Clinical trial NCT00729586: Temsirolimus With or Without Megestrol Acetate and Tamoxifen Citrate in Treating Patients With Advanced, Persistent, or Recurrent Endometrial Cancer
Official title: A Randomized Phase II Trial of Temsirolimus (NCI-Supplied Agent, NSC # 683864) or the Combination of Hormonal Therapy Plus Temsirolimus in Women With Advanced, Persistent, or Recurrent Endometrial Carcinoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Endometrial Carcinoma
Recurrent Uterine Corpus Carcinoma
Stage IIIA Uterine Corpus Cancer
Stage IIIB Uterine Corpus Cancer
Stage IIIC1 Uterine Corpus Cancer
Stage IIIC2 Uterine Corpus Cancer
Stage IVA Uterine Corpus Cancer
Stage IVB Uterine Corpus Cancer
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
Collaborators: name: NRG Oncology
First posted: 2008-08-07
Enrollment: 73
Sex: FEMALE
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This randomized phase II trial studies how well temsirolimus with or without megestrol acetate and tamoxifen citrate works in treating patients with endometrial cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment, has returned after a period of improvement, or is persistent. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Estrogen can cause the growth of endometrial cancer cells. Hormone therapy using megestrol acetate and tamoxifen citrate may fight endometrial cancer by blocking the use of estrogen by the tumor cells. It is not yet known whether temsirolimus is more effective when given alone or together with megestrol acetate and tamoxifen citrate in treating endometrial cancer.

Detailed description: PRIMARY OBJECTIVES:

I. To determine the response rate of patients with advanced, persistent, or recurrent endometrial cancer when treated with each of the arms of the trial; the proposed arms are: Arm #1 temsirolimus intravenously (IV) weekly, Arm #2 megestrol (megestrol acetate)/tamoxifen (tamoxifen citrate) plus temsirolimus IV weekly.

II. Time to progression and number of patients remaining on study therapy at 24 weeks.

SECONDARY OBJECTIVE:

I. To describe the toxicities of each of the arms of the trial when used for patients with advanced/metastatic endometrial cancer.

TERTIARY OBJECTIVES:

I. Explore whether immunohistochemical expression of hormone receptors (estrogen receptor-alpha, estrogen receptor-beta, progesterone receptors-A, progesterone receptor-B and the alternative estrogen receptor, G protein-coupled estrogen receptor \[GPR\]-30) or components of the mammalian target of rapamycin (mTOR) signaling pathway (normal and mutant phosphatase and tensin homolog \[PTEN\], total and phosphorylated v-akt murine thymoma viral oncogene homolog 1 \[Akt\] as well as total and phosphorylated p70S6 kinase) are associated with treatment, outcome or clinical characteristics.

II. Explore whether single nucleotide polymorphisms (SNPs) in the FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1) and regulatory associated protein of mTOR (RAPTOR) genes, mutations in phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), PTEN and paxillin or copy number abnormalities in PTEN and paxillin are associated with treatment, outcome or clinical characteristics.

OUTLINE: Patients are randomized to 1 of 2 treatment arms. (Closed to accrual as of 11/22/2010)

ARM I: Patients receive temsirolimus IV over 30 minutes once weekly for 6 weeks. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity.

ARM II (Closed to accrual as of 12/21/2009): Patients receive temsirolimus as in Arm I and megestrol acetate orally (PO) twice daily (BID) for 3 weeks alternating with tamoxifen citrate PO BID for 3 weeks. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 1 year.

Eligibility criteria: Inclusion Criteria:

* Patients must have histologically confirmed advanced (International Federation of Gynecologists and Obstetricians \[FIGO\] stage III or IV), persistent, or recurrent endometrial carcinoma, which is not likely to be curable by surgery or radiotherapy; histologic documentation of the recurrence is not required
* All patients must have measurable disease; measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest dimension to be recorded); each lesion must be \>= 20 mm when measured by conventional techniques, including palpation, plain x-ray, computed tomography (CT), and magnetic resonance imaging (MRI), or \>= 10 mm when measured by spiral CT
* Patients must have at least one "target lesion" to be used to assess response, as defined by Response Evaluation Criteria In Solid Tumors (RECIST); tumors within a previously irradiated field will be designated as "non-target" lesions unless progression is documented
* Prior chemoradiotherapy for a pelvic recurrence is permitted; prior chemotherapy in the adjuvant setting for stage I, II, or III disease is permitted

