A phase I surrogate endpoint study of SU6668 in patients with solid tumors.
OBJECTIVE
To evaluate the biologic effects of SU6668 in patients with solid tumors using comprehensive measures of pharmacokinetics (PK), functional imaging, and tissue correlative studies.


METHODS
Eligible patients with tumors accessible for core needle biopsy were treated with SU6668 at doses of 200 or 400 mg/m(2)/day. Functional computed tomography (CT) scan and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were performed at baseline and repeated 4 weeks and 12 weeks after treatment for analysis of tumor angiogenesis. The PK was analyzed using a high-performance liquid chromatography assay. Tumor specimens obtained via core needle biopsy at baseline and 4 weeks later were analyzed for the biologic effects of SU6668.


RESULTS
Six of a total of seven patients received treatment for at least 3 months and underwent comprehensive correlative studies, including PK, imaging, and tissue biopsy. Functional CT showed that five of six patients had decreased blood flow in tumors in response to treatment, and DCE-MRI results indicated significant change of area under the signal intensity vs. time curve (AUC) and/or maximum slope (maximum rate of signal intensity change) in two of four patients evaluated with this technique. PK studies showed that the mean apparent oral clearance (Cl(oral)) measured on day 1 was 6.3 +/- 2.7 L/hr/m(2), yielding a mean AUC of 16.6 +/- 4.3 mg/L.hr. By day 22, the Cl(oral) was 40% more than that observed on day 1.


CONCLUSIONS
It is feasible to evaluate the biologic effects of antiangiogenic agents using comprehensive surrogate measures.
Department of Gastrointestinal Medical Oncology, University of Texas, M. D. Anderson Cancer Center, Houston, TX, USA.
Henry Q
HQ
Xiong
Roy
R
Herbst
Silvana C
SC
Faria
Catherine
C
Scholz
Darren
D
Davis
Edward F
EF
Jackson
Timothy
T
Madden
David
D
McConkey
Marshall
M
Hicks
Kenneth
K
Hess
Chusilp Arthur
CA
Charnsangavej
James L
JL
Abbruzzese
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D023381:Endpoint Determination; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000098:blood supply / Q000000981:diagnostic imaging / Q000188:drug therapy*; D000078183:Oxindoles; D011422:Propionates; D011758:Pyrroles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013997:Time Factors; D014057:Tomography, X-Ray Computed
D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D007211:Indoles; D000078183:Oxindoles; D011422:Propionates; D011758:Pyrroles; C412603:orantinib