Abstract 8P
Background
NXP800 (CCT361814) is a Heat Shock Factor (HSF1) pathway inhibitor currently being studied in a phase 1 clinical trial (NCT05226507). NXP800 demonstrated substantial antitumor activity in cancer cell lines of different histologies, including ovarian clear cell and endometrioid carcinoma (OCCC and EOC), gastric carcinoma, and haematological cancers. Loss of function of ARID1A was identified as a predictive marker for response to NXP800 in OCCC and EOC. Here we describe an in vivo study of NXP800 versus cisplatin as an active control in cisplatin-resistant and cisplatin-sensitive ARID1A-mutated OCCC xenografts, supporting the clinical development of NXP800 in this indication.
Methods
In vivo studies were performed by generating subcutaneous tumors in Nude (nu/nu) mice using TOV-21G and SKOV3 cell lines. Loss of ARID1A was confirmed in western blot.
Results
Treatment with NXP800 resulted in substantial tumor growth inhibition (TGI) in both models. In the TOV-21G model, baseline tumor volumes for the vehicle, cisplatin and NXP800 groups were 201.71, 205.66 and 202.20 mm3, respectively; on Day 28, average tumor volumes were 399.84, 236.68 and 121.47 mm3, respectively, representing increases in tumor volume of 98% for the vehicle control group and 15% for the cisplatin group, and a decrease in tumor volume of 41% for the NXP800 group. In the SKOV3 model, baseline tumor volumes for the vehicle, cisplatin and NXP800 groups were 136.2, 138.5 and 134.7 mm3, respectively; on Day 28, average tumor volumes were 312.94, 253.71 and 53.33 mm3, respectively, representing increases in tumor volume of 130% for the vehicle control group and 80% for the cisplatin group, and a decrease in tumor volume of 60% for the NXP800 group.
Conclusions
NXP800 exhibits notable therapeutic activity in xenografts of OCCC – a condition of high unmet medical need with limited treatment options – including sustained tumour growth inhibition and regression both in cisplatin resistant (SKOV3) and sensitive (TOV-21G) OCCC models. Planned phase 1b expansion cohorts will include ovarian clear cell carcinoma and ovarian endometrioid carcinoma patients with ARID1A mutation.
Legal entity responsible for the study
The authors.
Funding
Nuvectis Pharma.
Disclosure
E. Poradosu: Financial Interests, Personal, Other, Employee: Nuvectis Pharma. A. Woods: Financial Interests, Personal, Other, Employee: Nuvectis Pharma. S. Shemesh: Financial Interests, Personal, Other, Employee: Nuvecitis Pharma. P. Workman: Financial Interests, Personal, Advisory Board: Nextech, Astex Pharmaceuticals, CV6 Therapeutics, Black Diamond Therapeutics, Vividion Therapeutics, Storm Therapeutics, Alterome Therapeutics, Epicombi Therapeutics, Nuvectis Pharma; Financial Interests, Personal, Stocks/Shares: Chroma Therapeutics, Storm Therapeutics, Nextech; Financial Interests, Personal, Member of the Board of Directors: Storm Therapeutics; Financial Interests, Institutional, Research Grant: Vernalis/Novartis, Merck KGaA, Cyclacel Pharmaceuticals, Piramed/Genentech/Roche, Astex/AstraZeneca, Sareum/Sierra Oncology, AstraZeneca; Financial Interests, Personal, Other, Former employee: AstraZeneca. S. Banerjee: Financial Interests, Personal, Advisory Board: Amgen, Immunogen, Mersana, Merck Sereno, MSD, Roche, AstraZeneca, GSK, Oncxerna, Shattuck Labs, Novartis, Epsilogen, Seagen, Eisai; Financial Interests, Personal, Invited Speaker: Clovis, Pfizer, AstraZeneca, GSK, Takeda, Amgen, Medscape, Research to Practice, Peerview; Financial Interests, Personal, Stocks/Shares: PerciHealth; Financial Interests, Institutional, Research Grant: AstraZeneca, GSK; Non-Financial Interests, Personal, Principal Investigator, Phase II clinical trial Global lead, ENGOTov60/GOG3052/RAMP201: Verastem; Non-Financial Interests, Personal, Principal Investigator, ENGOT-GYN1/ATARI phase II international trial (academic sponsored): AstraZeneca; Non-Financial Interests, Personal, Principal Investigator, Academic sponsored trial PI (MONITOR-UK): GSK; Non-Financial Interests, Personal, Other, Member of membership committee: ESGO; Non-Financial Interests, Personal, Advisory Role, Medical advisor to UK ovarian cancer charity: Ovacome Charity. All other authors have declared no conflicts of interest.