The European Commission approves ADCETRIS ® (brentuximab vedotin) for T-cell cutaneous lymphoma CD30 + after a...
Approval was based on the positive results of the Phase 3 ALCANZA study, which reported a clear statistical improvement in the objective response rate for at least four months, the median rate of progression-free survival, and the overall response, as well as of an improvement in the symptomatic load in the ADCETRIS group –
– This major step strengthens the role of ADCETRIS in improving results for patients with CD30 positive malignant diseases –
Takeda Pharmaceutical Company Limited (TSE: 4502) announced today that the European Commission (EC) has extended the current conditional authorization for the placing on the market of ADCETRIS ® (brentuximab Vedotin) and approved the ADCETRIS for the treatment Adult patients with T-cell cutaneous lymphoma (LCCT) CD30 + after at least one systemic treatment. ADCETRIS is an antibody-drug conjugate (CAM) targeting CD30, which is expressed on skin lesions in approximately 50 percent of patients with LCCT. The decision follows the favourable opinion of the Committee for Medicinal Products for human Use (CHMP) of 9 November 2017.
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"LCCT is a subtype of non-Hodgkin's lymphoma that affects the skin above all; It usually comes in the form of squamous or thickened red plaques, often resembling eczema or psoriasis, and can have a notorious impact on the patient's self-confidence. There are few approved therapeutic options for LCCT, and with limited efficacy, which creates an important unmet need for these patients ", says Julia Scarisbrick, D.M., Department of Dermatology, Birmingham University Hospital, United Kingdom. "The approval of ADCETRIS in this area provides an effective and highly anticipated therapeutic option for patients living with a LCCT, and I look forward to being able to offer this treatment to positive CD30 patients who have already had therapy Systemic. "
"This new endorsement marks a milestone for the LCCT community in Europe, and further strengthens the role that ADCETRIS can play in improving the results and quality of life of patients with CD30 positive malignant conditions." Explains Jesus Gomez Navarro, D.M., Vice-President, head of the R&D Oncology Clinic at Takeda. The clinical data supporting this approval are foolproof. We are proud to be the company that offers an innovative therapeutic option, an exceptional efficacy profile and a manageable safety profile, to eligible LCCT patients in the European Union. "
"As a specific subtype of non-Hodgkin's lymphoma, cutaneous lymphoma is usually visible on the skin, and can cause significant discomfort. This can lead to profound emotional distress and impact on the quality of life of patients, says Susan Thornton, CEO of the Cutaneous Lymphoma Foundation. "There is no known cure, and only a few new therapeutic options have been proposed in recent years. It is therefore with open arms that we welcome this new treatment for patients with cutaneous lymphoma in Europe. "
This approval is based on data from the randomized and open Phase 3 ALCANZA trial, which showed that single-agent ADCETRIS resulted in a clear statistical improvement in the overall response rate for at least four months (TRG4), Comparison with the methotrexate/Bexarotene control group, based on an independent assessment body evaluation (P-value < 0.0001). The TRG4 is 56.3 percent in the ADCETRIS group, compared to 12.5 percent in the control group. The trial also showed that the complete response rate, progression-free survival, and reduction of symptomatic load during treatment, as measured in questionnaire Skindex-29 1, all showed very high statistical relevance In favor of the ADCETRIS group. The safety profile associated with ADCETRIS as part of the ALCANZA study is generally consistent with existing prescription information. The most common side effects, any grade confounded, are: peripheral neuropathy, nausea, diarrhea, fatigue, vomiting, alopecia, pruritus, pyrexia, decreased appetite and hypertriglyceridemia. In the ADCETRIS group, the most common Grade 3 or 4 events are: Peripheral sensory neuropathy (no Grade 4 manifestation), fatigue, diarrhea, nausea, vomiting and pruritus. For the control group, the most common Grade 3 or 4 events are: hypertriglyceridemia, pruritus, fatigue and pyrexia. The updated results of the trial were recently presented at the 59th annual summit of the American Society of Hematology (ASH) in December 2017. Long-term analyses of the ALCANZA test continue to provide tangible evidence of improved response rates, progression-free survival, and quality of life with ADCETRIS in comparison with the control group.
