PIK3CA Mutation Stratified Trial of MK-2206 in Recurrent or Advanced Endometrial Cancer

• Progression-Free Survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  To determine the duration of progression-free survival.
• Toxicity [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
  To determine the nature and degree of toxicity of MK-2206 as assessed by version 4 of the NCI CTCAE in these cohorts of patients.
• Overall Survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  To determine the duration of overall survival
• Biomarkers [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  To explore the associations between select biomarkers and response to MK-2206 such as progression-free survival, objective tumor response, and overall survival as well as patient characteristics such as histological cell type.
• Target Inhibition [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  To explore the development of feed-back loop activation (post-treatment biopsy biomarker analysis) and target inhibition using MK-2206 via analysis of pretreatment and post-treatment biopsies in select patients enrolled in the trial.

• To determine the duration of progression-free survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Toxicity [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
  To determine the nature and degree of toxicity of MK-2206 as assessed by version 4 of the NCI CTCAE in these cohorts of patients.
• To determine the duration of overall survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]

MK-2206 is a drug that may stop cancer cells from growing. MK-2206 blocks a signal inside the cell that can cause abnormal cell growth. This drug has been used in other research studies and information from those studies suggests that this agent may help to keep cancer from growing in this research study. The investigators are looking to see how effective MK-2206 is in treating recurrent and metastatic endometrial cancer. Additionally, the investigators are looking to see if participants whose tumors contain a particular genetic make-up will have a better response to MK-2206. Participants' tumors will be tested for a mutation in a gene called PIK3CA, which makes a protein that helps cell to use energy and grow.

Based on results from the initial cohort in MK2206, an independent cohort of patients with endometrial serous histology has been added to this study.

• Participants will take the study drug, MK-2206, orally once a week. Each treatment cycle lasts four weeks (28 days). Participants will be asked to complete a drug diary stating when they took each dose and to give a reason if they did not take the drug. At the end of each cycle, participants will be asked to return the pill bottles and all of the remaining pills before starting the next cycle.
• At the beginning of each cycle the following procedures and tests will be performed: physical exam, evaluation of performance status, blood samples. Once a week for the first two cycles the following procedures and tests will be performed: participant will be called at home by a member of the study team to record any health problems, including side effects from the study drugs and blood samples.
• A CT scan or MRI of the chest, stomach area, and pelvis will be performed every 2 cycles to see if the cancer is increasing, decreasing, or staying the same size.

• Experimental: PIK3CA Mutation
  Tumors harbor PIK3CA mutation. 135 mg MK-2206 tablets, orally dosed weekly.
  Intervention: Drug: MK-2206
• Experimental: PIK3CA Wildtype
  Tumor is PIK3CA wildtype. 135 mg MK-2206 tablets, orally dosed weekly.
  Intervention: Drug: MK-2206
• Experimental: High-Grade Serous Histology
  Based on results from the initial cohort in MK2206, an independent cohort of patients with endometrial serous histology has been added to this study. 135 mg MK-2206 tablets, orally dosed weekly.
  Intervention: Drug: MK-2206

Inclusion Criteria:

• Participants must have histologically confirmed recurrent or persistent high grade endometrial carcinoma with a serous component, which is refractory to curative therapy or established treatments. Histologic confirmation of the original primary tumor is required.
• All patients must have measurable disease as defined by RECIST 1.1. Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded). Each lesion must be at least 10 mm when measured by CT, MRI or caliper measurement by clinical exam; or at least 20 mm when measured by chest x-ray. Lymph nodes must be at least 15 mm in short axis when measured by CT or MRI.
• Patients must have had at least one prior chemotherapeutic regimen for management of endometrial carcinoma. Initial treatment may include chemotherapy, chemotherapy and radiation therapy, and/or consolidation/maintenance therapy.
• Patients must have not received any class of drugs targeted to the PI3K pathway (including mTOR inhibitors) for management of recurrent or persistent disease.
• 18 years of age or greater
• Life expectancy of greater than 6 months
• ECOG performance status of 0, 1 or 2
• Normal organ and marrow function as outlined in the protocol
• Availability of formalin fixed paraffin embedded block of cancer tissue from the original or most recent biopsy for mutational analysis
• Women of childbearing potential must use two forms of contraception prior to study entry and for the duration of study participation.
• Toxicities of prior therapy (excepting alopecia) should be resolved to grade 1 or lower per CTCAE version 4.
• Subjects with treated limited-stage basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the breast or cervix are eligible. Subjects with stage I or II cancer treated with curative intent with no evidence of recurrent disease 5 years following diagnosis are eligible.
• Patients must be able to tolerate oral medications and not have gastrointestinal illnesses that would preclude absorption of MK-2206

Exclusion Criteria:

• Participants who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered to Grade 1 or less from adverse events due to agents administered more than 4 weeks earlier.
• Participants may not be receiving any other study agents
• Participants with known brain metastases
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to MK-2206
• Patients who require medications or substances that are strong inhibitors of inducers of CYP 450 3A4
• Patients with diabetes or in risk of hyperglycemia should not be excluded, but the hyperglycemia should be well controlled on oral agents before the patient enters the trial
• Baseline QTcF > 470msec
• 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.
• Pregnant or breastfeeding women
• Patients who are unable to tolerate oral medication. Patients with signs and symptoms of bowel obstruction or with uncontrolled, persistent diarrhea.
• HIV-positive individuals on combination antiretroviral therapy
• Patients may not use any natural herbal products or other "folk remedies" while on study

• Massachusetts General Hospital
• Memorial Sloan Kettering Cancer Center.
• M.D. Anderson Cancer Center
• National Cancer Institute (NCI)