Selumetinib in Treating Patients With Recurrent or Persistent Endometrial Cancer

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