A Phase I Study of Hydroxychloroquine and Suba-Itraconazole in Men with Biochemical Relapse of Prostate Cancer (HITMAN-PC) - Dose Escalation Results

Sep 22, 2026

Biochemical recurrence (BCR) of prostate cancer remains challenging because systemic options beyond androgen deprivation therapy (ADT) are limited, and ADT causes substantial morbidity. This Phase I HITMAN-PC trial tested suba-itraconazole (SI) and hydroxychloroquine (HCQ), guided by preclinical evidence that lysosomal homeostasis, including cholesterol trafficking and pH regulation, is a therapeutic vulnerability. In 11 enrolled men, SI 150 mg twice daily plus HCQ established an HCQ 600 mg twice-daily maximum tolerated dose. Toxicities were mainly grade 3 diarrhea and alanine aminotransferase elevation; PSA declines ≥50% were not observed, though many achieved stabilization. Lipidomic analyses identified treatment-associated lipid changes, including sphingomyelin and triacylglycerols correlating with PSA progression-free survival, supporting plasma lipidomics as a pharmacodynamic biomarker.

LanguageEnglish

CategoryHealthcare

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Pages11

Reading Time28 min

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Abstract

Purpose

Patients and Methods

Results

Conclusions

Significance

Introduction

RESEARCH ARTICLE [https://doi.org/10.1158/2767-9764.CRC-26-0010](https://doi.org/10.1158/2767-9764.CRC-26-0010) OPEN ACCESS A Phase I Study of Hydroxychloroquine and Suba-Itraconazole in Men with Biochemical Relapse of Prostate Cancer (HITMAN-PC): Dose Escalation Results Barak Talmor1, Stefano Marastoni2, Brandon Lau1,3, Andrew O. Yam1,4,5, Nicole Yeung4, Hui-Ming Lin4, Zhu Juan Li2, Henry Woo6,7,8, Ganes Pranavan9, Phillip D. Stricker4,10, Lisa G. Horvath4,5,6,10,11, Marianne Koritzinsky2, Bradly G. Wouters2, Megan Crumbaker1,4,5, and Anthony M. Joshua1,2,4,5,10 􀀶 ABSTRACT Purpose: Biochemical recurrence (BCR) of prostate cancer presents a clinical challenge with limited systemic treatment options beyond androgen deprivation therapy (ADT), which carries significant morbidity. Preclinical data suggest that lysosomal homeostasis, including cholesterol trafficking and pH regulation, is a therapeutic vulnerability in hormone-dependent cancers. We therefore conducted HITMAN-PC, a phase I trial evaluating suba-itraconazole (SI) and hydroxychloroquine (HCQ) in men with BCR. Patients and Methods: The synergy of SI and HCQ was validated in hormone-sensitive and castration-resistant prostate cancer cell lines. The HITMAN-PC trial (NCT03513211) then used a rolling-six design to establish the maximum tolerated dose (MTD) and recommended phase II dose of HCQ with a fixed SI dosage (150 mg twice daily). Secondary endpoints included safety, PSA kinetics [PSA progression-free survival (PFS) and time to ADT], and exploratory pharmacokinetic and lipidomic profiling. Results: Itraconazole showed dose-dependent cytotoxicity, with synergy in LNCaP-derived hormone-sensitive and-resistant lines. Eleven patients were enrolled. Two dose-limiting toxicities at HCQ 600 mg twice daily (grade 3 diarrhea and alanine aminotransferase elevation) defined this level as the MTD with SI 150 mg twice daily. Common adverse events were hypertension, QTc prolongation, diarrhea, and nausea; no grade 4 events occurred. No PSA declines ≥50% were observed although most patients achieved PSA stabilization. The median PSA-PFS, time to ADT, and metastasis-free survival were 5.5, 14.3, and 15.9 months, respectively. Lipidomic profiling revealed 240 treatment-associated lipid changes, with sphingomyelin and triacylglycerol species correlating with PSA-PFS. Conclusions: Despite limited clinical activity overall, the identified lipidomic signatures provide proof of concept for using plasma lipidomics to monitor pharmacodynamic activity in future metabolism-targeted trials. Significance: This study established a safe dose for HCQ and SI but found limited clinical efficacy in prostate cancer. Its significance lies in providing proof of biology that this combination alters systemic lipid metabolism. We identified specific plasma lipid species that correlate with clinical outcomes, highlighting the power of embedded biomarker analysis to generate valuable mechanistic insights and candidate biomarkers, even in the absence of a strong clinical response. Introduction Globally, prostate cancer imposes a substantial health burden, with more than 1.4 million new diagnoses in 2020 alone, ranking it as the second 1Kinghorn Cancer Centre, St Vincents Hospital, Sydney, Australia. 2Princess Margaret Cancer Centre, Toronto, Canada. 3Fiona Stanley Hospital, Perth, Australia. 4Garvan Institute of Medical Research, Sydney, Australia. 5School of Clinical Medicine, St Vincent’s Healthcare Clinical Campus, Faculty of Medicine and Health, UNSW Sydney, Sydney, Australia. 6Chris O’Brien Lifehouse, Camperdown, Australia. 7Department of Urology, Blacktown Hospital, Blacktown, Australia. 8Blacktown Mount Druitt Clinical School, Western Sydney University, Blacktown, Australia. 9Canberra Health Services, Canberra, Australia. 10St. Vincent’s Prostate Cancer Research Centre, Sydney, Australia. 11University of Sydney, Sydney, Australia. leading cancer worldwide ( 1) . Although t

FAQs

What was the purpose of the HITMAN-PC Phase I study?

The study evaluated suba-itraconazole and hydroxychloroquine in men with biochemical relapse of prostate cancer, aiming to determine safety, dosing, and pharmacodynamic effects relevant to lysosomal homeostasis vulnerabilities.

How were dose escalation and the maximum tolerated dose (MTD) determined?

The trial used a rolling-six design to define the MTD and recommended Phase II dose of HCQ while keeping SI fixed at 150 mg twice daily. Two dose-limiting toxicities at HCQ 600 mg twice daily established this level as the MTD.

What clinical activity and biomarker signals were observed?

No PSA declines of at least 50% were observed, although most patients achieved PSA stabilization. Lipidomic profiling detected treatment-associated lipid changes, with sphingomyelin and triacylglycerol species correlating with PSA progression-free survival, supporting plasma lipidomics for future metabolism-targeted trials.

Sep 22, 2026

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