  * Note: no prior chemotherapy in the setting of stage IV disease is permitted unless the patient was without evidence of disease at the completion of chemotherapy and had at least six months of progression-free survival since the completion of chemotherapy
  * Regardless of circumstances, no more than one prior chemotherapy regimen (including chemoradiotherapy) is permitted
* Patient must be able to take p.o. medications
* Performance status must be 0-2
* Absolute neutrophil count \>= 1,500/mcL
* Platelets \>= 100,000/mcL
* Total bilirubin within normal institutional limits
* Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) =\< 2.5 times institutional upper limit of normal v 3.0 (=\< 5 times upper limit of normal \[ULN\] for subjects with liver metastases)
* Alkaline phosphatase =\< 2.5 times institutional upper limit of normal v 3.0 (=\< 5 times ULN for subjects with liver metastases)
* Creatinine =\< 1.5 times normal institutional upper limit of normal
* Cholesterol =\< 350 mg/dL (fasting)
* Triglycerides =\< 400 mg/dL (fasting)
* Albumin \>= 3.0 mg/dL
* At least 4 weeks must have elapsed since the patient underwent any major surgery (e.g., major: hysterectomy, resection of a lung nodule-minor: a Port-A-Cath placement)
* Patients who have met the pre-entry requirements
* Patients must have signed an approved informed consent including Health Insurance Portability and Accountability Act (HIPAA) authorization

Exclusion Criteria:

* Patients with Gynecologic Oncology Group (GOG) performance status of 3 or 4
* Patients cannot be receiving enzyme-inducing antiepileptic drugs (EIAEDs; e.g., phenytoin, carbamazepine, phenobarbital) nor any other cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inducer such as rifampin or St. John's wort, as these may decrease temsirolimus levels; use of agents that potently inhibit CYP3A (and hence may raise temsirolimus levels), such as ketoconazole, is discouraged, but not specifically prohibited; the appropriateness of use of such agents is left to physician discretion

  * All concomitant medications must be recorded at baseline
* Patients on maintenance corticosteroids are ineligible with the exception of short term use (fewer than 5 days)
* Patients known to have congestive heart failure; patients with baseline requirement for oxygen; patients with serious concomitant illness that, in the opinion of the treating physician, will place patient at unreasonable risk from therapy on this protocol
* Patients with a history of unprovoked deep vein thrombosis (DVT) or pulmonary embolism (PE), unless patient is maintained on anticoagulation for the duration of the trial; while the exact definition of "provoked" is left to the treating physician, a DVT in the setting of pelvic surgery or trauma would be considered "provoked"
* Women of child-bearing potential must have a negative pregnancy test prior to treatment on study; breastfeeding should be discontinued if the mother is treated with temsirolimus

  * Women of child-bearing potential and men must agree to use adequate contraception (barrier method of birth control or abstinence; oral contraceptives \[also known as "the pill"\] are not acceptable) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
* Patients with a concomitant invasive malignancy or a history of other invasive malignancies, with the exception of non-melanoma skin cancer, are excluded if there is any evidence of other malignancy being present within the past five years; patients are also excluded if their previous cancer treatment contraindicates this protocol therapy
* Patients who have received hormonal therapy or biologic therapy as treatment for endometrial carcinoma
* Patients who have received chemotherapy directed at metastatic or recurrent endometrial carcinoma

