- Phase III Front-line Trial Planned in Advanced Stage Hodgkin Lymphoma Patients-
San Diego, CA – December 13, 2011 – Seattle Genetics, Inc. (Nasdaq: SGEN) and Millennium: The
Takeda Oncology Company with its parent company Takeda Pharmaceutical Company Limited
(TSE:4502), today announced interim results from a phase I clinical trial of ADCETRIS (brentuximab
vedotin) in combination with chemotherapy for the treatment of newly diagnosed advanced stage
Hodgkin lymphoma patients. The data were presented at the 53rd American Society of Hematology
(ASH) Annual Meeting and Exposition being held December 10-13, 2011 in San Diego, CA. ADCETRIS
is an antibody-drug conjugate (ADC) directed to CD30.
In the phase I trial, patients received ADCETRIS concomitantly with either ABVD (Adriamycin,
bleomycin, vinblastine and dacarbazine) or AVD, which removes bleomycin from the regimen. The
trial was designed to establish the safety profile and maximum tolerated dose when adding ADCETRIS
to ABVD or AVD.
Front-line Therapy with Brentuximab Vedotin Combined with ABVD or AVD in Patients with
Newly Diagnosed Advanced Stage Hodgkin Lymphoma (Abstract #955)
Data were reported from 44 patients treated to date on the study, including 25 in the ADCETRIS plus
ABVD cohorts and 19 in the ADCETRIS plus AVD cohorts. All patients were previously untreated with
Stage IIa bulky disease or Stage IIb-IV Hodgkin lymphoma. Key findings, which were presented by Dr.
Anas Younes from The University of Texas MD Anderson Cancer Center, included:
No dose-limiting toxicity was observed at the maximum planned dose of ADCETRIS (1.2 milligrams
per kilogram [mg/kg] every two weeks).
To date, no pulmonary toxicity events have been observed in the ADCETRIS plus AVD cohorts.
Ten out of 25 patients (40 percent) in the ADCETRIS plus ABVD cohorts had an event of pulmonary
toxicity, including three Grade 3 and two Grade 4 events. This compares to an overall rate of
pulmonary toxicity with bleomycin-based regimens reported in published literature of 10 to 25
percent (1,2).
Concomitant use of ADCETRIS with bleomycin is not recommended due to an increased incidence
of pulmonary adverse events; patients are no longer being treated on the ABVD cohorts of the study.
Among the 10 patients experiencing a pulmonary toxicity event in the ABVD combination cohorts,
seven discontinued bleomycin and completed treatment with ADCETRIS plus AVD.
Across all treatment cohorts, the most common adverse events were neutropenia (77 percent),
nausea (66 percent), peripheral sensory neuropathy (48 percent), fatigue (43 percent) and vomiting
(43 percent).
Across all treatment cohorts, Grade 3 or higher adverse events were neutropenia (77 percent), anemia (14 percent), febrile neutropenia (11 percent) and pulmonary toxicity (11 percent, all in the ABVD cohorts). No Grade 3 or 4 adverse events of peripheral neuropathy have been observed to date.
Among 25 patients in the ADCETRIS plus ABVD cohorts, all 15 patients who completed front-line therapy on study achieved a complete remission; five patients were unevaluable because they withdrew from the study prior to completing a full course of therapy and five patients were in ongoing treatment.
All patients in the ADCETRIS plus AVD cohorts are in ongoing treatment and response results are not yet available.
Thirty-six of 37 evaluable patients in both study arms had negative interim PET scans after Cycle 2 as assessed by central review, including 22 out of 22 (100 percent) in the ABVD cohorts and 14 out of 15 (93 percent) in the AVD cohorts.
“Front-line Hodgkin lymphoma is a setting in which a core research strategy for decades has been to enhance the activity of traditional chemotherapy regimens while reducing the significant toxicities and long-term side effects of such regimens. For example, bleomycin is commonly associated with an increased risk of pulmonary complications that have been shown to have a negative impact on the outcome of patients with Hodgkin lymphoma,” said Dr. Anas Younes, Professor of Medicine and Director, Clinical Investigation and Translational Research Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center. “Data from this trial support further evaluation of ADCETRIS administered concomitantly with AVD in previously untreated Hodgkin lymphoma patients.”
In this open-label trial, cohorts of patients received escalating doses of ADCETRIS ranging from 0.6 mg/kg to 1.2 mg/kg every two weeks concomitantly with ABVD or a dose of 1.2 mg/kg every two weeks concomitantly with AVD. The median age of patients across all cohorts of the trial was 32.5 years. Enrollment of a total of 51 patients to the trial is complete, including 25 in the ADCETRIS plus ABVD cohorts and 26 in the ADCETRIS plus AVD cohorts.
Seattle Genetics and Millennium: The Takeda Oncology Company are planning a phase III clinical trial in advanced stage front-line Hodgkin lymphoma patients. The randomized trial will compare progression-free survival in patients receiving ADCETRIS in combination with AVD to patients receiving ABVD alone.
About ADCETRIS
ADCETRIS (brentuximab vedotin) 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.
Seattle Genetics and Millennium are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and the Takeda Group has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics and the Takeda Group are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where the Takeda Group will be solely responsible for development costs.
ADCETRIS was granted accelerated approval by the U.S. Food and Drug Administration in August 2011 for two indications: (1) the treatment of patients with HL after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates, and (2) the treatment of patients with sALCL after failure of at least one prior multi-agent chemotherapy regimen. The indications for ADCETRIS are based on response rate. There are no data available demonstrating improvement in patient-reported outcomes or survival with ADCETRIS. ADCETRIS has not been approved for use in any front-line setting.
ADCETRIS is not approved for use outside the United States. The marketing authorization application for ADCETRIS in relapsed or refractory Hodgkin lymphoma and systemic ALCL, filed by Takeda Global Research & Development Centre (Europe), was accepted by the European Medicines Agency for review in June 2011.
About Hodgkin Lymphoma
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. Hodgkin lymphoma is distinguished from other types of lymphoma by the presence of one characteristic type of cell, known as the Reed-Sternberg cell. The Reed-Sternberg cell generally expresses CD30.
According to the American Cancer Society, more than 8,800 cases of Hodgkin lymphoma will be diagnosed in the United States during 2011 and approximately 1,300 people will die from the disease. Globally, there are more than 30,000 cases of Hodgkin lymphoma diagnosed each year. Although front-line combination chemotherapy can result in durable response rates, up to 30 percent of these patients relapse or are refractory to front-line treatment and have few therapeutic options beyond ASCT.
U.S. Important Safety Information
Warnings and Precautions:
Peripheral neuropathy: ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. Treating physicians should monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness and institute dose modifications accordingly.
Infusion reactions: Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an infusion reaction occurs, the infusion should be interrupted and appropriate medical management instituted. If anaphylaxis occurs, the infusion should be immediately and permanently discontinued and appropriate medical management instituted.
Neutropenia: Monitor complete blood counts prior to each dose of ADCETRIS and consider more frequent monitoring for patients with Grade 3 or 4 neutropenia. If Grade 3 or 4 neutropenia develops, manage by dose delays, reductions or discontinuation. Prolonged (≥1 week) severe neutropenia can occur with ADCETRIS.
Tumor lysis syndrome: Patients with rapidly proliferating tumor and high tumor burden are at risk of tumor lysis syndrome and these patients should be monitored closely and appropriate measures taken.
Stevens-Johnson syndrome: Stevens-Johnson syndrome has been reported with ADCETRIS. If Stevens-Johnson syndrome occurs, discontinue ADCETRIS and administer appropriate medical therapy.
Progressive multifocal leukoencephalopathy (PML): A fatal case of PML has been reported in a patient who received four chemotherapy regimens prior to receiving ADCETRIS.
Use in pregnancy: Fetal harm can occur. Pregnant women should be advised of the potential hazard to the fetus.
Adverse Reactions:
ADCETRIS was studied as monotherapy in 160 patients in two phase 2 trials. Across both trials, the most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough and vomiting.
Drug Interactions:
Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions.
For additional important safety information, please see the full U.S. prescribing information for ADCETRIS at www.seattlegenetics.com or www.ADCETRIS.com.
For Seattle Genetics:
Certain of the statements made in this press release are forward looking, such as those, among others, relating to the therapeutic potential of ADCETRIS and initiation of future clinical trials. Actual results or developments may differ materially from those projected or implied in these forward-looking statements. Factors that may cause such a difference include the inability to show sufficient activity in future clinical trials and the risk of adverse events as ADCETRIS advances in clinical trials. In addition, data from our clinical trials, including our pivotal trials which were the basis for FDA accelerated approval, may not necessarily be indicative of subsequent clinical trial results. More information about the risks and uncertainties faced by Seattle Genetics is contained in the company’s 10-Q for the quarter ended September 30, 2011 filed with the Securities and Exchange Commission. Seattle Genetics disclaims any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise.
1) Duggan DB, et.al. Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin's disease: report of an intergroup trial. 2003. J Clin Oncol 21: 607-14.
2) Hoskin PJ, et.al. Randomized comparison of the Stanford V regimen and ABVD in the treatment of advanced Hodgkin's Lymphoma: United Kingdom National Cancer Research Institute Lymphoma Group Study ISRCTN 64141244. 2009. J Clin Oncol 27: 5390-6.
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About Seattle Genetics
Seattle Genetics is a biotechnology company focused on the development and commercialization of monoclonal antibody-based therapies for the treatment of cancer. ADCETRIS was approved by the FDA on August 19, 2011 for two indications. ADCETRIS is being developed in collaboration with Millennium: The Takeda Oncology Company. In addition, Seattle Genetics has three other clinical-stage ADC programs: SGN-75, ASG-5ME and ASG-22ME. Seattle Genetics has collaborations for its ADC technology with a number of leading biotechnology and pharmaceutical companies, including Abbott, Bayer, Celldex Therapeutics, Daiichi Sankyo, Genentech, GlaxoSmithKline, Millennium, Pfizer and Progenics, as well as ADC co-development agreements with Agensys, an affiliate of Astellas, and Genmab. More information can be found at www.seattlegenetics.com.
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