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

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00072176
• Collaborator: (none)
• Enrollment: 62
• Location: 1
• Arm: 1
• Duration (Months): 63
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Endometrial Adenocarcinoma; Endometrial Adenosquamous Cell Carcinoma; Endometrial Clear Cell Carcinoma; Endometrial Papillary Serous Carcinoma; Recurrent Endometrial Carcinoma; Stage IIIA Endometrial Carcinoma; Stage IIIB Endometrial Carcinoma; Stage IIIC Endometrial Carcinoma; Stage IVA Endometrial Carcinoma; Stage IVB Endometrial Carcinoma	Drug: temsirolimus; Other: laboratory biomarker analysis	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. 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.

2. 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.

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

4. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 62 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of CCI-779 in Patients With Metastatic and/or Locally Advanced Recurrent Endometrial Cancer
• Study Start Date: May 1, 2004
• Actual Primary Completion Date: May 1, 2009
• Actual Study Completion Date: Aug 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (temsirolimus) 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.	Drug: temsirolimus; Given IV; Other Names: CCI-779 cell cycle inhibitor 779 Torisel ; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Objective Clinical Response Rate [Up to 5 years]

   Defined as proportion of patients with 30% decrease in the sum of the longest diameters of the target lesions (partial response) maintained for at least 4 weeks, or complete disappearance of disease and cancer related symptoms (complete response) and confirmed on independent radiology review.

2. Progression-free Survival (Tumor Progression) [5 years]

   Time to tumor progression or death

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Cancer Institute of Canada Clinical Trials Group	Kingston	Ontario	Canada	K7L 3N6

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Amit Oza, Canadian Cancer Trials Group

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00072176
• Other Study ID Numbers: NCI-2014-00649; NCI-2014-00649; I160; CAN-NCIC-IND160; IND.160; CDR0000335543; NCIC-160; NCIC-160
• First Posted: Nov 6, 2003
• Last Update Posted: Feb 23, 2015
• Last Verified: Mar 1, 2014

• Additional relevant MeSH terms: Carcinoma; Endometrial Neoplasms; Cystadenocarcinoma, Serous; Adenomyoepithelioma; Adenocarcinoma, Clear Cell; Carcinoma, Adenosquamous; Recurrence; Sirolimus

Study Results

Participant Flow

Recruitment Details	Patients were recruited from 10 participating centers across Canada between May 2004 and June 2007.

Arm/Group Title	Group A	Group B
Arm/Group Description	Chemotherapy naive 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. temsirolimus: Given IV laboratory biomarker analysis: Correlative studies	Chemotherapy treated 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. temsirolimus: Given IV laboratory biomarker analysis: Correlative studies
Period Title: Overall Study
STARTED	34	28
COMPLETED	33	27
NOT COMPLETED	1	1

Baseline Characteristics

Arm/Group Title	Group A	Group B	Total
Arm/Group Description	Chemotherapy naive 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. temsirolimus: Given IV laboratory biomarker analysis: Correlative studies	Chemotherapy treated 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. temsirolimus: Given IV laboratory biomarker analysis: Correlative studies	Total of all reporting groups
Overall Participants	33	27	60
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	66	60	63
Sex: Female, Male (Count of Participants)
Female	33 100%	27 100%	60 100%
Male	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Canada	33 100%	27 100%	60 100%

Outcome Measures

1. Primary Outcome

Title	Objective Clinical Response Rate
Description	Defined as proportion of patients with 30% decrease in the sum of the longest diameters of the target lesions (partial response) maintained for at least 4 weeks, or complete disappearance of disease and cancer related symptoms (complete response) and confirmed on independent radiology review.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

Patients who were evaluable for response.

Arm/Group Title	Group A	Group B
Arm/Group Description	Chemotherapy naive 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. temsirolimus: Given IV laboratory biomarker analysis: Correlative studies	Chemotherapy treated 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. temsirolimus: Given IV laboratory biomarker analysis: Correlative studies
Measure Participants	29	25
Number (95% Confidence Interval) [percentage of patients with response]	13.8	4.0

2. Primary Outcome

Title	Progression-free Survival (Tumor Progression)
Description	Time to tumor progression or death
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

All patients who were evaluable for response

Arm/Group Title	Group A	Group B
Arm/Group Description	Chemotherapy naive 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. temsirolimus: Given IV laboratory biomarker analysis: Correlative studies	Chemotherapy treated 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. temsirolimus: Given IV laboratory biomarker analysis: Correlative studies
Measure Participants	29	25
Median (95% Confidence Interval) [months]	7.33	3.25

