| General information |
| Database: | DB00705 |
| Objective: | To determine the biological modulatory dose of SU5416, they employed a novel trial design, where "dose deescalation" was based on demonstrable biological changes observed at the maximum tolerated dose. If such an effect was shown, dose deescalation to a predefined dose level would occur to determine if the lotheyr dose exhibited the same amount of pharmacodynamic effect as the higher dose. |
| Authors: | Dowlati A, et al |
| Title: | Novelphase I dose deescalation design trial to determine the biological modulatory dose of the antiangiogenic agent SU5416. |
| Journal: | Clin Cancer Res |
| Year: | 2005 |
| PMID: | 16278419 |
| Trial Design |
| Clinical Trial Id: | NA |
| Agent: | SU5416
|
| Target: | Vascular endothelial growth factor
|
| Cancer Type: | advanced solid tumors |
| Cancer Subtype: | advanced solid tumors |
| Therapy Type: | mono |
| Therapeutic Combination Type: | NA |
| Therapeutic Combination Content: | NA |
| Study Type: | Novelphase I Dose Deescalation Design Trial |
| Key Patients Feature: | Patients with solid tumors not amenable to curative or otherwiseeffective surgical, radiation therapy, or chemotherapy treatmentprograms were eligible. Other eligibility included Eastern CooperativeOncology Group performance status of 0, 1 or 2; life expectancy of atleast 12 weeks; at least 4 weeks must have elapsed since prior largefield radiation therapy, and patients must have been off previousanticancer therapy for at least 3 weeks and recovered from alltreatmentrelated toxicity; adequate hematologic variables (WBC>3, 500/L, platelets >100, 000/L, hemoglobin >9.0 g/dL); normalcoagulation screen; and adequate renal and hepatic variables(creatinine <1.5 mg/dL, bilirubin <1.6 mg/dL, aspartate aminotransferase and alanine aminotransferase more than twice the normal).Patients must have at least two distinct lesions of metastatic orprimary tumor >1 cm, which will permit biopsy of a single lesion forthe laboratory correlative studies and another lesion for DCEMRItumor perfusion studies. It was important that two distinct lesionswere identified so that correlative computed tomography/MRI-guidedvisceral tumor biopsy would not interfere with the correlative DCEMRI tumor perfusion (blood flow) studies. |
| Biomarker: | soluble Eselectin, soluble intercellular adhesion molecule, soluble vascular cell adhesion molecule, and plasma vascular endothelial growth factor were measured sequentially. |
| Biomark Analysis: | There was a significant increase in both soluble Eselectin and soluble intercellular adhesion molecule levels pretreatment versus levels at the time of removal of patients from study (P = 0.04 and P = 0.0007, respectively). Levels of serum fibrinogen rose with therapy. There was a trend toward increase in plasma vascular endothelial growth factor levels. |
| Control Group Info: | single arm |
| Treatment Info: | Ten patients with advanced solid tumors were enrolled at each dose level. |
| Primary End Point: | a (a) 35% decline in tumor blood flow as determined by dynamic contrastenhanced magnetic resonance imaging (DCEMRI) or (b) 35% decrease in microvessel density on sequential tumor biopsies |
| Secondary End Point: | NA |
| Patients Number: | 19 |
| Trial Results |
| DLT_MTD: | Doselimiting toxicity was achieved at190 mg/m2 and consisted of projectile vomiting and headache.The maximum tolerated dose (MTD) was determined to be 145mg/m2. |
| Objective Response Rate: | NA |
| Disease Control Rate: | NA |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | NA |
| Median OS A vs. C: | NA |
| Adverse Event(agent arm): | NA |
| Conclusions: | SU5416 does not result in decreased blood flow in tumors or a decrease in microvessel density. This corresponds to the lack of clinical activity seen with this agent. Our clinical trial design termed dose deescalation is a novel approach to determine the in vivo biological effects of targeted therapies in cancer patients. |