Ignite Creation Date:
2024-05-06 @ 11:25 AM
Last Modification Date:
2024-10-26 @ 12:45 PM
Study NCT ID:
NCT03513211
Status:
COMPLETED
Last Update Posted:
2023-11-22
First Post:
2018-04-17
Brief Title:
Phase III Study of Hydroxychloroquine With Itraconazole With Biochemically Recurrent Prostate Cancer
Sponsor:
St Vincents Hospital Sydney
Organization:
St Vincents Hospital Sydney
Study Overview
Official Title:
A Phase III Study of Hydroxychloroquine and Itraconazole as Therapy for Men With Androgen Normalised Prostate Cancer
Status:
COMPLETED
Status Verified Date:
2023-11
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:
HITMAN-PC
Brief Summary:
Recent pre-clinical work has suggested that Itraconazole has an anti-cancer effect that works synergistically with hydroxychloroquine This may delay the need for androgen deprivation therapy ADT and its associated toxicities in men with biochemically recurrent BCR prostate cancer This study aims to determine feasibility safety and efficacy of suba-itraconazole SI in combination with hydroxychloroquine HQ in the treatment of biochemically recurrent BCR prostate cancer as means of delaying time to commencement of androgen deprivation therapy
Detailed Description:
A rising PSA following treatment with definitive prostatectomy or radiation therapy for localised prostate cancer represents biochemical relapse BCR a disease state for which there is no consensus on optimal management A proportion of men with BCR will go on to develop metastatic disease but there may be a prolonged period of time between biochemical recurrence and overt clinic progression Though androgen deprivation therapy ADT may prolong metastasis-free survival it comes at a cost of significant morbidity Thus substantial efforts are underway to find treatments that may delay the need for ADT while maintaining quality of life in men with BCR prostate cancer
Autophagy inhibitors given in combination with cytotoxic agents have been found to suppress tumour growth and trigger cell death to a greater extent than chemotherapy alone both in vitro and in vivo Such inhibitors include the anti-malarial drug chloroquine CQ and its derivative hydroxychloroquine HCQ Taken together autophagy may represent a major mechanism for treatment resistance and thus represents a potential novel therapeutic target Moreover hydroxychloroquine has shown modest activity as a single agent in men with BCR prostate cancer
The antifungal drug itraconazole has shown some activity in prostate cancer These effects are attributed to inhibitory effects on endothelial cell proliferation and angiogenesis mTOR inhibition through effects on intracellular cholesterol trafficking hedgehog pathway inhibition and induction of autophagy With regards to cholesterol trafficking itraconazole causes depletion of plasma membrane cholesterol and cholesterol trapping in the late endosomes and lysosomes in part through inhibition of the cholesterol transporter NPC1
Pre-clinical studies have shown enhanced death of prostate cancer cells with treatment of itraconazole combined with hydroxychloroquine This treatment causes a dramatic increase in the accumulation of free cholesterol with a phenotype reminiscent of Niemann-Pick Syndrome a neurodegenerative disease characterised by accumulation of free cholesterol in late endosomeslysosomes due to mutations in NPC1 and NPC2 The investigators hypothesise that itraconazole synergises with hydroxychloroquine to induce sequestration of cholesterol in the lysosomes while inhibiting autophagy thereby inducing cell death through oxidation of the excess cholesterol and cell dysfunction as a result of the inaccessibility of the cholesterol This mechanism may be particularly potent in androgen sensitive prostate cancer where cholesterol use is destined for androgen synthesis
Non-castrating treatments for BCR and metastatic prostate cancer are an area of unmet need The aim of this study is to assess the tolerability safety and efficacy of hydroxychloroquine in combination with itraconazole as a strategy to delay time to ADT commencement in men with BCR prostate cancer
Autophagy inhibitors given in combination with cytotoxic agents have been found to suppress tumour growth and trigger cell death to a greater extent than chemotherapy alone both in vitro and in vivo Such inhibitors include the anti-malarial drug chloroquine CQ and its derivative hydroxychloroquine HCQ Taken together autophagy may represent a major mechanism for treatment resistance and thus represents a potential novel therapeutic target Moreover hydroxychloroquine has shown modest activity as a single agent in men with BCR prostate cancer
The antifungal drug itraconazole has shown some activity in prostate cancer These effects are attributed to inhibitory effects on endothelial cell proliferation and angiogenesis mTOR inhibition through effects on intracellular cholesterol trafficking hedgehog pathway inhibition and induction of autophagy With regards to cholesterol trafficking itraconazole causes depletion of plasma membrane cholesterol and cholesterol trapping in the late endosomes and lysosomes in part through inhibition of the cholesterol transporter NPC1
Pre-clinical studies have shown enhanced death of prostate cancer cells with treatment of itraconazole combined with hydroxychloroquine This treatment causes a dramatic increase in the accumulation of free cholesterol with a phenotype reminiscent of Niemann-Pick Syndrome a neurodegenerative disease characterised by accumulation of free cholesterol in late endosomeslysosomes due to mutations in NPC1 and NPC2 The investigators hypothesise that itraconazole synergises with hydroxychloroquine to induce sequestration of cholesterol in the lysosomes while inhibiting autophagy thereby inducing cell death through oxidation of the excess cholesterol and cell dysfunction as a result of the inaccessibility of the cholesterol This mechanism may be particularly potent in androgen sensitive prostate cancer where cholesterol use is destined for androgen synthesis
Non-castrating treatments for BCR and metastatic prostate cancer are an area of unmet need The aim of this study is to assess the tolerability safety and efficacy of hydroxychloroquine in combination with itraconazole as a strategy to delay time to ADT commencement in men with BCR prostate cancer
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None