MK-2206 and AZD6244 in Patients With Advanced Colorectal Carcinoma

• 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 Adver