A Phase I Study of AZD6244 in Combination With Capecitabine and Radiotherapy in Locally Advanced Adenocarcinoma of the Rectum

Study Overview
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Brief Summary
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Background: - The investigational anti-cancer drug Selumetinib (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. Objectives: - To determine safe and effective doses of AZD6244, along with radiation and chemotherapy, to treat rectal cancer. Eligibility: - 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. Design: 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.

Detailed Description
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Background: Local recurrences of rectal cancer are morbid and difficult to manage effectively. Colorectal cancers frequently harbor rat sarcoma (RAS) mutations and Epidermal growth factor (EGF)/epidermal growth factor receptor (EGFR) over-expression. AZD6244 is an orally available selective, adenosine triphosphate uncompetitive inhibitor of methyl ethyl ketone (MEK)1/2 that sensitizes tumor cells to radiation in vitro and in vivo. Objectives: Primary To define the maximum tolerable dose of AZD6244 Hyd-Sulfate delivered twice a day (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 Secondary To evaluate the pharmacokinetics of AZD6244 delivered alone and in combination with Capecitabine 825 mg/m(2) by mouth (PO) BID. To obtain exploratory information regarding the pathologic response rate obtained after treatment with the maximum tolerated dose (MTD) of AZD6244 Hyd-Sulfate in combination with Capecitabine and 50.4 Gray (Gy) of RT. To determine if changes in phosphorylated extracellular-signal regulated kinase (ERK) (pERK) in peripheral blood mononuclear cells correlates to changes in phosphorylated extracellular-signal regulated kinase (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. Eligibility: 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. Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2. Normal organ and marrow function. Design: 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.

Official Title
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A Phase I Study of AZD6244 in Combination With Capecitabine and Radiotherapy in Locally Advanced Adenocarcinoma of the Rectum

Conditions
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Non-Metastatic Adenocarcinoma of the Rectum

Intervention / Treatment
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* Procedure: Radiation Therapy
* Drug: Capecitabine
* Drug: AZD6244


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Patients must have histologically or cytologically confirmed locally advanced, non-metastatic adenocarcinoma of the rectum (clinical stage T3 anyN, T4 anyN, or AnyT N+). Patients with recurrent adenocarcinoma of the rectum with no clinically evident distant disease will be eligible if they are deemed to have pelvic nodal metastases or disease extending through the muscularis of the rectum. These patients should be evaluated by a Radiation Oncologist, Medical Oncologist and Surgeon prior to enrolling on study to confirm anticipated resectability. These patients should not have received prior radiotherapy for management of their rectal cancer. Age greater than or equal to 18 years. Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1 (Karnofsky greater than or equal to 70%). Patients must have normal organ and marrow function as defined below: leukocytes greater than or equal to 3,000/mcL absolute neutrophil count greater than or equal to 1,500/mcL platelets: greater than or equal to 100,000/mcL total bilirubin: within normal institutional limits except for patients with Gilbert's who must have a direct bilirubin of less than 1.0 mg/dL Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) less than or equal to 2.5 times the institutional upper limit of normal creatinine within normal institutional limits OR -- creatinine clearance greater than or equal to 60 mL/min/1.73 m(2) for patients with creatinine levels above institutional normal. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for six months after the completion of radiation. Women of child-bearing potential must have a negative pregnancy test prior to entry. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Adequate contraception for male patients should be used for 6 months after irradiation. Ability to understand and the willingness to sign a written informed consent document. Willingness to sign a release of medical records pertaining to previous and future treatment for rectal cancer. EXCLUSION CRITERIA: Chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or lack of recovery from adverse events due to agents administered more than 4 weeks earlier. Patients may not be receiving any other investigational agents. History of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD6244 or other agents used in study. Previous methyl ethyl ketone (MEK) inhibitor use. Contraindications to radiotherapy to the pelvis such as inflammatory bowel disease or known genetic sensitivity to ionizing radiation such as ataxia telangiectasia. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Patients with corrected QT interval (QTc) interval greater than 470 msecs or other factors that increase the risk of Q wave, T wave (QT) prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome) including heart failure that meets New York Heart Association (NYHA) class III and IV definitions are excluded. Required use of a concomitant medication that can prolong the QT interval. A comprehensive list of agents with the potential to cause QTc prolongation can be found at http://www.arizonacert.org/medical-pros/drug-lists/drug-lists.htm. Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g. inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption. Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy. Known dihydropyrimidine dehydrogenase deficiency. History of prior radiation to the pelvis For patients with newly diagnosed rectal cancer, prior therapy for adenocarcinoma of the rectum with the exception of diverting colostomy if required to relieve obstruction (including chemotherapy). Patients with recurrent rectal cancer may not have undergone prior radiotherapy for rectal adenocarcinoma or have received therapy for the recurrence with the exception of diverting colostomy if required to relieve obstruction. History of myocardial infarction within the past 6 months or history of ventricular arrhythmia Uncontrolled hypertension Pregnant or lactating females are excluded

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Selumetinib (AZD6244): 50 mg & Capecitabine: 825 mg/m^2<br>LEVEL 1 - Cycle = 49 days: AZD6244: 50 mg by mouth (PO) everyday (QD) Capecitabine: 825 mg/m^2 by mouth (PO) | Procedure: Radiation Therapy<br> <br> Drug: Capecitabine<br> <br> * Other names: Xeloda;Drug: AZD6244<br> <br> * Other names: Selumetinib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerable Dose of Selumetinib (AZD6244) Hyd-Sulfate in Combination With Radiation Therapy (RT) and Capecitabine in Participants With Locally Advanced Adenocarcinoma of the Rectum. | Maximum tolerable dose is defined as the dose level at which no more than 1 of 6 participants experience dose limiting toxicity (DLT) during treatment and the three weeks after completion. Examples of DLT is recurring and persistent Grade 3 diarrhea despite appropriate medical therapy, absolute neutrophil count <500 for more than 5 days or neutropenic fever, Grade 3 thrombocytopenia, Grade 4 fatigue, and Grade 4 dermatitis acneiform rash. | During treatment and within first 3 weeks after treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of Selumetinib (AZD6244) in Combination With Capecitabine | To evaluate the pharmacokinetics of AZD6244 in Combination with Capecitabine using logistic regression. | Pre-and post treatment | 
| Changes in Phosphorylated ERK (pERK) in Peripheral Blood Mononuclear Cells and Tumor, and Transforming Growth Factor Alpha (TGFa) Levels | Changes in phosphorylated ERK (pERK) in peripheral blood mononuclear cells and tumor, and TGFa levels measured by flow cytometry. | Pre-and post treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rectal Cancer, Radiation Therapy, Capecitabine, AZD6244