Nimorazole

Tumor hypoxia is an adverse prognostic factor in head and neck squamous cell carcinoma (HNSCC). We assessed whether patients with hypoxic HNSCC benefited from the addition of nimorazole to definitive intensity modulated radiation therapy (IMRT).

NIMRAD was a phase 3, multicenter, placebo-controlled, double-anonymized trial of patients with HNSCC unsuitable for concurrent platinum chemotherapy or cetuximab with definitive IMRT (NCT01950689). Patients were randomized 1:1 to receive IMRT (65 Gy in 30 fractions over 6 weeks) plus nimorazole (1.2 g/m² daily, before IMRT) or placebo. The primary endpoint was freedom from locoregional progression (FFLRP) in patients with hypoxic tumors, defined as greater than or equal to the median tumor hypoxia score of the first 50 patients analyzed (≥0.079), using a validated 26-gene signature. The planned sample size was 340 patients, allowing for signature generation in 85% and an assumed hazard ratio (HR) of 0.50 for nimorazole effectiveness in the hypoxic group and requiring 66 locoregional failures to have 80% power in a 2-tail log-rank test at the 5% significance level.

Three hundred thirty-eight patients were randomized by 19 centers in the United Kingdom from May 2014 to May 2019, with a median follow-up of 3.1 years (95% CI, 2.9-3.4). Hypoxia scores were available for 286 (85%). The median patient age was 73 years (range, 44-88; IQR, 70-76). There were 36 (25.9%) locoregional failures in the hypoxic group, in which nimorazole + IMRT did not improve FFLRP (adjusted HR, 0.72; 95% CI, 0.36-1.44; P = .35) or overall survival (adjusted HR, 0.96; 95% CI, 0.53-1.72; P = .88) compared with placebo + IMRT. Similarly, nimorazole + IMRT did not improve FFLRP or overall survival in the whole population. In total (N = 338), 73% of patients allocated nimorazole adhered to the drug for ≥50% of IMRT fractions. Nimorazole + IMRT caused more acute nausea compared with placebo + IMRT (Common Terminology Criteria for Adverse Events version 4.0 G1+2: 56.6% vs 42.4%, G3: 10.1% vs 5.3%, respectively; P < .05).

Addition of the hypoxia modifier nimorazole to IMRT for locally advanced HNSCC in older and less fit patients did not improve locoregional control or survival.

This study investigates the photon interaction mechanism of various small molecule radiosensitizers, including Hydrogen Peroxide, Nimorazole, 5-Fluorouracil, NVX-108, and others, using the MCNP 6.3 Monte Carlo simulation code. The simulations focused on quantifying the linear attenuation coefficients, mean free path, and accumulation factors of these radiosensitizers, as well as their interactions in a simulated spherical water phantom irradiated with a 100 keV mono-energetic X-ray source. Our findings reveal significant variations in deposited energy, collision events, and mean free path among the radiosensitizers, indicating different efficacy levels in enhancing radiation therapy. Notably, NVX-108 demonstrated the highest energy deposition, suggesting its potential as a highly effective radiosensitizer. The study also examined the individual attenuation properties of these radiosensitizers against energetic photons, with NVX-108 showing the highest attenuation coefficient and a shorter mean free path, further supporting its superior potential in effective radiosensitization. It can be concluded that NVX-108 has higher interaction tendency with the energetic photons comparing other small-molecules under investigation.