BACKGROUND: Small cell lung cancer (SCLC) cells express and secrete gastrin-releasing peptide (GRP) which binds to receptors and stimulates growth of these cells. A murine monoclonal antibody, 2A11, which binds GRP with high affinity, decreased growth of SCLC cells in vitro and in athymic nude mice. A phase 1 trial and pharmacokinetic modeling in patients with lung cancer has defined the phase 2 dose of 2A11 but the antitumor activity in patients is unknown. METHODS: Thirteen patients with previously treated SCLC received 2A11 at 250 mg/m2 over 1 h three times per week for 4 weeks. Serum GRP, urine GRP, serum levels of 2A11, and human antimouse antibodies (HAMA) were determined. RESULTS: One of 12 (8%; 95% confidence interval, 0 to 38%) evaluable patients had complete resolution of radiographically detectable tumor lasting 4 months. Four patients (33%) had stable disease. No toxic reactions were observed. The pretreatment serum GRP level of the responding patient was 3.1 fmol/mL and the median of nine nonresponding patients was 7.3 fmol/mL (range, <1.0 to 29.0). The mean trough serum 2A11 level was 49+/-18 microg/mL in the responding patient and 32 to 487 mg/mL (median, 117) in 10 nonresponding patients. HAMA did not increase during 2A11 administration in any patient. CONCLUSIONS: Interruption of the GRP autocrine growth factor loop with 2A11 results in clinical antitumor activity in a minority of patients with previously treated SCLC. Further evaluation of the antitumor effects of 2A11 is warranted to define characteristics associated with response to 2A11.
BACKGROUND:Small cell lung cancer (SCLC) cells express and secrete gastrin-releasing peptide (GRP) which binds to receptors and stimulates growth of these cells. A murine monoclonal antibody, 2A11, which binds GRP with high affinity, decreased growth of SCLC cells in vitro and in athymic nude mice. A phase 1 trial and pharmacokinetic modeling in patients with lung cancer has defined the phase 2 dose of 2A11 but the antitumor activity in patients is unknown. METHODS: Thirteen patients with previously treated SCLC received 2A11 at 250 mg/m2 over 1 h three times per week for 4 weeks. Serum GRP, urine GRP, serum levels of 2A11, and human antimouse antibodies (HAMA) were determined. RESULTS: One of 12 (8%; 95% confidence interval, 0 to 38%) evaluable patients had complete resolution of radiographically detectable tumor lasting 4 months. Four patients (33%) had stable disease. No toxic reactions were observed. The pretreatment serum GRP level of the responding patient was 3.1 fmol/mL and the median of nine nonresponding patients was 7.3 fmol/mL (range, <1.0 to 29.0). The mean trough serum 2A11 level was 49+/-18 microg/mL in the responding patient and 32 to 487 mg/mL (median, 117) in 10 nonresponding patients. HAMA did not increase during 2A11 administration in any patient. CONCLUSIONS: Interruption of the GRP autocrine growth factor loop with 2A11 results in clinical antitumor activity in a minority of patients with previously treated SCLC. Further evaluation of the antitumor effects of 2A11 is warranted to define characteristics associated with response to 2A11.
Authors: T Chile; M L Corrêa-Giannella; M A H Z Fortes; M D Bronstein; M B Cunha-Neto; D Giannella-Neto; R R Giorgi Journal: J Endocrinol Invest Date: 2011-01-26 Impact factor: 4.256
Authors: G Schwartsmann; L P DiLeone; M Horowitz; D Schunemann; A Cancella; A S Pereira; M Richter; F Souza; A Brondani da Rocha; F H Souza; P Pohlmann; G De Nucci Journal: Invest New Drugs Date: 2006-09 Impact factor: 3.850
Authors: Alberto A Chiappori; Hatem Soliman; William E Janssen; Scott J Antonia; Dmitry I Gabrilovich Journal: Expert Opin Biol Ther Date: 2010-06 Impact factor: 4.388