Impact of Temsirolimus Therapy on Circulating Tumor Cell Biology In Men With Castration Resistant Metastatic Prostate Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00887640
Recruitment Status : Terminated
First Posted : April 24, 2009
Results First Posted : January 10, 2014
Last Update Posted : February 26, 2014
National Comprehensive Cancer Network
Information provided by (Responsible Party):
Duke University

Brief Summary:
This is a single arm study of 11 men with treatment refractory metastatic Castrate Resistant Prostate Cancer (CRPC) who will receive temsirolimus IV at a dose of 25 mg weekly until progression. Progression will not include Prostate Specific Antigen (PSA) progression; however, upon PSA progression, the addition of an anti-androgen will be permitted. The primary objective of the study is to evaluate change in circulating tumor cell (CTC) counts over time in men with metastatic treatment-refractory CRPC in response to temsirolimus therapy.

Condition or disease Intervention/treatment Phase
Prostate Cancer Drug: Temsirolimus Drug: Diphenhydramine Phase 2

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 11 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Impact of Temsirolimus Therapy on Circulating Tumor Cell Biology In Men With Castration Resistant Metastatic Prostate Cancer
Study Start Date : July 2009
Actual Primary Completion Date : August 2012
Actual Study Completion Date : August 2012

Arm Intervention/treatment
Experimental: Temsirolimus 25 mg
Temsirolimus 25mg was administered by IV infusion each week (days 1, 8, 15, and 22 of each 28 day cycle). The infusion was to be administered over a period not less than 30 minutes and was to be completed within 60 minutes. Subjects were premedicated with 25 to 50 mg IV or PO diphenhydramine (or an alternative antihistamine in case of allergies) 30 minutes prior to the infusion.
Drug: Temsirolimus
dosage form: IV dosage, frequency and duration: 25mg weekly until clinical progression
Other Name: Torisel
Drug: Diphenhydramine
Dosage form: IV or PO Dosage, frequency and duration: 25-50mg, 30 minutes prior to Temsirolimus infusion
Other Name: Benadryl

Primary Outcome Measures :
  1. Change in Circulating Tumor Cell (CTC) Counts in Men With Metastatic Treatment-refractory Castration-resistant Prostate Cancer. [ Time Frame: Baseline to 8 weeks ]
    Median percent change in CTC count from baseline to 8 weeks of treatment. Percent change was calculated by determining the percentage increase or decrease in CTC count from baseline.

Secondary Outcome Measures :
  1. Percent Change in CTC Count From Baseline to 12 Weeks of Treatment. [ Time Frame: Baseline to 12 weeks ]
    To evaluate the change in CTC counts upon the addition of an anti-androgen upon PSA progression while on temsirolimus therapy

  2. Mean Percent of N-cadherin Expression at Baseline and 8 Weeks of Treatment. [ Time Frame: Baseline and 8 weeks ]
    Measures of epithelial plasticity on CTCs in response to Mammalian Target of Rapamycin (mTOR) inhibition with temsirolimus, using genomic and protein immunohistochemical methodology. N-cadherin was measured in CTCs captured using the CellSearch profile kit. The proportion of CTCs expressing N-cadherin was calculated and divided by the total number of CD45-negative, pan cytokeratin (CK) - positive, and 4',6-diamidino-2-phenylindole (DAPI+) intact cells to give a fractional expression of N-cadherin. Results are reported as a percentage.

  3. Percent Change in LDH [ Time Frame: Baseline to 12 weeks ]
    To evaluate and correlate changes in serum Lactate Dehydrogenase (LDH) with CTC count changes over time in men with Castrate Resistant Prostate Cancer (CRPC) treated with temsirolimus

  4. Median Progression-Free Survival (PFS) [ Time Frame: 2 years ]
    Time in months from the start of study treatment to the date of first progression according to Prostate Cancer Clinical Trial Working Group 2 (PCWG2) criteria, or to death due to any cause. Patients alive who had not progressed as of the last follow-up had PFS censored at the last follow-up date. Median PFS was estimated using a Kaplan-Meier curve. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Additionally, according to PCWG2 criteria, disease progression in bone is defined as 2 or more new lesions seen on bone scan compared with the baseline scan used for trial entry. Per PCWG2 guidelines, therapy was not discontinued solely due to a rise in PSA alone.

  5. Maximum Rate of Change of Prostate-Specific Antigen (PSA). [ Time Frame: Baseline to 7 months ]
    Percent change in PSA between baseline and the measurement time point where the largest change in PSA occurred. Note that a positive change (greater than 0) indicates an increase in PSA, and a negative change (less than 0) indicates a decrease.

  6. Time to PSA Progression [ Time Frame: 2 years ]
    Time in months from the start of study treatment to the date of first PSA progression . Patients alive who had not progressed as of the last follow-up or patients who had expired had time to PSA progression censored at the last follow-up date or death date. The median was estimated using a Kaplan-Meier curve.

