Based on encouraging data in patients with CD30-expressing relapsed or refractory diffuse large B-cell lymphoma or DLBCL, the most common type of aggressive non-Hodgkin Lymphoma (NHL), Seattle Genetics announced the initiation of a randomized phase II clinical trial of rituximab (Rituxan®; Genentech) and bendamustine* with or without brentuximab vedotin (Adcetris®).
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 (HL) and non-Hodgkin lymphoma (NHL). Non-Hodgkin lymphoma 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 blood cells that are responsible for defending the body against infection. The most common forms of non-Hodgkin lymphoma are diffuse large B-cell lymphoma (an aggressive subtype) and follicular lymphoma (an indolent subtype).
Study goals
The initiated study is intended to evaluate the activity and safety of the combination regimen of rituximab and bendamustine with or without brentuximab vedotin. Overall, brentuximab vedotin is being evaluated in more than 30 ongoing clinical trials, including the phase III Alcanza-trial and two additional phase III 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.
Brentuximab vedotin is an antibody-drug conjugate or ADC in which the monoclonal antibody cAC10 is directed to CD30, a protein found on the surface of certain types of cells, attached by a highly stable valine-citrulline protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary technology. The antibody-drug conjugate employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells. CD30 is expressed in several types of non-Hodgkin lymphoma, including at least 25% of patients with DLBCL.
Approval
Brentuximab vedotin for intravenous injection is currently not approved for the treatment of DLBCL, but has received approval from U.S. Food and Drug Administration (FDA) 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. The FDA has also granted approval for the treatment of classical HL patients at high risk of relapse or progression as post-auto-HSCT consolidation, and 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.
Building on single-agent activity
Diffuse large B-cell lymphoma, or DLBCL, is the most common type of aggressive non-Hodgkin lymphoma. DLBCL patients who relapse following initial treatment often receive salvage therapy sometimes followed by an autologous stem cell transplant, after which most patients will eventually relapse,” noted Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics (Photo 1.0). “This trial is designed to build on the single-agent activity we have observed with brentuximab vedotin in CD30-expressing DLBCL, including both relapsed and refractory status. Our goal is to improve long-term outcomes for relapsed and refractory DLBCL patients who express CD30 at detectable levels by combining brentuximab vedotin with rituximab and bendamustine, two agents that are commonly used in this disease setting.”
Trial design
In this phase II randomized, open-label, multi-center clinical trial, approximately 110 relapsed/refractory CD30-expressing DLBCL patients will receive rituximab and bendamustine either with or without brentuximab vedotin every three weeks for six cycles. Patients in the brentuximab vedotin combination arm who respond to treatment with a manageable safety profile may continue to receive single-agent brentuximab vedotin treatment for up to 10 additional cycles. The primary endpoint is to compare the objective response rates between the two study arms. Secondary endpoints include progression-free survival, complete remission rate, duration of response and overall survival. The study is being conducted at approximately 50 sites across North America and Europe.
At the 13th International Conference on Malignant Lymphoma (ICML), June 17-20, 2015, Lugano, Switzerland, data were presented from an ongoing phase II trial for relapsed/refractory CD30-positive non-Hodgkin lymphoma that included DLBCL patients who received single-agent brentuximab vedotin or in combination with rituximab every three weeks.
Of the 48 patients treated in the single-agent arm, the objective response rate was 44%, including 19% complete remissions and 25% partial remissions. Of the 13 patients treated in the combination arm, the objective response rate was 46%, including 15% complete remissions and 31% partial remissions. The most common treatment-emergent adverse events of any grade occurring in more than 15% of all patients enrolled were fatigue, nausea, neutropenia, diarrhea, peripheral sensory neuropathy, fever and vomiting. The most common treatment-emergent adverse event Grade 3 or higher was neutropenia.[1]
Additional trials: Newly diagnosed DLBCL
In a separate, ongoing, phase II trial, Seattle Genetics is evaluating brentuximab vedotin in combination with RCHP (rituximab, cyclophosphamide, doxorubicin and prednisone) in newly diagnosed DLBCL patients.
* Bendamustine (INN) trade names include Treakisym®/Symbenda® (Eisai Co. Ltd) , Ribomustin® (Janssen Pharmaceuticals), Levact® (MundiPharma), and Treanda® (Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd.); also known as SDX-105)
