Clinical Trials

Date: 2017-12-10

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at the 59th American Society of Hematology (ASH) Annual Meeting in Orlando

Company: Seattle Genetics (USA - WA)

Product: Adcetris® (brentuximab vedotin)

Action mechanism:

• monoclonal antibody/antibody drug conjugate (ADC). Adcetris® (Brentuximab Vedotin) is an antibody drug conjugate (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. 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 will be solely responsible for development costs. Adcetris has received marketing authorization by regulatory authorities in more than 45 countries. In addition, Adcetris® is being evaluated as an investigational agent in more than 30 ongoing clinical trials, including four phase 3 studies, across a variety of CD30-expressing malignances including HL.
• The FDA granted Breakthrough Therapy Designation for Adcetris® in combination with chemotherapy for the frontline treatment of patients with advanced classical Hodgkin lymphoma. Seattle Genetics submitted a supplemental Biologics License Application to the FDA on November 1, 2017. Takeda has begun to submit data from the ECHELON-1 trial to regulatory agencies in its territories, starting with the European Medicines Agency (EMA) on November 29, 2017.

Disease: Hodgkin lymphoma

Therapeutic area: Cancer - Oncology

Country: Australia, Belgium, Brazil, Canada, Czech Republic, Denmark, France, Hong Kong, Hungary, Italy, Japan, Republic of Korea, Norway, Poland, Russian Federation, South Africa, Spain, Taiwan, Turkey, UK, USA

Trial details:

• ECHELON-1  is an open-label, randomized, 2-arm, multicenter, phase 3 study comparing the modified progression-free survival (mPFS) obtained with brentuximab vedotin (Adcetris®) plus AVD (doxorubicin [Adriamycin], vinblastine, and dacarbazine; abbreviated A+AVD) versus that obtained with ABVD (doxorubicin [Adriamycin],bleomycin, vinblastine, and dacarbazine) for the frontline treatment of advanced classical Hodgkin lymphoma (HL).
• The trial is being conducted under a Special Protocol Assessment (SPA) agreement from the FDA and the trial also received European Medicines Agency (EMA) scientific advice.
• The primary endpoint is modified 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 and safety. The multi-center trial is being conducted in North America, Europe, South America, Australia, Asia and Africa. The study has enrolled approximately 1,300 patients who had histologically-confirmed diagnosis of Stage III or IV classical HL and had not been previously treated with systemic chemotherapy or radiotherapy. Data from the trial will be available when a pre-specified number of PFS events have occurred.
• The multi-center trial was conducted at 218 sites in 21 countries across North America, Europe, South America, Australia, Asia and Africa. (NCT01712490)

Latest news:

• • On December 10, 2017, Takeda Pharmaceutical and Seattle Genetics announced that data from the Phase 3 ECHELON-1 clinical trial evaluating Adcetris® (brentuximab vedotin) as part of a frontline combination chemotherapy regimen in untreated advanced classical Hodgkin lymphoma have been presented at the 59th American Society of Hematology (ASH) annual meeting. The data were also simultaneously published online in the New England Journal of Medicine and will be published in the print edition on January 25, 2017. The study enrolled 1,334 patients who had histologically-confirmed diagnosis of Stage III or IV Hodgkin lymphoma and had not been previously treated with systemic chemotherapy or radiotherapy. The median age of the patients enrolled in the study was 35 in the Adcetris®+AVD arm and 37 in the ABVD arm. Patients received Adcetris®+AVD or ABVD on Days 1 and 15 of each 28-day cycle for up to six cycles.
• Topline data were reported in June 2017 demonstrating the ECHELON-1 trial met its primary endpoint of a statistically significant improvement in modified progression-free survival (modified PFS) per Independent Review Facility (IRF) versus the control arm.
• Brentuximab Vedotin Plus Doxorubicin, Vinblastine, Dacarbazine (A+AVD) as Frontline Therapy Demonstrates Superior Modified Progression-Free Survival versus ABVD in Patients with Previously Untreated Stage III or IV Hodgkin Lymphoma (HL): The Phase 3 ECHELON-1 Study (Plenary Scientific Session) Key findings, which will be presented by Dr. Joseph M. Connors and published in the New England Journal of Medicine, include:
• The trial achieved its primary endpoint with the combination of Adcetris®+AVD resulting in a statistically significant improvement in modified PFS versus the control arm of ABVD as assessed by an Independent Review Facility (IRF) (HR 0.77; p-value=0.035). This corresponds to a 23 percent reduction in the risk of progression, death or need for additional anticancer therapy.
• Per IRF assessment, the two-year modified PFS rate for patients in the Adcetris®+AVD arm was 82.1 percent compared to 77.2 percent in the control arm. Per investigator assessment, the two-year modified PFS rate for patients in the Adcetris®+AVD arm was 81.0 percent compared to 74.4 percent in the control arm (HR 0.73; p-value=0.007). This corresponds to a 27 percent reduction in the risk of progression, death or need for additional anticancer therapy.
• All secondary endpoints trended in favor of the Adcetris®+AVD arm, including interim analysis of overall survival (OS; HR 0.72; p-value=0.19). Other secondary endpoints include: Complete response (CR) rate at the end of randomized regimen in the Adcetris®+AVD arm was 73 percent compared to 70 percent in the control arm (p-value=0.22). Objective response rate (ORR) at the end of randomized regimen in the Adcetris®+AVD arm was 86 percent compared to 83 percent in the control arm (p-value=0.12). Deauville score ?2 after completion of frontline therapy was 85 percent in the Adcetris®+AVD arm compared to 80 percent in the control arm (p-value=0.03). Certain pre-specified subgroups of patients appeared to benefit more with Adcetris®+AVD versus ABVD including: patients treated in North America; patients with involvement of >1 extranodal site; patients with International Prognostic Score (IPS) 4 – 7; males; patients with Stage IV disease; and patients aged <60 years. In the Adcetris®+AVD arm, 33 percent fewer patients received subsequent salvage chemotherapy or high-dose chemotherapy and transplant. The safety profile of Adcetris®+AVD in the ECHELON-1 trial was generally consistent with that known for the single-agent components of the regimen. The most common clinically relevant adverse events of any grade that occurred in at least 15 percent of patients in the Adcetris®+AVD and ABVD arms were: neutropenia (58 and 45 percent, respectively), constipation (42 and 37 percent, respectively), vomiting (33 and 28 percent, respectively), fatigue (both 32 percent), peripheral sensory neuropathy (29 and 17 percent, respectively), diarrhea (27 and 18 percent, respectively), pyrexia (27 and 22 percent, respectively), peripheral neuropathy (26 and 13 percent, respectively), abdominal pain (21 and 10 percent, respectively) and stomatitis (21 and 16 percent, respectively). In both the Adcetris®+AVD and ABVD arms, the most common Grade 3 or 4 events were neutropenia, febrile neutropenia and neutrophil count decrease.
• Febrile neutropenia was reduced through the use of prophylactic growth factors (G-CSF) in a subset of patients. In the Adcetris®+AVD arm of the study, the rate of febrile neutropenia without the use of G-CSF was 21 percent and with the use of G-CSF was reduced to 11 percent. G-CSF primary prophylaxis with Adcetris®+AVD resulted in overall comparable safety profile to ABVD, decreasing incidence of febrile neutropenia, neutropenia and serious adverse events. Primary prophylaxis with G-CSF was recommended for all patients.
• On the Adcetris®+AVD arm, peripheral neuropathy events were observed in 67 percent of patients compared to 43 percent on the control arm. In the Adcetris®+AVD arm, the majority of peripheral neuropathy events were Grade 1 or 2. Grade ?3 events were reported in 11 percent of patients and Grade 4 events were reported in less than one percent of patients. In the control arm, Grade ?3 events were reported in two percent of patients and there were no Grade 4 events. Two-thirds of the patients with peripheral neuropathy in the Adcetris®+AVD arm reported resolution or improvement at last follow-up. Pulmonary toxicity was reported in two percent of patients in the Adcetris®+AVD arm versus seven percent of patients in the ABVD arm; Grade ?3 events were reported in less than one percent versus three percent, in the Adcetris® and control arms respectively.
• Nine on study deaths occurred in the Adcetris®+AVD arm, of which seven were due to neutropenia or associated complications (all occurred in patients who had not received primary prophylaxis with G-CSF with the exception of one patient who entered the trial with pre-existing neutropenia). The remaining two deaths were due to myocardial infarction. In the control arm, there were 13 on study deaths, of which 11 were due to or associated with pulmonary-related toxicity, one was due to cardiopulmonary failure and one death had unknown cause.• On June 26, 2017,  Takeda Pharmaceutical and Seattle Genetics announced that the Phase 3 ECHELON-1 clinical trial met its primary endpoint of a statistically significant improvement in modified progression-free survival (PFS) versus the control arm.
• Patients in ECHELON-1 were randomized to receive either a combination of Adcetris®)+AVD (Adriamycin, vinblastine, dacarbazine) or ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine), a recognized standard of care for frontline Hodgkin lymphoma. The results of the ECHELON-1 trial demonstrated that combination treatment with Adcetris®) resulted in a statistically significant improvement in modified PFS versus the control arm as assessed by an Independent Review Facility (hazard ratio=0.770; p-value=0.035). The two-year modified PFS rate for patients in the Adcetris®) arm was 82.1 percent compared to 77.2 percent in the control arm. Interim analysis of overall survival (OS), the key secondary endpoint, also trended in favor of the Adcetris®)+AVD arm. An abstract will be submitted for data presentation at the American Society of Hematology (ASH) annual meeting, December 9-12, 2017, in Atlanta, Ga.
• The safety profile of  Adcetris®)+AVD in the ECHELON-1 trial was consistent with that known for the single-agent components of the regimen. There was an increased incidence of febrile neutropenia and peripheral neuropathy in the Adcetris®)+AVD arm. Febrile neutropenia was reduced through the use of prophylactic growth factors in a subset of patients, and peripheral neuropathy was managed through dose modifications. The control arm had an increased rate and severity of pulmonary toxicity.
• Takeda and Seattle Genetics plan to submit these results to regulatory authorities for approval in their respective territories.
• • On October 27, 2015, Seattle Genetics and Takeda Pharmaceutical announced that the companies have achieved completion of target patient enrollment in the phase 3 ECHELON-1 clinical trial. The trial has enrolled approximately 1,300 patients, although it remains open at select sites to complete enrollment of approximately 20 patients in an additional cohort to fulfill an ex-U.S. regulatory commitment related to measurement of drug levels during treatment (pharmacokinetics). This continued enrollment will not affect the expected timing of data readout from the trial in the 2017 to 2018 timeframe, based on anticipated event rates.
• Data previously presented at the ASH Annual Meeting in 2012 and 2014 from a phase 1 trial evaluating Adcetris® plus AVD demonstrated that 24 of 25 patients (96 percent) achieved a complete remission. Long-term follow-up data demonstrated three-year overall survival was 100 percent and three-year failure-free survival was 92 percent. The most common adverse events of any grade occurring in more than 30 percent of patients were neutropenia, nausea, peripheral sensory neuropathy, fatigue, vomiting, diarrhea,insomnia, bone pain, constipation and hair loss.

Is general: Yes