On October 29, 2018 Takeda Pharmaceutical Company Limited (TSE: 4502) reported that it will present a total of six company-sponsored abstracts, including two oral presentations, at the 11th International Symposium on Hodgkin Lymphoma ) from 27 to 29 October 2018 in Cologne, Germany (Press release, Takeda, OCT 29, 2018, View Source [SID1234530423]). This year’s presentations will highlight Phase 3 and other clinical data from ADCETRIS (brentuximab vedotin) and will continue to build on our research on CD30 positive lymphoma.
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"Data to be presented at this year’s ISHL continue to reinforce Takeda’s dedication to advancing treatment for people affected by Hodgkin’s lymphoma," said Jesús Gómez-Navarro, MD, Vice President and Chief Clinical Research and Development of Oncology of Takeda. "The progress we have made in the development of ADCETRIS serves as a true testimony to the leadership role we have played in the treatment of CD30-positive malignancies. We are eager to share positive data, including the results of the Phase 3 ECHELON-1 and AETHERA trials, which confirm the long-term benefits of ADCETRIS through treatment lines and support its role as an important therapy targeting Hodgkin lymphoma . "
During the invited oral presentation, Takeda will share the results of the ECHELON-1 study, which showed that ADCETRIS, as part of a front-line combination chemotherapy regimen, improved the outcome compared to a current standard of care in patients not previously treated with advanced Hodgkin’s lymphoma. The safety profile of the ADCETRIS arm in the ECHELON-1 assay was generally consistent with that known for the single agent components of the regimen. In addition to the findings presented earlier during the Plenary Scientific Session at the 59th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) in December 2017, the presentation of ISHL will highlight survival-free progression (PFS) results and data demonstrating the benefits of ADCETRIS in patients with stage IV disease. Additional data to be presented during the meeting include several sub-analyzes of the ECHELON-1 trial.
Takeda, in partnership with Seattle Genetics, will present five-year follow-up data from AETHERA’s Phase 3 trial, in which ADCETRIS demonstrated a sustained benefit in PFS as a consolidation treatment option for patients at high risk of relapse or progression after autologous stem cell transplantation (ASCT). The safety profile of ADCETRIS in the AETHERA trial was generally consistent with existing prescribing information.
Takeda will also disclose the results of a Phase 1/2 study evaluating ADCETRIS as part of a chemotherapy regimen in advanced pediatric Hodgkin’s lymphoma patients.
Also at the congress, ISHL invited Takeda to participate in PeD’s access to medical oncology program in Sub-Saharan Africa during the Developing Healthcare Environments workshop on Saturday, October 27, from 8:45 p.m. to 10:15 p.m. CET .
The six abstracts sponsored by Takeda Oncology accepted for submission during ISHL include:
Brentuximab vedotin frontline plus chemotherapy exhibits survival without modified upper progression compared to only chemotherapy in patients with stage III or IV Hodgkin’s lymphoma: ECHELON-1 Phase 3 study. Oral presentation: session "Advanced Placements". Monday, October 29, 7:30 a.m. – 9:00 p.m. CET. Poster: Abstract 0038. Sunday, October 28 – Monday, October 29.
Five-year progression-free survival results from a crucial Phase 3 study of the consolidation of brentuximab vedotin after autologous stem cell transplantation in patients with Hodgkin’s lymphoma at risk of recurrence or progression (AETHERA). Oral presentation. Session "Recidente / Refratário HL". Monday, October 29, 4:00 p.m. to 5:30 p.m. CET.
Phase 1/2 study of brentuximab vedotin + AVD in pediatric patients with recently diagnosed advanced stage classic Hodgkin’s lymphoma. Abstract 0149. Sunday, October 28 – Monday, October 29.
Serum CD30 and TARC do not correlate with evaluation of PET-based response in patients (Pcs) with stage III or IV classical Hodgkin’s lymphoma (cHL): ECHELON-1 Phase 3 study of brentuximab vedotin plus chemotherapy compared with only chemotherapy. Abstract 0159. Sunday, October 28 – Monday, October 29.
