Selumetinib in Treating Patients With Recurrent or Persistent Endometrial Cancer

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase II Evaluation of AZD6244 (NSC #748727) in the Treatment of Recurrent or Persistent Endometrial Carcinoma

Conditions
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Endometrial Adenocarcinoma, Endometrial Adenosquamous Carcinoma, Endometrial Clear Cell Adenocarcinoma, Recurrent Uterine Corpus Carcinoma

Intervention / Treatment
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* Other: Diagnostic Laboratory Biomarker Analysis
* Drug: Selumetinib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (selumetinib)<br>Patients receive selumetinib 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. | Other: Diagnostic Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Selumetinib<br>* Given PO<br>* Other names: MEK Inhibitor AZD6244;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With or Without Progression-free Survival for > 6 Months by Response Evaluation Criteria for Solid Tumors (RECIST) | Number of participants who survived progression-free for more than 6 months. Progression is defined using Response Evaluation Criteria for Solid Tumors (RECIST), as a 20% increase in the sum of the longest diameter of target lesions, or the appearance of one or more new lesions, or unequivocal progression of existing non-target lesions in the opinion of the treating physician, or global deterioration in health status attributable to the disease requiring a change in therapy without objective evidence of progression. | > 6 months from study entry | 
| Objective Tumor Response Rate Assessed by RECIST | Per Response Evaluation Criteria In Solid Tumors (RECIST) Criteria: Complete Response (CR) is disappearance of all target and non-target lesions and no evidence of new lesions documented by two disease assessments at least 4 weeks apart. Normalization of CA125, if elevated at study entry, is required; Partial Response (PR) is at least a 30% decrease in the sum of longest dimensions (LD) of all target measurable lesions taking as reference the baseline sum of LD; Increasing Disease is at least a 20% increase in the sum of LD of target lesions taking as references the smallest sum LD or the appearance of new lesions within 8 weeks of study entry; Stable Disease is any condition not meeting the above criteria. | From study entry, assessed up to 5 years | 
| Participants With Severity of Adverse Effects as Assessed by CTCAE v3.0 |  | Each cycle during treatment and 30 days after the last treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Progression-free Survival | Progression is defined according to RECIST v1.0 as at least a 20% increase in the sum of LD target lesions taking as reference the smallest sum LD recorded since study entry, the appearance of one or more new lesions, death due to disease without prior objective documentation of progression, global deterioration in health status attributable to the disease requiring a change in therapy without objective evidence of progression, or unequivocal progression of existing non-target lesions. | Every other cycle for the first 6 months; then every 3 months thereafter for up to 5 years | 
| Duration of Overall Survival | Overall survival is defined as the duration of time from study entry to time of death or the date of last contact. | Every cycle during treatment, then every 3 months for the first 2 years, then every six months for the next three years and then annually for the next 5 years. |