NXP800, a novel GCN2 kinase activator, has been granted orphan drug designation by the FDA for the potential treatment of patients with ARID1a-deficient ovarian, fallopian tube, and primary peritoneal cancers. This designation highlights the drug's promise in addressing a specific subset of ovarian cancers with a high unmet need.
Mechanism of Action and Preclinical Data
NXP800 is an oral small molecule that targets the HSF1 pathway. Preclinical studies in xenograft models have demonstrated strong antitumor effects of NXP800 in ARID1a-mutated ovarian carcinoma and other disease models. These findings suggest that NXP800 could offer a targeted approach to treating cancers with ARID1a deficiencies.
Clinical Development
In December 2022, the FDA granted fast track designation to NXP800 for platinum-resistant, ARID1a-mutated ovarian carcinoma. Subsequently, a phase 1b clinical trial (NCT05226507) was initiated in April 2023 to evaluate NXP800 in this patient population. The ongoing trial is designed to assess the safety, tolerability, and preliminary efficacy of NXP800.
Investigator Insights
Ron Bentsur, MBA, chairman and chief executive officer of Nuvectis, stated, "We are very pleased to have received this designation from the FDA for NXP800... we therefore believe that this orphan drug designation granted by the FDA for NXP800 for the treatment of a subset of ovarian cancer, specifically for patients with an ARID1a deficiency, provides further validation for NXP800's mechanism of action and the target patient population in our ongoing phase 1b clinical trial in patients with platinum-resistant, ARID1a-mutated ovarian cancer."
Phase 1b Trial Details
The phase 1b trial is enrolling patients aged 18 years and older with platinum-resistant ovarian cancer harboring ARID1a mutations. Key inclusion criteria include measurable disease per RECIST 1.1, disease progression within 6 months of completing platinum-based therapy, an ECOG performance status of 0 or 1, and prior treatment with one to five lines of systemic therapy, including at least one bevacizumab-containing regimen. Patients with BRCA mutations must have received prior PARP inhibitor treatment.
Early Phase 1a Data
As of April 2023, 18 patients had received at least one dose of NXP800 in the phase 1a portion of the study. The longest treatment duration reached 10 months, with some participants continuing treatment. Two dosing schedules were evaluated: once-daily (50 mg to 150 mg) and twice-daily (100 mg and 150 mg). Common treatment-emergent adverse events (AEs) included vomiting, nausea, diarrhea, fatigue, decreased appetite, and weight loss.
Dose Selection and Tolerability
In the phase 1b study, doses of 50 mg and 75 mg per day were evaluated. Preliminary population pharmacokinetics and pharmacodynamic analyses support these doses, indicating biologically active exposure with an acceptable safety and tolerability profile.
Trial Endpoints
The primary endpoint for part A of the phase 1b study is the number of patients with treatment-related AEs, clinical laboratory abnormalities, and dose-limiting toxicities. For part B, the primary endpoints are estimates of disease response by RECIST v 1.1 and the number of patients with treatment-related AEs and/or clinical laboratory abnormalities.
Upcoming Data
Nuvectis anticipates providing a data update from the phase 1b study in the fall.
