Temsirolimus With or Without Megestrol Acetate and Tamoxifen Citrate in Treating Patients With Advanced, Persistent, or Recurrent Endometrial Cancer

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.

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