Phase I trial involving the pharmacodynamic (PD) study of circulating tumour cells, of CP-751,871 (C), a monoclonal antibody against the insulin-like growth factor 1 receptor (IGF-1R), with docetaxel (D) in patients (p) with advanced cancer

Abstract

3023 Background: C is the first specific, fully human, monoclonal antibody to target IGF-1R in clinical trials. It potently inhibits IGF-1R signaling, enhancing D antitumour activity. This trial investigated the safety, feasibility, dose limiting toxicity (DLT), PK and antitumor activity of D administered with C every 3 weeks. PD studies evaluated circulating tumor cell (CTC) IGF-1R expression and CTC counts pre- and post-treatment. Methods: The C doses tested were 0.1, 0.4, 0.8, 1.5, 3.0, 6.0 and 10 mg/kg in sequential cohorts of 3–6 p. D was fixed at 75mg/m 2 . P achieving disease control continued on C alone if experiencing D toxicity. Results: 21 p (20 male) have received 100 courses of C with D. 7 p received 8 or more courses of the combination. A further 21 courses of C alone have been administered. No toxicity has been attributed to C to date with the observed toxicities being attributable to D. Grade 3/4 toxicities were neutropenia (16/21 p) and neutropenic fever in 2/21 p. Grade 3 diarrhea was reported in 3 p, but this was easily controlled with antidiarrheals. Transient grade 1 hyperglycaemia was noted largely on day 1, following steroid premedication (14 p), but no significant C related hyperglycemia has been observed. An MTD has not been reached. Serial echocardiograms demonstrated no cardiac toxicity. Of 18 castration resistant prostate cancer (CRPC) p treated, 4 have had a confirmed PR, with 2 unconfirmed PR and 2 having disease stabilization for > 6 months (median number of courses: 10; range: 3–12). 5 p have maintained SD with C alone for 2–7 courses. CTC were detected in 16 of 18 p (CTC numbers ranged from 1 to 202 in 7.5ml of blood). IGF-1R expression was detected in 12 p. CTC IGF-1R was undetectable following treatment with C at doses above 3 mg/kg. Conclusions: This combination is safe and feasible with no toxicity attributed to C and encouraging antitumor activity in CRPC. [Table: see text]