A phase I Study of hydroxychloroquine and suba-itraconazole in men with biochemical relapse of prostate cancer (HITMAN-PC): dose escalation results

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.