Seattle Genetics, Inc. (Nasdaq:SGEN) today announced 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 (HL) patients. The data were presented at the 54 th American Society of Hematology (ASH) Annual Meeting and Exposition being held December 8-11, 2012 in Atlanta, GA. ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of classical HL. ADCETRIS is currently not approved for use in the front-line treatment of HL. In the phase I trial, newly diagnosed patients received ADCETRIS concomitantly with either ABVD (Adriamycin, bleomycin, vinblastine and dacarbazine) or AVD, which removes bleomycin from the regimen. At the end of front-line therapy, 24 of 25 patients (96 percent) treated with ADCETRIS plus AVD and 21 of 22 (95 percent) patients treated with ADCETRIS plus ABVD had a complete remission. None of the patients treated in the ADCETRIS plus AVD cohort experienced pulmonary toxicity, compared with an expected rate of pulmonary toxicity caused by ABVD alone of 10-25 percent. The trial was designed to establish the safety profile and maximum tolerated dose when adding ADCETRIS to ABVD or AVD. Antitumor activity was assessed as a secondary endpoint. "For over 30 years, the standard of care for front-line HL has been a chemotherapy regimen called ABVD that has demonstrated a complete remission rate of 70 to 80 percent and is associated with considerable life-threatening toxicities. There is a significant need to identify better treatment options for patients in the front-line HL setting,” said Clay B. Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. "Our goal is to redefine front-line treatment of HL with the addition of ADCETRIS, and the encouraging results of this phase I trial clearly support this goal and provide rationale for the ongoing ADCETRIS phase III trial in this setting."
Front-line Therapy with Brentuximab Vedotin Combined with ABVD or AVD in Patients with Newly Diagnosed Advanced Stage Hodgkin Lymphoma (Abstract #798)In this open-label, multicenter trial, cohorts of patients received an escalating dose of ADCETRIS (0.6 milligrams per kilogram (mg/kg), 0.9 mg/kg, 1.2 mg/kg) every two weeks concomitantly with ABVD or a dose of 1.2 mg/kg every two weeks concomitantly with AVD. Fifty-one patients were enrolled in the phase I study and 47 were evaluable for response at trial completion. The 47 evaluable patients included 25 in the ADCETRIS plus AVD cohort and 22 in the ADCETRIS plus ABVD cohorts. All patients were previously untreated and 45 percent had Stage IV HL. The median age of patients across all cohorts of the trial was 33 years. Key findings, which were highlighted in an oral presentation by Dr. Stephen Ansell, Professor of Medicine, Division of Hematology, from the Mayo Clinic, included:
- Among the 25 evaluable patients in the ADCETRIS plus AVD cohort, 24 patients (96 percent) who completed front-line therapy on study achieved a complete remission and one patient (four percent) experienced disease progression.
- Among the 22 evaluable patients in the ADCETRIS plus ABVD cohorts, 21 patients (95 percent) who completed front-line therapy on study achieved a complete remission. One patient was not evaluable for response due to adverse events.
- Of the 48 evaluable patients in both study arms, 24 out of 26 (92 percent) in the AVD cohort and 22 out of 22 (100 percent) in the ABVD cohorts had negative interim PET scans after Cycle 2 as assessed by central review.
- No dose-limiting toxicity was observed at the maximum planned dose of ADCETRIS (1.2 mg/kg every two weeks).
- The most common adverse events noted in the ABVD and AVD cohorts, respectively, were nausea (72 percent, 85 percent), neutropenia (80 percent, 77 percent), peripheral sensory neuropathy (72 percent, 73 percent), vomiting (60 percent, 42 percent) and fatigue (44 percent, 50 percent).
- Grade 3 or higher adverse events occurring in more than one patient overall noted in the ABVD and AVD cohorts, respectively, were neutropenia (80 percent, 77 percent), anemia (20 percent, 12 percent), febrile neutropenia (20 percent, 8 percent) and pulmonary toxicity (24 percent, 0 percent). One patient experienced a Grade 3 peripheral neuropathy event.
- As previously reported in the interim analysis of this study, pulmonary toxicity was seen in the ADCETRIS plus ABVD cohorts, resulting in a contraindication for the concomitant administration of ADCETRIS and bleomycin. No pulmonary toxicity was observed in the ADCETRIS plus AVD cohort. In the ADCETRIS plus ABVD cohorts, 11 out of 25 patients (44 percent) had a pulmonary toxicity event, and events were resolved in nine of 11 patients (82 percent).
Seattle Genetics and Millennium: The Takeda Oncology Company have initiated a phase III clinical trial in advanced stage front-line HL patients. The randomized trial is comparing progression-free survival in patients receiving ADCETRIS in combination with AVD to patients receiving ABVD alone. For more information about the trial visit www.seattlegenetics.com or www.clinicaltrials.gov.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. ADCETRIS received accelerated approval from the U.S. Food and Drug Administration (FDA) in August 2011 for two indications: (1) the treatment of patients with Hodgkin lymphoma 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 systemic anaplastic large cell lymphoma (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 was granted conditional marketing authorization by the European Commission in October 2012 for the treatment of adult patients with relapsed or refractory CD30+ HL: (1) following autologous stem cell transplant (ASCT), or (2) following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option. ADCETRIS is indicated for the treatment of adult patients with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL). See important safety information below. 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.
About Hodgkin LymphomaLymphoma 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. 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. The U.S. Food and Drug Administration granted accelerated approval of ADCETRIS in August 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, Agensys (an affiliate of Astellas), Bayer, Celldex Therapeutics, Daiichi Sankyo, Genentech, GlaxoSmithKline, Millennium, Pfizer and Progenics, as well as ADC co-development agreements with Agensys and Genmab. More information can be found at www.seattlegenetics.com. U.S. Important Safety Information BOXED WARNING Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS. Contraindication: Concomitant use of ADCETRIS and bleomycin is contraindicated due to pulmonary toxicity. 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.
- Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed.
- Stevens-Johnson syndrome: Stevens-Johnson syndrome has been reported with ADCETRIS. If Stevens-Johnson syndrome occurs, discontinue ADCETRIS and administer appropriate medical therapy.
- Use in pregnancy: Fetal harm can occur. Pregnant women should be advised of the potential hazard to the fetus.
Drug Interactions:Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions. For additional important safety information, including Boxed WARNING, please see the full U.S. prescribing information for ADCETRIS at www.seattlegenetics.com or www.ADCETRIS.com . Certain of the statements made in this press release are forward looking, such as those, among others, relating to the therapeutic potential of ADCETRIS in the featured indication 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 the phase III trial 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, 2012 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.