Seattle Genetics Highlights ADCETRIS® (Brentuximab Vedotin) Frontline HL and MTCL Clinical Developme
Seattle Genetics Highlights ADCETRIS®(Brentuximab Vedotin) Frontline HL and MTCL Clinical Development Programs and Antibody-Drug Conjugate (ADC) Collaborator Data at ASCO Annual Meeting
-ADCETRIS Phase 3 ECHELON-1 and ECHELON-2 Trials Designed to Redefine Standard of Care for Frontline Treatment of HL and MTCL-
-Genentech Presents Encouraging Phase 1 Data from Two ADC Candidates Utilizing Seattle Genetics' Technology-
CHICAGO--(BUSINESS WIRE)-- Seattle Genetics, Inc. (NAS: SGEN) today highlighted ongoing clinical development programs for ADCETRIS (brentuximab vedotin) in frontline Hodgkin lymphoma (HL) and mature T-cell lymphoma (MTCL) and progress with collaborator antibody-drug conjugate (ADC) programs that were presented at the 49th Annual Meeting of the American Society of Clinical Oncology being held May 31 - June 4, 2013, in Chicago, IL. The phase 3 clinical trials, called ECHELON-1 and ECHELON-2, are evaluating ADCETRIS for the frontline treatment of HL and MTCL, including patients with systemic anaplastic large cell lymphoma (sALCL) and other types of peripheral T-cell lymphoma. ADCETRIS is an ADC directed to CD30, a defining marker of HL and sALCL, which was granted accelerated approval by the FDA in August 2011 for relapsed HL and relapsed sALCL. In addition, encouraging phase 1 data were presented from two ADC clinical programs being developed by Genentech, a member of the Roche Group (SWX:RO) (SWX:ROG)(OTCQX:RHHBY), using Seattle Genetics technology.
"ADCs represent an innovative and growing field in the fight against cancer, which is evident by the interest in this therapeutic approach at the ASCO annual meeting," said Clay B. Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. "As the first ADC to be approved by the FDA in this new class, we are focused on broadening the evaluation of ADCETRIS in earlier lines of therapy with our ongoing ECHELON-1 and ECHELON-2 global phase 3 trials, which are designed to redefine the standard of care for frontline treatment of HL and MTCL. While we advance our internal programs, our collaborators are making important progress utilizing our ADC technology. Notably, Genentech is presenting encouraging phase 1 data for two ADC candidates in solid tumor settings."
Seattle Genetics is the leader in developing ADCs, a technology designed to harness the targeting ability of antibodies to deliver cell-killing agents directly to cancer cells. Of the approximately 30 ADC candidates currently in development, more than half utilize Seattle Genetics' proprietary ADC technology.
Phase III Trial of Brentuximab Vedotin Plus Doxorubicin, Vinblastine, and Dacarbazine (A+AVD) Versus Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine (ABVD) as Front-line Treatment for Advanced Classical Hodgkin Lymphoma (HL) (Abstract #TPS8612)
Recent phase 1 data presented at the 2012 American Society of Hematology (ASH) Annual Meeting demonstrated that A+AVD, which removes bleomycin from the standard frontline ABVD regimen, was associated with a manageable safety profile and a complete remission (CR) rate of 96 percent in the treatment of newly diagnosed HL patients. A global phase 3 study, called ECHELON-1, is an ongoing open-label, randomized, multi-center trial designed to investigate A+AVD versus ABVD as frontline therapy in patients with advanced classical HL. The primary endpoint is modified progression free survival (mPFS) per independent review facility assessment using the Revised Response Criteria for malignant lymphoma (Cheson, 2007). Secondary endpoints include overall survival (OS), CR rate and safety. The trial is being conducted in North America, Europe, Latin America and Asia. The study will enroll approximately 1,040 eligible patients (approximately 520 patients per treatment arm) who have histologically-confirmed diagnosis of Stage III or IV classical HL and who have not been previously treated with systemic chemotherapy or radiotherapy.
