Phase I and imaging trial of a monoclonal antibody directed against gastrin-releasing peptide in patients with lung cancer

Small cell lung cancer (SCLC) cells express and secrete bombesin-like pepti des (BLP) that can activate specific receptors that stimulate the growth of these cells. A murine monoclonal antibody, 2A11, which binds to the BLP, g astrin-releasing peptide with high affinity, has been reported to decrease the growth of SCLC cells in vitro and in athymic nude mice. A Phase I trial in lung cancer patients was performed using multiple doses of 2A11, Thirte en patients with lung cancer received 12 doses of 2A11 antibody three times a week for 4 weeks at one of four dose levels. Serum samples were obtained prior to initiation and before each dose of 2A11 antibody therapy for meas urement of 2A11 antibody levels and determination of serum human antimouse antibody levels. A pilot imaging evaluation using In-111 conjugated 2A11 mo noclonal antibody was also performed in the same patients to aid in the stu dy of pharmacokinetics and biodistribution. No toxic reactions were observe d, and none of the patients developed detectable human antimouse antibody; however, no objective antitumor responses were observed. The mean trough se rum 2A11 levels in patients increased with increasing dose level: 0.26 +/- 0.2 mu g/ml, 6.7 +/- 6 mu g/ml, 71.5 +/- 60 mu g/ml, 248 +/- 184 mu g/ml fo r dose levels 1 mg/m(2), 10 mg/m(2), 100 mg/m(2), and 250 mg/m(2), respecti vely, At each dose level, sustained detectable serum levels of the monoclon al antibody were achieved. Tumor uptake was noted in 11 of 12 patients who were injected with In-111 conjugated 2A11, Because no dose-limiting clinica l toxicity was observed, a mathematical model was used to define the recomm ended Phase II dose of 250 mg/m(2). This trial established that repeated do ses of monoclonal antibody 2A11 could be given safely to patients, and sust ained levels could be achieved for a 1-week schedule. Further evaluation of the antitumor effects of 2A11 is warranted.