Ignite Creation Date:
2024-05-06 @ 1:24 PM
Last Modification Date:
2024-10-26 @ 1:13 PM
Study NCT ID:
NCT04011410
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2024-04-10
First Post:
2019-07-01
Brief Title:
Hydroxychloroquine to Increase Tumor Suppressor PAR-4 Levels in Oligometastatic Prostate Cancer
Sponsor:
Patrick Hensley
Organization:
University of Kentucky
Study Overview
Official Title:
Phase 2 Study of Hydroxychloroquine to Increase Tumor Suppressor PAR-4 Levels in Oligometastatic Prostate Cancer
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2024-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Treatment of recurrent oligometastatic prostate cancer may be enhanced by the addition of Hydroxychloroquine to the current treatment regimens Potential benefits of Hydroxychloroquine include delayed disease progression and delayed initiation of androgen deprivation therapy ADT thus lessening morbidity distressing side effects and improving functioning and quality of life in men with recurrent prostate cancer
Building on prior research at Markey patients recently diagnosed with recurrent oligometastatic prostate cancer will be approached about participating in this study Per standard of care these patients undergo either surgery or radiation in addition participants of this clinical trial will also receive Hydroxychloroquine 400 mg per day oral medication for 3 months
It is expected that a participant will exhibit a 50 increase of tumor suppressor PAR-4 as well as few if any negative side effects from Hydroxychloroquine
Building on prior research at Markey patients recently diagnosed with recurrent oligometastatic prostate cancer will be approached about participating in this study Per standard of care these patients undergo either surgery or radiation in addition participants of this clinical trial will also receive Hydroxychloroquine 400 mg per day oral medication for 3 months
It is expected that a participant will exhibit a 50 increase of tumor suppressor PAR-4 as well as few if any negative side effects from Hydroxychloroquine
Detailed Description:
This investigator-initiated clinical trial IIT builds on and extends research on autophagy in prostate cancer with PAR-4 and HCQ conducted by a transdisciplinary investigative team and is sponsored by funding from Markey Cancer Center
Prostate cancer is the most common cancer in men and the 2nd most common cause of cancer death in men Secondary to the greying of the US population and increasing life expectancy metastatic prostate cancer mPCa rates are increasing Androgen deprivation therapy ADT has been the primary treatment for metastatic prostate cancer The survival benefit of ADT is juxtaposed against significant adverse effects including cardiovascular morbidity skeletal fractures diabetes sexual dysfunction and a decrease in cognitive function Recent studies have indicated a potential benefit to treatment of metastatic lesions in men with limited metastatic disease and have identified a potential delay in initiation of ADT in men whose limited metastatic lesions were treated with stereotactic radiotherapy Prostate apoptosis response-4 PAR-4 is a tumor suppressor protein that facilitates apoptosis in numerous types of cancer cells Hydroxychloroquine HCQ has been found to induce PAR-4 expression and subsequently promote apoptosis of cancer cells and inhibit metastatic progression HCQ has also been reported to both inhibit and enhance immune responses via changes in Th1 Th2 Th17 and Treg subsets and reduce inflammatory markers It also acidifies lysosomes which potentially inhibits antigen presentation by antigen-presenting cells and can be measured with LysoSensor YellowBlue DND-160 by flow cytometry and induces autophagy which can be detected by measuring up-regulation of the microtubule associated protein LC3B Treatment of oligometastatic prostate cancer may be enhanced by the addition of Hydroxychloroquine to either surgical resection or radiation treatment of metastatic lesions Potential benefits of Hydroxychloroquine include delayed disease progression and delayed initiation of ADT lessening morbidity and increasing quality of life in men with oligometastatic prostate cancer
A single-arm open-label phase II trial will be conducted in a population of men with recurrent oligometastatic prostate cancer following primary treatment of localized disease The oligometastatic sites will be treated with either surgical resection or stereotactic radiation per standard of care in addition to 400 mg of Hydroxychloroquine per day for a period of 3 months
Sample Size
Based on an ongoing Phase I trial of HCQ the proportion of patients who will exhibit a 50 induction in PAR-4 from baseline levels is equal to 050 compared to a null hypothesis of 020 A sample of 18 patients will provide 84 power to detect this hypothesized difference in proportion based on a two-sided test with 5 significance level Prior studies at Markey Cancer Center in this population have demonstrated an attrition rate of less than a 10 Thus a total of 20 patients will be enrolled into the study
Specific and Secondary Aims
The primary objective is to assess the rate of attainment of a 50 increase in tumor suppressor PAR-4 levels from baseline in patients treated with 3-months of hydroxychloroquine HCQ in combination with radiation or surgery for recurrent oligometastatic prostate cancer
Secondary aims of the trial include assessment of median progression-free survival 1- and 3-year ADT-free survival treatment toxicity and quality of life
Correlative studies of the trial comprise assessment of immunological effect of Hydroxychloroquine by analyzing peripheral blood mononuclear cells PBMCs
Statistical Analytic Plan
Descriptive statistics will be calculated to summarize PAR-4 levels at each time point of follow-up Percent change from baseline compared to each follow-up time point will likewise be calculated The proportion of patients who exhibit a 50 induction in PAR-4 compared to baseline within the 3-month therapy period will be calculated and a one-sample test for proportion will be performed Secondary analyses of the primary endpoint will also be performed Continuous changes in PAR-4 levels will also be assessed using paired t-test or nonparametric analog Linear mixed models will be employed to analyzed repeatedly measured levels of PAR-4 and association with clinical parameters as well as PSA levels
Other secondary analyses will include summary of the PAR-4 induction profile over the 3-month treatment period and after end of therapy period PSA levels will be assessed and PSA doubling time will be calculated Association of PSA levels with PAR-4 levels will be determined using Spearman or Pearsons correlation coefficient Quality of life as measured by the EORTC QLQ-C30 supplemented with QLQ-PR25 will be evaluated and descriptive statistics of QOL scores will be calculated Association of QOL with PAR-4 PSA and other clinical endpoints will be determined in an exploratory manner using correlations and survival analysis models
