Seattle Genetics, Inc. and Bristol-Myers Squibb announced that the companies have initiated a phase 1/2 clinical trial of Adcetris (brentuximab vedotin) in combination with Opdivo (nivolumab) for patients with CD30-expressing relapsed or refractory B-cell and T-cell non-Hodgkin lymphomas (NHL), including diffuse large B-cell lymphoma (DLBCL), peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL).

This is the second of two trials being conducted under a previously announced clinical trial collaboration agreement between Bristol-Myers Squibb Company and Seattle Genetics. Adcetris is an antibody-drug conjugate (ADC) directed to CD30, a marker expressed on Hodgkin lymphoma (HL) and several types of NHL, which combines the targeting ability of a monoclonal antibody with a highly potent cell-killing agent. Recent preclinical data suggest that Adcetris causes immunogenic cell death of tumour cells, providing rationale for combination with Opdivo, a human antibody that targets and inhibits the programmed death receptor-1 (PD-1), resulting in T-cell activation. Opdivo is part of a new class of cancer immunotherapy treatments known as 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.

“This is the second corporate-sponsored clinical trial to evaluate Adcetris combined with a checkpoint inhibitor to determine if the combination can improve patient outcomes,” said Jonathan Drachman , M.D., chief medical officer and executive vice president, research and development at Seattle Genetics. “This study is a part of a broad development programme that includes more than 70 ongoing clinical trials evaluating Adcetris in multiple lines of therapy for Hodgkin and non-Hodgkin lymphoma and as part of novel combinations that could result in improved clinical benefit with manageable safety profiles. Our goal is to establish Adcetris as the foundation of care for CD30-expressing lymphomas.”

The phase 1/2 open-label, multi-center, clinical trial is designed to evaluate the safety, tolerability and antitumour activity of Adcetris in combination with Opdivo in patients with relapsed or refractory CD30-expressing NHL. The study will consist of a phase 1 dose evaluation portion followed by a single-arm phase 2 portion that will expand enrollment to treat disease-specific cohorts with relapsed or refractory DLBCL, PTCL or CTCL at the recommended dose level and treatment schedule. The primary endpoints are safety, tolerability and objective response rate of the combination of Adcetris with Opdivo. The secondary endpoints include duration of response, complete response rate with the combination regimen, duration of complete response, progression-free survival and overall survival. The trial is being conducted at multiple centres in the United States, Canada and Europe and is designed to enroll approximately 120 patients.

“Bristol-Myers Squibb continues to strengthen its industry-leading development program for Opdivo and its rapidly expanding hematology portfolio,” said Michael Giordano , senior vice president, head of development, oncology, Bristol-Myers Squibb . “We are pleased to collaborate with Seattle Genetics on clinical research that focuses on novel combination regimens in areas of serious unmet need.”

In addition to the two ongoing Opdivo combination trials under the collaboration with Bristol-Myers Squibb, Adcetris is being evaluated in more than 70 ongoing clinical trials including the ECHELON-1 phase 3 trial in frontline HL, the ECHELON-2 phase 3 trial in frontline mature T-cell lymphoma and the ALCANZA phase 3 trial in CTCL. Opdivo is being evaluated either as monotherapy or in combination with other therapies in some of the hardest-to-treat hematologic cancers, including multiple myeloma, chronic myelogenous leukemia, and Hodgkin and non-Hodgkin lymphomas including follicular and DLBCL. Opdivo has Breakthrough Therapy designation for the treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant and brentuximab vedotin.

Adcetris is not currently approved for frontline treatment or for the treatment of NHL other than relapsed systemic anaplastic large cell lymphoma (sALCL). Opdivo is not currently approved for the treatment of lymphoma.

Adcetris 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. CD30 is a member of the tumour necrosis factor receptor (TNFR) superfamily. In HL, CD30 may be involved in tumour cell proliferation by interacting with immune cells in the tumour microenvironment.

Adcetris for intravenous injection has received approval from the FDA for three indications: (1) regular approval 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, (2) regular approval for the treatment of classical HL patients at high risk of relapse or progression as post-auto-HSCT consolidation, and (3) 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. Continued approval for the sALCL indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Health Canada granted ADCETRIS approval with conditions for relapsed or refractory HL and sALCL.

Adcetris was granted conditional marketing authorisation by the European Commission in October 2012 for two indications: (1) for the treatment of adult patients with relapsed or refractory CD30-positive HL following autologous stem cell transplant (ASCT), or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, and (2) the treatment of adult patients with relapsed or refractory sALCL. ADCETRIS has received marketing authorisation by regulatory authorities in more than 55 countries. See important safety information below.

Seattle Genetics and Takeda Pharmaceutical Company Limited (Takeda) are jointly developing Adcetris. Under the terms of the collaboration agreement, Seattle Genetics has US and Canadian commercialisation rights and Takeda has rights to commercialise Adcetris in the rest of the world. Seattle Genetics and Takeda are funding joint development costs for Adcetris on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.

Bristol-Myers Squibb has a broad, global development programme to study Opdivo in multiple tumour types consisting of more than 50 trials – as monotherapy or in combination with other therapies – in which more than 8,000 patients have been enrolled worldwide. Opdivo is the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world in July 2014, and currently has regulatory approval in more than 40 countries including the United States, Japan, and in the European Union.

Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: HL and 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 categorised into indolent (low-grade) or aggressive, including DLBCL. DLBCL is the most common type of NHL.