Phase I study of a novel S1P inhibitor, NOX66, in combination with radiotherapy in patients with metastatic castration-resistant prostate cancer.

Abstract

5533 Background: NOX66 is a new formulation of the small molecule, idronoxil. The primary mechanism of action of idronoxil stems from its binding to the transmembrane enzyme ENOX2 expressed on cancer cells, resulting in reduced S1P and increased ceramide levels, thereby promoting apoptosis. Additional intracellular effects include the inhibition of DNA repair mechanisms. There is growing evidence that S1P is a promotor of tumour resistance to immune cell infiltration, highlighting NOX66’s potential to modulate the immune response against cancer. Methods: This two-part phase 1b open-label study enrolled patients with late-stage progressive mCRPC. Part 1 was a dose-escalation safety assessment of three doses of NOX66 (400 mg, n = 4; 800 mg, n = 6 and 1200 mg, n = 15) administered daily for 14 days with radiation therapy (20 Gy) delivered in 5 fractionated doses to one or more symptomatic lesion/s. Part 2 was an expansion cohort with NOX66 at 1200 mg in conjunction with radiation therapy. The primary endpoint of safety was assessed by the frequency and grade of treatment-emergent adverse events (TEAEs). At 6 weeks, 3- and 6-month follow up, treatment response was assessed radiographically by RECIST1.1 and by PSA >50% reduction. Results: 25 patients received and completed treatment. TEAEs considered related to NOX66 alone were mild (Grade 1) cases of dry mouth and oral mucositis; mild (Grade 1) fatigue was considered related to both NOX66 and radiation. None of the 21 Grade ≥3 TEAEs were considered related to NOX66. At 6 months, of the 15 evaluable patients by RECIST1.1, 9 had SD and 1 had PR and these same patients had maintained this response from 3 months. Five of the 16 PSA-evaluable patients achieved a PSA response (61-98% PSA reduction) at 6 months, which again was maintained from 3 months. Conclusions: NOX66 in combination with low-dose radiation therapy was found to be safe and well tolerated with promising signals of durable efficacy in patients with late-stage mCRPC. Responses of lesions outside the radiation field are being reviewed. Clinical trial information: NCT03307629 .

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)

“…NOX66 is a suppository formulation of idronoxil, minimising phase 2 metabolism in the liver via rectal administration [17]. The safety of the combination of NOX66 and external beam radiotherapy has been tested in men with symptomatic mCRPC [18]. We hypothesised that the addition of NOX66 to LuPSMA-617 may act as a radiosensitiser, which could improve treatment responses while contributing minimal additional toxicity.…”

The role of isoflavones in augmenting the effects of radiotherapy

“…However, there is limited clinical data available on isoflavone antitumor efficacy when combined with radiation therapy (Table 1). Several clinical trials have investigated the efficiency of idronoxil in combination with irradiation in late stage metastatic chemotherapy resistant prostate cancer (mCRPC) patients and in head and neck cancer patients (Table 1) (181)(182)(183)(184)(185). PoC and dose confirmation DARRT study in late-stage prostate cancer patients has addressed safety and potential indications of efficacy of the combination of 1 of 3 doses of idronoxil, given as suppository (NOX66) in dose-escalated fashion (400mg, 800mg and 1200mg) in combination with 20Gy of EBRT given over 5 daily fractions to selected target lesion/s for all cohorts.…”

Factores que influyen en la mortalidad cáncer específica en las distintas etapas de la secuenciación en el tratamiento del cáncer de próstata resistente a la castración

“…A los 6 meses del tratamiento, de los 15 pacientes evaluados según RECIST1.1, 9 tenían enfermedad estable y 1 tenían respuesta parcial y estos mismos pacientes habían mantenido esta respuesta a los 3 meses siguientes. Cinco de los 16 pacientes en los que se evaluó PSA tuvieron una respuesta (61-98% de reducción de PSA) a los 6 meses, que nuevamente se mantuvo a partir de 3 meses siguientes(133).El ensayo clínico Keynote 199(134). es un estudio en fase 2 (NCT02787005) en pacientes con CPRC M1 que no habían recibido tratamiento previo con quimioterapia, tratados con pembrolizumab y enzalutamida después de la progresión a ésta última y que tenían enfermedad medible según criterios RECIST (C4) o de predominio óseo (C5).…”