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FDA advisory panel unanimously recommends further evaluation of vandetanib
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The FDA’s Oncologic Drugs Advisory Committee voted 10-0 in favor of exploring additional dosing regimens or schedules for vandetanib for the treatment of unresectable locally advanced or metastatic medullary thyroid cancer.
A new drug application for the use of vandetanib in patients with unresectable locally advanced or metastatic medullary thyroid cancer has been submitted by iPR Pharmaceuticals and AstraZeneca. Data from a randomized phase 3 study, two phase 2 studies and extensive safety database support the application. The phase 3 trial results were previously reported by Endocrine Today.
The FDA has identified three issues for review:
- The appropriate patient population for the use of vandetanib.
- The optimal dose of vandetanib.
- The substantial toxicity profile of vandetanib.
Much of the panel’s discussion focused on the relationship between the dosing levels and the toxicity associated with the drug. Issues in the toxicity profile include adverse events such as prolongation in QT, ischemic arterial events, interstitial lung disease and skin diseases, including Stevens-Johnson syndrome. It was suggested that adjustments in the dosing could yield lower toxicity rates with similar efficacy.
At the request of the chair, panel members noted why they voted the way they did. Armando Giuliano, MD, clinical professor of surgery at the University of California, Los Angeles, and chief of science and medicine at the John Wayne Cancer Institute, said that further exploration would be a “reasonable way to obtain dose toxicities.”
Several others expressed concerns about the toxicity issue, including Ralph Freedman, MD, PhD, clinical professor in the department of gynecologic oncology at the University of Texas MD Anderson Cancer Center.
“There were patients who actually left the study without a dose reduction, which suggests that there is an issue there,” Freedman noted.
Brent Logan, PhD, associate professor of biostatistics in the division of biostatistics at the Medical College of Wisconsin, noted somewhat unclear trial results.
“There is mixed evidence that the dose can be reduced and still maintain high efficacy,” Logan said. “But there is also evidence that if the dose is increased, toxicity will increase.”
Wyndham Wilson, MD, PhD, chair of the committee and chief of the Lymphoma Therapeutics Section of the Metabolism Branch at the NCI’s Center for Cancer Research, commented on the steady-state levels.
“Pharmacology data suggest that you could get steady-state levels at a lower dose rate and still have equal or more effectiveness with fewer side effects,” he said.
William Kelly, DO, professor of medical oncology and urology at Thomas Jefferson University in Philadelphia, cautioned that, “Just because you get pharmacological steady state levels, it is efficacy at the end of the day that we have to keep our eye on.”
Finally, Margaret Tempero, MD, deputy director of the UCSF Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, said that both the dose and the dosing schedule should be evaluated.
“Why do we need to give this drug every day?” she asked. “Intermittent dosing might be reasonable.” – by Rob Volansky