Phase I study of recombinant human CD40 ligand in cancer patients.
OBJECTIVE
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.


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 biopsy-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.


CONCLUSIONS
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.
Vonderheide
R H
RH
Department of Adult Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. robert_vonderheide@dfci.harvard.edu
Dutcher
J P
JP
Anderson
J E
JE
Eckhardt
S G
SG
Stephans
K F
KF
Razvillas
B
B
Garl
S
S
Butine
M D
MD
Perry
V P
VP
Armitage
R J
RJ
Ghalie
R
R
Caron
D A
DA
Gribben
J G
JG
D000328:Adult; D000368:Aged; D018941:Antigens, CD19 / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015704:CD4 Antigens / Q000187:drug effects; D023201:CD40 Ligand / Q000494:pharmacology* / Q000627:therapeutic use; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000276:immunology; D008231:Lymphopenia / Q000139:chemically induced; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology; D011994:Recombinant Proteins
D018941:Antigens, CD19; D000970:Antineoplastic Agents; D015704:CD4 Antigens; D011994:Recombinant Proteins; D023201:CD40 Ligand