Brentuximab vedotin plus chemotherapy in patients with advanced high-risk classical Hodgkin’s lymphoma (cHL): results from pre-specified subgroup analyzes from the ECHELON-1 study. Abstract 0136. Sunday, October 28 – Monday, October 29.
Pharmacokinetic population modeling and assessment of response to exposure to efficacy and safety of brentuximab vedotin in patients with advanced classical Hodgkin lymphoma from the ECHELON-1 Phase 3 study. Abstract 0137. Sunday, October 28 – Monday, October 29.
* In partnership with Seattle Genetics
For more information, the ISHL program is available here: View Source .
About Hodgkin Lymphoma
Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two main categories of lymphoma: Hodgkin’s lymphoma and non-Hodgkin’s lymphoma. Hodgkin’s lymphoma is distinguished from other types of lymphoma by the presence of a characteristic cell type, known as the Reed-Sternberg cell. The Reed-Sternberg cell expresses CD30.
According to the Lymphoma Coalition, approximately 67,000 people worldwide are diagnosed with Hodgkin’s lymphoma every year, and more than 25,000 people die from this cancer.
About 30 percent of patients newly diagnosed with Hodgkin’s lymphoma progress after first-line therapy, depending on the stage of the disease. Only 50 percent of patients with relapsed or refractory Hodgkin’s lymphoma gain long-term remission with high dose chemotherapy and an autologous stem cell transplantation (ASCT), a treatment used historically, highlighting the importance of first- successful.
About ADCETRIS
ADCETRIS is an ADC comprising an anti-CD30 monoclonal antibody linked by a protease cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), using proprietary technology from Seattle Genetics. The ADC employs a binding system that is designed to be stable in the bloodstream, but to release MMAE after internalization into CD30-expressing tumor cells.
Intravenous infusion ADCETRIS injection received FDA approval for five indications in adult patients with: (1) untreated classic Hodgkin’s lymphoma (HLC), stage III or IV, in combination with chemotherapy, (2) high-risk cHL relapse or progression such as consolidation of post-autologous hematopoietic stem cell transplantation (auto-HSCT), (3) LCH after self-HSCT failure or failure of at least two multi-agent chemotherapy regimens in patients who are not candidates for self- TCTH, (4) sALCL after failure of at least one previous multiagent chemotherapy regimen, and (5) primary cutaneous anaplastic cutaneous lymphoma (pcALCL) or mycosis fungoides (MF) expressing CD30 that received prior systemic treatment.
Health Canada granted approval of ADCETRIS with conditions for relapsed or refractory Hodgkin’s lymphoma and sALCL in 2013, and unconditional approval for post-autologous stem cell transplantation (ASCT) consolidation treatment of patients with Hodgkin’s lymphoma at risk increased relapse or progression.
ADCETRIS received a conditional marketing authorization from the European Commission in October 2012. The indications approved in Europe are: (1) for the treatment of adult patients with relapsed or refractory Hodgkin’s lymphoma after ASCT or after at least two therapies when treating ASCT or multi-agent chemotherapy is not a treatment option, (2) treating adult patients with recurrent or refractory slam, (3) for the treatment of adult patients with CD30 positive Hodgkin’s lymphoma at increased risk of relapse or progression after ASCT, and (4) for the treatment of adult patients with cutaneous CD30-positive T-cell lymphoma (CTCL) after at least one prior systemic therapy.
ADCETRIS has been approved by regulatory authorities in 70 countries for relapsed or refractory Hodgkin’s lymphoma and sALCL See important safety information below.
ADCETRIS is being extensively evaluated in more than 70 clinical trials, including a Phase 3 study in first-line Hodgkin’s lymphoma (ECHELON-1) and another Phase 3 study in first-line CD30-positive peripheral T cell lymphomas ( ECHELON-2) as well as assays in many additional types of CD30-positive malignancies.
Seattle Genetics and Takeda are developing ADCETRIS together. Under the terms of the collaboration agreement, Seattle Genetics has marketing rights in the US and Canada, and Takeda has the right to market ADCETRIS in the rest of the world. Seattle Genetics and Takeda are funding the joint development costs for ADCETRIS on a half-way basis, except in Japan, where Takeda is solely responsible for development costs.
