Phase I/II Study of Hydroxychloroquine With Itraconazole With Biochemically Recurrent Prostate Cancer

  • End date
    Mar 30, 2023
  • participants needed
  • sponsor
    St Vincent's Hospital, Sydney
Updated on 11 March 2021
antiandrogen therapy
androgen suppression
serum testosterone
recurrent prostate cancer


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.


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.

Condition Malignant neoplasm of prostate, Prostatic disorder, Prostate Disorders, Prostate Cancer, Early, Recurrent, Prostate Cancer, prostate carcinoma, prostate cancers
Treatment hydroxychloroquine, SUBA-itraconazole
Clinical Study IdentifierNCT03513211
SponsorSt Vincent's Hospital, Sydney
Last Modified on11 March 2021


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Inclusion Criteria

Males 18 years of age with histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features
Prostate cancer initially treated by radical prostatectomy, radiotherapy (including brachytherapy) or both, with curative intent
PSA 1 ng/ml with at least two sequential rises at least 1 week apart according to PCWG3
Serum testosterone 5 nmol/L
QTc 470 msec using Fridericia correction formula
Adequate bone marrow function with platelets 100 x 10^9/L, ANC 1.5 x 10^9/L, Hb 100 g/L in the absence of transfusion
Adequate liver function with ALT/AST < 1.5 x ULN, bilirubin < 1.5 x ULN
Adequate renal function with creatinine clearance > 50 ml/min
ECOG Performance Status 1
Able to start study treatment within 28 days of consent
Willing and able to comply with all study requirements, including treatment (e.g. able to swallow tablets), timing and/or nature of required assessments
Signed, written informed consent

Exclusion Criteria

Contraindications to investigational product including hypersensitivity, treatment with any CYP3A4 inducer or inhibitor or known G6PD deficiency. If on a statin, must be changed to rosuvastatin or ceased, as appropriate
Evidence of metastatic disease on conventional WBBS or CT. However low volume regional nodes ( N1, up to the aortic bifurcation) may be accepted in asymptomatic patients
PSA doubling time 3 months calculated using MSKCC calculator (<>)
Prior systemic therapy for advanced cancer prostate cancer such as hormonal therapy or chemotherapy; neo/adjuvant hormonal therapy allowed if 24 months total duration and ceased 12 months prior to enrolment
Life expectancy of 1 year
History of another invasive cancer within 3 years before screening with the exception of fully treated cancer with remote probability of recurrence
Concurrent illness, including severe infection that may jeopardize the ability of the patient to undergo the procedures outlined in this protocol with reasonable safety
Use of hydroxychloroquine and/or itraconazole for any indication in the preceding 2 years or at any time for treatment of prostate cancer
Serious medical or psychiatric conditions that might limit the ability of the patient to comply with the protocol
Men must have been surgically sterilised or use a barrier method of contraception
Pre-existing retinopathy, keratopathy or other ocular pathologies that, in the opinion of an ophthalmologist would put the patient at risk of hydroxychloroquine induced retinopathy 11. History of cardiac failure or recent history if ischaemic heart disease (<2 years)
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