Anticancer agent - CP-751871
The hormones insulin-like growth factors 1 and 2 are involved in regulating the cell cycle, and the tyrosine kinase IGF-1 receptor is expressed on numerous different tumour cells. When it is activated, the receptor triggers the phosphatidylinositol 3 kinase pathway and other signalling pathways, and a high level of the receptor in the serum is thought to increase the risk of cancer developing
The hormones insulin-like growth factors 1 and 2 are involved in regulating the cell cycle, and the tyrosine kinase IGF-1 receptor is expressed on numerous different tumour cells. When it is activated, the receptor triggers the phosphatidylinositol 3 kinase pathway and other signalling pathways, and a high level of the receptor in the serum is thought to increase the risk of cancer developing
As a result, inhibiting IGF-1R may provide a useful anticancer strategy. Several different approaches are in development, including Pfizer's CP-751871, a fully human IgG2 monoclonal antibody that inhibits the IGF-1R receptor.1
Several trials have been carried out. In one Phase I study, 24 patients with solid tumours were given the antibody intravenously on the first day of each 21 day cycle.2 A total of 110 cycles were given at four dose levels, and the maximum tolerable dose was lower than the highest feasible dose of 20mg/kg. At this dose, 10 of 15 patients achieved stable disease, and in two of these cases it was long term. There were no objective responses.
Another Phase I trial has been carried out in patients with multiple myeloma.3 In total, 47 patients with relapsed or refractory disease were enrolled in 11 dose escalation cohorts and given doses from 0.025 to 20mg/kg for four weeks. Those who experienced less than a partial response could also be given oral dexamethasone, and those in the 10 and 20mg/kg cohorts could also be given rapamycin with or without dexamethasone if they achieved less than a partial response. Nine responses were observed in patients given the drug in combination with dexamethasone.
In a Phase II trial in 156 patients with non-small cell lung cancer, treatment naïve subjects with advanced disease were given the antibody along with paclitaxel and carboplatin, or paclitaxel and carboplatin alone, every three weeks for up to six cycles.4 Those not receiving the antibody whose disease progressed could be switched to receive it. A total of 54% of those given the antibody had an objective response, compared with 42% of those who had not; 16 of the 23 patients given the antibody as an open label add-on responded. The trial suggests that it is both safe and effective in this form of cancer.