A Phase 2 Study of AZD6244 in Biliary Cancers
I. To evaluate the objective response rate (complete response [CR] and partial response
[PR]) in patients with unresectable biliary carcinoma treated with AZD6244 (selumetinib).
I. To evaluate the toxicity profile of this drug in these patients. II. To evaluate the 6-
and 12-month survival, 6-month progression-free survival, and overall survival rates of
patients treated with this drug.
III. To correlate genetic mutations, epigenetic silencing, and/or protein levels of
RAS/RAF/MEK/ERK signaling pathway activation with therapeutic efficacy of AZD6244 in these
IV. To genotype tumors for the presence of RAS mutations (i.e., NRAS, KRAS, HRAS) and BRAF
mutations (e.g., V600E) in biliary tumor samples from these patients.
V. To assess the presence of activation of the MEK1, MEK2, ERK, and/or Akt pathways in tumor
samples from these patients.
VI. To assess the epigenetic alterations (i.e., methylation) affecting the level of
gene/protein expression of RASSF1A, NORE1A, and NORE1B in tumor samples from these patients.
Patients receive oral selumetinib twice daily on days 1-28. Courses repeat every 28 days in
the absence of disease progression or unacceptable toxicity.
Formalin fixed paraffin-embedded tissue blocks or fresh tissue samples are obtained from all
patients prior to treatment. Tissue samples are analyzed by immunohistochemistry for the
expression level of target proteins (MEK, p-MEK, ERK, p-ERK, Akt, p-AKT, RASSF1A, NORE1A and
NORE1B); PCR for mutational status of target genes RAS, BRAF and EGFR); and in
methylation-specific PCR for methylation of target gene promoters (promoters for RASSF1A,
NORE1A and NORE1B). Samples are also analyzed by quantitative real-time PCR to compare
methylation status. Fresh frozen tissue, when available, is evaluated by Western analysis to
measure expression levels of target proteins.
After completion of study treatment, patients are followed up for 4 weeks.
Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Objective response rate (CR and PR)
Response will be evaluated in this study using the new international criteria proposed by Response Evaluation Criteria in Solid Tumors (RECIST) committee. Only those patients who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response. A Simon 2-stage minimax design, which minimizes the maximum sample size given specified alpha and beta error rates will be utilize.
Every 8 weeks
Ohio State University
United States: Food and Drug Administration
|H. Lee Moffitt Cancer Center and Research Institute||Tampa, Florida 33612|
|Vanderbilt University||Nashville, Tennessee 37232-6305|
|University of North Carolina||Chapel Hill, North Carolina 27599|
|Emory University||Atlanta, Georgia 30322|
|Wayne State University||Detroit, Michigan 48202|
|Ohio State University Medical Center||Columbus, Ohio 43210|
|University of Michigan Cancer Center (UMCC) Research Base||Ann Arbor, Michigan 48109-0352|