Neoadjuvant Study of In-situ REIC/Dkk-3 in Prostate Cancer
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase I Neoadjuvant Study of In-situ REIC/Dkk-3 Therapy Followed By Prostatectomy in Patients With High Risk Localized Prostate Cancer|
- Maximum Tolerated Dose [ Time Frame: 7-days ] [ Designated as safety issue: Yes ]To define the Maximum Tolerated Dose (MTD) for intertumoral injection (IT) of Ad-REIC/Dkk-3 viral vector.
- Safety evaluation of adverse drug experiences compared with historical precedence [ Time Frame: 28-days ] [ Designated as safety issue: Yes ]To assess the safety of in-situ therapy with REIC/Dkk-3 gene in prostate cancer patients with high risk of local recurrence after radical prostatectomy. Safety events will be evaluated and assessed with regards to causality and in comparison with historical precedence for this patient population.
- Pharmacodynamic Efficacy Markers [ Time Frame: 28-days ] [ Designated as safety issue: No ]To assess the effectiveness of Ad-REIC/Dkk-3 in the treatment of prostate cancer as evaluated by the PSA biomarker and histologic examination of extracted prostate tissue.
|Study Start Date:||September 2010|
|Study Completion Date:||December 2010|
|Primary Completion Date:||December 2010 (Final data collection date for primary outcome measure)|
Experimental: Ad-REIC/Dkk-3 Arm
Active arm on Ad-REIC/Dkk-3
REIC (Reduced Expression in Immortalized Cells) protein is down regulated in a variety of cancer cell lines including prostate tumors. The REIC gene is identical to the Dickkopf-3 (Dkk-3) gene that is a member of the Dickkopf gene family. Ad-REIC/Dkk-3 is designed as a viral vector that delivers a DNA plasmid capable of producing intracellular REIC protein. The expression plasmid includes the full-length human cDNA sequence for REIC. The adenovirus vector is a transport mechanism to infuse the REIC/Dkk-3 plasmid into the cell providing a temporary transfusion of REIC protein.
This is a phase I neoadjuvant gene therapy followed by prostatectomy, open-label, dose-escalation trial for prostate cancer patients with high risk of local recurrence after radical prostatectomy. Patients entered into this trial will have Prostate Cancer of Clinical stage T1c, T2 or T3 with a Gleason Score of between 7 (4+3) and 10 at the time of enrollment.
Patients will receive three 1 mL injections (3 mL total volume) of Ad-REIC/Dkk-3 into the prostate under transrectal ultrasound-guidance (TRUS) and, patients will undergo a radical prostatectomy four weeks after the injection.
Patients will receive treatment at one of three dose levels in a sequential dose-escalating design.
Three patients will be treated at each dose level unless a dose-limiting toxicity (DLT) is observed or MFD (defined as 1 x 10e12 vp/treatment) is achieved. Enrollment will proceed to the next dose level if 0 of 3 patients experiences a DLT; if one of the first 3 patients experiences a DLT, three additional patients will be enrolled until a second patient experiences a DLT (which defines the toxic dose) or until six total patients have been treated at that dose level, whichever comes first. If a second DLT is not experienced within that cohort, dose escalation may continue.
Additional patients will be enrolled a minimum of 14 days after treatment of the first patient in the cohort (sentinel patient).
If 2 DLTs are observed within a cohort, enrollment into the cohort will cease and the dose level immediately preceding that dose will be determined to be the MTD. If 2 non-lethal DLTs are observed in Cohort 1, a lower dose cohort (Cohort -1) may be initiated.
Once the MTD is defined, an additional 3-6 patients may be enrolled at that dose level to further evaluate safety of the MTD.
Patients will undergo a scheduled radical prostatectomy approximately 4 weeks after the Ad-REIC/Dkk-3 injection. The prostate tissue removed will be retained and for those patients treated at the MTD, assessed for REIC expression and evidence of apoptosis by TUNEL staining.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01197209
|United States, New York|
|Mount Sinai School of Medicine|
|New York, New York, United States, 10029|
|Principal Investigator:||Simon Hall, MD||Icahn School of Medicine at Mount Sinai|