A Phase 2 Study of AZD6244 in Advanced or Metastatic Hepatocellular Carcinoma
I. To ascertain the objective response rate (complete response and partial response) in
patients with locally advanced or metastatic hepatocellular carcinoma treated with AZD6244
I. To assess the safety and tolerability of AZD6244 when administered to patients with
hepatocellular carcinoma and mild (Child's A to compensated Child's B) liver dysfunction.
II. To describe the pharmacokinetics (PK) of AZD6244 in this patient population and compare
in exploratory fashion to the established PK profile in patients with normal hepatic
III. To estimate the time to event functions of progression, progression-free survival
(PFS), (and PFS associated with treatment), and overall survival.
IV. To explore, preliminarily, the possible correlations between baseline mitogen-activated
protein kinase (MEK) activation (i.e., presence of phospho-MEK) and radiographic response or
time to progression.
V. To investigate the effects of AZD6244 on MEK kinase activity in peripheral blood
mononuclear cells from patients treated with this drug.
Patients receive a single dose of selumetinib on day 1 and undergo blood collection for
pharmacokinetic (PK) sampling pre-dose (within 30 min of dosing), 15 and 30 minutes and 1,
2, 4, 8, 12, 24 and 48 hours post-dose. Beginning 48 hours after the initial dose and
continuing until day 21, patients receive oral selumetinib twice daily. Patients also
undergo blood collection for PK sampling on day 15 of course 1. In all subsequent courses,
patients receive selumetinib on days 1-21. Treatment repeats every 21 days in the absence of
disease progression or unacceptable toxicity.
Selumetinib blood concentrations are quantified by high performance liquid chromatography.
Patients also undergo tumor biopsy by CT or ultrasound guidance at baseline and on day 8.
Peripheral blood mononuclear cells and tumor tissue are evaluated for mitogen-activated
protein kinase baseline activity and post-treatment activity.
After completion of study treatment, patients are followed periodically for up to 2 years.
Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Number of Participants With Radiographic Objective Response (OR)
To ascertain the objective response rate (Complete Response + Partial Response [CR+PR]) of patients with the single-agent AZD6244. Our study utilized Response Evaluation Criteria in Solid Tumors (RECIST) to evaluate response. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
H. Lee Moffitt Cancer Center and Research Institute
United States: Food and Drug Administration
|H. Lee Moffitt Cancer Center and Research Institute||Tampa, Florida 33612|
|Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center||Columbus, Ohio 43210-1240|
|Vanderbilt University||Nashville, Tennessee 37232-6305|
|University of North Carolina||Chapel Hill, North Carolina 27599|
|Emory University||Atlanta, Georgia 30322|
|Virginia Commonwealth University||Richmond, Virginia|