A Phase I Study of AZD6244 in Combination With Capecitabine and Radiotherapy in Locally Advanced Adenocarcinoma of the Rectum
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|ClinicalTrials.gov Identifier: NCT01134601|
Recruitment Status : Terminated
First Posted : June 2, 2010
Last Update Posted : September 12, 2018
- The investigational anti-cancer drug AZD6244 prevents a protein found in rectal cancer from working properly, which may slow tumor growth and allow radiation and chemotherapy treatments to destroy more cancer cells. Researchers are interested in determining whether AZD6244 can be used to improve treatment outcomes in individuals who have rectal cancer that has spread outside the rectum into the surrounding pelvis.
- To determine safe and effective doses of AZD6244, along with radiation and chemotherapy, to treat rectal cancer.
- Individuals at least 18 years of age who have been diagnosed with rectal cancer that has spread outside the inner wall of the rectum or into lymph nodes in the pelvis.
- Eligible participants will be screened with a physical examination, blood and tumor samples, and imaging studies.
- Participants will receive AZD6244 twice a day by mouth for 1 full week (7 days) before starting radiation and chemotherapy and every week thereafter until the end of the radiation and chemotherapy treatment.
- Participants will have radiation therapy daily, 5 days per week, for approximately 6 weeks.
- Participants will receive chemotherapy (capecitabine) twice daily, 5 days per week, for approximately 6 weeks.
- Approximately 4 to 8 weeks after completing the AZD6244, radiation, and chemotherapy treatment, participants may have surgery to remove any tumors and affected lymph nodes. This surgery is not part of the treatment delivered on this protocol.
- Participants will have a follow-up exam 3 weeks after the end of treatment, every 3 months for the first year, and then in the second and third year after the end of treatment. These visits will involve a full medical examination and imaging studies.
|Condition or disease||Intervention/treatment||Phase|
|Non-Metastatic Adenocarcinoma of the Rectum||Procedure: Radiation Therapy Drug: Capecitabine Drug: AZD6244||Phase 1|
- 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 AZD6244.
- 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 response.
- 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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||1 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase I Study of AZD6244 in Combination With Capecitabine and Radiotherapy in Locally Advanced Adenocarcinoma of the Rectum|
|Study Start Date :||May 24, 2010|
|Actual Primary Completion Date :||October 22, 2012|
|Actual Study Completion Date :||October 22, 2012|
- 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.
- To evaluate the pharmacokinetics. To obtain exploratory information regarding the pathologic response rate. To determine changes in phosphorylated ERK (pERK) in peripheral blood mononuclear cells.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01134601
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
|Principal Investigator:||Deborah E Citrin, M.D.||National Cancer Institute (NCI)|