A Phase I Study of AZD6244 in Combination With Capecitabine and Radiotherapy in Locally Advanced Adenocarcinoma of the Rectum
- Local recurrences of rectal cancer are morbid and difficult to manage effectively.
- Colorectal cancers frequently harbor RAS mutations and EGF/EGFR over-expression.
- AZD6244 is an orally available selective, adenosine triphosphate-uncompetitive
inhibitor of MEK1/2 that sensitizes tumor cells to radiation in vitro and in vivo.
- To define the maximum tolerable dose of AZD6244 Hyd-Sulfate delivered BID, 7 days per
week, in combination with radiation therapy (RT) and Capecitabine in patients with
locally advanced adenocarcinoma of the rectum without distant metastases.
- To define the dose-limiting toxicities and toxicity profile associated with
administration of AZD6244 Hyd-Sulfate delivered BID, 7 days per week in combination
with RT and Capecitabine
- To evaluate the pharmacokinetics of AZD6244 delivered alone and in combination with
Capecitabine 825 mg/m(2) PO BID.
- To obtain exploratory information regarding the pathologic response rate obtained after
treatment with the MTD of AZD6244 Hyd-Sulfate in combination with Capecitabine and 50.4
Gy of RT.
- To determine if changes in phosphorylated ERK (pERK) in peripheral blood mononuclear
cells correlates to changes in pERK in rectal tumors in the setting of treatment with
- To perform an exploratory analysis to determine if the presence of activating mutations
in RAS or BRAF in tumor or changes in plasma transforming growth factor-alpha
(TGFalpha) levels and tumor pERK/total ERK with AZD6244 treatment alone and after
AZD6244 in combination with Capecitabine and RT predicts for down staging or pathologic
- Histologically or cytologically confirmed locally advanced, non-metastatic
adenocarcinoma of the rectum (clinical stage T3AnyN, T4AnyN, or AnyTN+).
- Age greater than or equal to 18 years.
- ECOG performance status less than or equal to 2.
- Normal organ and marrow function.
- All patients will receive 50.4 Gy of RT to the pelvis and rectal tumor delivered
concurrently with Capecitabine and AZD6244. AZD6244 will be delivered BID daily, 7 days
per week, in a dose escalated fashion. AZD6244 will begin one week prior to
Capecitabine and RT and will conclude on the last day of Capecitabine and RT.
- Capecitabine will be delivered at 825 mg/m(2) PO every 12 hours, 5 days per week,
starting on the first day of RT and continuing until the last day of RT.
- Biopsies of tumor tissue will be obtained prior to treatment, after one week of
AZD6244, and after one week of AZD6244, RT, and Capecitabine for correlative assays.
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To define the maximum tolerable dose and toxicity profile of AZD6244 Hyd-Sulfate delivered BID, 7 days per week, in combination with radiation therapy (RT) and Capecitabine in patients with locally advanced adenocarcinoma of the rectum.
Ramaprasad Srinivasan, M.D.
National Cancer Institute (NCI)
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|