An Open Label Phase I Study of Gemcitabine/Oxaliplatin (GEMOX) and Vandetanib (ZACTIMA; ZD6474) Combination in Patients With Advanced Solid Malignancy (IRUSZACT0070) (UPCI 07-025)
This is a Phase I, open-label, dose-escalating, non-randomized study of the safety and
tolerability of vandetanib in combination with a fixed dose of gemcitabine and oxaliplatin
(GemOx) in the treatment of patients with advanced solid malignancy. EGFR is an important
target for therapeutic drug development. It is widely expressed in most cancers and has a
vital role in the regulation of proliferation signals. EGFR is expressed in a high degree
(>80%) of pancreatic tumors and is a rational target for therapy. Vandetanib selectively
inhibits EGFR tyrosine kinase activity and VEGF-2 receptor. It has good oral bioavailability
and has growth inhibitory activity in a wide variety of human cell lines including cells
with acquired resistance to other EGFR inhibitors. The growth inhibitory property of
vandetanib in vivo correlates more with its anti VEGF property, especially in cell lines
with acquired resistance to EGFR inhibition. The combination of gemcitabine and oxaliplatin
(GEMOX) is a well-established regimen that has demonstrated encouraging antitumor activity
in pancreaticobiliary cancers in phase II studies. Recent clinical trials have also shown
activity in hepatobiliary and germ cell tumors. The combination of vandetanib and
gemcitabine has potential advantages and may result in an additive or synergistic effect.
The GEMOX regimen is well tolerated, and toxicity does not overlap with the most common
toxicity of rash or diarrhea observed with vandetanib. Thus, the combination of vandetanib
and GEMOX is expected to be a well tolerated, and an easily administered regimen with
improved efficacy and no overlapping toxicities.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To establish the Maximum Tolerated Dose (MTD) and toxicities of vandetanib (Zactima; ZD6474) in combination with fixed dose of GEMOX (gemcitabine/oxaliplatin) and to establish the recommended phase II dose of the GEMOX and vandetanib regimen
The MTD (and recommended phase II dose) is defined as the highest dose at which <2 of 6 patients experience DLT. The observation period for DLT is the first cycle of therapy.
Leonard J. Appleman, M.D., Ph.D.
University of Pittsburgh
United States: Food and Drug Administration
|University of Pittsburgh Cancer Institute / Hillman Cancer Center||Pittsburgh, Pennsylvania 15232|