A Phase I Study of AZD6244 in Combination With Capecitabine and Radiotherapy in Locally Advanced Adenocarcinoma of the Rectum
Condition: Non-Metastatic Adenocarcinoma of the Rectum
MeSH terms: Adenocarcinoma; Rectal Neoplasms
Intervention: Radiation Therapy; Capecitabine; AZD6244
Intervention MeSH terms: Capecitabine
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 1.0
Sex: All
Minimum age: 18 Years
Maximum age: 99 Years
Healthy volunteers: No
Keywords: Rectal Cancer; Radiation Therapy; Capecitabine; AZD6244

Summary:

      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.
    

Eligibility criteria:

        -  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