A Phase I Study of Humanized Anti-CD40 Immunotherapy with SGN-40 in Non-Hodgkin’s Lymphoma.

The vast majority of B-cell malignancies express CD40, a member of the TNF receptor family. This receptor, along with the cognate ligand (CD154), mediates cell survival and proliferation of normal B-cells and can regulate apoptosis as well as survival in transformed cells, making this pathway an appealing target for B-cell lymphoma. Both in vitro and in vivo preclinical studies support the development of anti-CD40 immunotherapy for non-Hodgkin’s lymphoma (NHL). Accordingly, a phase I single-arm dose escalation trial was initiated to test the safety, pharmacokinetics, and antitumor activity of SGN-40, a humanized anti-CD40 antibody, in patients with NHL. The protocol was designed to treat patients with follicular, mantle cell, diffuse large B-cell, small lymphocytic, and marginal zone lymphomas in cohorts using SGN-40 infusions at doses of 2, 4, 8, or 16 mg/kg/week for four weeks. We report results for cohort 1 (n = 6) treated at 2 mg/kg/week. Four of 6 patients completed the planned 4 weekly infusions. No grade 4 toxicity was observed. Two grade 3 toxicities were seen, both in the same patient (unilateral conjunctivitis and ipsilateral loss of vision in a patient with pre-existing macular degeneration). Grade 2 loss of balance was also seen in the same patient. Imaging studies with CT and MRI did not reveal a stroke or leptomeningeal disease nor were there inflammatory or malignant cells in the CSF. All these adverse events resolved over six weeks, including vision which returned to baseline acuity. The only other severe adverse event reported was a deep venous thrombosis in the setting of bulky ipsilateral pelvic adenopathy, which was considered to be unrelated to SGN-40. Dose escalation was temporarily suspended to evaluate these unexplained toxicities and the report of severe headaches, attributed to cytokine release reaction, at the next dose level (i.e. 4 mg/kg) in a parallel phase I protocol for multiple myeloma. Although none of the NHL patients in this study developed headaches or clinical symptoms, several patients demonstrated a significant increase in plasma cytokine levels (i.e. TNF-alpha, IL-6) following the first infusion but not subsequent treatments with SGN-40, raising the possibility that a first-dose cytokine release effect may be involved in the grade 3 toxicities observed. Pharmacokinetic samples for the NHL patients were collected and are currently being analyzed. Preliminary antitumor activity at the 2 mg/kg dose is reflected in one patient who had stable disease as determined by serial CT scans and in another patient who had subjective improvement in B symptoms during therapy but was found to have disease progression based on CT scans 4 weeks after completing therapy. An amended protocol is actively accruing patients that will address the concern for first-dose cytokine release and allow continued dose escalation. Clinical and pharmacokinetic data from these additional cohorts will be presented.