ADCETRIS (brentuximab vedotin) Important safety information (European Union)
Consult the Summary of Product Characteristics (RCM) before prescribing.
CONTRAINDICATIONS
ADCETRIS is contraindicated in 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): reactivation of John Cunningham virus (JCV) resulting in progressive multifocal leukoencephalopathy (PML) and death may occur in ADCETRIS-treated patients. PML has been reported in patients receiving ADCETRIS after receiving multiple prior chemotherapy regimens. PML is a rare demyelinating disease of the central nervous system that results from the reactivation of latent JCV and is often fatal.
Carefully monitor patients for new or worsening neurological, cognitive or behavioral signs or symptoms, which may be suggestive of PML. Suggested evaluation of PML includes neurological consultation, magnetic resonance imaging of the brain with gadolinium, and analysis of cerebrospinal fluid for JCV DNA by polymerase chain reaction (PCR) or brain biopsy with evidence of JCV. A negative JCV PCR does not exclude PML. Additional monitoring and evaluation may be necessary if no alternative diagnosis can be established. Maintain dosage for any suspected case of PML and permanently discontinue ADCETRIS if a PML diagnosis is confirmed.
Be aware of PML symptoms that the patient may not notice (for example, cognitive, neurological, or psychiatric symptoms).
Pancreatitis: Acute pancreatitis was observed in patients treated with ADCETRIS. Fatal outcomes were reported. Monitor patients closely for new or aggravating abdominal pains, which may be suggestive of acute pancreatitis. Patient assessment may include physical examination, laboratory evaluation of serum amylase and serum lipase, and abdominal imaging such as ultrasound and other appropriate diagnostic measures. Discontinue ADCETRIS in 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 no causal association has been established with ADCETRIS, the risk of pulmonary toxicity can not be ruled out. Evaluate promptly and treat new or worsened lung symptoms adequately. Consider dosing during evaluation and even symptomatic improvement.
Severe infections and opportunistic infections: severe 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 ADCETRIS-treated patients. Carefully monitor patients during treatment for possible serious and opportunistic infections.
Infusion-related reactions (IRR): immediate and late IRR, as well as anaphylaxis, occurred with ADCETRIS. Monitor patients closely during and after an infusion. If anaphylaxis occurs, immediately and permanently discontinue administration of ADCETRIS. Appropriate medical treatment should be given. If an IRR occurs, stop the infusion and institute appropriate medical treatment. The infusion can be restarted at a slower rate after resolution of symptoms. Patients who had a previous IRR should be pre-medicated 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 administer them according to best medical practice.
Peripheral neuropathy (PN): treatment with ADCETRIS may cause PN, both sensory and motor. PN induced by ADCETRIS is typically cumulative and reversible in most cases. Monitor patients for NP symptoms such as hypoaesthesia, hyperesthesia, paresthesia, discomfort, burning sensation, neuropathic pain, or weakness. Patients who present with new or worsening PN may require a delay and a reduction in the dose or discontinuation of ADCETRIS.
Hematologic toxicities: grade 3 or grade 4 anemia, thrombocytopenia and prolonged grade 3 neutropenia (equal to or greater than 1 week) may occur with ADCETRIS. Monitor complete blood counts before each dose is given.
Febrile neutropenia: Febrile neutropenia was reported. Carefully monitor patients for fever and manage according to best medical practice in case of developing febrile neutropenia.
Stevens-Johnson Syndrome (SJS): SJS and toxic epidermal necrolysis (TEN) have been reported with ADCETRIS. Fatal outcomes were reported. Discontinue treatment with ADCETRIS if SJS or TEN occurs and administer appropriate medical therapy.
Gastrointestinal (GI) complications : gastrointestinal complications, some with fatal outcomes including intestinal obstruction, ileus, enterocolitis, neutropenic colitis, erosion, ulceration, perforation and hemorrhage have been reported. Promptly evaluate and treat patients if new or aggravating gastrointestinal symptoms occur.
