MK-2206 and AZD6244 in Patients With Advanced Colorectal Carcinoma
Condition: Colorectal Neoplasms
MeSH terms: Colorectal Neoplasms
Intervention: MK-2206 + AZD6244
Intervention description: MK-2206 and AZD6244 hydrogen sulfate are selective inhibitors of human AKT and MEK, respectively, with preclinical and clinical anti-tumor activity as single agents and in combination with a variety of drugs. Combination treatment in mouse cancer models harboring mutations in both the PI3K and RAS pathways was more potent compared to either agent used alone, and resulted in substantial tumor inhibition, including tumor regression.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 21.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Targeted Therapy; KRAS Mutation; Metastatic Colorectal Cancer; Colorectal Cancer

Summary:

      Background:

      - MK-2206 and AZD6244 (Selumetinib) are experimental cancer treatment drugs that block the
      effect of certain proteins that cancer cells need to grow and survive. These drugs may be
      effective treatments for some types of colorectal cancer that has not responded to or has
      relapsed after standard treatment. Researchers are interested in studying how MK-2206 and
      AZD6244 affect levels of certain proteins in colorectal cancer tumor, and how well the drugs
      work against cancer cells by examining cells from a tumor sample collected before the drugs
      are given and again after the drugs are given.

      Objectives:

      - To evaluate the safety and effectiveness of MK-2206 and AZD6244 in individuals with
      advanced colorectal carcinoma that has not responded to standard treatments.

      Eligibility:

      - Individuals at least 18 years of age who have been diagnosed with advanced colorectal
      carcinoma that has not responded to at least one type of standard chemotherapy.

      Design:

        -  Participants will be screened with a physical examination, medical history, blood tests,
           and tumor imaging studies.

        -  Participants will take MK-2206 and AZD6244 by mouth for 4-week cycles of treatment, with
           one dose of MK-2206 per week and one dose of AZD6244 every day. (If participants have
           negative side effects from the medications, the doses will be adjusted to a smaller
           dose). Participants will keep a diary to record doses and keep track of any side
           effects.

        -  During treatment, participants will have regular visits to the clinical center,
           involving blood and urine tests, tumor biopsies, and other examinations to monitor the
           effects of treatment. Participants will have imaging studies every two cycles (8 weeks)
           to study the cancer's response to the treatment.

        -  Participants will continue to have cycles of treatment for as long as the treatment
           continues to be effective and the side effects are not severe enough to stop
           participation in the study....
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  Patients must have histologically confirmed metastatic colorectal cancer, which has
             recurred or progressed following oxaliplatin- and irinotecan-based chemotherapy
             regimens administered for the treatment of metastatic disease, except if the patient
             was not a candidate for either agent or refused treatment with oxaliplatin or
             irinotecan. The diagnosis must be confirmed by the Laboratory of Pathology at the
             Clinical Center, NIH (National Institutes of Health), prior to patient enrollment.

          -  Results of KRAS (Kirsten-Ras) mutation analysis must be available prior to patient
             enrollment.

          -  Patients must have disease amenable to biopsy, and must be willing to undergo pre- and
             post-treatment tumor biopsies.

          -  Patients must have completed any major surgery chemotherapy, radiation therapy, or
             biologic therapy greater than or equal to 4 weeks prior to entering the study (6 weeks
             for nitrosoureas or mitomycin C). Patients must be greater than or equal to 2 weeks
             since any prior administration of a study drug in an exploratory IND (investigational
             new drug) /Phase 0 study. Patients must have recovered to eligibility levels from any
             prior surgery, toxicity, or adverse events.

          -  Age greater than or equal to 18 years. Because no dosing or adverse event data are
             currently available on the use of MK-2206 in combination with AZD6244 in patients less
             than 18 years of age, children are excluded from this study.

          -  Life expectancy of greater than 3 months.

          -  ECOG (Eastern Cooperative Oncology Group) performance status less than 2.

