Seattle Genetics, Inc. (Nasdaq:SGEN) today announced the initiation of a phase 2 clinical trial evaluating ADCETRIS (brentuximab vedotin) in combination with RCHOP (A+RCHOP), the current standard frontline therapy, for newly diagnosed patients with diffuse large B-cell lymphoma (DLBCL). The study is intended to evaluate the complete remission rate and safety of the A+RCHOP regimen. ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30. ADCETRIS is currently not approved for the treatment of DLBCL. “The encouraging data we have observed in our phase 2 trial of ADCETRIS in relapsed non-Hodgkin lymphoma, including DLBCL patients, support evaluation in earlier lines of therapy for patients with this aggressive lymphoma type,” said Clay B. Siegall., Ph.D., President and Chief Executive Officer at Seattle Genetics. “This trial will provide us with data on the tolerability of the combination, as well as the antitumor activity achieved by adding ADCETRIS to the current standard frontline regimen. In addition, based on interim findings from our trial in the relapsed setting in which objective responses were observed among patients with low or undetectable levels of CD30 by conventional screening methods, we will enroll high-risk DLBCL patients to this frontline trial without prescreening for CD30 expression.” In this phase 2, open-label clinical trial, approximately 50 frontline high-risk DLBCL patients will receive ADCETRIS in combination with the standard of care consisting of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (A+RCHOP). Patients will be randomized to receive standard dose RCHOP with either 1.2 milligrams per kilogram (mg/kg) or 1.8 mg/kg of ADCETRIS. The trial will enroll patients regardless of CD30 expression level by immunohistochemistry (IHC) to further explore previously reported interim data from an ongoing phase 2 trial for relapsed B-cell lymphomas, including DLBCL, demonstrating objective responses in patients with varying levels of CD30. The primary endpoints are to assess the complete remission rate and safety profile of the combination. Secondary endpoints include objective response rate, progression-free survival and overall survival.
At the International Conference on Malignant Lymphoma in June 2013, data were presented from an ongoing phase 2 trial for relapsed B-cell lymphomas that included 44 relapsed patients who received single-agent ADCETRIS, including 25 with DLBCL. Among DLBCL patients, the objective response rate was 44 percent (11 of 25), including 20 percent complete remissions and 24 percent partial remissions. Eighty-one percent of patients achieved tumor reduction. Among 44 B-cell lymphoma patients enrolled, the most common treatment-emergent adverse events were neutropenia (43 percent), fatigue (36 percent), nausea (34 percent) and diarrhea (32 percent). The most common Grade 3 or 4 adverse events were neutropenia (25 percent Grade 3; 11 percent Grade 4) and anemia (9 percent Grade 3).More information about the ongoing phase 2 frontline or relapsed DLBCL trials, including enrolling centers, is available by visiting www.clinicaltrials.gov. About Diffuse Large B-Cell 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. Non-Hodgkin lymphoma (NHL) represents a diverse group of cancers that develop in the lymphatic system and are characterized by uncontrolled growth and accumulation of abnormal lymphocytes. Lymphocytes are a type of white blood cells that are responsible for defending the body against infection. The most common forms of NHL are follicular (slow growth) and diffuse large B-cell lymphoma (a faster growing sub-type). 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 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
- Phase 1 / 2 trial in combination with bendamustine for first relapse HL
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 treating patients with DLBCL. 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 this clinical trial for DLBCL and the risk of adverse events as ADCETRIS advances in this and other 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 June 30, 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.