Temsirolimus in Treating Patients With Metastatic or Locally Advanced Recurrent Endometrial Cancer

A Phase II Study of CCI-779 in Patients With Metastatic and/or Locally Advanced Recurrent Endometrial Cancer

This phase II trial studies how well temsirolimus works in treating patients with endometrial cancer that has spread to other parts of the body or has spread from where it started to nearby tissue or lymph nodes and has come back after a period of time during which the cancer could not be detected. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. To assess the efficacy (response rate & duration of stable disease) of CCI-779 (temsirolimus) given intravenously (IV) weekly in patients with metastatic and/or locally advanced recurrent carcinoma of the endometrium.

II. To assess the adverse events, time to progression and response duration of CCI-779 given IV weekly in patients with metastatic and/or locally advanced recurrent carcinoma of the endometrium.

III. To correlate objective tumor response with phosphatase and tensin homolog gene (PTEN) expression in the tumor tissue obtained at diagnosis (primary tumor).

IV. To explore the relationship between objective tumor response with other molecular measures in diagnostic tumor tissue.

OUTLINE:

Patients receive temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 4 weeks and then every 3 months.

Inclusion Criteria:

• Patients must have histologically confirmed metastatic and/or locally advanced recurrent adenocarcinoma (papillary serous, papillary, villoglandular, mucinous, clear cell), endometrioid or adenosquamous carcinoma of the endometrium, incurable by standard therapies

• Patients must have tumour tissue from their primary tumor available to assess molecular markers of CCI-779 activation (paraffin block or unstained slides)

• Presence of clinically and/or radiologically documented disease; at least one site of disease must be unidimensionally measurable as follows:

  • X-ray, physical exam >= 20 mm
  • Spiral computed tomography (CT) scan >= 10 mm
  • Non-spiral CT scan >= 20 mm
  • All radiology studies must be performed within 28 days prior to registration (within 35 days if negative)

• Patients must have a life expectancy of at least 12 weeks

• Eastern Cooperative Oncology Group (ECOG) performance status of 0,1 or 2

• Previous therapy:

  • Hormonal therapy:

    • Group A: One prior hormonal treatment (progestational or aromatase inhibitor) as either adjuvant therapy or for treatment of metastatic disease
    • Group B: No limit to number of prior hormonal treatments given (progestational or aromatase inhibitor) as either adjuvant therapy or for treatment of metastatic disease
    • Time since last hormone: >= 1 week since last dose of hormonal therapy (applies to both Groups)

  • Chemotherapy:

    • Group A: No prior chemotherapy
    • Group B: Patients must have had one prior regimen of chemotherapy for metastatic disease; patients must be 4 weeks since last dose of chemotherapy

  • Radiation: Patients may have had prior radiation therapy; a minimum of 28 days must have elapsed between the end of radiotherapy and registration onto the study; (exceptions may be made however, for low dose, palliative radiotherapy; patients must have recovered from any acute toxic effects from radiation prior to registration

  • Previous surgery: Previous major surgery is permitted provided that it has been at least 21 days prior to patient registration and that wound healing has occurred

• Granulocytes (absolute granulocyte count [AGC]) >= 1.5 x 10^9/L

• Platelets >= 100 x 10^9/L

• Bilirubin =< upper normal limit (UNL)

• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x UNL

• Serum creatinine =< 1.5 x UNL or creatinine clearance >= 50 ml/min; creatinine clearance to be measured directly by 24 hour urine sampling or as calculated by Cockcroft Formula

• Fasting serum cholesterol =< 9.0 mmol/L

• Fasting triglycerides =< 4.56 mmol/L

• Patient consent must be obtained according to local Institutional and/or University Human Experimentation Committee requirements; it will be the responsibility of the local participating investigators to obtain the necessary local clearance, and to indicate in writing to the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) Study Coordinator that such clearance has been obtained, before the trial can commence in that centre; because of differing requirements, a standard consent form for the trial will not be provided but a sample form is given; a copy of the initial full board Research Ethics Board (REB) approval and approved consent form must be sent to the central office; the patient must sign the consent form prior to randomization or registration; please note that the consent form for this study must contain a statement which gives permission for the NCIC CTG and monitoring agencies to review patient records

• Patients must be accessible for treatment and follow-up; patients registered on this trial must be treated and followed at the participating center; this implies there must be reasonable geographical limits (for example: 1 ½ hour's driving distance) placed on patients being considered for this trial; investigators must assure themselves the patients registered on this trial will be available for complete documentation of the treatment, adverse events, response assessment and follow-up

• In accordance with NCIC CTG policy, protocol treatment is to begin within 5 working days of patient registration

Exclusion Criteria:

• Patients with a history of other malignancies, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumors curatively treated with no evidence of disease for >= 5 years

• Patients must not have had prior treatment with an mammalian target of rapamycin (mTOR) inhibitor

• Uterine sarcomas (leiomyosarcoma), mixed mullerian tumours (MMT) and/or adenosarcomas

• Patients with non-measurable disease only; (please note that bone metastases are considered non-measurable)

• Pregnant or lactating women; pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with CCI-779; most patients enrolled on this trial will have had a prior hysterectomy or pelvic irradiation; however, if the patient is of childbearing potential, a urine beta-human chorionic gonadotropin (HCG) must be proved negative within 7 days prior to registration; women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) 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 known brain metastases; (a head CT is not necessary to rule out brain metastases, unless there is clinical suspicion of central nervous system [CNS] involvement)

• Patients with serious cardiovascular illness such as myocardial infarction within 6 months prior to entry, congestive heart failure (even if medically controlled), unstable angina, active cardiomyopathy, unstable ventricular arrhythmia or uncontrolled hypertension

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to CCI-779

• Patients receiving concurrent treatment with other anti-cancer therapy or other investigational agents

• Serious illness or medical condition which would not permit the patient to be managed according to the protocol including, but not limited to:

  • History of significant neurologic or psychiatric disorder which would impair the ability to obtain consent or limit compliance with study requirements
  • Active uncontrolled infection
  • Active peptic ulcer disease
  • Any other medical conditions that might be aggravated by treatment