This decision by the European Commission means that the ADCETRIS is now authorised to be placed on the market for this indication in the 28 member states of the European Union, Norway, Liechtenstein and Iceland.
For further information on the European Commission's decision, please visit the European Medicines Agency website:
About LCCT
Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two broad categories of lymphoma: Hodgkin's lymphoma and non-Hodgkin's lymphoma. There are more than 60 subtypes of non-Hodgkin's lymphoma, and each requires different approaches in terms of diagnostic assessment and treatment. Cutaneous lymphomas are a category of non-Hodgkin's lymphoma primarily attacking the skin. According to the Cutaneous Lymphoma Foundation, LCCT is the most common type of cutaneous lymphoma and is usually found in the form of squamous or thickened red plaques on the skin, which often resemble eczema or chronic dermatitis. Progression since the limited skin attack can be accompanied by the formation of tumors, ulceration and exfoliation, which are complicated by itching and infections. Advanced stages are defined by the attack of lymph nodes, peripheral blood organs and internal organs. According to the medical literature, CD30 antigen is expressed on LCCT lesions in about 50 percent of patients. About the ADCETRIS
ADCETRIS is an antibody-drug conjugate (CAM) comprising a monoclonal anti-CD30 antibody set by a protease clivable to a microtubule disrupting agent, monomethyl auristatine E (AMME), using proprietary technology Seattle Genetics. The CAM uses a binding system designed to be stable in the blood but to release AMME when internalizing in CD30 + cancer cells.
Injection of ADCETRIS by intravenous infusion has been approved by the FDA for four indications: (1) standard approval for patients with LAGCCP or MF expressing CD30, and having previously received systemic therapy, (2) Standard approval for the treatment of patients with classical Hodgkin's lymphoma after failure of autologous hematopoietic stem cell graft (self-GCSH) or after failure of at least two chemotherapy protocols with agents Patients who are not candidates for self-GCSH, (3) standard approval for the treatment of patients with classical Hodgkin's lymphoma with a high risk of relapse or progression as post consolidation Self-GCSH, and (4) accelerated approval for the treatment of patients with large systemic cell anaplastic lymphoma (LAGCs) after the failure of at least one multiple agent chemotherapy protocol. Continuous approval for the indication of LAGCs may be subject to the verification and description of clinical benefits in confirmatory tests.
In 2013, health Canada issued an approval for ADCETRIS for recurrent or refractory Hodgkin's lymphoma and LAGCs, and unconditional approval for post-GATS consolidation treatment for patients with Increased risk of relapse or progression.
ADCETRIS has received a conditional authorisation for the placing on the market of the European Commission for four indications: (1) for the treatment of adult patients with LH CD30 + recurrent or refractory following a stem cell autotransplantation (GATS), Or following at least two therapies when the GATS or multiple agent chemotherapy is not a treatment option, (2) for the treatment of adult patients with recurrent or refractory LAGCs, (3) for the treatment of adult patients With LH CD30 + with an increased risk of recurrence or progression following a GATS, and (4) for the treatment of adult patients with T-cell cutaneous lymphoma (LCCT) CD30 + after at least one systemic treatment.
ADCETRIS has received authorization to market regulatory authorities in more than 65 countries for recurrent or refractory Hodgkin's lymphoma and LAGCs. Check out the important security information below.
ADCETRIS is currently being evaluated in more than 70 clinical trials, including a Phase 3 study for first-line Hodgkin's lymphoma (ECHELON-1), and another Phase 3 study on CD30 + T-cell peripheral lymphomas in First intention (ECHELON-2), as well as tests on many other types of CD30 + malignancies.
Seattle Genetics and Takeda jointly develop ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics owns the marketing rights in the United States and Canada, and Takeda owns the marketing rights of ADCETRIS in the rest of the world. Seattle Genetics and Takeda jointly finance ADCETRIS's development costs, with equal proportions, except in Japan, where Takeda assumes full responsibility for development costs.
About Takeda Pharmaceutical Company
Takeda pharmaceutical company Limited is a global pharmaceutical company focused on research and development, whose mission is to improve the health and future of patients by translating science into drugs that can change the outcome. Takeda focuses its efforts on R&D in the therapeutic areas of oncology, gastroenterology and the central nervous system, as well as on vaccines. Takeda carries out its R&D both internally and with partners in order to stay at the forefront of innovation. Its new innovative products, particularly in oncology and gastroenterology, as well as its presence in emerging markets, stimulate the growth of Takeda. More than 30 000 employees of Takeda are committed to improving the quality of life of patients by collaborating with our partners in more than 70 countries. For more information,
Further information on Takeda is available on the . company website, and additional information about Takeda Oncology, the trademark of Takeda Pharmaceutical Company Limited's Global oncology business Unit, are available on its website www.takedaoncology.com.
Important Safety information on ADCETRIS (brentuximab vedotin) in the European Union
Please refer to the summary of product characteristics before prescribing.
Contraindications
ADCETRIS is contraindicated for patients with hypersensitivity to brentuximab Vedotin and its excipients. In addition, the combined use of ADCETRIS with bleomycin causes pulmonary toxicity.
Special warnings and precautions
Progressive multifocal leukoencephalopathy (PML): A reactivation of the John Cunningham virus (JC) resulting in PML and death may occur in patients treated with ADCETRIS. Cases of PML have been reported in patients receiving ADCETRIS after having followed multiple chemotherapy protocols. PML is a rare demyelinating disease of the central nervous system caused by the reactivation of latent JC virus and often has a fatal outcome.
Carefully monitor patients to detect the onset or worsening of neurological, cognitive, or behavioural signs or symptoms that may suggest a PML. The suggested evaluation of PML includes neurological consultation, brain gadolinium magnetic resonance imaging, and cerebrospinal fluid analysis to detect JC DNA by polymerase chain reaction or biopsy Of the brain with confirmation of the JC virus. A negative PCR of the JC virus does not exclude PML. Additional monitoring and evaluation can be done if no alternative diagnosis can be made. Suspend the taking of ADCETRIS in case of suspected PML and stop the treatment definitively as soon as the diagnosis is confirmed.
Stay alert to detect any symptoms of PML that the patient would not have detected (e.g., cognitive, neurological or psychiatric symptoms).
Pancreatitis: Cases of acute pancreatitis have been observed in patients treated with ADCETRIS. Fatal issues have been reported. Patients should be monitored closely to check for the onset or aggravation of abdominal pain, which may suggest acute pancreatitis. The patient's assessment may include physical examination, laboratory evaluation for serum amylase and lipase, as well as abdominal imaging such as ultrasound and other appropriate diagnostic measures. The taking of ADCETRIS should be suspended for any suspected case of acute pancreatitis. The ADCETRIS should be stopped if a diagnosis of acute pancreatitis is confirmed.
Pulmonary toxicity: Cases of pulmonary toxicity, some with fatal outcomes, including pneumonitis, interstitial pneumonia and acute respiratory distress syndrome (ARDS), have been reported in patients treated with ADCETRIS. Although no causal association with ADCETRIS has been established, the risk of pulmonary toxicity cannot be ruled out. In the event of the onset or worsening of pulmonary symptoms, a rapid assessment should be made and appropriately treated. Consider the interruption of the catch during the evaluation and until symptomatic improvement.
Serious and opportunistic infections: serious infections such as pneumonia, staphylococcus bacteremia, sepsis/septic shock (including fatal cases) and shingles, as well as opportunistic infections such as Pneumocystis pneumonia Jiroveci and oral candidiasis have been reported in patients treated with ADCETRIS. Patients should be closely monitored during treatment to verify the possible onset of serious or opportunistic infections.
Infusion-related reactions: immediate and delayed perfusion-related reactions, as well as anaphylaxis, occurred with ADCETRIS. Patients should be closely monitored during and after an infusion. If anaphylaxis occurs, the administration of ADCETRIS must be interrupted immediately and permanently, and appropriate medical treatment should be administered. In the case of an infusion-related reaction, the perfusion must be interrupted and appropriate medical care must be put in place. The perfusion can be restarted with a slower flow after symptoms disappear. Patients who have already undergone an infusion-related reaction must be premedicated during subsequent infusions. Infusion-related reactions are more frequent and more severe in patients with antibodies to ADCETRIS.
