Impact of Temsirolimus Therapy on Circulating Tumor Cell Biology In Men With Castration Resistant Metastatic Prostate Cancer
Primary Purpose
Prostate Cancer
Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Temsirolimus
Diphenhydramine
Sponsored by
About this trial
This is an interventional treatment trial for Prostate Cancer focused on measuring metastatic, Temsirolimus, prostate, cancer
Eligibility Criteria
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.
Sites / Locations
- Duke University Medical Center
- Virginia Oncology Associates
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Temsirolimus 25 mg
Arm Description
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.
Outcomes
Primary Outcome Measures
Change in Circulating Tumor Cell (CTC) Counts in Men With Metastatic Treatment-refractory Castration-resistant Prostate Cancer.
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
Percent Change in CTC Count From Baseline to 12 Weeks of Treatment.
To evaluate the change in CTC counts upon the addition of an anti-androgen upon PSA progression while on temsirolimus therapy
Mean Percent of N-cadherin Expression at Baseline and 8 Weeks of Treatment.
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.
Percent Change in LDH
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
Median Progression-Free Survival (PFS)
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.
Maximum Rate of Change of Prostate-Specific Antigen (PSA).
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.
Time to PSA Progression
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.
Time to Second PSA Progression After Addition of Anti-androgen Therapy
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.
Change Over Time in CTC Gene Expression Profile
Percent change in CTC gene expression from baseline to 8 or 12 weeks of treatment.
Safety and Tolerability of Temsirolimus
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 ClinicalTrials.gov.
Full Information
NCT ID
NCT00887640
First Posted
April 23, 2009
Last Updated
January 24, 2014
Sponsor
Duke University
Collaborators
National Comprehensive Cancer Network
1. Study Identification
Unique Protocol Identification Number
NCT00887640
Brief Title
Impact of Temsirolimus Therapy on Circulating Tumor Cell Biology In Men With Castration Resistant Metastatic Prostate Cancer
Official Title
Impact of Temsirolimus Therapy on Circulating Tumor Cell Biology In Men With Castration Resistant Metastatic Prostate Cancer
Study Type
Interventional
2. Study Status
Record Verification Date
January 2013
Overall Recruitment Status
Terminated
Study Start Date
July 2009 (undefined)
Primary Completion Date
August 2012 (Actual)
Study Completion Date
August 2012 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Duke University
Collaborators
National Comprehensive Cancer Network
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Prostate Cancer
Keywords
metastatic, Temsirolimus, prostate, cancer
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
11 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Temsirolimus 25 mg
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Temsirolimus
Other Intervention Name(s)
Torisel
Intervention Description
dosage form: IV dosage, frequency and duration: 25mg weekly until clinical progression
Intervention Type
Drug
Intervention Name(s)
Diphenhydramine
Other Intervention Name(s)
Benadryl
Intervention Description
Dosage form: IV or PO Dosage, frequency and duration: 25-50mg, 30 minutes prior to Temsirolimus infusion
Primary Outcome Measure Information:
Title
Change in Circulating Tumor Cell (CTC) Counts in Men With Metastatic Treatment-refractory Castration-resistant Prostate Cancer.
Description
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.
Time Frame
Baseline to 8 weeks
Secondary Outcome Measure Information:
Title
Percent Change in CTC Count From Baseline to 12 Weeks of Treatment.
Description
To evaluate the change in CTC counts upon the addition of an anti-androgen upon PSA progression while on temsirolimus therapy
Time Frame
Baseline to 12 weeks
Title
Mean Percent of N-cadherin Expression at Baseline and 8 Weeks of Treatment.
Description
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.
Time Frame
Baseline and 8 weeks
Title
Percent Change in LDH
Description
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
Time Frame
Baseline to 12 weeks
Title
Median Progression-Free Survival (PFS)
Description
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.
Time Frame
2 years
Title
Maximum Rate of Change of Prostate-Specific Antigen (PSA).
Description
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.
Time Frame
Baseline to 7 months
Title
Time to PSA Progression
Description
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.
Time Frame
2 years
Title
Time to Second PSA Progression After Addition of Anti-androgen Therapy
Description
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.
Time Frame
2 years
Title
Change Over Time in CTC Gene Expression Profile
Description
Percent change in CTC gene expression from baseline to 8 or 12 weeks of treatment.
Time Frame
12 weeks
Title
Safety and Tolerability of Temsirolimus
Description
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 ClinicalTrials.gov.
Time Frame
2 years
10. Eligibility
Sex
Male
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Andrew Armstrong, MD, ScM
Organizational Affiliation
Duke Unversity Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
Virginia Oncology Associates
City
Norfolk
State/Province
Virginia
ZIP/Postal Code
23502
Country
United States
12. IPD Sharing Statement
Learn more about this trial
Impact of Temsirolimus Therapy on Circulating Tumor Cell Biology In Men With Castration Resistant Metastatic Prostate Cancer
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