Selumetinib in Treating Patients With Recurrent or Persistent Endometrial Cancer

Phase 2

Completed

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

Interventions: Other: Diagnostic Laboratory Biomarker Analysis
Drug: Selumetinib

Registration Number: NCT01011933

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 54

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (selumetinib)	Diagnostic Laboratory Biomarker Analysis	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.
Treatment (selumetinib)	Selumetinib	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.

Primary Outcome Measures

Name	Time	Method
Number of Participants With or Without Progression-free Survival for > 6 Months by Response Evaluation Criteria for Solid Tumors (RECIST)	> 6 months from study entry	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.
Participants With Severity of Adverse Effects as Assessed by CTCAE v3.0	Each cycle during treatment and 30 days after the last treatment.
Objective Tumor Response Rate Assessed by RECIST	From study entry, assessed up to 5 years	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.

Secondary Outcome Measures

Name	Time	Method
Duration of Progression-free Survival	Every other cycle for the first 6 months; then every 3 months thereafter for up to 5 years	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.
Duration of Overall Survival	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.	Overall survival is defined as the duration of time from study entry to time of death or the date of last contact.

Trial Locations

Locations (72): University of Chicago Comprehensive Cancer Center
🇺🇸
Chicago, Illinois, United States
Smilow Cancer Hospital Care Center at Saint Francis
🇺🇸
Hartford, Connecticut, United States
Rush University Medical Center
🇺🇸
Chicago, Illinois, United States
Sudarshan K Sharma MD Limted-Gynecologic Oncology
🇺🇸
Hinsdale, Illinois, United States
USC / Norris Comprehensive Cancer Center
🇺🇸
Los Angeles, California, United States
Hartford Hospital
🇺🇸
Hartford, Connecticut, United States
The Hospital of Central Connecticut
🇺🇸
New Britain, Connecticut, United States
Abington Memorial Hospital
🇺🇸
Abington, Pennsylvania, United States
Borgess Medical Center
🇺🇸
Kalamazoo, Michigan, United States
Lankenau Medical Center
🇺🇸
Wynnewood, Pennsylvania, United States
Mercy Medical Center-West Lakes
🇺🇸
West Des Moines, Iowa, United States
Bronson Methodist Hospital
🇺🇸
Kalamazoo, Michigan, United States
CoxHealth South Hospital
🇺🇸
Springfield, Missouri, United States
Memorial Medical Center
🇺🇸
Springfield, Illinois, United States
University of Iowa/Holden Comprehensive Cancer Center
🇺🇸
Iowa City, Iowa, United States
Allegiance Health
🇺🇸
Jackson, Michigan, United States
West Michigan Cancer Center
🇺🇸
Kalamazoo, Michigan, United States
Bryn Mawr Hospital
🇺🇸
Bryn Mawr, Pennsylvania, United States
Liberty Hospital
🇺🇸
Liberty, Missouri, United States
State University of New York Downstate Medical Center
🇺🇸
Brooklyn, New York, United States
Riverside Methodist Hospital
🇺🇸
Columbus, Ohio, United States
Methodist West Hospital
🇺🇸
West Des Moines, Iowa, United States
Mercy Cancer Center-West Lakes
🇺🇸
Clive, Iowa, United States
Oklahoma Cancer Specialists and Research Institute-Tulsa
🇺🇸
Tulsa, Oklahoma, United States
Saint Luke's East - Lee's Summit
🇺🇸
Lee's Summit, Missouri, United States
MedStar Franklin Square Medical Center/Weinberg Cancer Institute
