Date: 2016-04-18
Type of
information: Presentation of results at a congress
phase: 1-2a
Announcement: presentation of results at the American Association for Cancer Research (AACR) Annual Meeting 2016 in New Orleans.
Company: Celldex Therapeutics (USA - NJ) BMS (USA - NY)
Product: varlilumab and Opdivo® (nivolumab)
Action
mechanism:
- monoclonal antibody/immune checkpoint inhibitor. 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.
- Nivolumab is a PD-1 blocking antibody indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following Yervoy (ipilimumab) and, if BRAF V600 mutation positive, a BRAF inhibitor.
Disease: advanced non-small cell lung cancer (NSCLC), metastatic melanoma (MEL), colorectal cancer (CRC), ovarian cancer, and head and neck squamous cell carcinoma (SCCHN)
Therapeutic
area: Cancer - Oncology
Country: USA
Trial
details:
- The Phase 1 dose-escalation portion of the study will assess the safety and tolerability of varlilumab at doses ranging from 0.1 to 10 mg/kg when administered with Opdivo (3mg/kg). Following dose escalation, a Phase 2 portion of the study will include 5 disease specific cohorts, with either 18 (CRC, SCCHN, ovarian) or 35 (NSCLC and MEL) patients in each cohort. 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 Opdivo. The primary objective of the Phase 2 study is overall response rate. Secondary objectives include pharmacokinetics assessments, determining the immunogenicity of varlilumab when given in combination with Opdivo and further assessing the anti-tumor activity of combination treatment, including duration of response, time to response, progression-free survival and overall survival.
Latest
news:
- • On April 18, 2016, Celldex Therapeutics announced new safety and immune response data from the Phase 1 portion of a Phase 1/2 dose escalation and cohort expansion study examining the investigational combination of varlilumab, Celldex's CD27 targeting investigational immune-activating antibody, and BMS's anti-PD-1 immunotherapy Opdivo® (nivolumab). The data were presented in a poster at the American Association for Cancer Research (AACR) Annual Meeting 2016 in New Orleans. The Phase 1 portion of the study, conducted in patients with solid tumors, has completed enrollment (n=36) and primarily enrolled patients with colorectal (n=20) and ovarian cancer (n=8). The primary objective of the Phase 1 portion of the study was to evaluate the safety and tolerability of the combination. The Phase 2 portion of the study is open to enrollment.
- Key Highlights: Combining the potent immune activator, varlilumab, with the PD-1 inhibitor, nivolumab, showed acceptable tolerability and safety across all dose levels without any evidence of increased autoimmunity or inappropriate immune activation.
Combination therapy led to marked changes in the tumor microenvironment including increased infiltrating CD8+ T cells and increased PD-L1 expression, which have been shown to correlate with a greater magnitude of treatment effect from checkpoint inhibitors in other clinical studies.
Additional favorable immune biomarkers, such as increase in inflammatory chemokines and decrease in T regulatory cells, were also noted.
In a subset of patients (n=17) on study who had both pre- and post-tumor biopsies available, preliminary evidence suggest a correlation between biomarker data and stable disease or better in seven of these patients (4 ovarian cancer, 2 colorectal cancer, 1 squamous cell carcinoma of the head and neck).
- The safety profile of the varlilumab and nivolumab combination has been consistent with that of each agent individually, and no unexpected toxicities have been observed. The most frequent treatment related adverse events, occurring in more than 10% of patients, were fatigue (25.7%), lymphopenia (20%), nausea (20%), chills (17.1%), arthralgia (14.3%), pruritus (14.3%) and rash (11.4%), the majority of which were grade 1 or 2. Two patients experienced drug-related serious adverse events. In the 10 mg/kg cohort, grade 4 hepatitis and grade 3 renal insufficiency was observed in a patient with ovarian cancer. Also in the 10 mg/kg cohort, grade 2 paresthesia (tingling/numbness) was observed in a patient with colorectal cancer.
- Biomarker data from all varlilumab dose levels indicate increases in inflammatory chemokines and decreases in circulating T regulatory cells, which is generally consistent with varlilumab monotherapy. Importantly, in tissue biopsies from patients, the authors noted, where pre-treatment and on-study specimens were available (n=17), a marked increase of tumor infiltrating lymphocytes and an increase in PD-L1 expression. Although the Phase 1 portion of the study was focused on immune response and safety, a correlation between this biomarker readout and stable disease or better (n=7) was observed in this preliminary dataset.
The Phase 2 portion of the trial is now open to enrollment across six different indications. It includes cohorts in advanced non-small cell lung cancer (n=35), colorectal cancer (n=18), ovarian cancer (n=18), head and neck squamous cell carcinoma (n=18), renal cell carcinoma (n=25) and glioblastoma (n=20). The primary objective of the Phase 2 study is overall response rate for all cohorts except glioblastoma, where the primary objective is the rate of 12-month overall survival. Secondary objectives include pharmacokinetics assessments, determining the immunogenicity of varlilumab when given in combination with nivolumab and further assessing the anti-tumor activity of combination treatment, including duration of response, time to response, progression-free survival and overall survival. The study is being conducted by Celldex under a clinical trial collaboration with Bristol-Myers Squibb Company. The companies are sharing development costs.
- • On January 29, 2015, Celldex Therapeutics and BMS announced the initiation of a Phase 1/2 dose escalation and cohort expansion study examining the investigational combination of varlilumab, Celldex's CD27 targeting investigational immune-activating antibody and BMS’ immunotherapy Opdivo® (nivolumab). The study will be conducted in adult patients with advanced non-small cell lung cancer (NSCLC), metastatic melanoma (MEL), colorectal cancer (CRC), ovarian cancer, and head and neck squamous cell carcinoma (SCCHN). This study will evaluate the safety and tolerability of the combination and address the hypothesis that the combination of these two mechanisms enhance the anti-tumor activity compared to either agent alone. Celldex is responsible for conducting the study and development costs will be shared.
Is
general: Yes