Hepatotoxicity: elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have been reported. Severe cases of hepatotoxicity, including fatal outcomes, also occurred. Test liver function before starting treatment and routinely monitor patients receiving ADCETRIS for hepatic elevations. Patients with hepatotoxicity may require a delay, dose modification or discontinuation of ADCETRIS.
Hyperglycemia: Hyperglycemia has been reported during studies in patients with a high body mass index (BMI), with or without a history of diabetes mellitus. Monitor serum glucose closely in patients experiencing an event of hyperglycemia. Administer antidiabetic treatment as appropriate.
Renal and hepatic impairment: There is limited experience in patients with renal and hepatic impairment. Available data indicate that clearance of MMAE may be affected by severe renal insufficiency, hepatic insufficiency, and low serum albumin concentrations.
CD30 + CTCL: The size of the treatment effect on CD30 + CTCL subtypes other than mycosis fungoides (MF) and primary cutaneous anaplastic large cell lymphoma (pcALCL) is unclear due to lack of high level evidence. In two ADCETRIS single-arm phase II studies, disease activity was demonstrated in the Sézary syndrome (SS), lymphomatoid papulosis (LyP) and mixed histology of LCTC subtypes. These data suggest that efficacy and safety can be extrapolated to other subtypes of CD30 + CTCL. Carefully consider the risk benefit per patient and be careful in other types of patients with CTCL + CDCL.
Sodium content in the excipients: ADCETRIS contains a maximum of 2.1 mmol (or 47 mg) sodium per dose. Take this into consideration for patients on a controlled sodium diet.
Interactions
Patients receiving a strong CYP3A4 or P-gp inhibitor concomitantly with ADCETRIS may be at increased risk of neutropenia and should be monitored closely. Concomitant administration of ADCETRIS with a CYP3A4 inducer did not alter the plasma exposure of ADCETRIS but appeared to reduce the plasma concentrations of the metabolites of MMAE that could be tested. ADCETRIS is not expected to alter exposure to drugs metabolised by CYP3A4 enzymes.
PREGNANCY: Inform women of childbearing potential to use two effective contraceptive methods during ADCETRIS treatment and up to six months after treatment. There are no data on the use of ADCETRIS in pregnant women, although animal studies 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 on whether ADCETRIS or its metabolites are excreted in human milk, so it is not possible to rule out a risk to the newborn / infant. At the potential risk, a decision should be made on discontinuation of breastfeeding or discontinuation / abstention from treatment with ADCETRIS.
FERTILITY: In non-clinical studies, treatment with ADCETRIS resulted in testicular toxicity and may alter male fertility. Inform men on ADCETRIS treatment not to be parents during treatment and up to six months after the last dose.
Effects on the ability to drive and use machines: ADCETRIS may have a minor influence on the ability to drive and use machines.
SIDE EFFECTS
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, related reactions with perfusion, pruritus, constipation, dyspnea, weight loss, 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 syndrome of Stevens-Johnson. Serious adverse drug reactions occurred in 12% of patients. The frequency of serious adverse drug reactions was ≤1%.
ADCETRIS (brentuximab vedotin) Important safety information in the USA
WARNING IN THE BOX: PROGRESSIVE MULTIFOCAL LEUCOENCEPHALOPATHY (PML)
JC virus infection resulting in PML and death may occur in patients treated with ADCETRIS.
Contraindication
ADCETRIS concomitant with bleomycin due to pulmonary toxicity (eg, infiltration and / or interstitial inflammation).
Warnings and Precautions
Peripheral neuropathy (PN): ADCETRIS causes PN to be predominantly sensory. Cases of motor PN were also reported. The PN induced by ADCETRIS is cumulative. Monitor symptoms such as hypoaesthesia, hyperesthesia, paresthesia, discomfort, burning sensation, neuropathic pain or weakness. Establish dose modifications accordingly.
Anaphylaxis and infusion reactions : Infusion- related reactions (IRR), including anaphylaxis, have occurred with ADCETRIS. Monitor the patients during infusion. If an IRR occurs, stop the infusion and institute appropriate medical treatment. If anaphylaxis occurs, immediately and continuously discontinue the infusion and administer appropriate medical treatment. Pre-med the patients with IRR before the subsequent infusions. Pre-medication may include acetaminophen, an antihistamine, and a corticosteroid.