          -  Patients must have normal organ and marrow function as defined below:

               -  Absolute neutrophil count greater than or equal to 1,500/microL

               -  Platelets greater than or equal to 100,000/microL

               -  Total bilirubin less than or equal to 1.5 times institutional ULN (upper limit of
                  normal)

               -  AST (aspartate aminotransferase) /ALT (alanine aminotransferase) less than or
                  equal to 3.0 times institutional ULN; less than or equal to 5.0 times
                  institutional ULN if liver metastases

               -  Creatinine less than 1.5 times ULN; OR

               -  Measured creatinine greater than or equal to 60 mL/minute for patients with
                  clearance creatinine levels greater than or equal to 1.5 times ULN

               -  INR (International Normalized Ratio) less than or equal to 1.4

               -  PTT (partial thromboplastin time) less than or equal to 40 seconds unless due to
                  lupus anticoagulant

          -  The effects of MK-2206 and of AZD6244 on the developing human fetus at the recommended
             therapeutic dose are unknown. For this reason 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 4
             weeks after dosing with study medication ceases. However, adequate contraception for
             male patients should be used for 16 weeks post- last dose due to sperm life cycle.
             Should a woman become pregnant or suspect she is pregnant while she or her partner is
             participating in this study, she should inform her treating physician immediately.
             Women of child-bearing potential must have a negative pregnancy test prior to entry.

          -  Patients must be able to swallow whole tablets and capsules. Tablets must not be
             crushed or chewed; capsules must not be opened.

          -  Ability to understand and the willingness to sign a written informed consent document.

        EXCLUSION CRITERIA:

          -  Patients who are receiving any other investigational agents.

          -  Patients with known brain metastases or carcinomatous meningitis are excluded from
             this clinical trial, with the exception of patients whose brain metastatic disease
             status has remained stable for greater than or equal to 4 weeks after treatment of the
             brain metastases, without steroids. Patients on stable doses of antiseizure
             medications with no history of seizures in the past 4 weeks will be eligible.

          -  Poorly controlled diabetes defined as fasting blood glucose of greater than 160 mg/dL
             (CTCAE (Common Terminology Criteria for Adverse Events)) Grade greater than or equal
             to 2) or HgA1c (glycated hemoglobin) greater than 8%.

          -  QTc (corrected QT interval) prolongation greater than 450 msec (male) or QTc greater
             than 470 msec (female) by Bazetts formula or use of medications that may cause QTc
             interval prolongation. A comprehensive list of agents with the potential to cause QTc
             prolongation can be found at http://www.azcert.org/medical-pros/drug-
             lists/bycategory.cfm.

          -  Patients with clinically significant intercurrent illnesses, including but not limited
             to, interstitial pneumonitis, pulmonary fibrosis, uncontrolled infection, psychiatric
             illness or social situations that would limit compliance with study requirements.

          -  Patients with symptomatic congestive heart failure, unstable angina, uncontrolled
             cardiac arrhythmia, myocardial infarction in the past 6 months, left ventricular
             ejection fraction (LVEF) less than or equal to 50%, are not eligible to participate.

          -  Uncontrolled hypertension (blood pressure [BP] of greater than or equal to 150/95
             despite optimal therapy).

          -  Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g., inflammatory
             bowel disease), or significant bowel resection that would preclude adequate
             absorption.

          -  HIV (human immunodeficiency virus) -positive patients on combination antiretroviral
             therapy are ineligible because of the potential for pharmacokinetic interactions with
             MK-2206 and AZD6244.

          -  Patients currently on warfarin (Coumadin) are ineligible. Otherwise eligible patients
             requiring anticoagulant treatment should have their warfarin switched to a low
             molecular weight heparin such as enoxaparin injections.

          -  Patients on strong cytochrome P450 system inducers or inhibitors are ineligible.

        INCLUSION OF WOMEN AND MINORITIES:

        -Both men and women of all races and ethnic groups are eligible for this trial.