Cancer Res Treat.  2016 Jan;48(1):28-36. 10.4143/crt.2014.258.

Phase I Study of CKD-516, a Novel Vascular Disrupting Agent, in Patients with Advanced Solid Tumors

• Oh DY
• Kim TM
• Han SW
• Shin DY
• Lee YG
• Lee KW
• Kim JH
• Kim TY
• Jang IJ
• Lee JS
• Bang YJ

• KMID: 2152257
• DOI: http://doi.org/10.4143/crt.2014.258

Abstract

PURPOSE
CKD-516 is a newly developed vascular disrupting agent. This phase I dose-escalation study of CKD-516 was conducted to determine maximum-tolerated dose (MTD), safety, pharmacokinetics, and preliminary antitumor efficacy in patients with advanced solid tumors.
MATERIALS AND METHODS
Patients received CKD-516 intravenously on D1 and D8 every 3 weeks, in a standard 3+3 design. Safety was evaluated by National Cancer Institute Common Terminology Criteria for Adverse Events ver. 4.02 and response was assessed by Response Evaluation Criteria in Solid Tumor ver. 1.1.
RESULTS
Twenty-three patients were treated with CKD-516 at seven dosing levels: 1 mg/m2/day (n=3), 2 mg/m2/day (n=3), 3.3 mg/m2/day (n=3), 5 mg/m2/day (n=3), 7 mg/m2/day (n=3), 9 mg/m2/day (n=6), and 12 mg/m2/day (n=2). Mean age was 54 and 56.5% of patients were male. Two dose-limiting toxicities, which were both grade 3 hypertension, were observed in two patients at 12 mg/m2/day. The MTD was determined as 12 mg/m2/day. Most common adverse events were gastrointestinal adverse events (diarrhea, 34.8% [30.4% grade 1/2, 13.0% grade 3]; nausea, 21.7% [all grade 1/2]; vomiting, 21.7% [all grade 1/2]), myalgia (17.4%, all grade 1/2), and abdominal pain (21.7% [21.7% grade 1/2, 4.3% grade 3]). The pharmacokinetic study showed the dose-linearity of all dosing levels. Among 23 patients, six patients (26.1%) showed stable disease. Median progression-free survival was 39 days (95% confidence interval, 37 to 41 days).
CONCLUSION
This study demonstrates feasibility of CKD-516, novel vascular disrupting agent, in patients with advanced solid tumor. MTD of CKD-516 was defined as 12 mg/m2/day on D1 and D8 every 3 weeks.

Keyword

CKD-516; Vascular disrupting agent; Phase I clinical trial; Solid tumor

MeSH Terms

Abdominal Pain
Disease-Free Survival
Humans
Hypertension
Male
Myalgia
National Cancer Institute (U.S.)
Nausea
Pharmacokinetics
Vomiting

Figure

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  Fig. 1. Mean plasma concentration-time profiles of CKD-516 (A) and S-516 (B) after a single intravenous dose. The inserts show the profiles by log-linear scale. Bars represent standard deviations.

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  Fig. 2. Regression analysis of maximum concentration (Cmax) of CKD-516 (A) and S-516 (B) by dose. Solid lines are regression lines and dotted lines represent 95% confidence intervals.

Reference

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