Prostate CancerPhase 1/2HITMAN-PCNCT03513211
Phase I/II Study of Hydroxychloroquine With Itraconazole With Biochemically Recurrent Prostate Cancer
A Phase 1/2 study testing SUBA-itraconazole and Hydroxychloroquine in people with Prostate Cancer, run by St Vincent's Hospital, Sydney at 1 site in Australia.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older, men only
- Conditions the study is for
- Prostate Cancer
- What is being tested?
- SUBA-itraconazole and Hydroxychloroquine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 12 participants
- Where
- 1 siteAustralia
- Study dates
- 23 Aug 2018to 30 Oct 2023
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Men only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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 (https://www.mskcc.org/nomograms//prostate/psa-doubling-time)
- 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
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- 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.
- 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)
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Phase I/II Study of Hydroxychloroquine and Itraconazole as Therapy for Men With Androgen Normalised 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.
Read the 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.
- Conditions
- Prostate Cancer
- Being tested
- SUBA-itraconazole, Hydroxychloroquine
- Keywords
- Biochemically recurrent prostate cancer, Hormone sensitive prostate cancer
- Medical subject headings
- Prostatic Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
SUBA-itraconazoleDrug
150mg PO BD
Escalating doses in Rolling 6 Phase I
| Study group | Role | What they receive |
|---|---|---|
| Dose escalation arm | Experimental | Suba-itraconazole in combination dose escalating hydroxychloroquine H Receives: Drug: SUBA-itraconazole; Drug: Hydroxychloroquine |
| Phase II: Dose expansion arm | Experimental | Suba-itraconazole with recommended phase II dose of hydroxychloroquine as determined by phase I arm. Receives: Drug: SUBA-itraconazole; Drug: Hydroxychloroquine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Determination of Recommended Phase II Dose of Hydroxychloroquine in combination with Suba-itraconazole
Recommended Phase II Dose
Measured: 6 months
Secondary outcomes (4)
PSA response rate
Fall in PSA >/=50% from baseline
Measured: 1 year
Composite safety
Rate of adverse events defined by CTCAE criteria
Measured: 1 year
Time to ADT commencement
Time to start of ADT
Measured: 1 year
Metastasis-free survival
Time from commencement of treatment to first metastatic lesion on CT or WBBS
Measured: 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 May 2018
- Study start23 Aug 2018
- Primary completion30 Aug 2023
- Study completion30 Oct 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Prostate CancerStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Model description
- Phase I intra-patient dose escalation study Phase II Simon 2-stage cohort expansion
- Masking
- None (open label)
- Enrolment
- 12 participants (actual)
Sponsor and investigators
- Lead sponsor
- St Vincent's Hospital, Sydney
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Anthony Joshua, FRACP, St Vincent's Hospital, Sydney
- Investigators
- Anthony Joshua, MBBS(Hons) PhD, Principal investigator, St Vincent's Hospital, Sydney
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03513211
- Sponsor's protocol ID
- HITMAN
- Acronym
- HITMAN-PC
- Status last verified
- Nov 2023
- First submitted
- 17 Apr 2018
- Last updated
- 22 Nov 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Suzman DL, Antonarakis ES. High-dose itraconazole as a noncastrating therapy for a patient with biochemically recurrent prostate cancer. Clin Genitourin Cancer. 2014 Apr;12(2):e51-3. doi: 10.1016/j.clgc.2013.11.015. Epub 2013 Nov 14. No abstract available.
PubMed 24332506Farrow JM, Yang JC, Evans CP. Autophagy as a modulator and target in prostate cancer. Nat Rev Urol. 2014 Sep;11(9):508-16. doi: 10.1038/nrurol.2014.196. Epub 2014 Aug 19.
PubMed 25134829
Study at a glance
From the registry record, last updated by the sponsor on 22 Nov 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I/II Study of Hydroxychloroquine and Itraconazole as Therapy for Men With Androgen Normalised Prostate Cancer
- ClinicalTrials.gov ID
- NCT03513211
- Acronym / sponsor ID
- HITMAN-PC / HITMAN
- Conditions
- Prostate Cancer
- Keywords
- Biochemically recurrent prostate cancer, Hormone sensitive prostate cancer
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 12 participants (actual)
- Lead sponsor
- St Vincent's Hospital, SydneyUniversity, hospital or other
- Study start
- 23 Aug 2018 (actual)
- Primary completion
- 30 Aug 2023 (actual)
- Study completion
- 30 Oct 2023 (actual)
- First posted
- 1 May 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 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 design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- Phase I intra-patient dose escalation study Phase II Simon 2-stage cohort expansion
| Arm | Type | Receives |
|---|---|---|
| Dose escalation arm | Experimental | Drug: SUBA-itraconazole, Drug: HydroxychloroquineSuba-itraconazole in combination dose escalating hydroxychloroquine H |
| Phase II: Dose expansion arm | Experimental | Drug: SUBA-itraconazole, Drug: HydroxychloroquineSuba-itraconazole with recommended phase II dose of hydroxychloroquine as determined by phase I arm. |
Who may qualify
- Ages
- 18 years and older
- Sex
- Male only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (12 listed)
- 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
Key exclusion criteria (11 listed)
- 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 (https://www.mskcc.org/nomograms//prostate/psa-doubling-time)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| SUBA-itraconazole150mg PO BD | Drug | Dose escalation arm, Phase II: Dose expansion arm |
| HydroxychloroquineEscalating doses in Rolling 6 Phase I | Drug | Dose escalation arm, Phase II: Dose expansion arm |
Primary outcome
Determination of Recommended Phase II Dose of Hydroxychloroquine in combination with Suba-itraconazole
Time frame: 6 months
Recommended Phase II Dose
4 secondary outcomes
PSA response rate
Time frame: 1 year
Composite safety
Time frame: 1 year
Time to ADT commencement
Time frame: 1 year
Metastasis-free survival
Time frame: 1 year
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Nov 2023.
- Background: PubMed 24332506Suzman DL, Antonarakis ES. High-dose itraconazole as a noncastrating therapy for a patient with biochemically recurrent prostate cancer. Clin Genitourin Cancer. 2014 Apr;12(2):e51-3. doi: 10.1016/j.clgc.2013.11.015. Epub 2013 Nov 14. No abstract available.
- Background: PubMed 25134829Farrow JM, Yang JC, Evans CP. Autophagy as a modulator and target in prostate cancer. Nat Rev Urol. 2014 Sep;11(9):508-16. doi: 10.1038/nrurol.2014.196. Epub 2014 Aug 19.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Anthony Joshua, MBBS(Hons) PhD principal investigator
St Vincent's Hospital, Sydney
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing SUBA-itraconazole and Hydroxychloroquine in people with Prostate Cancer, run by St Vincent's Hospital, Sydney at 1 site in Australia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 22 Nov 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Australia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Determination of Recommended Phase II Dose of Hydroxychloroquine in combination with Suba-itraconazole (time frame: 6 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03513211, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Nov 2023.