Background and Aim: NOX66 is a new formulation of the isoflavone derivative, idronoxil, in a proprietary lipophilic base. The primary mechanism of action of idronoxil stems from its selective binding to a tumour-specific NADH oxidase, ENOX2, inhibiting Sphingosine kinase activity, leading to inhibition of the PI3K/Akt pathway and induction of apoptosis. While this suggests a direct cytotoxic effect as a monotherapy, research has focused on using lower doses of idronoxil to enhance the effect of standard therapies. This first-in-human Phase 1 study evaluated the safety profile of NOX66 as a monotherapy and in combination with carboplatin and initial signals of radiological efficacy of treatment.
Methods: Patients with metastatic end stage solid tumours were enrolled to two dose cohorts, NOX66 400mg and 800mg, respectively. Following a 14-day monotherapy (with 7-day break), patients received 3 cycles of combined therapy with carboplatin (AUC4) increasing to carboplatin (AUC6) for next 3 cycles. NOX66 was administered PR on days 1-7 and carboplatin IV on Day 2 of each 28-day cycle.
Results: Nineteen male and female patients were recruited between 17 March and 26 October 2017, with 18 patients receiving at least one dose of NOX66. 15 patients completed monotherapy, 18 commenced combination treatment (3 without monotherapy), 13 completed up to 3 cycles and of these 9 completed 6 cycles. There were no adverse events considered associated with NOX66 that led to study discontinuation, including 4 SAEs (3 deaths).
Of the 16 patients evaluable for radiological response, in dose Cohort 1, 4 out of 6 patients had stable disease at cycle 3, one of whom disease remained stable until cycle 6. In dose Cohort 2, 7 out of 10 patients had evidence of stable disease, in 4 of these patients, disease remained stable until cycle 6 and one (1) with evidence of a partial response.
Conclusions: NOX66 in combination with carboplatin is very well tolerated, with preliminary efficacy for patients receiving combination therapy suggesting that NOX66 may sensitize end stage solid tumours to chemotherapy and warrants further investigation of NOX66 in combination with platinum-based therapies.
Clinical trial identification: Protocol NOX66-001A (ClinicalTrials.gov Identifier: NCT02941523)