All participants who received HCQ will be included in the safety analysis Frequency and incidence tables of toxicity and AEs will be generated
Immune outcome endpoints including markers of immune functionactivation and systemic inflammation will be summarized at each time point of follow-up Linear mixed models will be utilized to model these repeatedly measured immune endpoints to determine changes over time Associations between markers and PAR-4 levels will be assessed via calculation and comparison of correlation coefficients Data processing data analysis pipelines and bioinformatics methods for NGS data will be employed in collaboration with MCC Shared Resource Facilities False discovery rate FDR q values will be calculated for multiple comparison adjustment with threshold significance set to 005
Prostate cancer is the most common cancer in men and the 2nd most common cause of cancer death in men Secondary to the greying of the US population and increasing life expectancy metastatic prostate cancer mPCa rates are increasing Androgen deprivation therapy ADT has been the primary treatment for metastatic prostate cancer The survival benefit of ADT is juxtaposed against significant adverse effects including cardiovascular morbidity skeletal fractures diabetes sexual dysfunction and a decrease in cognitive function Recent studies have indicated a potential benefit to treatment of metastatic lesions in men with limited metastatic disease and have identified a potential delay in initiation of ADT in men whose limited metastatic lesions were treated with stereotactic radiotherapy Prostate apoptosis response-4 PAR-4 is a tumor suppressor protein that facilitates apoptosis in numerous types of cancer cells Hydroxychloroquine HCQ has been found to induce PAR-4 expression and subsequently promote apoptosis of cancer cells and inhibit metastatic progression HCQ has also been reported to both inhibit and enhance immune responses via changes in Th1 Th2 Th17 and Treg subsets and reduce inflammatory markers It also acidifies lysosomes which potentially inhibits antigen presentation by antigen-presenting cells and can be measured with LysoSensor YellowBlue DND-160 by flow cytometry and induces autophagy which can be detected by measuring up-regulation of the microtubule associated protein LC3B Treatment of oligometastatic prostate cancer may be enhanced by the addition of Hydroxychloroquine to either surgical resection or radiation treatment of metastatic lesions Potential benefits of Hydroxychloroquine include delayed disease progression and delayed initiation of ADT lessening morbidity and increasing quality of life in men with oligometastatic prostate cancer
A single-arm open-label phase II trial will be conducted in a population of men with recurrent oligometastatic prostate cancer following primary treatment of localized disease The oligometastatic sites will be treated with either surgical resection or stereotactic radiation per standard of care in addition to 400 mg of Hydroxychloroquine per day for a period of 3 months
Sample Size
Based on an ongoing Phase I trial of HCQ the proportion of patients who will exhibit a 50 induction in PAR-4 from baseline levels is equal to 050 compared to a null hypothesis of 020 A sample of 18 patients will provide 84 power to detect this hypothesized difference in proportion based on a two-sided test with 5 significance level Prior studies at Markey Cancer Center in this population have demonstrated an attrition rate of less than a 10 Thus a total of 20 patients will be enrolled into the study
Specific and Secondary Aims
The primary objective is to assess the rate of attainment of a 50 increase in tumor suppressor PAR-4 levels from baseline in patients treated with 3-months of hydroxychloroquine HCQ in combination with radiation or surgery for recurrent oligometastatic prostate cancer
Secondary aims of the trial include assessment of median progression-free survival 1- and 3-year ADT-free survival treatment toxicity and quality of life
Correlative studies of the trial comprise assessment of immunological effect of Hydroxychloroquine by analyzing peripheral blood mononuclear cells PBMCs
Statistical Analytic Plan
Descriptive statistics will be calculated to summarize PAR-4 levels at each time point of follow-up Percent change from baseline compared to each follow-up time point will likewise be calculated The proportion of patients who exhibit a 50 induction in PAR-4 compared to baseline within the 3-month therapy period will be calculated and a one-sample test for proportion will be performed Secondary analyses of the primary endpoint will also be performed Continuous changes in PAR-4 levels will also be assessed using paired t-test or nonparametric analog Linear mixed models will be employed to analyzed repeatedly measured levels of PAR-4 and association with clinical parameters as well as PSA levels
Other secondary analyses will include summary of the PAR-4 induction profile over the 3-month treatment period and after end of therapy period PSA levels will be assessed and PSA doubling time will be calculated Association of PSA levels with PAR-4 levels will be determined using Spearman or Pearsons correlation coefficient Quality of life as measured by the EORTC QLQ-C30 supplemented with QLQ-PR25 will be evaluated and descriptive statistics of QOL scores will be calculated Association of QOL with PAR-4 PSA and other clinical endpoints will be determined in an exploratory manner using correlations and survival analysis models
All participants who received HCQ will be included in the safety analysis Frequency and incidence tables of toxicity and AEs will be generated
Immune outcome endpoints including markers of immune functionactivation and systemic inflammation will be summarized at each time point of follow-up Linear mixed models will be utilized to model these repeatedly measured immune endpoints to determine changes over time Associations between markers and PAR-4 levels will be assessed via calculation and comparison of correlation coefficients Data processing data analysis pipelines and bioinformatics methods for NGS data will be employed in collaboration with MCC Shared Resource Facilities False discovery rate FDR q values will be calculated for multiple comparison adjustment with threshold significance set to 005
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
True
Is an FDA AA801 Violation?:
None