Adverse Events

Arm/Group Title	Group A		Group B
Arm/Group Description	Chemotherapy naive 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. temsirolimus: Given IV laboratory biomarker analysis: Correlative studies		Chemotherapy treated 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. temsirolimus: Given IV laboratory biomarker analysis: Correlative studies
All Cause Mortality
	Group A		Group B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Group A		Group B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/33 (33.3%)		9/27 (33.3%)
Blood and lymphatic system disorders
Limb Edema	1/33 (3%)		0/27 (0%)
Hospitalization for Anemia	0/33 (0%)		1/27 (3.7%)
Thrombosis	0/33 (0%)		1/27 (3.7%)
Ear and labyrinth disorders
Hospitalization for Ear Pain	0/33 (0%)		1/27 (3.7%)
Gastrointestinal disorders
Hospitalization for dehydration	1/33 (3%)		2/27 (7.4%)
Hospitalization for bowel obstruction and enteritis	1/33 (3%)		0/27 (0%)
Hospitalization for anorexia	1/33 (3%)		0/27 (0%)
Hospitalization for bowel obstruction	1/33 (3%)		0/27 (0%)
Hospitalization for Nausea	0/33 (0%)		1/27 (3.7%)
Hospitalization for Vomiting	0/33 (0%)		2/27 (7.4%)
Hospitalization for diarrhea	0/33 (0%)		2/27 (7.4%)
Hospitalization for Fistula	0/33 (0%)		1/27 (3.7%)
General disorders
Hospitalization for chest pain	1/33 (3%)		0/27 (0%)
hospitalization for abdominal pain	1/33 (3%)		0/27 (0%)
Hospitalization for gastrointestinal pain	1/33 (3%)		0/27 (0%)
Hospitalization for leg pain	1/33 (3%)		0/27 (0%)
Hospitalization for Fatigue	0/33 (0%)		1/27 (3.7%)
Infections and infestations
Hospitalization for Urosepsis	0/33 (0%)		1/27 (3.7%)
Investigations
Hospitalization for hyperglycemia	1/33 (3%)		0/27 (0%)
Hospitalization for hypokalemia	1/33 (3%)		2/27 (7.4%)
Hospitalization for Hyponatremia	0/33 (0%)		1/27 (3.7%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hospitalization for Impending Fracture of Lytic Lesion	0/33 (0%)		1/27 (3.7%)
Nervous system disorders
Hospitalization for spinal cord compression	1/33 (3%)		1/27 (3.7%)
Hospitalization for Facial Nerve & Vocal Cord Paralysis	0/33 (0%)		1/27 (3.7%)
Renal and urinary disorders
Renal failure	1/33 (3%)		0/27 (0%)
Hospitalization for renal obstruction	1/33 (3%)		0/27 (0%)
Respiratory, thoracic and mediastinal disorders
Hospitalization for pulmonary embolism	1/33 (3%)		0/27 (0%)
Hospitalization for pneumonitis	1/33 (3%)		1/27 (3.7%)
Hospitalization for Dyspnea	0/33 (0%)		1/27 (3.7%)
Other (Not Including Serious) Adverse Events
	Group A		Group B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	33/33 (100%)		27/27 (100%)
Blood and lymphatic system disorders
Hemorrhage pulmonary Nose	8/33 (24.2%)		4/27 (14.8%)
Hemorrhage, GU Urinary NOS	2/33 (6.1%)		0/27 (0%)
Hemorrhage, GU Vagina	3/33 (9.1%)		1/27 (3.7%)
Edema: head and neck	2/33 (6.1%)		0/27 (0%)
Edema: limb	19/33 (57.6%)		5/27 (18.5%)
Cardiac disorders
Supraventricular arrhythmia Atrial tachycardia	2/33 (6.1%)		0/27 (0%)
Supraventricular arrhythmia Sinus tachycardia	1/33 (3%)		3/27 (11.1%)
Supraventricular arrhythmia Tachycardia	1/33 (3%)		3/27 (11.1%)
Hypertension	4/33 (12.1%)		1/27 (3.7%)
Hypotension	2/33 (6.1%)		0/27 (0%)
Cardiac General - Other	2/33 (6.1%)		1/27 (3.7%)
Endocrine disorders
Hot flashes	1/33 (3%)		2/27 (7.4%)
Eye disorders
Dry eye	2/33 (6.1%)		1/27 (3.7%)
Watery eye	2/33 (6.1%)		0/27 (0%)
Ocular - Other	2/33 (6.1%)		1/27 (3.7%)
Gastrointestinal disorders
