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Published on: August 11, 2017
A phase I dose-escalation study of ZD6474 in Japanese patients with solid, malignant tumors
Tomohide Tamura1, Hironobu Minami, Yasuhide Yamada
1National Cancer Center Hospital, Chuo-ku, Tokyo, Japan. ttamura@ncc.go.jp
Introduction:
ZD6474 (vandetanib) is an orally available inhibitor of vascular endothelial growth factor receptor, epidermal growth factor receptor, and RET receptor tyrosine kinase activity. This study assessed the safety and tolerability of escalating doses of ZD6474 in Japanese patients with solid, malignant tumors.
Methods:
Adult patients with solid tumors refractory to standard therapy received a once-daily oral dose of ZD6474 (100-400 mg) in 28-day cycles, until disease progression or unacceptable toxicity was observed.
Results:
Eighteen patients were treated at doses of 100 mg (n = 3), 200 mg (n = 6), 300 mg (n = 6), and 400 mg (n = 3). Dose-limiting toxicities at the completion of cycle 2 were hypertension (n = 3), diarrhea (n = 1), headache (n = 1), toxic skin eruption (n = 1), and alanine aminotransferase increase (n = 1). A dose of 400 mg/day was considered to exceed the maximum tolerated dose (MTD). Toxicities were manageable with dose interruption and/or reduction. Objective tumor response was observed in four of nine patients with non-small cell lung cancer (NSCLC) at doses of either 200 or 300 mg. Terminal half-life was about 90-115 hours. Plasma trough concentrations achieved steady-state conditions after approximately 1 month of daily dosing.
Conclusions:
It was concluded that a dose of 400 mg/day was considered to exceed the MTD, and doses for phase II study were thought to be not more than 300 mg/day. The objective response observed in some NSCLC patients is encouraging for further studies in this tumor type.
Insights
The maximum tolerated dose of ZD6474 (vandetanib) in Japanese patients with solid tumors was determined to be below 400 mg/day. Encouraging responses were seen in non-small cell lung cancer (NSCLC) patients.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- ZD6474 (vandetanib) is an oral inhibitor targeting VEGFR, EGFR, and RET tyrosine kinases.
- This study evaluated escalating doses of ZD6474 in Japanese patients with solid tumors.
Purpose of the Study:
- To assess the safety and tolerability of ZD6474.
- To determine the maximum tolerated dose (MTD) of ZD6474 in this population.
Main Methods:
- Adult patients with refractory solid tumors received daily oral ZD6474 (100-400 mg) in 28-day cycles.
- Treatment continued until disease progression or unacceptable toxicity.
Main Results:
- Eighteen patients were treated across dose levels (100-400 mg).
- Dose-limiting toxicities included hypertension and diarrhea; 400 mg/day exceeded the MTD.
- Objective tumor responses were observed in 4/9 non-small cell lung cancer (NSCLC) patients at 200 or 300 mg.
Conclusions:
- The MTD of ZD6474 was determined to be below 400 mg/day.
- Recommended doses for Phase II studies are ≤300 mg/day.
- Observed responses in NSCLC warrant further investigation.
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