🇺🇸
Baltimore, Maryland, United States
Main Line Health NCORP
🇺🇸
Wynnewood, Pennsylvania, United States
Genesys Regional Medical Center-West Flint Campus
🇺🇸
Flint, Michigan, United States
Cancer Research for the Ozarks NCORP
🇺🇸
Springfield, Missouri, United States
Indiana University/Melvin and Bren Simon Cancer Center
🇺🇸
Indianapolis, Indiana, United States
Saint Vincent Oncology Center
🇺🇸
Indianapolis, Indiana, United States
Women's Cancer Center of Nevada
🇺🇸
Las Vegas, Nevada, United States
Lyndon Baines Johnson General Hospital
🇺🇸
Houston, Texas, United States
University of Cincinnati
🇺🇸
Cincinnati, Ohio, United States
Kansas City NCI Community Oncology Research Program
🇺🇸
Prairie Village, Kansas, United States
Menorah Medical Center
🇺🇸
Overland Park, Kansas, United States
University of Mississippi Medical Center
🇺🇸
Jackson, Mississippi, United States
Los Angeles County-USC Medical Center
🇺🇸
Los Angeles, California, United States
MedStar Washington Hospital Center
🇺🇸
Washington, District of Columbia, United States
Medical Oncology and Hematology Associates-West Des Moines
🇺🇸
Clive, Iowa, United States
Saint Luke's South Hospital
🇺🇸
Overland Park, Kansas, United States
Oakwood Hospital and Medical Center
🇺🇸
Dearborn, Michigan, United States
Hurley Medical Center
🇺🇸
Flint, Michigan, United States
Sparrow Hospital
🇺🇸
Lansing, Michigan, United States
Saint Mary Mercy Hospital
🇺🇸
Livonia, Michigan, United States
Saint Joseph Mercy Port Huron
🇺🇸
Port Huron, Michigan, United States
Saint Joseph Mercy Oakland
🇺🇸
Pontiac, Michigan, United States
Saint John Macomb-Oakland Hospital
🇺🇸
Warren, Michigan, United States
Heartland Regional Medical Center
🇺🇸
Saint Joseph, Missouri, United States
Saint Joseph Oncology Inc
🇺🇸
Saint Joseph, Missouri, United States
Paoli Memorial Hospital
🇺🇸
Paoli, Pennsylvania, United States
Women and Infants Hospital
🇺🇸
Providence, Rhode Island, United States
M D Anderson Cancer Center
🇺🇸
Houston, Texas, United States
Saint John Hospital and Medical Center
🇺🇸
Detroit, Michigan, United States
University of Oklahoma Health Sciences Center
🇺🇸
Oklahoma City, Oklahoma, United States
Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States
Saint Mary's of Michigan
🇺🇸
Saginaw, Michigan, United States
University of Colorado Cancer Center - Anschutz Cancer Pavilion
🇺🇸
Aurora, Colorado, United States
Iowa Methodist Medical Center
🇺🇸
Des Moines, Iowa, United States
Iowa-Wide Oncology Research Coalition NCORP
🇺🇸
Des Moines, Iowa, United States
Medical Oncology and Hematology Associates-Des Moines
🇺🇸
Des Moines, Iowa, United States
Medical Oncology and Hematology Associates-Laurel
🇺🇸
Des Moines, Iowa, United States
Mercy Medical Center - Des Moines
🇺🇸
Des Moines, Iowa, United States
Iowa Lutheran Hospital
🇺🇸
Des Moines, Iowa, United States
Saint Joseph Mercy Hospital
🇺🇸
Ann Arbor, Michigan, United States
Michigan Cancer Research Consortium CCOP
🇺🇸
Ann Arbor, Michigan, United States
North Kansas City Hospital
🇺🇸
Kansas City, Missouri, United States
Truman Medical Center
🇺🇸
Kansas City, Missouri, United States
Saint Luke's Hospital of Kansas City
🇺🇸
Kansas City, Missouri, United States
Saint Joseph Health Center
🇺🇸
Kansas City, Missouri, United States
Heartland Hematology and Oncology Associates Incorporated
🇺🇸
Kansas City, Missouri, United States
Research Medical Center
🇺🇸
Kansas City, Missouri, United States