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

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.

Study Overview

• Status: Terminated
• Conditions: Prostate Cancer
• Intervention / Treatment: Drug: Temsirolimus; Drug: Diphenhydramine

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Virginia
    • Norfolk, Virginia, United States, 23502
      • Virginia Oncology Associates

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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 Names: Torisel; Drug: Diphenhydramine; Dosage form: IV or PO Dosage, frequency and duration: 25-50mg, 30 minutes prior to Temsirolimus infusion; Other Names: Benadryl

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline to 8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Baseline to 12 weeks
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.	Baseline and 8 weeks
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	Baseline to 12 weeks
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.	2 years
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.	Baseline to 7 months
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.	2 years
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.	2 years
Change Over Time in CTC Gene Expression Profile	Percent change in CTC gene expression from baseline to 8 or 12 weeks of treatment.	12 weeks
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.	2 years

Collaborators and Investigators

• Sponsor: Duke University
• Collaborators: National Comprehensive Cancer Network
• Investigators: Principal Investigator: Andrew Armstrong, MD, ScM, Duke Unversity Medical Center

Study record dates

Study Major Dates

• Study Start: July 1, 2009
• Primary Completion (Actual): August 1, 2012
• Study Completion (Actual): August 1, 2012

Study Registration Dates

• First Submitted: April 23, 2009
• First Submitted That Met QC Criteria: April 23, 2009
• First Posted (Estimate): April 24, 2009

Study Record Updates

• Last Update Posted (Estimate): February 26, 2014
• Last Update Submitted That Met QC Criteria: January 24, 2014
• Last Verified: January 1, 2013

More Information

Terms related to this study

• Keywords: cancer; metastatic; prostate; Temsirolimus
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Neoplastic Processes; Neoplasm Metastasis; Prostatic Neoplasms; Neoplastic Cells, Circulating; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Sensory System Agents; Anesthetics; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Dermatologic Agents; Anti-Bacterial Agents; Hypnotics and Sedatives; Anesthetics, Local; Antibiotics, Antineoplastic; Antifungal Agents; Anti-Allergic Agents; Sleep Aids, Pharmaceutical; Histamine H1 Antagonists; Histamine Antagonists; Histamine Agents; Antipruritics; Diphenhydramine; Promethazine; Sirolimus
• Other Study ID Numbers: Pro00016256