Seattle Genetics, a biotechnology company focused on the development and commercialization of innovative antibody-based therapies for the treatment of cancer, has initiated a phase 1/2 clinical trial of brentuximab vedotin (Adcetris®) in combination with nivolumab (Opdivo®) for patients with relapsed or refractory Hodgkin lymphoma (HL) after failure of frontline treatment. The trial is being conducted as part of a clinical trial collaboration agreed between Bristol-Myers Squibb Company and Seattle Genetics.

A second trial under the collaboration is planned to begin later in 2015 for relapsed or refractory B-cell and T-cell non-Hodgkin lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL).

Lymphatic system
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). HL 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. NHL is further categorized into indolent (low-grade) or aggressive, including DLBCL. DLBCL is the most common type of non-Hodgkin lymphoma or NHL.

Antibody-drug Conjugate
Brentuximab vedotin is an antibody-drug conjugate or ADC directed to CD30, a defining marker of classical HL, which combines the targeting ability of a monoclonal antibody via a protease-cleavable linker to a highly potent, microtubule disrupting, cell-killing, agent called monomethyl auristatin E (MMAE). 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.

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Checkpoint inhibitors
Nivolumab is a human antibody that targets and inhibits the programmed death receptor-1 or PD-1, resulting in T-cell activation. The drug is part of a new class of cancer immunotherapy treatments known as immune checkpoint inhibitors, which are designed to harness the body’s own immune system in fighting cancer by targeting distinct regulatory components of the immune system.

Among the most exciting features of these immune checkpoint inhibitors is that they provide impressive tumor responses in metastatic cancers of different histologies.  Furthermore, the remarkable antitumor activity of these novel agents has generated an unprecedented wave of interest for immune checkpoint inhibitors in the field of oncology and hematology.  The potential of these compounds given alone or in combination with existing therapeutics is, according to a number of experts, enormous.

The strategy to harness the host’s immune system to fight cancer and hematological disorders has been a cornerstone of immunotherapy in oncology and hematology. This strategy has, with the emergence of immune checkpoint inhibitors, gained substantial momentum These agents block inhibitory receptors such as cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), programmed death receptor-1 (PD-1) and its ligand PD-L1, and thus liberate tumour-specific T cells to exert their effector function against tumor cells.

Combination therapy
“This is the first corporate-sponsored clinical trial to evaluate brentuximab vedotin combined with an immune checkpoint inhibitor to determine if the combination can improve patient outcomes,” noted Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development.

“The trial supports our strategy to establish brentuximab vedotin as the foundation of care for CD30-expressing malignancies, and to test novel combinations that could benefit patients. We are executing a broad clinical program with brentuximab vedotin to potentially expand into earlier lines of therapy and new indications, including the ECHELON-1 trial in frontline Hodgkin lymphoma, the ECHELON-2 trial in frontline mature T-cell lymphoma, the ALCANZA trial in cutaneous T-cell lymphoma and both ongoing and planned trials in diffuse large B-cell lymphoma,” Drachman further noted.

Trial design
The phase 1/2 open-label trial will enroll relapsed or refractory HL patients who have failed frontline therapy. The primary objective is to assess the safety and antitumor activity of brentuximab vedotin in combination with nivolumab. After completion of four cycles of combination therapy, patients are eligible to undergo autologous stem cell transplant (ASCT). Patients at high risk of relapse or progression following ASCT will be eligible to receive brentuximab vedotin in the commercial setting. All patients will be assessed for progression-free survival after ASCT. The trial is being conducted at multiple centers in the United States and is designed to enroll up to approximately 60 patients.

Brentuximab vedotin is not currently approved for the treatment of second-line, transplant eligible HL or for the treatment of NHL other than relapsed systemic anaplastic large cell lymphoma. Nivolumab is currently not approved for the treatment of lymphoma.