Bothell, Washington-based Seattle Genetics, Inc. — a biotechnology company focused on development and commercialization of innovative antibody-based therapies for the treatment of cancer —
and Takeda Pharmaceutical Company Limited of Osaka, Japan, with U.S. headquarters in Cambridge, Massachusetts, have announced that completion of target patient enrollment in the companies’ Phase 3 ECHELON-1 clinical trial has been achieved.
ECHELON-1 (ClinicalTrials.gov Identifier: NCT01712490) is an open-label, randomized, two-arm, multicenter, Phase 3 trial evaluating Seattle Genetics’ drug product ADCETRIS (brentuximab vedotin) as part of a frontline combination chemotherapy regimen. It is indicated for treatment of patients with classical Hodgkin lymphoma (HL) 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, and also for systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen. ECHELON-1 data is anticipated in a 2017–2018 timeframe.
Accelerated approval was granted for the sALCL indication based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials in patients with previously untreated advanced classical Hodgkin lymphoma (HL) — one of the two major lymphoma categories: HL and non-Hodgkin lymphoma. There are six types of classical HL, which are distinguished from other lymphomas by the characteristic presence of CD30-positive Reed-Sternberg cells that are derived from a B-lymphocyte and only present in Hodgkin lymphoma. Classical HL is a relatively uncommon form of lymphoma. According to the American Cancer Society, approximately 9,050 cases of HL will be diagnosed in the United States during 2015 and more than 1,150 will die from the disease. The Lymphoma Coalition estimates that more than 62,000 people worldwide are diagnosed with HL each year and approximately 25,000 people die annually from this cancer.
Seattle Genetics and Takeda are jointly developing ADCETRIS, a CD30-targeted antibody-drug conjugate (ADC) directed to CD30, a defining marker of classical HL. In collaboration with Takeda Pharmaceutical Company Limited, ADCETRIS was granted conditional marketing authorization by the European Commission in October 2012 for two indications: 1) for treatment of adult patients with relapsed or refractory CD30-positive HL 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 is commercially available in more than 55 countries, including the U.S., Canada, Japan, and members of the European Union.
An antibody-drug conjugate (ADC) directed to CD30, a defining marker of classical HL, and which is currently not approved for frontline treatment of HL, ADCETRIS, utilizing Seattle Genetics proprietary technology, works by compromising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE). 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.
Under terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda, which is the largest pharmaceutical company in Japan and one of the global leaders of the industry, 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.
ADCETRIS for intravenous injection has received approval from the FDA for three indications: 1) regular approval for the treatment of patients with classical HL 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 treatment of classical HL 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 has granted ADCETRIS approval with conditions for relapsed or refractory HL and sALCL.
Patients in ECHELON-1 have been randomized to receive either ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine), a recognized standard of care for frontline HL, or a novel combination consisting of ADCETRIS+AVD, which removes bleomycin from the regimen. The trial has thus far enrolled approximately 1,300 patients, but 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). The corporate sponsors say continued enrollment will not affect expected timing of data readout from the trial (2017–18), based on anticipated event rates. The ECHELON-1 trial is being conducted under a Special Protocol Assessment (SPA) agreement from the U.S. Food and Drug Administration (FDA) and has also received European Medicines Agency (EMA) scientific advice.
“In the majority of the world, the standard of care for newly diagnosed Hodgkin lymphoma has not changed in more than three decades, and is based on the globally recognized ABVD regimen of four chemotherapy drugs. With the ECHELON-1 clinical trial, our goal is to redefine the standard of care with a novel ADCETRIS-based combination treatment regimen that improves patient outcomes with a manageable safety profile,” says Clay Siegall, PhD, President and Chief Executive Officer of Seattle Genetics in a release. “We look forward to reporting results from the ECHELON-1 trial to potentially support an ADCETRIS supplemental Biologics License Application seeking a label expansion for use in this setting.”
“Approximately 25 percent of newly diagnosed Hodgkin lymphoma patients do not respond to initial therapy or relapse within the first two years. There is a significant need to identify additional potential therapies in this patient population that may provide a more durable response and fewer incidences of relapse,” says Dirk Huebner, MD, Global Clinical Lead, Takeda Oncology.
Data previously presented at the American Society of Hematology (ASH) Annual Meetings 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.
The ECHELON-1 Trial’s 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 with histologically confirmed diagnosis of Stage III or IV classical HL and who 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.
