been reported with ADCETRIS. Patients with rapidly proliferating tumor and high tumor burden are at risk of TLS. Monitor these patients closely and managed according to best medical practice.
Peripheral neuropathy (PN): ADCETRIS treatment may cause PN, both sensory and motor. ADCETRIS-induced PN is typically cumulative and reversible in most cases. Monitor patients for symptoms of PN, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Patients experiencing new or worsening PN may require a delay and a dose reduction or discontinuation of ADCETRIS.
Hematological toxicities: Grade 3 or Grade 4 anemia, thrombocytopenia, and prolonged (equal to or greater than one week) Grade 3 or Grade 4 neutropenia can occur with ADCETRIS. Monitor complete blood counts prior to administration of each dose.
Febrile neutropenia: Febrile neutropenia has been reported. Closely monitor patients for fever and manage according to best medical practice if febrile neutropenia develops.
Gastrointestinal (GI) Complications: GI complications, some with fatal outcomes, including intestinal obstruction, ileus, enterocolitis, neutropenic colitis, erosion, ulcer, perforation and haemorraghe, have been reported. Promptly evaluate and treat patients if new or worsening GI symptoms occur.
Hepatotoxicity: Elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have been reported. Serious cases of hepatotoxicity, including fatal outcomes, have also occurred. Test liver function prior to treatment initiation and routinely monitor patients receiving ADCETRIS for liver elevations. Patients experiencing hepatotoxicity may require a delay, dose modification, or discontinuation of ADCETRIS.
Hyperglycemia: Hyperglycemia has been reported during trials in patients with an elevated body mass index (BMI) with or without a history of diabetes mellitus. Closely monitor serum glucose for patients who experiences an event of hyperglycemia. Administer anti-diabetic treatment as appropriate.
Renal and Hepatic Impairment: There is limited experience in patients with renal and hepatic impairment. Available data indicate that MMAE clearance might be affected by severe renal impairment, hepatic impairment, and by low serum albumin concentrations.
CD30+ CTCL: The size of the treatment effect in CD30 + CTCL subtypes other than mycosis fungoides (MF) and primary cutaneous anaplastic large cell lymphoma (pcALCL) is not clear due to lack of high level evidence. In two single arm phase II studies of ADCETRIS, disease activity has been shown in the subtypes Sézary syndrome (SS), lymphomatoid papulosis (LyP) and mixed CTCL histology. These data suggest that efficacy and safety can be extrapolated to other CTCL CD30+ subtypes. Carefully consider the benefit-risk per patient and use caution in other CD30+ CTCL patient types.
Sodium content in excipients: ADCETRIS contains a maximum of 2.1 mmol (or 47 mg) of sodium per dose. Take this into consideration for patients on a controlled sodium diet.
Patients who are receiving a strong CYP3A4 and P-gp inhibitor, concomitantly with ADCETRIS may have an increased risk of neutropenia and should be closely monitored. Co-administration of ADCETRIS with a CYP3A4 inducer did not alter the plasma exposure of ADCETRIS but it appeared to reduce plasma concentrations of MMAE metabolites that could be assayed. ADCETRIS is not expected to alter the exposure to drugs that are metabolized by CYP3A4 enzymes.
PREGNANCY: Advise women of childbearing potential to use two methods of effective contraception during treatment with ADCETRIS and until 6 months after treatment. There are no data from the use of ADCETRIS in pregnant women, although studies in animals have shown reproductive toxicity. Do not use ADCETRIS during pregnancy unless the benefit to the mother outweighs the potential risks to the fetus.
LACTATION (breast-feeding): There are no data as to whether ADCETRIS or its metabolites are excreted in human milk, therefore a risk to the newborn/infant cannot be excluded. With the potential risk, a decision should be made whether to discontinue breast-feeding or discontinue/abstain from therapy with ADCETRIS.
FERTILITY: In nonclinical studies, ADCETRIS treatment has resulted in testicular toxicity, and may alter male fertility. Advise men being treated with ADCETRIS not to father a child during treatment and for up to 6 months following the last dose.
Effects on ability to drive and use machines: ADCETRIS may have a minor influence on the ability to drive and use machines.
The most frequent adverse reactions (≥10%) were infections, peripheral sensory neuropathy, nausea, fatigue, diarrhoea, pyrexia, upper respiratory tract infection, neutropenia, rash, cough, vomiting, arthralgia, peripheral motor neuropathy, infusion-related reactions, pruritus, constipation, dyspnoea, weight decreased, myalgia and abdominal pain.
Serious adverse drug reactions were: pneumonia, acute respiratory
distress syndrome, headache, neutropenia, thrombocytopenia,
constipation, diarrhea, vomiting, nausea, pyrexia, peripheral motor
neuropathy, peripheral sensory neuropathy, hyperglycemia, demyelinating
polyneuropathy, tumor lysis syndrome, and
Forward-Looking Statements for
Certain of the statements made in this press release are forward
looking, such as those, among others, relating to the therapeutic
potential of ADCETRIS (brentuximab vedotin) as a potential treatment in
frontline peripheral T-cell lymphoma, anticipated presentation of data
from ECHELON-2 at ASH in 2018 and plans and timing for submission for
supplemental regulatory approval to and obtaining regulatory approval