Phase II Study of Clinical Activity and Proteomic Pathway Profiling of the Vascular Endothelial Growth Factor 2 (VEGFR2) Inhibitor, ZD6474 (Vandetanib) in Women With Relapsed or Refractory Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
- Epithelial ovarian cancer requires neovascularization for growth and metastasis.
Anti-angiogenesis agents have been shown to have promise in the treatment of recurrent
disease. Expression of vascular endothelial growth factor 2 (VEGFR2) and epidermal
growth factor receptor (EGFR) has been demonstrated in ovarian cancer specimens in
stroma and tumor. Blocking autocrine and paracrine loops acting through these receptors
may inhibit downstream phosphorylation targets in the mitogen activated protein kinase
(MAPK) and AKT pathways, thereby influencing disease progression and patient outcome.
- The multi-kinase inhibitor ZD6474 (vandetanib, AstraZeneca, Zactima) blocks
angiogenesis by targeting VEGFR2, and shows in vitro activity against a number of other
receptor tyrosine kinases including resonance energy transfer (RET), vascular
endothelial growth factor 3 (VEGFR3) and EGFR.
- Clinical efficacy of ZD6474 (vandetanib) in women with refractory or relapsed
epithelial ovarian cancer is unknown, but preclinical data suggests potential value.
- The maximum tolerated dose of ZD6474 (vandetanib) has been determined at 300mg/day,
limited by the dose-responsive adverse effect of prolonged (Q wave, T wave)QT interval.
- To assess the clinical activity (CR - complete response, PR - partial response, or
disease stabilization) of the VEGFR2 inhibitor ZD6474 (vandetanib), 300mg/d, in women
with ovarian, fallopian tube or primary peritoneal cancer.
- To study target signal events: quantity and activation of VEGFR2, EGFR, AKT and
extracellular signal-regulated kinases (ERK).
- Women with biopsy-proven epithelial ovarian, fallopian tube or primary peritoneal
cancer that is relapsed and/or refractory to prior therapy.
- Women must have measurable disease by NCI Response Evaluation Criteria in Solid Tumors
(RECIST) criteria and a sentinel lesion adequate for core biopsy through percutaneous
- Women must have had no more than four prior treatment regimens.
- Women will receive 300mg of ZD6474 (vandetanib) daily, orally in 28-day cycles until
disease progression, excessive toxicity, or withdrawal from study.
- Biopsy of tumor will be performed prior to starting ZD6474 (vandetanib) and after six
weeks of treatment. The quantity of phosphorylated VEGFR2, EGFR, ERK and AKT in the
biopsy tissue will be analyzed.
- Clinical outcome and toxicity will be measured and correlated with target inhibition.
- Women will also undergo serial imaging with dynamic contrast-enhanced MRI to estimate
tumor blood flow.
- Research blood samples will be taken to assess changes in circulating cytokine
- Quality of life will be assessed during treatment.
Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Number of Participants With Clinical Efficacy
Defined as complete response (CR), partial response (PR), or disease stabilization lasting 6 months or longer per RECIST criteria. CR-total disappearance of all evaluable disease. PR->30% reduction in the sum of the longest diameters (LD) of target lesions. Stable disease (SD) is <30% decrease and <20% increase in the sum of the LD of all target lesions. See the protocol Link module for full RECIST criteria.
Elise C Kohn, M.D.
National Cancer Institute, National Institutes of Health
United States: Federal Government
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