Entry Detail
| General information | |
| Database: | DB00904 |
| Objective: | To determine the maximum tolerated dose (MTD) and safety, and explore efficacy and biomarkers of vandetanib with cetuximab and irinotecan in secondline metastatic colorectal cancer. |
| Authors: | Meyerhardt JA, et al |
| Title: | Phase I study of cetuximab, irinotecan, and vandetanib (ZD6474) as therapy for patients with previously treated metastastic colorectal cancer. |
| Journal: | PLoS One. |
| Year: | 2012 |
| PMID: | 22701615 |
| Trial Design | |
| Clinical Trial Id: | NCT00436072 |
| Agent: | vandetanib |
| Target: | Epidermal growth factor receptor Vascular endothelial growth factor receptor 2 Protooncogene tyrosineprotein kinase receptor ret |
| Cancer Type: | colorectal cancer |
| Cancer Subtype: | advanced colorectal cancer |
| Therapy Type: | com |
| Therapeutic Combination Type: | 13 |
| Therapeutic Combination Content: | Vandetanib+standard dosed cetuximab+irinotecan |
| Study Type: | Phase I study |
| Key Patients Feature: | patients were eligible if they had metastatic colorectal adenocarcinoma and had received 1-2 prior chemotherapy regimens for metastatic disease |
| Biomarker: | plasma angiogenesis biomarkers (VEGF, PlGF, bFGF, sVEGFR1, sVEGFR2, IL1¦Â, IL6, IL8, TNF¦Á, SDF1¦Á) |
| Biomark Analysis: | Vandetanib and cetuximab treatment induced a sustained increase in plasma PlGF and a transient decrease in plasma sVEGFR1, but no changes in plasma VEGF and sVEGFR2. |
| Control Group Info: | single arm |
| Treatment Info: | Vandetanib was combined at 100 mg, 200 mg, or 300 mg daily with standard dosed cetuximab and irinotecan (3+3 doseescalation design). |
| Primary End Point: | maximum tolerated dose (MTD) and safety, efficacy and biomarkers |
| Secondary End Point: | NA |
| Patients Number: | 27 |
| Trial Results | |
| DLT_MTD: | Two doselimiting toxicities (grade 3 QTc prolongation and diarrhea) were detected at 300 mg of vandetanib with cetuximab and irinotecan resulting in 200 mg being the MTD. |
| Objective Response Rate: | 7% |
| Disease Control Rate: | 66% |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | 3.6 months (95% CI, 3.25.6) |
| Median OS A vs. C: | 10.5 months (95% CI, 5.120.7) |
| Adverse Event(agent arm): | n considering the entire cohort, all patients developed some level of a rash, with 11% being classified as grade 3. Electrolyte changes were also very common (85% of patients) though only 5 patients (19%) experienced grade 3 or 4 abnormalities, 4 with hypomagnesium and 1 with hypokalemia. Fatigue was seen in 78% of patients, though all were classified as grade 1 or 2. |
| Conclusions: | Vandetanib can be safely combined with cetuximab and irinotecan for metastatic colorectal cancer. Exploratory biomarker analyses suggest differential effects on certain plasma biomarkers for VEGFR inhibition when combined with EGFR blockade and a potential correlation bettheyen baseline sVEGFR1 and response. Hotheyver, while the primary endpoint was safety, the observed efficacy raises concern for moving forward with this combination. |