Tumor lysis syndrome (SLT): An incidence of tumor lysis syndrome was reported during ADCETRIS treatment. Patients with a fast-proliferating tumor and a high tumor charge present a risk of developing a SLT. Carefully monitor these patients and apply the best medical practices.
Peripheral neuropathy (NP): ADCETRIS treatment can cause NP, both sensory and motor. A ADCETRIS-induced NP is generally cumulative and reversible in most cases. Carefully monitor patients to detect symptoms of NP, such as Hypoesthesia, Hyperesthesia, paresthesia, discomfort, burning sensation, neuropathic pain, or weakness. In the event of the onset or worsening of NP, consider postponing the intake, reducing the doses or interrupting the taking of ADCETRIS.
Hematologic toxicity: Level 3 or 4 anemia, thrombocytopenia, and prolonged neutropenia (one week or more) of level 3 or 4 may occur during ADCETRIS treatment. Perform a complete CBC before each dose is administered.
Febrile neutropenia: Incidence of febrile neutropenia has been reported. Carefully monitor patients to detect signs of fever and apply best medical practices if febrile neutropenia develops.
Stevens-Johnson Syndrome (SJS): Effects of Stevens-Johnson Syndrome and Toxic Epidermal necrolysis (TEN) have been reported with ADCETRIS, some with fatal outcomes. In case of SJS or TEN, discontinue treatment with ADCETRIS and administer appropriate medical treatment.
Gastrointestinal complications: Gastrointestinal complications, some with fatal outcomes, have been reported. They include cases of intestinal occlusion, ileus, enterocolitis, neutropenic colitis, erosion, ulcer, perforation and hemorrhage. In case of onset or worsening of gastrointestinal symptoms, quickly conduct an assessment and treat.
Hepatotoxicity: Elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels have been reported. Serious cases of hepatotoxicity, including fatal outcomes, have also occurred. Test liver function before starting treatment and perform routine monitoring of patients receiving ADCETRIS. Patients with hepatotoxicity may require a postponement, a dose change, or the abandonment of ADCETRIS.
Hyperglycemia: An incidence of hyperglycemia was reported during trials in patients with a high body mass index (BMI), with or without a history of diabetes mellitus. However, carefully monitor the serum glucose of any patient suffering from a hyperglycemia event. Administer an anti-diabetic treatment if necessary.
Renal and hepatic insufficiency: we have limited experience with this treatment in patients with renal and hepatic insufficiency. Available data indicate that the clearance of AMME may be affected by severe renal failure, hepatic insufficiency, and low serum albumin concentrations.
LCCT CD30 +: The degree of therapeutic effect for subtypes of LCCT CD30 + other than fungoides fungus (MF) and primary cutaneous large cell anaplastic lymphoma (LAGCCP) is unclear due to lack of tangible evidence. In two single-group Phase II Studies on ADCETRIS, pathological activity was demonstrated in the subtypes of Sezary syndrome (SS), Lymphomatoid papulosis (PL), and mixed LCCT histology. These data suggest that efficacy and safety can be extrapolated to other subtypes of LCCT CD30 +. Carefully evaluate the benefits and risks to the patient, and proceed with caution with other types of LCCT CD30 +.
Sodium content of excipients: This drug contains a maximum content of 2.1 mmol (or 47 mg) of sodium per dose. Take into account this content for patients following a low sodium diet.
Interactions
Patients receiving a potent inhibitor of CYP3A4 and P-glycoprotein simultaneously with ADCETRIS may present an increased risk of neutropenia and should be closely monitored. Joint administration of ADCETRIS with a CYP3A4 inducer did not alter the plasma exposure of ADCETRIS, but it was found to reduce the plasma concentrations of AMME metabolites that could be analyzed. ADCETRIS should not alter exposure to drugs that are metabolized by CYP3A4 enzymes.
