Lipton, A.

3587 Background: The Insulin like Growth Factor I receptor (IGF-IR), a tyrosine kinase, is widely expressed in human tissues. IGF- IR and its ligands (IGF-I and IGF-II) are expressed by many human cancers (e.g., breast, prostate, colorectal and non-small cell lung). Binding of the ligands to the IGF-IR activates key cellular signaling pathways important for stimulating cellular proliferation and inhibiting apoptosis. IGF- I and IGF-II are present in the circulation, but also locally expressed in neoplastic tissue. Bioavailability of these ligands is regulated by a family of IGF binding proteins (IGFBPs1–6). CP-751,871, a fully human monoclonal antibody, is a highly specific and potent inhibitor of IGF-IR activation. In vitro experiments show that binding of CP 751,871 to IGF-IR induces receptor internalization and degradation. This antibody has been shown to have antineoplastic activity using both in vivo and in vitro pre-clinical models. Methods: Blood samples were collected for characterization of the pharmacokinetic and pharmacodynamic properties of CP-751,871 in phase 1 trials of this agent given to cancer patients either alone or in combination with chemotherapy. The endpoints assessed included among others: CP-751,871 plasma concentrations, total and free IGF-I, IGFBP-3, soluble IGF-IR and IGF-IR expression on granulocytes and tumor cells. Results: CP 751,871 exposure increased with dose over the 800-fold dose range investigated. Pharmacokinetic profiles were consistent with target-mediated disposition. A dose-dependent downregulation of soluble IGF-IR serum concentration and IGF-IR expression was observed, with sustained inhibition for the entire dosing period (3–4 week cycles) observed at doses ≥ 1.5 mg/kg. As predicted for an agent that interferes with IGF-I action, IGF-I and IGFBP-3 serum levels were up-regulated in a similar dose-dependent manner. Conclusions: The pharmacodynamic endpoints of clinical trials provide evidence that CP-751,871 targets IGF-IR in granulocytes, tumor cells and tissues involved in regulation of the growth hormone -IGF-I axis. These data provide proof of principle for the use of CP-751,871 as a first-in-class therapeutic approach to inhibit the IGF-IR pathway in cancer patients. No significant financial relationships to disclose.

Abstract Abstract #6074 Objective: To analyze blood-serum biomarkers (HER2, EGFR, uPA, and TIMP-1) for prediction of response to treatment in conjunction with Study 96-32-55, a multicenter phase II trial assessing the efficacy and tolerability of two irinotecan schedules in anthracycline- or taxane-refractory MBC patients.
 Methods: MBC patients who experienced disease progression after one to three chemotherapy regimens, including at least one anthracycline- or taxane-based regimen, were randomly assigned to irinotecan in 6-week cycles comprising 100 mg/m2 weekly for 4 weeks, then a 2-week rest or 240 mg/m2 every 3 weeks. During this study the serum samples from each patient were collected at a possibility of three time points; prior to treatment, at the first occurrence of response, and at completion of or withdrawal from treatment. Response prediction was analyzed using predetermined elevated/non-elevated serum biomarker cutoffs. Percentage changes from baseline to first response and disease progression were analyzed.
 Results: In the weekly arm, the objective response (CR+PR) rate was 23% (95% CI, 13% to 37%), and in the every-3-weeks arm, the objective response rate was 14% (95% CI, 6% to 26%). Serum biomarker levels were determined for HER2, EGFR, uPA, and TIMP-1 prior to treatment for 91 patients. Of these 91 patients, 17 had serum measurements at first response, and 38 had serum measurements at their completion of study due to disease progression. Only 7 patients had serum-levels collected at all three event-points. The baseline levels of sHER2, EGFR, uPA, and TIMP-1 were not different among responders and non-responders (Fisher's Exact p=0.41, 0.26, 0.68, 0.75). sHER2 level increased by 20.6% from baseline to disease progression (p=0.01). TIMP-1 level was 15.2% lower than baseline at first response (p=0.03), 16.5% higher than baseline at disease progression (p=0.01), and for 7 patients with all three event-point measures, TIMP-1 was 21.8% lower than baseline at first response and was 22.3% higher than baseline at disease progression (p=0.02, 0.04).
 Conclusions: In this study, serum levels of HER2, EGFR, uPA, and TIMP-1 do not appear to be predictive of response. However, interpretation of the data is compromised due to limited availability of serum at all 3 points. Serum HER2 appears higher at disease progression than at baseline. Serum TIMP-1 appears to decrease from baseline to first response, and then appears to increase at disease progression. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6074.