  7. Time to Second PSA Progression After Addition of Anti-androgen Therapy [ Time Frame: 2 years ]
    Time in months from the time of anti-androgen therapy to the date of second PSA progression . Patients alive who had not progressed as of the last follow-up or patients who had expired had time to second PSA progression censored at the last follow-up date or death date. The median was estimated using a Kaplan-Meier curve.

  8. Change Over Time in CTC Gene Expression Profile [ Time Frame: 12 weeks ]
    Percent change in CTC gene expression from baseline to 8 or 12 weeks of treatment.

  9. Safety and Tolerability of Temsirolimus [ Time Frame: 2 years ]
    Total number of grade 3, 4, and 5 adverse events at least possibly related to temsirolimus therapy. Adverse events were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 and were converted to 4.0 for the purposes of reporting to

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Histologically confirmed carcinoma of the prostate. Histologic evidence may be confirmed through local or metastatic biopsy review
  • Radiographic Evidence of metastatic disease
  • Evidence of disease progression despite castrate levels of testosterone.
  • A circulating timor cell count using FDA approved CellSearch methodology of ≥ 10 per 7.5 cc whole blood, drawn within 4 weeks of study registration
  • Serum PSA greater than or equal to 2ng/dl at registration
  • At least 4 weeks since prior palliative radiation therapy and/or major surgery, and resolution of all toxic effects of prior therapy NCI Common Toxicity Criteria for Adverse Effects (CTCAE) Grade less than or equal to 1
  • Age ≥ 18 years
  • Adequate laboratory parameters
  • Karnofsky Performance Status ≥ 60
  • Life expectancy of at least 3 months

Exclusion Criteria:

  • History of or active central nervous system metastases
  • The use of cytotoxic, biologic, or hormonal therapies within 4 weeks of study entry.
  • Subjects receiving known strong Cytochrome P450 3A4 (CYP3A4) isoenzyme inhibitors and/or inducers
  • Major surgery, open biopsy, traumatic injury, or radiotherapy within 4 weeks of the screening visit
  • Have not recovered from prior biopsy, surgery, traumatic injury, and/or radiation therapy.
  • Presence of non-healing wound or ucer
  • Grade ≥ 3 hemorrhage in the past month to study entry
  • Hypertension with systolic blood pressure of ≥ 180 mmHg and/or diastolic pressure ≥ 100 mmHg (Anti-hypertensive medications are permitted)
  • Subjects with Class 2-4 heart disease or any history of congestive heart failure with an ejection fraction <50% or a recent (within 12 months) cardiovascular event.
  • Anticoagulation with warfarin
  • Diabetes mellitus with glycosylated hemoglobin A1c ≥ 10% despite therapy
  • History of interstitial pneumonitis
  • Subjects with active autoimmune disorder(s) being treated with immunosuppressive agents within 4 weeks prior to screening visit
  • Subjects receiving immunosuppressive agents and those with chronic viral/bacterial/fungal illnesses. Replacement doses of corticosteroids are permitted.
  • Active infection(s), active antimicrobial therapy or serious intercurrent illness.
  • History of other prior malignancy in past 5 years, other than basal cell carcinoma, squamous cell carcinoma of the skin, cervical carcinoma in sity, localized prostate cancer, or superficial bladder cancer.
  • Agreement to use medically acceptable contraceptive methods while on study and for 3 months after the last dose of temsirolimus.
  • Any other major medical or psychiatric illness that, in the investigator's judgment, will substantially increase the risk associated with the subject's participation in this study, including inability to absorb oral medications.
  • Known hypersensitivity to any of the components in the temsirolimus infusion or other medical reasons for not being able to receive adequate premedication.
  • Corrected QT interval on baseline EKG of >500 milliseconds
  • the use of agents that significantly prolong the Corrected QT interval and who are unable to stop medications prior to study initiation.
  • Prior exposure to an Mammalian Target of Rapamycin (mTOR) inhibitor
  • Presence of nephrotic syndrome as determined by clinical evaluation of 24 hour urine.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00887640

United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
United States, Virginia
Virginia Oncology Associates
Norfolk, Virginia, United States, 23502
Sponsors and Collaborators
Duke University
National Comprehensive Cancer Network
Principal Investigator: Andrew Armstrong, MD, ScM Duke Unversity Medical Center

Responsible Party: Duke University Identifier: NCT00887640     History of Changes
Other Study ID Numbers: Pro00016256
First Posted: April 24, 2009    Key Record Dates
Results First Posted: January 10, 2014
Last Update Posted: February 26, 2014
Last Verified: January 2013

Keywords provided by Duke University:

Additional relevant MeSH terms:
Prostatic Neoplasms
Neoplastic Cells, Circulating
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Genital Diseases, Male
Prostatic Diseases
Neoplasm Metastasis
Neoplastic Processes
Pathologic Processes
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Anesthetics, Local
Central Nervous System Depressants
Sensory System Agents
Peripheral Nervous System Agents
Autonomic Agents