Celldex presents varlilumab proof-of-concept data

HAMPTON, N.J.—Celldex Therapeutics Inc. has presented a comprehensive review of the company’s Phase 1 single-agent study of varlilumab, focusing on biomarker analyses and confirming significant immunological effects consistent with CD27 costimulation. Varlilumab (CDX-1127) 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 antitumor 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, CDX-1127 has an additional mechanism through a direct antitumor effect.

Varlilumab is an immunotherapy designed to harness the body’s natural immune response by enhancing the activation of T cells that can specifically recognize and kill cancer cells. The clinical and immunological activity data recently presented add to a growing body of literature supporting the broad study of varlilumab in combination with a number of other anticancer agents, including checkpoint inhibitors, chemotherapies, targeted therapies and vaccines, the company said in a statement. Varlilumab will enter multiple combination studies in the coming months, Dr. Thomas Davis, executive vice president and chief medical officer of Celldex Therapeutics, tells DDNews. The data were presented in a poster session entitled, “Immune Correlates of Varlilumab (CDX-1127) Treated Cancer Patients are Consistent with CD27 Costimulatory Activity” at the most recent Society for the Immunotherapy of Cancer Annual Meeting.

“In this first-in-man study of varlilumab, we have observed a consistent pattern of immunologic changes that correspond with the immune-activating effect of the antibody,” said Dr. Tim Bullock, associate professor of pathology at the University of Virginia School of Medicine, who led the immune monitoring of the Phase 1 varlilumab study. “Some of the salient features include the release of serum cytokines, activation of T cells, an expansion of natural killer cells and a decrease in regulatory T cells. Interestingly, these immunologic changes were most prominent in the dose-escalation patients that had a delay between their first dose and subsequent doses, suggesting that less-frequent dosing of varlilumab may provide optimal immunologic effects.”

“We believe the Phase 1 experience with varlilumab has established clear proof of concept for this program by demonstrating a benign safety profile, clear biological effects that are consistent with the predicted mechanism of action and enduring clinical responses in this advanced patient population,” added Davis. “Based on these data, as well as the strong preclinical data supporting combination therapy, we are eager to see varlilumab through its next stage of clinical studies in combination with other therapies. Importantly, these studies are designed to investigate varying dosing regimens of varlilumab to identify the optimal dose and regimen when used in combination with other therapies.”

The analyses included patients with solid tumors and hematologic malignancies from the dose escalation portion of the Phase 1 study (dosed at 0.1, 0.3, 1.0, 3.0 and 10 mg/kg with a one-month delay between the initial dose and the four weekly multidoses) and patients from expansion cohorts in metastatic melanoma and renal cell carcinoma (dosed at 3 mg/kg weekly). All cohorts showed a consistent change in specific immune biomarkers; however, the immune correlates were generally stronger or more consistent with the dose-escalation portion of the study, hence the idea that less-frequent dosing may provide the best regimen for promoting sustained CD27 activation with varlilumab.

Pharmacokinetic assessments revealed good exposure, including at lower dose levels, with a half-life of 10 to 13 days. No anti-varlilumab antibody responses have been detected to date, and varlilumab demonstrated continuous binding to circulating T cells even at doses as low as 0.3 mg/kg for at least 29 days post-infusion.

Biomarker analysis demonstrated significant immunological effects consistent with CD27 costimulation across all dose levels. A serum biomarker profile of the 1mg/kg cohort (selected because it had the largest patient population) demonstrated robust and transient stimulation of multiple cytokines and chemokines consistent with varlilumab activation of CD27 signaling. Further assessment of immune cell subsets demonstrated no depletion of B cells or CD8+ T cells, with a concomitant decrease in CD4+ T cells and regulatory T cells (Treg, CD4+ and FoxP3+). Evidence for functional activation of T cells was demonstrated by upregulation of the activation marker, HLA-DR and new or enhanced melanoma antigen-specific T cell responses in select melanoma patients.

A total of 86 patients have been dosed, and of those, 55 patients have been dosed in dose-escalation cohorts (various solid and hematologic B-cell tumors) and 31 patients have been dosed in the expansion cohorts (melanoma and RCC) at 3 mg/kg. In both the solid tumor and hematologic dose-escalations, the prespecified maximum dose level (10 mg/kg) was reached without identification of a maximum tolerated dose. The majority of adverse events related to treatment have been mild to moderate (Grade 1/2) in severity, with only three serious adverse events related to treatment reported. No significant immune-mediated adverse events (colitis, hepatitis, etc.) typically associated with checkpoint blockade have been observed.

Two patients experienced objective responses. A patient with Hodgkin lymphoma experienced a complete response after three cycles at 0.3 mg/kg, which continues at 18.9+ months. This patient’s response was delayed, and there was no detectable CD27 on their tumor cells, leading the company to conclude the response was immune-mediated response and not antibody-dependent cellular cytotoxicity-mediated. A patient with renal cell carcinoma treated in the expansion cohort experienced a partial response after one cycle at 3 mg/kg that further improved on the second cycle and continues at 5.5+ months. This patient had five target lesions that have all regressed, including a lung lesion that has completely disappeared.

Based on the results observed in hematologic malignancies, an expansion cohort has been added to enroll up to 15 patients with Hodgkin lymphoma and an abbreviated dose escalation in T cell hematologic malignancies is ongoing.

Celldex is developing targeted therapeutics to address devastating diseases for which available treatments are inadequate, Davis notes, with five programs in the clinic aimed at generating the strongest immune effects over time. Davis joined the company in 2005 about six months after it was spun out of Medarex, which had been acquired by Bristol-Myers Squibb.