Date: 2015-12-08
Type of information: Initiation of the trial
phase: 1- 2
Announcement: initiation of the trial
Company: Celldex Therapeutics (USA - NJ)
Product: varlilumab and Tecentriq® (atezolizumab) (MPDL3280A)
Action
mechanism: immunotherapy product/monoclonal antibody/immune checkpoint inhibitor. Anti-PDL1 antibody MPDL3280A is an investigational monoclonal antibody designed to make cancer cells more vulnerable to the body’s immune system by interfering with a protein called PD-L1. PD-L1 is found on the surface of cells in tumours and is believed to act as a “stop sign,” preventing the immune system from destroying cancer cells. By inhibiting PD-L1, MPDL3280A may enable the activation of T cells, restoring their ability to effectively detect and attack tumour cells. MPDL3280A is being studied in clinical trials to understand whether blocking PD-L1 will help the immune system respond to cancer. In February 2015, MPDL3280A received Breakthrough Therapy from the FDA for the treatment of people whose NSCLC expresses PD-L1 and who progressed during or after standard treatments (e.g., platinum-based chemotherapy and appropriate targeted therapy for EGFR mutation-positive or ALK-positive disease). Roche’s Biologics Licence Application (BLA) for NSCLC was granted Priority Review with an action date of 19 October 2016. Roche has eight Phase III lung studies underway evaluating Tecentriq® alone or in combination with other treatments in patients with early and advanced stages of lung cancer. Varlilumab is a fully human monoclonal antibody that targets CD27, a critical molecule in the activation pathway of lymphocytes. 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. Preclinical data suggest the combination of these two mechanisms are synergistic and may enhance anti-tumor immune response compared to either agent alone. In Celldex's Phase 1 study of varlilumab in multiple solid tumors, promising signs of clinical activity in patients with refractory renal cell carcinoma were observed, including a durable partial response (11.0+ months) that has continued to decrease in tumor volume over time and prolonged stable disease (4 patients with a range of 5.3 to 30.7+ months).
Disease: unresectable stage III or IV renal cell carcinoma (RCC)unresectable stage III or IV melanoma, triple negative breast cancer, bladder cancer, head and neck cancer or non-small cell lung cancer (NSCLC)
Therapeutic area: Cancer - Oncology
Country: USA
Trial
details: This phase 1/2 study is to determine the clinical benefit (how well the drug works), safety and tolerability of combining varlilumab and atezolizumab. 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). 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. (NCT02543645)
Latest
news: * On December 8, 2015, Celldex Therapeutics announced the initiation of an open-label, Phase 1/2 safety and tolerability study examining the investigational combination of varlilumab and Roche's atezolizumab (MPDL3280A) in patients with unresectable stage III or IV renal cell carcinoma (RCC). Celldex previously announced the collaboration with Roche to evaluate the novel immunotherapy combination in March 2015 (See below). Varlilumab is designed to bind and activate 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. 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). 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. * On August 28, 2015, a Phase 1/2 trial sponsored by Celldex Therapeutics was published on the NIH website ClinicalTrials.gov for varlilumab and atezolizumab and is currently recruiting participants. * On March 17, 2015, Celldex Therapeutics announced that it has entered into a clinical trial collaboration with Roche to evaluate the safety, tolerability and preliminary efficacy of varlilumab, Celldex's CD27 targeting investigational antibody, and MPDL3280A (atezolizumab- anti-PDL1), Roche's investigational cancer immunotherapy in a Phase 1/2 study in renal cell carcinoma. Under the terms of this agreement, Roche will provide study drug and Celldex will be responsible for conducting and funding the study, which is expected to begin in 2015.
