MK-2206 and AZD6244 in Patients With Advanced Colorectal Carcinoma

Background:

- The PI3K-AKT (protein kinase B) and RAF/MEK (methyl ethyl ketone)/ERK
(extracellular-signal regulated kinase) pathways are two of the most frequently
activated signaling pathways in cancer, including colorectal cancer (CRC). KRAS
(Kirsten Rat Sarcoma Viral Oncogene Homolog) mutations are detected in approximately
40% of patients with CRC and predict for resistance to EGFR (epidermal growth factor
receptor) inhibitors. AKT is upregulated in approximately 60% of CRC.

- Preclinical studies demonstrate that activating mutations in the PI3K-AKT pathway and
increased phosphorylated Akt through a MEK-EGFR-PI3K feedback loop are implicated in
resistance to the antitumor effect of MEK inhibition.

- 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 (Rat Sarcoma) pathways was more potent
compared to either agent used alone, and resulted in substantial tumor inhibition,
including tumor regression. The combination is being studied in a Phase I trial and
appears tolerable.

Primary Objectives:

- Determine reduction of pERK and pAKT in tumor biopsies on C1D1 (cycle 1 day 1)
post-administration of the combination of AZD6244 hydrogen sulfate and MK-2206 in
patients with advanced colorectal cancer, stratified for KRAS mutation status.

- Evaluate for recovery of pAKT levels in tumor biopsy samples obtained on C1D4 (cycle 1,
day 4) after administration of the combination of AZD6244 hydrogen sulfate and MK-2206
in patients with advanced colorectal cancer, stratified for KRAS mutation status.

- Determine reduction of Ki-67 in tumor biopsies post-administration of the combination
of AZD6244 hydrogen sulfate and MK-2206 in patients with advanced colorectal cancer,
stratified for KRAS mutation status.

Secondary Objectives:

- Evaluate reduction of pERK and pAKT in peripheral blood mononuclear cells (PBMCs) after
administration of the combination of AZD6244 hydrogen sulfate and MK-2206 and correlate
these reductions with those seen in tumor biopsy samples.

- Evaluate antitumor activity of the combination of MK-2206 with AZD6244 hydrogen
sulfate.

Eligibility:

-Patients with histologically documented colorectal cancer that has progressed or recurred
after oxaliplatin- and irinotecan-based chemotherapy for metastatic disease. KRAS mutation
analysis results must be available prior to enrollment. Patients must have disease amenable
to biopsy, and be willing to undergo pre-and post-treatment tumor biopsies.

Study Design:

- MK-2206 135 mg PO (by mouth) once weekly and AZD6244 hydrogen sulfate 100 mg PO (by
mouth) once daily will be administered in 28-day cycles, beginning on C1D1 (cycle 1,
day 1).

- Patients will be stratified for KRAS mutation status.

- Blood samples and paired mandatory tumor biopsies will be obtained for pharmacodynamic
studies.

- CT (computed tomography) scans will be performed every 2 cycles for restaging.

- 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.