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Phase I/II Study of Hydroxychloroquine With Itraconazole With Biochemically Recurrent Prostate Cancer (HITMAN-PC)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03513211
Recruitment Status : Recruiting
First Posted : May 1, 2018
Last Update Posted : September 18, 2019
Information provided by (Responsible Party):
Anthony Joshua, FRACP, St Vincent's Hospital, Sydney

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.

Condition or disease Intervention/treatment Phase
Prostate Cancer Drug: SUBA-itraconazole Drug: Hydroxychloroquine Phase 1 Phase 2

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 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 27 participants
Allocation: Non-Randomized
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)
Primary Purpose: Treatment
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

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Prostate Cancer

Arm Intervention/treatment
Experimental: Dose escalation arm
Suba-itraconazole in combination dose escalating hydroxychloroquine H
Drug: SUBA-itraconazole
150mg PO BD

Drug: Hydroxychloroquine
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.
Drug: SUBA-itraconazole
150mg PO BD

Drug: Hydroxychloroquine
Escalating doses in Rolling 6 Phase I

Primary Outcome Measures :
  1. Determination of Recommended Phase II Dose of Hydroxychloroquine in combination with Suba-itraconazole [ Time Frame: 6 months ]
    Recommended Phase II Dose

Secondary Outcome Measures :
  1. PSA response rate [ Time Frame: 1 year ]
    Fall in PSA >/=50% from baseline

  2. Composite safety [ Time Frame: 1 year ]
    Rate of adverse events defined by CTCAE criteria

  3. Time to ADT commencement [ Time Frame: 1 year ]
    Time to start of ADT

  4. Metastasis-free survival [ Time Frame: 1 year ]
    Time from commencement of treatment to first metastatic lesion on CT or WBBS

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Males ≥ 18 years of age with histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features
  2. Prostate cancer initially treated by radical prostatectomy, radiotherapy (including brachytherapy) or both, with curative intent
  3. PSA ≥ 1 ng/ml with at least two sequential rises at least 1 week apart according to PCWG3.
  4. Serum testosterone ≥ 5 nmol/L
  5. QTc ≤ 470 msec using Fridericia correction formula
  6. 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
  7. Adequate liver function with ALT/AST < 1.5 x ULN, bilirubin < 1.5 x ULN
  8. Adequate renal function with creatinine clearance > 50 ml/min
  9. ECOG Performance Status ≤ 1
  10. Able to start study treatment within 28 days of consent
  11. Willing and able to comply with all study requirements, including treatment (e.g. able to swallow tablets), timing and/or nature of required assessments
  12. Signed, written informed consent

Exclusion Criteria:

  1. 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
  2. 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.
  3. PSA doubling time ≤ 3 months calculated using MSKCC calculator (
  4. 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
  5. Life expectancy of ≤ 1 year
  6. History of another invasive cancer within 3 years before screening with the exception of fully treated cancer with remote probability of recurrence
  7. Concurrent illness, including severe infection that may jeopardize the ability of the patient to undergo the procedures outlined in this protocol with reasonable safety
  8. Use of hydroxychloroquine and/or itraconazole for any indication in the preceding 2 years or at any time for treatment of prostate cancer.

8. Serious medical or psychiatric conditions that might limit the ability of the patient to comply with the protocol.

9. Men must have been surgically sterilised or use a barrier method of contraception.

10. 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)

Information from the National Library of Medicine

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 identifier (NCT number): NCT03513211

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Contact: Robert Kent +61293555611

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Australia, New South Wales
St Vincent's Hospital Recruiting
Darlinghurst, New South Wales, Australia, 2010
Contact: Robert Kent    61 2 9355 5611   
Sponsors and Collaborators
St Vincent's Hospital, Sydney
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Principal Investigator: Anthony Joshua, MBBS(Hons) PhD St Vincent's Hospital, Sydney

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Responsible Party: Anthony Joshua, FRACP, Head of Medical Oncology, The Kinghorn Cancer Centre, St Vincent's Hospital, Sydney Identifier: NCT03513211     History of Changes
Other Study ID Numbers: HITMAN
First Posted: May 1, 2018    Key Record Dates
Last Update Posted: September 18, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Anthony Joshua, FRACP, St Vincent's Hospital, Sydney:
Biochemically recurrent prostate cancer
Hormone sensitive prostate cancer
Additional relevant MeSH terms:
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Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Genital Diseases, Male
Prostatic Diseases
Antifungal Agents
Anti-Infective Agents
14-alpha Demethylase Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Steroid Synthesis Inhibitors
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Cytochrome P-450 CYP3A Inhibitors
Antiprotozoal Agents
Antiparasitic Agents
Antirheumatic Agents