Celldex previously announced the collaboration with Roche to evaluate the novel immunotherapy combination in March 2015.
Under the terms of the agreement, Roche will provide atezolizumab, and Celldex will be responsible for conducting and funding the study. Varlilumab is currently being studied in five Phase 1/2 combination studies.
Varlilumab is Celldex’s fully human monoclonal agonist antibody that binds and activates CD27, a critical co-stimulatory molecule in the immune activation cascade. Atezolizumab is designed to target PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, preventing PD-L1 from binding to PD-1 and B7.1 on anti-tumor T cells.
By inhibiting PD-L1, atezolizumab may enable the activation of anti-tumor T cells. These two antibodies are part of a new class of investigational medicines known as cancer immunotherapies. They are designed to harness the body’s own immune system to fight cancer through separate yet complementary mechanisms of action that may enable the activation of T cells, restoring their ability to effectively detect and attack tumor cells.
Data from multiple preclinical tumor models suggest the combination of these two mechanisms are synergistic and enhance anti-tumor immune response compared to either agent alone.
Also, in a Phase 1 study of varlilumab in multiple solid tumors, promising signs of clinical activity in patients with refractory RCC were observed, including a durable partial response (duration of response = 13.6+ months) that continued to decrease in tumor volume over time and prolonged stable disease (four patients with a range of 5.3 to 36.2+ months).
Celldex Therapeutics executive vice president and chief medical officer Thomas Davis said: "Together, preclinical and clinical data suggest that combining varlilumab and atezolizumab may enhance anti-tumor immune responses compared to monotherapy.
"Varlilumab is an attractive candidate for combination immunotherapy across a variety of cancers due to its target’s restricted expression and strong activity in a variety of tumor models, as well as positive data and a favorable safety profile from our Phase 1 study."
Study Design
Phase 1 study portion
The Phase 1, dose-escalation portion of the study will assess the safety and tolerability of varlilumab at 0.3, 1.0 and 3.0 mg/kg combined with atezolizumab at 1200 mg in order to identify a recommended dose for the Phase 2 portion of the study. The Phase 1 portion will enroll patients with unresectable stage III or IV melanoma, RCC, triple negative breast cancer, bladder cancer, head and neck cancer or non-small cell lung cancer (NSCLC).
Phase 2 study portion
The Phase 2 portion of the study will enroll patients with RCC. The primary objective of this portion of the study is to assess the preliminary anti-tumor efficacy of the varlilumab/atezolizumab combination measured by objective response rate (ORR). Secondary objectives include safety and tolerability, pharmacokinetics, immunogenicity and further assessment of anti-tumor activity across a broad range of endpoints.
In total, the Phase 1/2 study is anticipated to include up to 10 sites in the United States and enroll approximately 60 patients. In each 12-week cycle for both phases of the trial, varlilumab and atezolizumab will be administered once every three weeks (four doses). Patients will be treated with varlilumab until intolerance, disease progression or completion of up to 4 cycles. There is no limit on the duration of treatment with atezolizumab.
About Varlilumab
Varlilumab is a fully human monoclonal agonist antibody that binds and activates CD27, a critical co-stimulatory molecule in the immune activation cascade. CD27 can be effectively manipulated with activating antibodies to induce potent anti-tumor responses and may result in fewer toxicities due to its restricted expression and regulation. Varlilumab is a potent anti-CD27 agonist that induces activation and proliferation of human T cells when combined with T cell receptor stimulation.
In lymphoid malignancies that express CD27 at high levels, varlilumab may have an additional mechanism of action through a direct anti-tumor effect. Varlilumab has completed a Phase 1 dose-escalation study, demonstrating potent immunologic activity consistent with its mechanism of action and anti-tumor activity in patients with advanced, refractory disease.
No maximum tolerated dose was reached and minimal toxicities were observed. Celldex has initiated a broad development program for varlilumab to explore its role as an immune activator in combination with a number of complementary investigational and approved oncology drugs.