Anorexia	13/33 (39.4%)		16/27 (59.3%)
Constipation	14/33 (42.4%)		11/27 (40.7%)
Dehydration	4/33 (12.1%)		2/27 (7.4%)
Diarrhea	9/33 (27.3%)		14/27 (51.9%)
Distension	6/33 (18.2%)		1/27 (3.7%)
Dry mouth	7/33 (21.2%)		3/27 (11.1%)
Flatulence	4/33 (12.1%)		1/27 (3.7%)
Heartburn	4/33 (12.1%)		7/27 (25.9%)
Hemorrhoids	2/33 (6.1%)		0/27 (0%)
Mucositis (clinical exam) Oral cavity	2/33 (6.1%)		0/27 (0%)
Mucositis (functional/symptomatic) Oral cavity	21/33 (63.6%)		18/27 (66.7%)
Nausea	16/33 (48.5%)		15/27 (55.6%)
Taste alteration	14/33 (42.4%)		8/27 (29.6%)
Vomiting	12/33 (36.4%)		10/27 (37%)
GI - Other	3/33 (9.1%)		2/27 (7.4%)
General disorders
Fatigue	28/33 (84.8%)		21/27 (77.8%)
Fever	6/33 (18.2%)		3/27 (11.1%)
Insomnia	9/33 (27.3%)		7/27 (25.9%)
Rigors/chills	5/33 (15.2%)		4/27 (14.8%)
Pain Abdomen NOS	20/33 (60.6%)		14/27 (51.9%)
Pain Back	9/33 (27.3%)		10/27 (37%)
Pain Bladder	5/33 (15.2%)		4/27 (14.8%)
Pain Bone	2/33 (6.1%)		3/27 (11.1%)
Pain Chest wall	2/33 (6.1%)		2/27 (7.4%)
Pain Chest/thorax NOS	3/33 (9.1%)		1/27 (3.7%)
Pain Esophagus	2/33 (6.1%)		1/27 (3.7%)
Pain Extremity-limb	5/33 (15.2%)		3/27 (11.1%)
Pain Head/headache	10/33 (30.3%)		5/27 (18.5%)
Pain Joint	6/33 (18.2%)		4/27 (14.8%)
Pain Muscle	7/33 (21.2%)		2/27 (7.4%)
Pain Neuralgia/peripheral nerve	2/33 (6.1%)		0/27 (0%)
Pain - Other	3/33 (9.1%)		1/27 (3.7%)
Flu-like syndrome	1/33 (3%)		4/27 (14.8%)
Immune system disorders
Allergic reaction	2/33 (6.1%)		1/27 (3.7%)
Rhinitis	7/33 (21.2%)		2/27 (7.4%)
Infections and infestations
Infection with normal ANC Lip/perioral	4/33 (12.1%)		1/27 (3.7%)
Infection with normal ANC Lung	2/33 (6.1%)		0/27 (0%)
Infection with normal ANC Skin	4/33 (12.1%)		0/27 (0%)
Infection with normal ANC Ungual	3/33 (9.1%)		0/27 (0%)
IInfection with normal ANC Upper airway NOS	2/33 (6.1%)		1/27 (3.7%)
Musculoskeletal and connective tissue disorders
Arthritis	2/33 (6.1%)		1/27 (3.7%)
Muscle weakness Extremity-lower	2/33 (6.1%)		3/27 (11.1%)
Nervous system disorders
Dizziness	3/33 (9.1%)		4/27 (14.8%)
Mood alteration Anxiety	6/33 (18.2%)		5/27 (18.5%)
Mood alteration Depression	4/33 (12.1%)		2/27 (7.4%)
Neuropathy-sensory	7/33 (21.2%)		10/27 (37%)
Somnolence	2/33 (6.1%)		1/27 (3.7%)
Neurology - Other	1/33 (3%)		3/27 (11.1%)
Renal and urinary disorders
Incontinence, urinary	2/33 (6.1%)		1/27 (3.7%)
Renal failure	2/33 (6.1%)		0/27 (0%)
Urinary frequency	6/33 (18.2%)		1/27 (3.7%)
Urinary retention	2/33 (6.1%)		1/27 (3.7%)
Reproductive system and breast disorders
Vaginal discharge	3/33 (9.1%)		5/27 (18.5%)
Respiratory, thoracic and mediastinal disorders
Bronchospasm	2/33 (6.1%)		0/27 (0%)
Cough	13/33 (39.4%)		11/27 (40.7%)
Dyspnea	13/33 (39.4%)		10/27 (37%)
Pneumonitis	15/33 (45.5%)		10/27 (37%)
Voice changes	2/33 (6.1%)		0/27 (0%)
Pulmonary - Other	2/33 (6.1%)		0/27 (0%)
Skin and subcutaneous tissue disorders
Acne	5/33 (15.2%)		3/27 (11.1%)
Alopecia	3/33 (9.1%)		4/27 (14.8%)
Bruising	7/33 (21.2%)		2/27 (7.4%)
Dry skin	7/33 (21.2%)		4/27 (14.8%)
Injection site reaction	3/33 (9.1%)		0/27 (0%)
Nail changes	6/33 (18.2%)		2/27 (7.4%)
Pruritus	14/33 (42.4%)		4/27 (14.8%)
Rash	16/33 (48.5%)		13/27 (48.1%)
Wound complication, non-infectious	2/33 (6.1%)		0/27 (0%)
Dermatology - Other	4/33 (12.1%)		3/27 (11.1%)
Vascular disorders
Phlebitis	3/33 (9.1%)		0/27 (0%)
hrombosis/thrombus/embolism	2/33 (6.1%)		1/27 (3.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.