Primary outcomes:
measure: Percentage of Participants With a Confirmed Objective Tumor Response Using RECIST Version 1.0
timeFrame: Radiologic tumor evaluations at baseline and every 6 weeks for the first 24 weeks; then repeated every 12 weeks until disease progression. Repeat after treatment discontinuation if patient was taken off study for reasons other than progression.
Secondary outcomes:
measure: Duration of Overall Survival (OS)
timeFrame: Every 6 weeks during treatment, then every 3 months for one year.
measure: Duration of Progression-free Survival (PFS)
timeFrame: Radiologic tumor evaluations at baseline and every six weeks for the first 24 weeks and then repeated every 12 weeks until disease progression. Repeat after treatment discontinuation if patient was taken off study for reasons other than progression.
measure: Incidence of Adverse Effects (Grade 3 or Higher) as Assessed by Common Terminology Criteria for Adverse Events Version 3.0
timeFrame: Assessed every 6 weeks while on treatment, 30 days after the last cycle of treatment.
Other outcomes:
measure: Number of Participants and Their Levels of Expression of the Candidate Markers
timeFrame: Baseline
Locations:
city: Burbank
country: United States
facility: Providence Saint Joseph Medical Center/Disney Family Cancer Center
state: California
city: Palo Alto
country: United States
facility: Stanford Cancer Institute
state: California
city: San Diego
country: United States
facility: University of California San Diego
state: California
city: Aurora
country: United States
facility: Colorado Gynecologic Oncology Group
state: Colorado
city: Aurora
country: United States
facility: University of Colorado Cancer Center - Anschutz Cancer Pavilion
state: Colorado
city: Hartford
country: United States
facility: Hartford Hospital
state: Connecticut
city: Hartford
country: United States
facility: Smilow Cancer Hospital Care Center at Saint Francis
state: Connecticut
city: New Britain
country: United States
facility: The Hospital of Central Connecticut
state: Connecticut
city: Lewes
country: United States
facility: Beebe Medical Center
state: Delaware
city: Newark
country: United States
facility: Christiana Care Health System-Christiana Hospital
state: Delaware
city: Columbus
country: United States
facility: John B Amos Cancer Center
state: Georgia
city: Savannah
country: United States
facility: Memorial University Medical Center
state: Georgia
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Comprehensive Cancer Center
state: Illinois
city: Hinsdale
country: United States
facility: Sudarshan K Sharma MD Limted-Gynecologic Oncology
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University/Melvin and Bren Simon Cancer Center
state: Indiana
city: Indianapolis
country: United States
facility: Saint Vincent Hospital and Health Care Center
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa/Holden Comprehensive Cancer Center
state: Iowa
city: Overland Park
country: United States
facility: Menorah Medical Center
state: Kansas
city: Overland Park
country: United States
facility: Radiation Oncology Practice Corporation Southwest
state: Kansas
city: Overland Park
country: United States
facility: Saint Luke's South Hospital
state: Kansas
city: Shawnee Mission
country: United States
facility: Shawnee Mission Medical Center-KCCC
state: Kansas
city: Baltimore
country: United States
facility: Sinai Hospital of Baltimore
state: Maryland
city: Baltimore
country: United States
facility: MedStar Franklin Square Medical Center/Weinberg Cancer Institute
state: Maryland
city: Elkton
country: United States
facility: Union Hospital of Cecil County
state: Maryland
city: Worcester
country: United States
facility: University of Massachusetts Memorial Health Care
state: Massachusetts
city: Worcester
country: United States
facility: University of Massachusetts Medical School
state: Massachusetts
city: Ann Arbor
country: United States
facility: Saint Joseph Mercy Hospital
state: Michigan
city: Ann Arbor
country: United States
facility: Michigan Cancer Research Consortium NCORP
state: Michigan
city: Battle Creek
country: United States
facility: Bronson Battle Creek
state: Michigan
city: Big Rapids
country: United States
facility: Spectrum Health Big Rapids Hospital
state: Michigan
city: Dearborn
country: United States
facility: Beaumont Hospital-Dearborn
state: Michigan
city: Detroit
country: United States
facility: Saint John Hospital and Medical Center
state: Michigan
city: Escanaba
country: United States
facility: Green Bay Oncology - Escanaba
state: Michigan
city: Flint
country: United States
facility: Hurley Medical Center
state: Michigan
city: Flint
country: United States
facility: Genesys Regional Medical Center-West Flint Campus
state: Michigan
city: Grand Rapids
country: United States
facility: Cancer Research Consortium of West Michigan NCORP
state: Michigan
city: Grand Rapids
country: United States
facility: Mercy Health Saint Mary's
state: Michigan
city: Grand Rapids
country: United States
facility: Spectrum Health at Butterworth Campus
state: Michigan
city: Iron Mountain
country: United States
facility: Green Bay Oncology - Iron Mountain
state: Michigan
city: Jackson
country: United States
facility: Allegiance Health
state: Michigan
city: Lansing
country: United States
facility: Sparrow Hospital
state: Michigan
city: Livonia
country: United States
facility: Saint Mary Mercy Hospital
state: Michigan
city: Muskegon
country: United States
facility: Mercy Health Mercy Campus
state: Michigan
city: Pontiac
country: United States
facility: Saint Joseph Mercy Oakland
state: Michigan
city: Port Huron
country: United States
facility: Lake Huron Medical Center
state: Michigan
city: Royal Oak
country: United States
facility: William Beaumont Hospital-Royal Oak
state: Michigan
city: Saginaw
country: United States
facility: Saint Mary's of Michigan