Phase III Trial of Brentuximab Vedotin and CHP Versus CHOP in the Frontline Treatment of Patients with CD30+ Mature T-Cell Lymphomas (MTCL) (Abstract #TPS8611)
Recent phase 1 data presented at the 2012 ASH Annual Meeting demonstrated that ADCETRIS in combination with cyclophosphamide, doxorubicin and prednisone (A+CHP) in the frontline treatment of MTCL was associated with a manageable safety profile and 100 percent objective response rate, including 88 percent CRs. A global phase 3 study, called ECHELON-2, is an ongoing randomized, double-blind, placebo-controlled, multi-center trial designed to investigate A+CHP versus cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) as frontline therapy in patients with CD30-expressing MTCL. Approximately 300 patients (approximately 150 patients per treatment arm) will be randomized to receive A+CHP or CHOP for six to eight cycles every three weeks. The primary endpoint is progression-free survival (PFS) per independent review facility assessment using the Revised Response Criteria for malignant lymphoma. Secondary endpoints include OS, CR rate and safety. The trial is being conducted in North America, Europe and Asia.
ADCETRIS is currently not approved for frontline treatment of HL and MTCL. For more information about ECHELON-1 and ECHELON-2, visit www.clinicaltrials.gov.
A Phase I Study of the Safety and Pharmacokinetics of DNIB0600A, an Anti-Napi2b-vc-MMAE Drug Conjugate, in Patients with Non-Small Cell Lung Cancer (NSCLC) and Platinum-Resistant Ovarian Cancer (OC) (Abstract #2507)
A phase 1 clinical trial is being conducted by Genentech to evaluate the safety and activity of DNIB0600A (RG7599) in patients with non-small cell lung cancer (NSCLC) or ovarian cancer (OC). DNIB0600A is an ADC consisting of an anti-NaPi2b monoclonal antibody conjugated to the cytotoxic agent MMAE using Seattle Genetics' ADC technology. In this analysis, 46 patients were evaluable (30 OC, 16 NSCLC), with 30 patients (14 OC, 16 NSCLC) in the dose-escalation cohorts and 16 patients (all OC) in the dose expansion cohort.
Key findings presented in an oral presentation included:
- Patients enrolled in the study were diagnosed with non-squamous NSCLC or non-mucinous platinum-resistant OC. All patients had non-curable, locally advanced or metastatic disease and were heavily pretreated, with a median of four (NSCLC) or five (OC) prior systemic therapies. The median age of patients enrolled was 60.
- Patients received a median of three doses ranging from 0.2 milligrams per kilogram (mg/kg) to 2.8 mg/kg on an every three week basis. A dose of 2.4 mg/kg was selected for the dose expansion cohort and determined to be the recommended phase 2 dose.
- Among the 18 patients with OC treated at dose levels 1.8 to 2.4 mg/kg with IHC staining scores of 2+ or 3+, five patients (27 percent) had confirmed objective responses. In addition, one patient with NSCLC dosed at 1.8 mg/kg experienced a confirmed partial response.
- Most adverse events were Grade 1 and 2. The most frequent adverse events at the recommended 2.4 mg/kg dose included fatigue, nausea, vomiting, headache and peripheral neuropathy. Peripheral neuropathy was manageable with dose delays and/or reductions in most patients.
A Phase I Study of the Safety and Pharmacokinetics of DSTP3086S, an Anti-STEAP1 Antibody-Drug Conjugate (ADC), in Patients with Metastatic Castration-Resistant Prostate Cancer (CRPC) (Abstract #5020)
A phase 1 clinical trial is being conducted by Genentech to evaluate the safety and activity of DSTP3086S (RG7450) in patients with metastatic castrate-resistant prostate cancer (CRPC). DSTP3086S is an ADC candidate consisting of an anti-STEAP1 monoclonal antibody conjugated to the cytotoxic agent MMAE using Seattle Genetics' ADC technology. In this analysis, 28 patients were evaluable from the dose-escalation portion of this ongoing trial.
Key findings included:
- All patients had metastatic CRPC and were heavily pretreated, with a median of two prior non-hormonal systemic regimens and four hormonal systemic therapies in addition to either docetaxel or cabazitaxel chemotherapy. The median age of patients enrolled was 65.
- Patients received doses ranging from 0.3 mg/kg to 2.8 mg/kg on an every three week basis. A dose of 2.8 mg/kg was selected as the recommended dose for the expansion cohort, which is currently ongoing.
- Antitumor activity was observed in the dose escalation cohorts, including two patients who experienced a partial response in the 2.8 mg/kg cohort. Additional patients across the dose-escalation cohorts experienced prolonged stable disease.
- The most common adverse events occurring in more than 10 percent of patients were fatigue, nausea, constipation, decreased appetite, diarrhea and vomiting. Most adverse events were Grade 1 or 2, and the majority did not require intervention.
The phase 1 trials evaluating both DNIB0600A and DSTP3086S are ongoing. For more information, visit www.clinicaltrials.gov.
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 was granted accelerated approval by the FDA in August 2011 and approval with conditions by Health Canada in February 2013 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 was granted conditional marketing authorization by the European Commission in October 2012 for the treatment of adult patients with relapsed or refractory CD30+ Hodgkin lymphoma (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 sALCL. See important safety information below.
ADCETRIS is being evaluated in more than 20 ongoing clinical trials across both corporate and investigator-sponsored studies. The trials are designed to broadly evaluate the potential of ADCETRIS in earlier lines of its approved indications as well as in many additional types of CD30-positive malignancies, including cutaneous T-cell lymphoma (CTCL), B-cell lymphomas and mature T-cell lymphomas (MTCL). For more information, visit www.clinicaltrials.gov. The clinical trials include:
- ALCANZA, a phase 3 trial in relapsed CD30-positive CTCL
- ECHELON-1, a phase 3 frontline trial in HL
- ECHELON-2, a phase 3 frontline trial in MTCL
- Phase 2 trial for relapsed or refractory CD30-positive non-Hodgkin lymphomas
- Phase 2 trial for frontline HL in patients age 60 and older
- Phase 2 trial for CD30-positive non-lymphoma malignancies
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 is solely responsible for development costs.
About Hodgkin and Non-Hodgkin Lymphomas
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. Non-Hodgkin lymphomas are broadly divided into two major groups: B-cell lymphomas, which develop from abnormal B-lymphocytes, and T-cell lymphomas, which develop from abnormal T-lymphocytes. The World Health Organization identifies 22 subtypes of mature T- and NK-cell neoplasms, including systemic ALCL which is an aggressive type of T-cell non-Hodgkin lymphoma that expresses CD30. Other mature T-cell lymphomas include peripheral T-cell lymphoma (PTCL), angioimmunoblastic T-cell lymphoma and adult T-cell lymphoma.
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 company's lead program, ADCETRIS (brentuximab vedotin), received accelerated approval from the U.S. Food and Drug Administration in August 2011 and approval with conditions from Health Canada in February 2013 for two indications. In addition, under a collaboration with Millennium: The Takeda Oncology Company, ADCETRIS received conditional approval from the European Commission in October 2012. Seattle Genetics also has four other clinical-stage ADC programs: SGN-75, ASG-5ME, ASG-22ME and SGN-CD19A. Seattle Genetics has collaborations for its ADC technology with a number of leading biotechnology and pharmaceutical companies, including AbbVie, Agensys (an affiliate of Astellas), Bayer, Celldex, 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
Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS.
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.
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.
Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions.
Certain of the statements made in this press release are forward looking, such as those, among others, relating to the company's ongoing clinical trials. Factors that may cause such a difference include that adverse events may occur that require modification or discontinuation of clinical trials. More information about the risks and uncertainties faced by Seattle Genetics is contained in the company's 10-Q for the quarter ended March 31, 2013 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.
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