Pregnancy: Women of childbearing age must use two effective contraceptive methods during treatment with ADCETRIS and up to 6 months after it. There are no data on the use of ADCETRIS in pregnant women. However, studies carried out on animals have shown reproductive toxicity. Do not use ADCETRIS during pregnancy, unless the benefits to the mother outweigh the risks to the fetus.
Lactation (Breastfeeding): There is no data on the possible excretion of ADCETRIS or its metabolites in human milk. The risk to the newborn/infant cannot therefore be excluded. Because of this potential risk, the decision must be made to stop breastfeeding or to interrupt/renounce treatment with ADCETRIS.
Fertility: In non-clinical studies, treatment with ADCETRIS has presented testicular toxicity, which may alter male fertility. Men treated with this medication are advised not to have children during treatment and up to six months after the last dose.
Effects on the ability to drive and use machines: ADCETRIS can have a minor influence on the ability to drive and use machines.
Adverse reactions
The most common adverse reactions (≥ 10%) were: infections, peripheral sensory neuropathy, nausea, fatigue, diarrhea, pyrexia, upper respiratory tract infection, neutropenia, rash, cough, vomiting, Arthralgia, peripheral motor neuropathy, perfusion-related reactions, pruritus, constipation, dyspnea, weight loss, myalgia and abdominal pain.
Serious adverse reactions were: pneumonia, acute respiratory distress syndrome, headache, neutropenia, thrombocytopenia, constipation, diarrhea, vomiting, nausea, pyrexia, peripheral motor neuropathy, sensory neuropathy Peripheral, hyperglycemia, demyelinating polyneuropathy, tumor lysis syndrome and Stevens-Johnson syndrome. Serious adverse reactions occurred in 12% of patients. The frequency of single serious adverse reactions was ≤ 1%.
Important Safety information on ADCETRIS (brentuximab vedotin) in the United States
Sidebar Warning: PROGRESSIVE multifocal leukoencephalopathy (PML)
An infection with the JC virus causing PML and death can occur in patients treated with ADCETRIS.
Contraindication
Concomitant Administration of ADCETRIS with bleomycin, due to pulmonary toxicity (e.g. infiltration and/or interstitial inflammation).
Warnings and precautions
Peripheral neuropathy (NP): ADCETRIS causes peripheral neuropathy of a sensory type. Cases of motor NP have also been reported. A ADCETRIS-induced NP is cumulative. Patients should be monitored to check for symptoms such as Hypoesthesia, Hyperesthesia, paresthesia, discomfort, burning sensation, neuropathic pain, or weaknesses. Change the doses according to.
Anaphylaxis and infusion-related reactions: perfusion-related reactions, including anaphylaxis, were observed with ADCETRIS. Monitor patients during an infusion. In the case of an infusion-related reaction, the perfusion must be interrupted and appropriate medical care must be put in place. If anaphylaxis occurs, immediately and definitively interrupt the perfusion, and administer appropriate medical treatment. Patients who have undergone a previous perfusion reaction must be premedicated during subsequent infusions. Premedication can be done with acetaminophen, an antihistamine, and a corticosteroid.
Hematologic toxicity: ADCETRIS is likely to cause prolonged severe neutropenia (≥ 1 week) and a Grade 3 or 4 thrombocytopenia or anemia. Febrile Neutropenia was reported with ADCETRIS. The complete blood count must be checked before each dose of ADCETRIS is administered. Consider more frequent monitoring for patients with grade 3 or 4 neutropenia. Monitor patient temperature If Grade 3 or 4 neutropenia develops, consider postponing, reducing, stopping or prophylaxis by G-CSF with subsequent doses.
Serious and opportunistic infections: infections such as pneumonia, bacteremia, sepsis or septic shock (including fatal cases) have been reported in patients treated with ADCETRIS. Monitor patients closely during treatment to detect possible bacterial, fungal or viral infection.
Tumor lysis Syndrome: Patients with a rapidly proliferating tumor or a high tumor mass should be closely monitored.