state: Michigan
city: Traverse City
country: United States
facility: Munson Medical Center
state: Michigan
city: Warren
country: United States
facility: Saint John Macomb-Oakland Hospital
state: Michigan
city: Wyoming
country: United States
facility: Metro Health Hospital
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota/Masonic Cancer Center
state: Minnesota
city: Independence
country: United States
facility: Centerpoint Medical Center LLC
state: Missouri
city: Kansas City
country: United States
facility: Truman Medical Center
state: Missouri
city: Kansas City
country: United States
facility: Saint Luke's Hospital of Kansas City
state: Missouri
city: Kansas City
country: United States
facility: Radiation Oncology Practice Corporation South
state: Missouri
city: Kansas City
country: United States
facility: Saint Joseph Health Center
state: Missouri
city: Kansas City
country: United States
facility: North Kansas City Hospital
state: Missouri
city: Kansas City
country: United States
facility: Heartland Hematology and Oncology Associates Incorporated
state: Missouri
city: Kansas City
country: United States
facility: Research Medical Center
state: Missouri
city: Kansas City
country: United States
facility: Radiation Oncology Practice Corporation - North
state: Missouri
city: Lee's Summit
country: United States
facility: Saint Luke's East - Lee's Summit
state: Missouri
city: Liberty
country: United States
facility: Liberty Radiation Oncology Center
state: Missouri
city: Saint Joseph
country: United States
facility: Heartland Regional Medical Center
state: Missouri
city: Saint Joseph
country: United States
facility: Saint Joseph Oncology Inc
state: Missouri
city: Springfield
country: United States
facility: Mercy Hospital Springfield
state: Missouri
city: Las Vegas
country: United States
facility: Women's Cancer Center of Nevada
state: Nevada
city: Camden
country: United States
facility: Cooper Hospital University Medical Center
state: New Jersey
city: New Brunswick
country: United States
facility: Rutgers Cancer Institute of New Jersey
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico Cancer Center
state: New Mexico
city: Albuquerque
country: United States
facility: Southwest Gynecologic Oncology Associates Inc
state: New Mexico
city: Albany
country: United States
facility: Women's Cancer Care Associates LLC
state: New York
city: Manhasset
country: United States
facility: North Shore University Hospital
state: New York
city: New Hyde Park
country: United States
facility: Long Island Jewish Medical Center
state: New York
city: New Hyde Park
country: United States
facility: North Shore-LIJ Health System/Center for Advanced Medicine
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Stony Brook
country: United States
facility: Stony Brook University Medical Center
state: New York
city: Chapel Hill
country: United States
facility: UNC Lineberger Comprehensive Cancer Center
state: North Carolina
city: Charlotte
country: United States
facility: Carolinas Medical Center/Levine Cancer Institute
state: North Carolina
city: Charlotte
country: United States
facility: Novant Health Presbyterian Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati/Barrett Cancer Center
state: Ohio
city: Cleveland
country: United States
facility: MetroHealth Medical Center
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Tulsa
country: United States
facility: Oklahoma Cancer Specialists and Research Institute-Tulsa
state: Oklahoma
city: Portland
country: United States
facility: Legacy Good Samaritan Hospital and Medical Center
state: Oregon
city: Portland
country: United States
facility: Providence Portland Medical Center
state: Oregon
city: Portland
country: United States
facility: Compass Oncology Rose Quarter
state: Oregon
city: Abington
country: United States
facility: Abington Memorial Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital
state: Pennsylvania
city: West Reading
country: United States
facility: Reading Hospital
state: Pennsylvania
city: Providence
country: United States
facility: Women and Infants Hospital
state: Rhode Island
city: Rapid City
country: United States
facility: Black Hills Obstetrics and Gynecology
state: South Dakota
city: Dallas
country: United States
facility: Parkland Memorial Hospital
state: Texas
city: Dallas
country: United States
facility: Clements University Hospital
state: Texas
city: Dallas
country: United States
facility: UT Southwestern/Simmons Cancer Center-Dallas
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute/University of Utah
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia Cancer Center
state: Virginia
city: Roanoke
country: United States
facility: Carilion Clinic Gynecological Oncology
state: Virginia
city: Green Bay
country: United States
facility: Green Bay Oncology at Saint Vincent Hospital
state: Wisconsin
city: Green Bay
country: United States
facility: Saint Vincent Hospital Cancer Center Green Bay
state: Wisconsin
city: Green Bay
country: United States
facility: Green Bay Oncology Limited at Saint Mary's Hospital
state: Wisconsin
city: Green Bay
country: United States
facility: Saint Vincent Hospital Cancer Center at Saint Mary's
state: Wisconsin
city: La Crosse
country: United States
facility: Gundersen Lutheran Medical Center
state: Wisconsin
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics
state: Wisconsin
city: Manitowoc
country: United States
facility: Holy Family Memorial Hospital
state: Wisconsin
city: Marinette
country: United States
facility: Bay Area Medical Center
state: Wisconsin
city: Oconto Falls
country: United States
facility: Green Bay Oncology - Oconto Falls
state: Wisconsin
city: Sturgeon Bay
country: United States
facility: Green Bay Oncology - Sturgeon Bay
state: Wisconsin
Study officials:
affiliation: NRG Oncology
name: Gini Fleming
role: PRINCIPAL_INVESTIGATOR
References: