r at the recommended human dose) for 1 month.
. Animal Pharmacology and/or Toxicology
In an animal model of wound-healing, mice dosed with Vandetanib had reduced skin-breaking strength compared with controls. This suggests that Vandetanib slows but does not prevent wound healing. The appropriate interval between discontinuation of Vandetanib and subsequent elective surgery required to avoid the risks of impaired wound healing has not been determined.
Nodular masses were observed in a 6-month toxicology study in rats during treatment with ≥5 mg/kg/day Vandetanib (approximately 0.22 or 0.40 times, respectively, the AUC in patients with cancer at the recommended human dose of 300 mg/day). Masses were palpable during clinical assessments as early as week 13, were observed in multiple organs, and were associated with hemorrhagic or inflammatory findings.
14. CLINICAL STUDIES
A double-blind, placebo-controlled study randomized patients with unresectable locally advanced or metastatic medullary thyroid cancer to Vandetanib 300 mg (n=231) versus Placebo (n=100).
The primary objective was demonstration of improvement in progression-free survival (PFS) with Vandetanib compared to placebo. Other endpoints included eva luation of overall survival and overall objective response rate (ORR). Centralized, independent blinded review of the imaging data was used in the assessment of PFS and ORR. Upon objective disease progression based on the investigator’s assessment, patients were discontinued from blinded study treatment and given the option to receive open-label Vandetanib. Nineteen percent (44/231) of the patients initially randomized to Vandetanib opted to receive open-label Vandetanib after disease progression, and 58% (58/100) of the patients initially randomized to placebo opted to receive open-label Vandetanib after disease progression.
The result of the PFS analysis, based on the central review RECIST assessment, showed a statistically significant improvement in PFS for patients randomized to Vandetanib (Hazard Ratio (HR) = 0.35; 95% Confidence Interval (CI) = 0.24-0.53; p<0.0001). Analyses in the subgroups of patients who were symptomatic or had progressed within 6 months prior to their enrollment showed similar PFS results (HR = 0.31 95% CI: 0.19, 0.53 for symptomatic patients; HR = 0.41 95% CI: 0.25, 0.66 for patients who had progressed within 6 months prior to enrollment).
At the time of the primary analysis of PFS, 15% of the patients had died and there was no significant difference in overall survival between the two treatment groups. The overall objective response rate (ORR) for patients randomized to Vandetanib was 44% compared to 1% for patients randomized to placebo. All objective responses were partial responses.
Figure 1- Progression Free Survival
Table 3: Summary of key efficacy findings Progression-Free Survival (PFS) N* Median PFS (95% CI) HR† 95% CI p-value‡
N = Number of events/number of randomized patients
HR= Hazard Ratio, Cox Proportional Hazards Model
Logrank test
NE = non-estimatable
15. REFERENCES
1.NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004 165.
2.OSHA Technical |
