A randomized, phase II study of the anti-insulin-like growth factor receptor type 1 (IGF-1R) monoclonal antibody robatumumab (SCH 717454) in patients with advanced colorectal cancer

Edward H Lin, Heinz-Josef Lenz, Mansoor N Saleh, Mary J Mackenzie, James A Knost, Kumudu Pathiraja, Ronald B Langdon, Siu-Long Yao, Brian D Lu, Edward H Lin, Heinz-Josef Lenz, Mansoor N Saleh, Mary J Mackenzie, James A Knost, Kumudu Pathiraja, Ronald B Langdon, Siu-Long Yao, Brian D Lu

Abstract

Overexpression of insulin-like growth factor receptor type 1 (IGF-1R) may promote tumor development and progression in some cancer patients. Our objective was to assess tumor uptake of fluorodeoxyglucose by positron-emission tomography in patients with chemotherapy-refractory colorectal cancer treated with an anti-insulin-like growth factor receptor type 1 (anti-IGF-1R) monoclonal antibody, robatumumab. This was a randomized, open-label study with two periods (P1 and P2). Patients were randomized 3:1 into treatment arms R/R and C/R that received, respectively, one cycle of 0.3 mg/kg robatumumab or one or more cycles of second-line chemotherapy in P1, followed in either case by 10 mg/kg robatumumab biweekly in P2. The primary measure of fluorodeoxyglucose uptake was maximum standardized uptake value (SUV(max)). The primary endpoint was the proportion of patients in the R/R arm having a mean percent decrease from baseline in SUV(max) (DiSUV) greater than 20% 12-14 days postdose in P2. Secondary endpoints included Response Evaluation Criteria in Solid Tumors (RECIST)-defined tumor response and pharmacodynamic measures of target engagement. Among 41 patients who were evaluable for the primary endpoint, seven (17%, 95% CI 7%-32%) had DiSUV greater than 20%. Fifty robatumumab-treated patients were evaluable for RECIST-defined tumor response and six (12%) had stable disease lasting greater than or equal to 7 weeks in P2. Pharmacodynamic endpoints indicated target engagement after dosing with 10 mg/kg robatumumab, but not 0.3 mg/kg. The most frequently reported adverse events were fatigue/asthenia, nausea, anorexia, and gastrointestinal disturbances. In this study, few patients with chemotherapy-refractory colorectal cancer appeared to benefit from treatment with the IGF-1R antagonist robatumumab.

Keywords: Colorectal cancer; IGF-1R; monoclonal antibody; robatumumab.

© 2014 Merck & Co., Inc. Cancer Medicine published by John Wiley & Sons Ltd.

Figures

Figure 1
Figure 1
Study design.
Figure 2
Figure 2
Patient disposition.
Figure 3
Figure 3
Distributions of change from baseline in mean SUVmax (A) in patients in the R/R group in P1 and P2, and in patients in the C/R treatment arm in P1 after their first cycle of chemotherapy. The threshold for positive metabolic response was predefined as decrease in mean SUVmax (DiSUV) greater than 20% (dark shading). (B) The timecourse of changes in mean SUVmax in the subset of patients in the R/R group who had DiSUV greater than 20% either in P1 or 2, or both. Horizontal bars indicate timing and doses of robatumumab.
Figure 4
Figure 4
Serum concentrations of pharmacodynamic protein biomarkers and in percent of PBMC that were positive for surface IGF-1R prior to the first infusion of study drug (in P1/C1) and at posttreatment timepoints P2/C1, P2/C2, and P2/C3. Means ±SE are shown; the numbers of patients evaluable at each timepoint are indicated in parentheses.

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