Hematologic toxicities: severe prolonged neutropenia (≥1 week) and thrombocytopenia or Grade 3 or 4 anemia may occur with ADCETRIS. Severe and fatal cases of febrile neutropenia have been reported with ADCETRIS. Monitor complete blood counts before each dose of ADCETRIS. Consider more frequent monitoring for patients with Grade 3 or 4 neutropenia. Monitor fever in patients. If Grade 3 or 4 neutropenia occurs, consider delays, reductions, discontinuation, or prophylaxis with G-CSF at subsequent doses.
Severe 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. Monitor closely the patients during treatment of bacterial, fungal, or viral infections.
Tumor lysis syndrome: follow closely the patients with tumor of rapid proliferation and high tumor burden.
Increased toxicity in the presence of severe renal impairment: the frequency of adverse reactions and ≥ Grade 3 deaths was greater in patients with severe renal impairment compared with patients with normal renal function. Avoid use in patients with severe renal impairment.
Increased toxicity in the presence of moderate or severe hepatic impairment: The frequency of adverse reactions and deaths in Grade 3 was greater in patients with moderate or severe hepatic impairment compared to patients with normal hepatic function. Avoid use in patients with moderate or severe hepatic impairment .
Hepatotoxicity : Severe and fatal cases occurred in patients treated with ADCETRIS. Cases were consistent with hepatocellular damage, including elevations of transaminases and / or bilirubin, and occurred after the first dose or recount of ADCETRIS. Pre-existing liver disease, elevated basal liver enzymes and concomitant medications may increase risk. Monitor liver enzymes and bilirubin. Patients with recent, aggravated or recurrent hepatotoxicity may require a delay, dose change or discontinuation of ADCETRIS.
PML: fatal cases of JC virus infection resulting in PML and death were reported in patients treated with ADCETRIS. The first onset of symptoms occurred at various times from the start of ADCETRIS therapy, with some cases occurring within three months of the initial exposure. Other possible contributory factors other than ADCETRIS include previous treatments and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in patients with signs and symptoms of recent onset of central nervous system abnormalities. Stop ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed.
Pulmonary toxicity: Severe and fatal non-infectious pulmonary toxicity events including pneumonitis, interstitial lung disease and acute respiratory distress syndrome have been reported. Monitor patients for signs and symptoms, including cough and dyspnea. In case of new or aggravated pulmonary symptoms, administer the ADCETRIS dose during evaluation and until symptomatic improvement.
Severe dermatological reactions: severe and fatal cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (NET) have been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate medical treatment.
Gastrointestinal (GI) complications: Severe and fatal cases of acute pancreatitis have been reported in patients treated with ADCETRIS. Other serious and fatal gastrointestinal complications include perforation, bleeding, erosion, ulceration, intestinal obstruction, enterocolitis, neutropenic colitis and ileus have been reported in ADCETRIS-treated patients. Lymphoma with preexisting gastrointestinal involvement may increase the risk of perforation. In case of new or aggravated gastrointestinal symptoms, perform an immediate diagnostic evaluation and treat appropriately.
Fetal embryonal toxicity: Based on the mechanism of action and animal studies, ADCETRIS may cause fetal damage. Inform women about the potential reproductive potential of the potential risk to the fetus and to avoid pregnancy during treatment with ADCETRIS and for at least six months after the last dose of ADCETRIS.
Common adverse reactions (≥20%): neutropenia, anemia, peripheral sensory neuropathy, nausea, fatigue, constipation, diarrhea, vomiting and pyrexia.
Drug interactions
Concomitant use of strong inhibitors or inducers of CYP3A4, or inhibitors of P-gp, has the potential to affect 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.
Inform men with female sexual partners with reproductive potential to use effective contraceptive methods during ADCETRIS treatment and for at least six months after the last dose of ADCETRIS.
Inform patients to report pregnancy immediately and avoid breastfeeding while receiving ADCETRIS.