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Phase I Study of Recombinant Human CD40 Ligand in Cancer Patients

From the Department of Adult Oncology, Dana-Farber Cancer Institute; Department of Medicine, Brigham and Women’s Hospital; and Harvard Medical School, Boston, MA; Cancer Center, Our Lady of Mercy Hospital, New York Medical College, Bronx, NY; Cancer Therapy and Research Center, Institute for Drug Development, San Antonio, TX; and Immunex Corp, Seattle, WA.

Address reprint requests to R.H. Vonderheide, MD, DPhil, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; email: robert_vonderheide{at}dfci.harvard.edu

PURPOSE: To determine the toxicity, maximum-tolerated dose (MTD), and pharmacokinetics of recombinant human CD40 ligand (rhuCD40L) (Avrend; Immunex Corp, Seattle, WA), suggested in preclinical studies to mediate cytotoxicity against CD40-expressing tumors and immune stimulation.

PATIENTS AND METHODS: Patients with advanced solid tumors or intermediate- or high-grade non-Hodgkin’s lymphoma (NHL) received rhuCD40L subcutaneously daily for 5 days in a phase I dose-escalation study. Subsequent courses were given until disease progression.

RESULTS: Thirty-two patients received rhuCD40L at three dose levels. A total of 65 courses were administered. The MTD was 0.1 mg/kg/d based on dose-related but transient elevations of serum liver transaminases. Grade 3 or 4 transaminase elevations occurred in 14%, 28%, and 57% of patients treated at 0.05, 0.10, and 0.15 mg/kg/d, respectively. Other toxicities were mild to moderate. At the MTD, the half-life of rhuCD40L was calculated at 24.8 ± 22.8 hours. Two patients (6%) had a partial response on study (one patient with laryngeal carcinoma and one with NHL). For the patient with laryngeal cancer, a partial response was sustained for 12 months before the patient was taken off therapy and observed on no additional therapy. Three months later, the patient was found to have a complete response and remains biospy-proven free of disease at 24 months. Twelve patients (38%) had stable disease after one course, which was sustained in four patients through four courses.

CONCLUSION: The MTD of rhuCD40L when administered subcutaneously daily for 5 days was defined by transient serum elevations in hepatic transaminases. Encouraging antitumor activity, including a long-term complete remission, was observed. Phase II studies are warranted.

Presented in part at the Forty-First Annual Meeting of the American Society of Hematology, New Orleans, LA, December 3-7, 1999.

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