Prostate Cancer
Conditions
Keywords
metastatic, Temsirolimus, prostate, cancer
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.
Interventions
DRUGTemsirolimus
dosage form: IV dosage, frequency and duration: 25mg weekly until clinical progression
DRUGDiphenhydramine
Dosage form: IV or PO Dosage, frequency and duration: 25-50mg, 30 minutes prior to Temsirolimus infusion
Sponsors
National Comprehensive Cancer Network
Duke University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Circulating Tumor Cell (CTC) Counts in Men With Metastatic Treatment-refractory Castration-resistant Prostate Cancer. | 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
| Measure | Time frame | Description |
|---|---|---|
| Mean Percent of N-cadherin Expression at Baseline and 8 Weeks of Treatment. | 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. |
| Percent Change in LDH | 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 |
| Median Progression-Free Survival (PFS) | 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. |
| Maximum Rate of Change of Prostate-Specific Antigen (PSA). | 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. |
| Percent Change in CTC Count From Baseline to 12 Weeks of Treatment. | 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 |
| Time to Second PSA Progression After Addition of Anti-androgen Therapy | 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. |
| Change Over Time in CTC Gene Expression Profile | 12 weeks | Percent change in CTC gene expression from baseline to 8 or 12 weeks of treatment. |
| Safety and Tolerability of Temsirolimus | 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 ClinicalTrials.gov. |
| Time to PSA Progression | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 11 |
| Total | 11 |
Baseline characteristics
| Characteristic | Temsirolimus 25 mg |
|---|---|
| Age, Continuous | 61 years |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 9 / 11 |
| serious Total, serious adverse events | 4 / 11 |
Outcome results
Primary
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.
Time frame: Baseline to 8 weeks
Population: CTC count at both baseline and week 8 were assessable in 8 of the 11 patients as CTCs were collected at both time points in these patients. Missing CTC data for 3 of the 11 patients due to laboratory error or no CTC available at various time points.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Temsirolimus 25 mg | Change in Circulating Tumor Cell (CTC) Counts in Men With Metastatic Treatment-refractory Castration-resistant Prostate Cancer. | -20 percent change |
Secondary
Change Over Time in CTC Gene Expression Profile
Percent change in CTC gene expression from baseline to 8 or 12 weeks of treatment.
Time frame: 12 weeks
Population: Data were insufficient to evaluate this outcome. Data not collected. This outcome was not performed due to availability and feasibility of the tests involved.
Secondary
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 frame: Baseline to 7 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Temsirolimus 25 mg | Maximum Rate of Change of Prostate-Specific Antigen (PSA). | 48 Percent change |
Secondary
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.
Time frame: Baseline and 8 weeks
Population: N-cadherin expression at both baseline and 8 weeks was evaluable in 7 patients.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Temsirolimus 25 mg | Mean Percent of N-cadherin Expression at Baseline and 8 Weeks of Treatment. | Expression at 8 weeks | 92 Percent expression |
| Temsirolimus 25 mg | Mean Percent of N-cadherin Expression at Baseline and 8 Weeks of Treatment. | Expression at baseline | 91 Percent expression |
Secondary
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.
Time frame: 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Temsirolimus 25 mg | Median Progression-Free Survival (PFS) | 1.9 Months |
Secondary
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
Time frame: Baseline to 12 weeks
Population: Data were insufficient to evaluate this outcome. Outcome not available at 12 weeks. CTCs were not collected at week 12 and thus were not analyzed.
Secondary
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
Time frame: Baseline to 12 weeks
Population: Data were insufficient to evaluate this outcome. Data not collected. This outcome was not performed due to availability and feasibility of the tests involved.
Secondary
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.
Time frame: 2 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Temsirolimus 25 mg | Safety and Tolerability of Temsirolimus | Grade 3 Adverse Events | 28 Adverse Events |
| Temsirolimus 25 mg | Safety and Tolerability of Temsirolimus | Grade 4 Adverse Events | 2 Adverse Events |
| Temsirolimus 25 mg | Safety and Tolerability of Temsirolimus | Grade 5 Adverse Events | 0 Adverse Events |
Secondary
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 frame: 2 years
Population: Data were insufficient to evaluate this outcome. Data not collected. PSA responses were not observed in this study and PSA progression dates would essentially be the same as the radiographic PFS dates.
Secondary
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.
Time frame: 2 years
Population: Data were insufficient to evaluate this outcome. Data not collected. Patients progressed radiographically before 2nd PSA progression occurred.