Phase I/II Trial of the Combination of 177Lutetium Prostate specific Membrane Antigen 617 and Idronoxil (NOX66) in Men with End-stage Metastatic Castration-resistant Prostate Cancer (LuPIN).

BACKGROUND: Trials of lutetium prostate specific membrane antigen (PSMA) in men with metastatic castration-resistant prostate cancer (mCRPC) have demonstrated good safety and efficacy, but combination strategies may improve outcomes. Idronoxil is a synthetic flavonoid derivative with radiosensitising properties. OBJECTIVE: To evaluate the safety and activity of 177Lu PSMA 617 (LuPSMA-617) in combination with idronoxil suppositories (NOX66) in patients with end-stage mCRPC. DESIGN, SETTING, AND PARTICIPANTS: Thirty-two men with progressive mCRPC previously treated with taxane-based chemotherapy (91% treated with both docetaxel and cabazitaxel) and abiraterone and/or enzalutamide were enrolled in this phase I dose escalation study with phase II dose expansion. INTERVENTION: Screening with 68Ga PSMA and 18F-fludeoxyglucose positron emission tomography (PET)/computed tomography (CT) was performed. Men received up to six cycles of LuPSMA-617 (7.5 GBq) on day 1, with escalating doses of NOX66 on days 1-10 of a 6-wk cycle. Cohort 1 (n = 8) received 400 mg and cohort 2 (n = 24) 800 mg of NOX66. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Adverse events (AEs), pain inventory scores, prostate-specific antigen (PSA) response, progression-free survival, and overall survival were evaluated. RESULTS AND LIMITATIONS: Fifty-six men were screened and 32 (57%) were enrolled with a screen failure rate of 21% for PET imaging criteria. Dosing was as follows: 97% (31/32) received two or more doses and 47% (15/32) completed six doses. Common AEs included xerostomia, fatigue, and anaemia. Anal irritation attributable to NOX66 occurred in 28%. PSA responses were as follows: 91% (29/32) had any PSA response (median -74%; 95% confidence interval [CI] 76-97) and 62.5% (20/32) had a PSA fall of >50% (95% CI 45-77). The median PSA progression-free survival was 6.1 mo (95% CI 2.8-9.2) and median overall survival was 17.1 mo (95% CI 6.5-27.1). CONCLUSIONS: NOX66 with LuPSMA-617 is a safe and feasible therapeutic strategy in men treated with third-line therapy and beyond for mCRPC. PATIENT SUMMARY: Addition of NOX66 to 177Lu prostate-specific membrane antigen 617 is safe, and further studies are needed to assess its potential to augment the anticancer effects of LuPSMA-617.

Topical Vitamin D May Modulate Human Sinonasal Mucosal Responses to House Dust Mite Antigen.

BACKGROUND: Respiratory epithelium is a key defense against inhaled pathogens. Vitamin D3 (VD) has been suggested to modulate airway inflammation; however, its effect on innate airway defenses, the physical barrier, mucociliary apparatus, and cytokine release remains unclear. OBJECTIVE: To investigate the outcomes of VD application prior to challenge in an in vitro model of human sinonasal epithelium, through assessment of epithelial transepithelial resistance (TER), cilia beat frequency (CBF), and interleukin (IL)-6 release, and secondarily to determine whether topical VD is beneficial to patients with inflammatory sinonasal pathology. METHODS: Primary human sinonasal epithelial cells from patients with eosinophilic chronic rhinosinusitis (eCRS) and healthy controls were cultured in air-liquid interface (ALI). Well-differentiated cultures from each patient were pretreated for 24 hours with 4 different VD doses. Toxicity was quantified at 24 hours in unchallenged ALI by lactate dehydrogenase (LDH) assay. Innate responses were assessed by measuring TER and CBF before and up to 24 hours after house dust mite Dermatophagoides pteronyssinus challenge. IL-6 release was evaluated 24-hour postchallenge. RESULTS: Fifteen patients (53 ± 13.5 years, 60% females, 53% eCRS) representing 120 ALI wells were assessed. VD (0, 25, 50, 150 IU/mL) released less LDH than vehicle, indicating noncytotoxicity (0.15 ± 0.02; 0.15 ± 0.00; 0.14 ± 0.02; 0.11 ± 0.01 vs 0.17 ± 0.03, P = .004). VD increased TER for eCRS wells at 5 minutes (50 IU/mL: Δ6.76 ± 3.93 vs Δ3.87 ± 2.46, P = .04) and 24 hours (50 IU/mL: Δ0.88 ± 0.49 vs Δ0.40 ± 0.42, P = .02; 150 IU/mL: Δ1.06 ± 0.58 vs Δ0.47 ± 0.46, P = .01). CBF increased at 1 hour for eCRS wells (50 IU/mL: Δ0.62 ± 0.14 vs Δ0.41 ± 0.13, P = .001; 150 IU/ml: Δ0.60 ± 0.13 vs Δ0.38 ± 0.11, P < .001). IL-6 release was similar between normal and eCRS wells. CONCLUSION: Topical VD supplementation in eCRS patients may be beneficial for innate epithelial defenses. VD is noncytotoxic and does not adversely affect the physical barrier, mucociliary apparatus, or IL-6 release. Further studies should clarify its potential as a therapeutic agent.