Selumetinib in Treating Patients With Recurrent or Persistent Endometrial Cancer
Selumetinib in Treating Patients With Recurrent or Persistent Endometrial Cancer
This phase II trial is studying how well selumetinib works in treating patients with
 recurrent or persistent endometrial cancer that has come back or is persistent. Selumetinib
 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
PRIMARY OBJECTIVES:

 I. To assess the activity of AZD6244 (selumetinib) for patients with recurrent or persistent
 endometrial cancer with the frequency of patients who survive progression-free for at least 6
 months after initiating therapy or have objective tumor response.

 II. To determine the nature and degree of toxicity of AZD6244 as assessed by CTCAE v3.0 in
 this cohort of patients.

 SECONDARY OBJECTIVE:

 I. To determine the duration of progression-free survival and overall survival.

 EXPLORATORY OBJECTIVES:

 I. To explore the associations between select biomarkers and response to AZD6244
 (progression-free survival status >6 months and objective tumor response), measures of
 clinical outcome (progression-free survival and overall survival) or disease status including
 histologic cell type.

 II. Mutations and single nucleotide polymorphisms in BRAF, KRAS2, FGFR2, PI3KCA, AKT1, AKT2,
 AKT3 and PTEN in DNA from formalin-fixed and paraffin-embedded (FFPE) tumor and/or normal
 blood cells.

 III. Immunohistochemical expression of ERK, pERK, GSK3betta, pGSK3betta, PR-A, PR-B, pPR,
 ER-alpha, ER-beta, BRAF, KRAS, PTEN, EGFR, pEGFR, EGF, PELP1 and MTA1s in FFPE tumor.

 IV. To explore the relationship among the panel of biomarkers evaluated in this cohort
 including mutations and single nucleotide polymorphisms in BRAF, KRAS2, FGFR2, PI3KCA, AKT1,
 AKT2, AKT3 and PTEN as well as immunohistochemical expression of ERK, pERK, GSK3betta,
 pGSK3betta, PR-A, PR-B, pPR, ER-alpha, ER-beta, BRAF, KRAS, PTEN, EGFR, pEGFR, EGF, PELP1 and
 MTA1s.

 OUTLINE: This is a multicenter study.

 Patients receive selumetinib orally (PO) twice daily on days 1-28. Courses repeat every 28
 days in the absence of disease progression or unacceptable toxicity. Blood and archived tumor
 tissue samples are collected for biomarker studies.

 After completion of study therapy, patients are followed up every 3 months for 2 years and
 then every 6 months for 3 years.
Inclusion Criteria:

 -  Histologically confirmed* endometrial epithelial carcinoma, including any of the
 following cell types:

 -  Endometrioid adenocarcinoma

 -  Serous adenocarcinoma

 -  Undifferentiated carcinoma

 -  Clear cell adenocarcinoma

 -  Mixed epithelial carcinoma

 -  Adenocarcinoma not otherwise specified

 -  Mucinous adenocarcinoma

 -  Squamous cell carcinoma

 -  Transitional cell carcinoma

 -  Mesonephric carcinoma

 -  Recurrent or persistent disease that is refractory to curative therapy or established
 treatments

 -  Measurable disease, defined as ≥ 1 lesion that can be measured in ≥ 1 dimension
 (longest dimension to be recorded)

 -  Each lesion must be ≥ 20 mm when measured by conventional techniques (palpation,
 plain x-ray, CT scan, or MRI) OR ≥ 10 mm when measured by spiral CT scan

 -  Must have ≥ 1 target lesion to be used to assess response, as defined by RECIST
 criteria

 -  Tumors within a previously irradiated field are designated as "non-target"
 lesions unless progression is documented or a biopsy is obtained to confirm
 persistence ≥ 90 days following completion of radiotherapy

 -  Must have received 1 prior chemotherapeutic regimen for the management of endometrial
 carcinoma

 -  Chemotherapy administered as a radiosensitizer in conjunction with primary
 radiotherapy is considered a systemic chemotherapy regimen

 -  Not eligible for a higher priority GOG protocol, if one exists (e.g., any active phase
 III GOG protocol for the same patient population)

 -  No prior or concurrent CNS disease (treated or untreated) by physical examination,
 including primary brain tumor or brain metastases

 -  GOG performance status (PS) 0-2 (for patients who received 1 prior treatment regimen)

 -  GOG PS 0-1 (for patients who received 2 prior treatment regimens)

 -  ANC ≥ 1,500/mm^3

 -  Platelet count ≥ 100,000/mm^3

 -  Creatinine ≤ 1.5 times upper limit of normal (ULN)

 -  Bilirubin ≤ 1.5 times ULN

 -  SGOT ≤ 2.5 times ULN

 -  Alkaline phosphatase ≤ 2.5 times ULN

 -  PT/INR ≤ 1.5 OR in-range INR (between 2 and 3) if patient is on a stable dose of
 therapeutic warfarin

 -  PTT ≤ 1.5 times ULN

 -  Oxygen saturation ≥ 88% on room air

 -  QTc < 450 msec by EKG

 -  LVEF normal

 -  Not pregnant or nursing

 -  Negative pregnancy test

 -  Fertile patients must use effective contraception during and for ≥ 6 months after
 completion of study therapy

 -  No neuropathy (sensory or motor) > grade 1

 -  No active infection requiring antibiotics

 -  Uncomplicated urinary tract infection allowed

 -  No other invasive malignancy within the past 5 years except for nonmelanoma skin
 cancer

 -  No serious, non-healing wound, ulcer, or bone fracture

 -  No history of abdominal fistula or gastrointestinal perforation

 -  No intra-abdominal abscess within the past 28 days

 -  No active bleeding or pathological condition that would carry a high risk of bleeding
 (e.g., bleeding disorder, coagulopathy, or tumor involving major vessels)

 -  No seizures not controlled with standard medical therapy

 -  No clinically significant cardiovascular disease including, but not limited to, any of
 the following:

 -  Uncontrolled hypertension, defined as systolic BP > 140 mm Hg or diastolic BP >
 90 mm Hg

 -  Myocardial infarction or unstable angina within the past 6 months

 -  NYHA class II-IV congestive heart failure

 -  Serious cardiac arrhythmia requiring medication, including atrial fibrillation
 requiring rate-controlling medication

 -  Peripheral vascular disease ≥ grade 2

 -  Cerebrovascular accident (i.e., CVA, stroke), transient ischemic attack, or
 subarachnoidal hemorrhage within the past 6 months

 -  No evidence of serious ventricular arrhythmia (i.e., ventricular tachycardia or
 ventricular fibrillation ≥ 3 beats in a row) by EKG

 -  Concurrent low molecular weight heparin for treatment of venous thromboembolic disease
 allowed provided patient is considered clinically stable on this regimen

 -  Recovered from prior surgery, radiotherapy, or chemotherapy

 -  At least 1 week since prior hormonal therapy directed at the malignant tumor

 -  At least 3 weeks since prior radiotherapy or chemotherapy (6 weeks for nitrosoureas or
 mitomycin C)

 -  At least 3 weeks since other prior therapy directed at the malignant tumor, including
 immunologic agents

 -  One prior cytotoxic regimen for the management of recurrent or persistent endometrial
 disease allowed

 -  No prior non-cytotoxic chemotherapy for the management of endometrial cancer, except
 hormonal therapy

 -  No prior anticancer therapy that contraindicates study therapy

 -  No prior MEK inhibitor AZD6244 or other specific MEK/ERK/MAPK pathway targeted therapy

 -  No prior chemotherapy for any abdominal or pelvic tumor other than for the treatment
 for endometrial cancer within the past 5 years

 -  Prior adjuvant chemotherapy for localized breast cancer allowed provided it was
 completed > 3 years ago AND the patient remains free of recurrent or metastatic
 disease

 -  No prior radiotherapy to any portion of the abdominal cavity or pelvis other than for
 the treatment of endometrial cancer within the past 5 years

 -  Prior radiotherapy for localized cancer of the breast, head and neck, or skin is
 allowed provided it was completed > 3 years ago AND the patient remains free of
 recurrent or metastatic disease

 -  No concurrent medication that may prolong the QTc interval

 -  No other concurrent investigational therapy

 -  No concurrent combination antiretroviral therapy for HIV-positive patients