Howard A. Burris, MD
A phase I study reported by Howard A. Burris, MD, of Sarah Cannon Research Institute, Tennessee Oncology, and colleagues in the Journal of Clinical Oncology has shown that the first-in-class agonist anti-CD27 antibody varlilumab is well tolerated and active in patients with advanced solid tumors. CD27 is a co-stimulatory molecule on T cells that induces intracellular signaling for cellular activation, proliferation, effector function, and survival upon binding with its ligand CD70 (normally transiently expressed on antigen-presenting cells).
In a dose-escalation phase, 25 patients with solid tumors (primarily colorectal cancer and melanoma) received a single intravenous dose of varlilumab at 0.1, 0.3, 1.0, 3.0, or 10 mg/kg with a 28-day observation period, followed by up to 5 multidose cycles (1 dose per week for 4 weeks) depending on tumor response. In expansion cohorts, 16 patients with melanoma and 15 patients with renal cell carcinoma were started at a dose of 3.0 mg/kg. All patients had stage IV disease, and most were heavily pretreated.
Only one dose-limiting toxicity was observed, consisting of grade 3 transient asymptomatic hyponatremia at a dose of 1.0 mg/kg. No maximum tolerated dose was identified. Overall, patients received a median of 4 doses (range = 1–21), with 10 patients receiving at least 1 treatment cycle. Among all 56 patients, treatment-related toxicities were generally grade 1 or 2 and included fatigue, rash, nausea, and diarrhea; grade ≥ 3 treatment-related adverse events consisted of 1 case each of grade 3 hyponatremia, decreased appetite, and decreased lymphocyte count and 1 case of grade 4 asthma and bronchospasm.
Evidence of biologic activity, including chemokine induction, T-cell stimulation, and regulatory T-cell depletion, was observed across dose levels. One patient with metastatic renal cell carcinoma had a partial response, with progression-free survival of 2.3 years. Eight patients experienced stable disease for > 3 months, including 4 with renal cell carcinoma, 3 with melanoma, and 1 with colorectal adenocarcinoma.
The investigators concluded: “Dose escalation of varlilumab to 10 mg/kg was well tolerated without identification of a maximum tolerated dose. Varlilumab was biologically and clinically active.”
The study was supported by Celldex Therapeutics.
