Investigators Will Assess NXP800 in ARID1A-Mutated Ovarian Cancer

In December 2022, the FDA granted fast track designation to NXP800 for the treatment of patients with platinum-resistant, ARID1A-mutated ovarian cancer.

Investigators of the phase 1b ENGOT-GYN5/NCRI/NXP800-101 trial (GOG-3087; NCT05226507) will assess the novel GCN2 kinase activator NXP800 as a treatment for those with platinum-resistant ovarian cancer harboring ARID1A mutations, according to a presentation at the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer.¹

The primary end points of the trial are objective response rate, duration of response, incidence of adverse effects (AEs), and laboratory abnormalities.

“Ovarian cancer is comprised of several subtypes based on histopathology. ARID1A loss is most prevalent in 2 histologic forms of ovarian carcinoma: ovarian clear cell carcinoma (OCCC) and ovarian endometrioid carcinoma,” Susana N. Banerjee, MBBS, MA, PhD, FRCP, and colleagues, wrote in a poster presentation. Banerjee is a consultant medical oncologist at The Royal Marsden NHS Foundation Trust and team leader in Women’s Cancers at The Institute of Cancer Research in London.

NXP800 is an antineoplastic, oral, small molecule activator of the GCN2 kinase. In preclinical models, it displayed robust antitumor activity, including in ARID1A-mutated ovarian carcinoma, endometrial carcinoma, and cholangiocarcinoma.

Previously reported data from the phase 1a portion of the trial showed that the most common treatment-emergent AEs in patients with various types of non-target, advanced solid tumors, consisted of vomiting, nausea, diarrhea, fatigue, decreased appetite, and weight loss. Common lab abnormalities included transient changes in platelets, liver enzymes, and red blood cells. No drug-related grade 4 or grade 5 AEs were reported.²

Based on initial pharmacokinetic and pharmacodynamic data from phase 1a, 50 mg of NXP800 per day and 75 mg of NXP800 per day were selected as the doses for phase 1b.

Phase 1b is enrolling patients with clear cell ovarian carcinoma or endometrioid ovarian carcinoma harboring pathogenic ARID1A mutations, as determined by DNA-based next-generation sequencing. Patients are required to have measurable disease per RECIST v1.1 criteria and must have received at least 1 and no more than 5 prior lines of systemic therapy, including at least 1 line of therapy that contained bevacizumab (Avastin).¹ However, prior bevacizumab is not required for patients who did not receive the agent due to recto-sigmoid involvement by pelvic examination, bowel involvement on CT scan, or clinical symptoms of bowel obstruction.

The trial is excluding patients whose disease did not respond to, or has progressed during or within 4 weeks of, the last dose of first-line, platinum-containing chemotherapy.

Pharmacokinetics parameters will serve as a secondary end point. Change in expression of CHAC1, ATF3, ATF4, HSP27 and other proteins at RNA or protein level before and after treatment with NXP800 is a key exploratory end point.

The phase 1b portion of the trial is currently open for enrollment in the United Kingdom and the United States.

In December 2022, the FDA granted fast track designation to NXP800 for the treatment of patients with platinum-resistant, ARID1A-mutated ovarian cancer.³ Additionally, in August 2023, the regulatory agency granted an orphan drug designation to NXP800 for the treatment of patients with cholangiocarcinoma.⁴

References

1. Banerjee SN, Eskander RN, Roxburgh P, et al. A phase 1b multicenter, open-label, study of NXP800, a novel GCN2 kinase activator, in patients with platinum resistant, ARID1a-mutated ovarian cancer (ENGOT-GYN5/NCRI/NXP800-101; GOG-3087; NCT05226507) (trial in progress). Presented at: 2024 SGO Annual Meeting on Women’s Cancer; March 16-18, 2024; San Diego, CA.
2. Nuvectis Pharma announces initiation of the phase 1b study for NXP800 in platinum-resistant, ARID1a-mutated ovarian carcinoma. News release. Nuvectis Pharma. April 10, 2023. Accessed March 19, 2024. https://s3.amazonaws.com/b2icontent.irpass.cc/2609/rl117355.pdf
3. FDA grants fast track designation to Nuvectis Pharma's NXP800 for the treatment of platinum-resistant, ARID1A-mutated ovarian carcinoma. News release. Nuvectis Pharma. December 1, 2022. Accessed March 19, 2024. https://www.globenewswire.com/news-release/2022/12/01/2565889/0/en/FDA-Grants-Fast-Track-Designation-to-Nuvectis-Pharma-s-NXP800-for-the-Treatment-of-Platinum-Resistant-ARID1A-Mutated-Ovarian-Carcinoma.html
4. Nuvectis Pharma announces orphan drug designation granted by the FDA to NXP800 for the treatment of cholangiocarcinoma. News release. Nuvectis Pharma. August 17, 2023. Accessed March 19, 2024. https://nuvectis.com/press-release-view/?i=121906