Phase I/II Study of Hydroxychloroquine With Itraconazole With Biochemically Recurrent Prostate Cancer (HITMAN-PC)
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|ClinicalTrials.gov Identifier: NCT03513211|
Recruitment Status : Recruiting
First Posted : May 1, 2018
Last Update Posted : September 6, 2018
|Condition or disease||Intervention/treatment||Phase|
|Prostate Cancer||Drug: SUBA-itraconazole Drug: Hydroxychloroquine||Phase 1 Phase 2|
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 endosomes/lysosomes 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 Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||27 participants|
|Intervention Model:||Sequential Assignment|
|Intervention Model Description:||Phase I intra-patient dose escalation study Phase II Simon 2-stage cohort expansion|
|Masking:||None (Open Label)|
|Official Title:||A Phase I/II Study of Hydroxychloroquine and Itraconazole as Therapy for Men With Androgen Normalised Prostate Cancer|
|Actual Study Start Date :||August 23, 2018|
|Estimated Primary Completion Date :||March 30, 2020|
|Estimated Study Completion Date :||March 30, 2021|
Experimental: Dose escalation arm
Suba-itraconazole in combination dose escalating hydroxychloroquine H
150mg PO BD
Escalating doses in Rolling 6 Phase I
Experimental: Phase II: Dose expansion arm
Suba-itraconazole with recommended phase II dose of hydroxychloroquine as determined by phase I arm.
150mg PO BD
Escalating doses in Rolling 6 Phase I
- Determination of Recommended Phase II Dose of Hydroxychloroquine in combination with Suba-itraconazole [ Time Frame: 6 months ]Recommended Phase II Dose
- PSA response rate [ Time Frame: 1 year ]Fall in PSA >/=50% from baseline
- Composite safety [ Time Frame: 1 year ]Rate of adverse events defined by CTCAE criteria
- Time to ADT commencement [ Time Frame: 1 year ]Time to start of ADT
- Metastasis-free survival [ Time Frame: 1 year ]Time from commencement of treatment to first metastatic lesion on CT or WBBS
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03513211
|Contact: Robert Kent||+61293555611||SVHS.CancerResearch@svha.org.au|
|Australia, New South Wales|
|St Vincent's Hospital||Recruiting|
|Darlinghurst, New South Wales, Australia, 2010|
|Contact: Robert Kent 61 2 9355 5611 firstname.lastname@example.org|
|Principal Investigator:||Anthony Joshua, MBBS(Hons) PhD||St. Vincent's Hospital-Manhattan|