Patient Enrollment in Phase III ECHELON-2 Clinical Trial of Brentuximab Vedotin in Frontline Mature T-cell Lymphoma Completed

This week, Seattle Genetics and Takeda Pharmaceutical Co. confirmed that enrollment in the ECHELON-2 clinical trial, a global phase III randomized trial evaluating brentuximab vedotin (Adcetris®) as part of a frontline combination chemotherapy regimen in patients with previously untreated CD30-positive mature T-cell lymphoma (MTCL) has been completed.

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 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 (WHO) identifies 22 subtypes of mature T- and NK-cell neoplasms, including systemic anaplastic large cell lymphoma (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.


“… The Goal is… to establish brentuximab vedotin as the foundation of care for CD30-expressing lymphomas and redefine frontline treatment in Hodgkin lymphoma and MTCL through… a broad, late-stage clinical development program currently underway. The ECHELON-2 clinical trial represents our fourth phase III study to complete enrollment”


Antibody-drug Conjugate
Brentuximab vedotin is an antibody-drug conjugate or ADC directed to CD30, which is expressed on several types of non-Hodgkin lymphoma, including subsets of MTCL, as well as Hodgkin lymphoma. The drug is currently not approved for the frontline treatment of MTCL.

ADC Bio
MabPlex
Lonza
 

The agent includes an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to monomethyl auristatin E (MMAE), a microtubule disrupting agent, 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.

Brentuximab vedotin is being evaluated broadly in more than 70 ongoing clinical trials, including two phase III studies, ECHELON-1 in frontline classical Hodgkin lymphoma and ECHELON-2 in frontline mature T-cell lymphomas, as well as trials in many additional types of CD30-expressing malignancies, including B-cell lymphomas.

The ECHELON-2 trial is a double-blind, placebo-controlled global phase III trial is investigating brentuximab vedotin plus CHP versus CHOP as frontline therapy in patients with CD30-positive MTCL. The primary endpoint is progression-free survival per independent review facility assessment using the Cheson 2007 Revised Response Criteria for Malignant Lymphoma. Secondary endpoints include overall survival, complete remission rate and safety.

Why important
The unmet need in T-cell lymphoma is quite significant. CD30-positive mature T-cell lymphoma (MTCL) is a generally aggressive form of non-Hodgkin lymphoma that is currently underserved by existing chemotherapy regimens. The goal of Seattle Genetics’ ECHELON clinical program is to redefine the frontline standard of care for mature T-cell lymphomas, so that brentuximab vedotin is hopefully part of the regimen called A plus CHP.

Brentuximab vedotin is proving to be an important addition to clinicians’ current arsenal of therapies. Since the approval of the agent in the U.S. five years ago, more than 30,000 lymphoma patients have been treated worldwide, with meaningful impacts on patient outcomes. The ECHELON-2 clinical trial is the company’s fourth phase III trial to complete enrollment.

The trial represents a key component of late-stage clinical development strategy to establish brentuximab vedotin as foundation of care for CD30-expressing lymphomas. Study results from the trial  are expected in late 2017 or early 2018.

Trial design
Patients in ECHELON-2 were randomized to receive a novel combination regimen consisting of brentuximab vedotin plus cyclophosphamide (C), doxorubicin (H) and prednisone (P), referred to as A+CHP, versus cyclophosphamide, doxorubicin, vincristine (O) and prednisone, referred to as CHOP, the recognized standard of care treatment regimen for frontline MTCL. The trial enrolled 452 patients. The ECHELON-2 trial is being conducted under a Special Protocol Assessment (SPA) agreement from the U.S. Food and Drug Administration (FDA) and the trial also received European Medicines Agency (EMA) scientific advice.

NCT01777152 (ECHELON-2) (CLINICAL TRIAL / BRENTUXIMAB VEDOTIN / SGN-035 / ADCETRIS®)
Figure 1.0: ECHELON-2 (NCT01777152) is a Clinical Trial designed to establish brentuximab vedotin (Adcetris®) as the foundation of care for CD30-expressing lymphomas and redefine frontline treatment in Hodgkin lymphoma and mature T-cell lymphoma (MTCL), a generally aggressive form of non-Hodgkin lymphoma that is currently underserved by existing chemotherapy regimens. © Sunvalley Communication. Used with permission.

Foundation of care
“Our goal is to establish brentuximab vedotin as the foundation of care for CD30-expressing lymphomas and redefine frontline treatment in Hodgkin lymphoma and MTCL through our broad, late-stage clinical development program currently underway. The ECHELON-2 clinical trial represents our fourth phase III study to complete enrollment,” noted Naomi Hunder, M.D., Vice President, Clinical Development at Seattle Genetics.

“We look forward to the results of the ECHELON-2 frontline MTCL study in the 2017 to 2018 timeframe and expect to refine the timeline in the future. The ultimate goal of this phase III trial is to improve outcomes for frontline patients with CD30-expressing MTCL and, if the trial results are positive, to submit data from this trial to regulatory agencies to expand the label for brentuximab vedotin use in the frontline setting,” Hunder added.

Changing the standard of care
“Mature T-cell lymphoma is a rare, aggressive type of cancer in which the standard of care chemotherapy regimen has not changed in decades,” explained Dirk Huebner, M.D., Executive Medical Director, Oncology Therapeutic Area Unit, Takeda Pharmaceutical Company.

“Achieving target enrollment represents a key milestone for ECHELON-2 as we evaluate the efficacy and safety of brentuximab vedotin in newly diagnosed mature T-cell lymphoma patients, and to our ultimate goal of bringing important new therapies to patients with CD30-positive malignancies,” Huebner added.

American Society of Hematology
Data from a phase I trial evaluating brentuximab vedotin plus CHP in MTCL were previously presented at the American Society of Hematology (ASH) Annual Meetings in 2012 and 2015.  An analysis of these results demonstrated that 26 of 26 patients (100%) achieved an objective response (OR), including 23 (88%) with a complete remission (CR) and three patients (12%) with a partial remission (PR).

Long-term follow-up data estimated the three-year overall survival was 80% and three-year progression-free survival was 52%, with no patients receiving a consolidative stem cell transplant in first remission. Three-year overall survival and progression-free survival rates of less than 40% and 30%, respectively, have previously been reported for patients in this setting treated with CHOP [1][2] .

The most common adverse events of any grade occurring in more than 30% of patients in this phase I trial were peripheral sensory neuropathy, diarrhea, fatigue and hair loss. Additional four-year follow-up data from this trial will be presented in a poster presentation at the 2016 ASH Annual Meeting in December.