Increased toxicity in the presence of severe renal failure: the frequency of adverse events ≥ to Grade 3 and death was higher in patients with severe renal failure compared with patients with renal function Normal. Avoid use with patients with severe renal failure.
Increased toxicity in the presence of moderate or severe hepatic impairment: the frequency of adverse reactions ≥ to Grade 3 and death was higher in patients with moderate or severe hepatic impairment compared with patients with normal hepatic function. Avoid use with patients with moderate or severe hepatic impairment.
Hepatotoxicity: Serious cases, some with fatal outcomes, have occurred in patients treated with ADCETRIS. The cases were consistent with hepatocellular lesions, including elevations of transaminase and/or bilirubin, and occurred after the first dose of ADCETRIS or reexposure. Pre-existing liver disease, a high base level of hepatic enzymes, and concomitant medication intake may increase the risk. Monitor liver enzymes and bilirubin. The onset, aggravation or recurrence of hepatotoxicity may require a postponement, a modification of the dosage or the stopping of the taking of ADCETRIS.
PML: A JC virus infection leading to PML and death was reported in patients treated with ADCETRIS. The first onset of symptoms occurred at various stages of ADCETRIS treatment initiation, with some cases occurring within 3 months of initial exposure. Other contributing factors other than ADCETRIS include previous treatments and an underlying disease that could cause immunosuppression. Consider a diagnosis of PML in patients with signs and symptoms of central nervous system abnormalities. Interrupt the taking of ADCETRIS in case of suspected PML, and abandon the taking of ADCETRIS if the PML is confirmed.
Pulmonary toxicity: Manifestations of non-infectious pulmonary toxicity have been found, including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome, some with fatal outcomes. Monitor patients for possible signs and symptoms, including cough or dyspnea. In case of onset or worsening of the pulmonary symptoms, stop the taking of ADCETRIS during the evaluation and until the symptoms are improved.
Serious dermatological reactions: cases of Stevens-Johnson syndrome (SSJ) and Toxic Epidermal necrolysis (NET), including fatal outcomes, have been reported with ADCETRIS. In case of SSJ or NET, stop taking ADCETRIS and administer appropriate medical care.
Gastrointestinal Complications: Cases of acute pancreatitis, including fatal outcomes, have been reported in patients treated with ADCETRIS. Other serious and fatal gastrointestinal complications, including puncture, hemorrhage, erosion, ulcer, intestinal occlusion, enterocolitis, neutropenic colitis and ileus have been reported in ADCETRIS-treated patients. Pre-existing lymphoma and involving the gastrointestinal tract may increase the risk of perforation. In case of onset or worsening of gastrointestinal symptoms, perform a rapid diagnostic assessment and treat in an appropriate manner.
Embryonic and fetal toxicity: based on its mechanism of action and the results obtained on animals, ADCETRIS may harm the fetus. Inform women of childbearing age of potential risk to the fetus and avoid pregnancy during ADCETRIS treatment and for at least six months after the final dose of ADCETRIS.
Most common adverse reactions (≥ 20%): Peripheral sensory neuropathy, fatigue, nausea, diarrhea, neutropenia, upper respiratory tract infection, and pyrexia.
Interactions
Concomitant use of potent inhibitors or inducers of CYP3A4, or P-GP inhibitors, is likely to affect exposure to monomethyl auristatine E (AMME).
Use in specific populations
Moderate or severe hepatic insufficiency, or severe renal failure: exposure to AMME and adverse reactions are increased. Avoid use.
Advising men with female sexual partners of childbearing age to use effective contraception during and at least six months after the final dose of ADCETRIS treatment.
Advise patients to immediately report pregnancy and avoid breastfeeding while taking ADCETRIS.
For important additional safety information, including the sidebar warning, please refer to the full ADCETRIS prescription information at . or www.ADCETRIS.com.
1 The Skindex-29 is widely used as a questionnaire for evaluating the three-dimensional quality of life in dermatology. Twenty-nine elements are combined to constitute three categories: symptoms, emotions and functioning. Scores by category and overall score are expressed on a scale of 100 points. High scores report lower levels of quality of life.
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