Data from two investigator-sponsored Phase 2 clinical trials evaluating ADCETRIS in relapsed CTCL were recently published in the Journal of Clinical Oncology (JCO) by physicians at Stanford University and the University of Texas MD Anderson Cancer Center. Results of these two clinical trials demonstrated objective response rates of 70 and 73 percent, respectively, in relapsed CTCL patients having variable levels of CD30 expression treated with ADCETRIS. This compares to objective response rates of 30 to 45 percent from published trials utilizing standard of care treatments in this disease setting. The most common adverse events in these trials were peripheral neuropathy, fatigue, nausea, skin rash, hair loss, diarrhea, muscle pain and neutropenia.
The following are highlights of data summaries from the JCO publications.
Phase II Investigator-Initiated Study of Brentuximab Vedotin in Mycosis Fungoides and Sézary Syndrome With Variable CD30 Expression Level: A Multi-Institution Collaborative Project (Published on July 20, 2015)
The Phase 2 investigator-sponsored trial enrolled CTCL patients with MF or Sézary syndrome, which are types of CTCL. Of the 32 patients enrolled in the study, 30 were evaluable for efficacy and more than half had received three or more prior systemic therapies. The primary endpoint of the trial was objective clinical response rate. The study was led by principal investigator Dr. Youn H. Kim from Stanford University School of Medicine in Stanford, California. Key findings include:
• Twenty-one of 30 patients (70 percent) achieved an objective response across all stages of disease, including Stage IB, Stage IIB and Stage IV/SS. Overall, one patient had a complete response, 20 patients had a partial response, four patients had stable disease and five patients had progressive disease. Two patients were not evaluable for response. Of the patients who had partial responses, seven had near complete responses with over 90 percent skin improvement as measured by modified Severity-Weighted Assessment Tool (mSWAT) scores and eight were still responding to therapy.
• Responses appeared to be durable; six- and 12-month Kaplan-Meier estimates indicated continuing responses in 90 percent and 79 percent of patients, respectively.
• The most common related adverse events of any grade were peripheral neuropathy (66 percent), fatigue (47 percent), nausea (28 percent), hair loss (22 percent) and neutropenia (19 percent).
• The most common Grade 3 or 4 related adverse events were neutropenia (four patients), rash (three patients) and peripheral neuropathy (one patient).
Data were published from a Phase 2 investigator-sponsored trial evaluating the use of ADCETRIS in CD30-positive CTCL patients, including lymphomatoid papulosis (LyP), primary cutaneous anaplastic large cell lymphoma (pcALCL) or MF. The study was conducted by Dr. Madeleine Duvic from the University of Texas MD Anderson Cancer Center in Houston, Texas. Among 54 patients enrolled, 48 patients were evaluable at the time of analysis. The primary endpoint of the trial was to evaluate the safety and efficacy of ADCETRIS in CD30-positive CTCL. The key findings include:
• Thirty-five of 48 patients (73 percent) achieved an objective response, including 20 of 20 (100 percent) with LyP and/or pcALCL and 15 of 28 (54 percent) with MF. Seventeen patients (35 percent) achieved a complete response.
• The most common adverse events were peripheral neuropathy (67 percent), fatigue (35 percent), skin rash (24 percent), diarrhea (15 percent), muscle pain (17 percent), localized skin infection (15 percent), neutropenia (15 percent) and hair loss (11 percent).
• The most common Grade 3 or 4 adverse events were neutropenia (three patients), nausea (two patients), unstable angina or myocardial infarction (two patients), infection (two patients), joint pain (two patients), fatigue (one patient), deep vein thrombosis (one patient), pulmonary embolism (one patient), aminotransferase elevation (one patient) and dehydration (one patient).
Seattle Genetics notes that ADCETRIS is being evaluated broadly in more than 30 ongoing clinical trials, including the Phase 3 ALCANZA randomized clinical trial evaluating ADCETRIS (brentuximab vedotin) versus investigator’s choice of methotrexate or bexarotene in 132 patients with CD30-expressing cutaneous T-cell lymphoma (CTCL) who received prior systemic therapy, and in two additional Phase 3 studies, one in frontline classical HL and one in frontline mature T-cell lymphomas, as well as trials in many additional types of CD30-expressing malignancies, including B-cell lymphomas. The ALCANZA trial is being conducted under a Special Protocol Assessment (SPA) agreement from the FDA, and Takeda has received EMA scientific advice. In 2012, the FDA granted ADCETRIS orphan drug designation for the treatment of mycosis fungoides (MF), which is the most common type of CTCL. ADCETRIS is currently not approved for the treatment of CTCL. ALCANZA data is anticipated in the second half of 2016.
Seattle Genetics, Inc.
Takeda Pharmaceutical Company Limited
Journal of Clinical Oncology (JCO)
American Cancer Society
American Society of Hematology (ASH)