The FDA has granted fast track designation to ZEN-3694 for use in combination with abemaciclib (Verzenio) for the treatment of patients with unresectable or metastatic NUT carcinoma who have received at least 1 prior line of chemotherapy.1
The agent is currently under evaluation in a phase 1 trial (NCT05372640) in combination with abemaciclib in adult and pediatric patients with unresectable or metastatic NUT carcinoma, breast cancer, and other solid tumors.2
“We are thrilled that the FDA has recognized the strong potential of ZEN-3694 in benefiting patients with NUT carcinoma, an extremely aggressive, deadly cancer, for which there are no effective or approved treatments,” Donald McCaffrey, president and chief executive officer of Zenith Epigenetics, stated in a news release.1 “Fast track designation will accelerate ZEN-3694’s clinical NUT carcinoma program by expediting its development and review, and allow us to deliver this potentially life-saving drug to patients sooner.”
Mechanistic Rationale
In NUT carcinoma, the NUTM1 gene is fused with a transcriptional regulator such as a BET protein in most cases, driving expression of cancer-causing genes. This leads to unregulated growth of tumors.
ZEN-3694 is a potent, selective, orally administered BET inhibitor that interrupts the activity of the NUT fusion protein, which has translated to antitumor activity alone and in combination with abemaciclib in NUT carcinoma. Notably, the combination of ZEN-3694 and abemaciclib has shown improved responses compared with BET inhibitors alone by inhibiting common resistance mechanisms. The agent has also proven tolerable with long-term use, showcasing a favorable adverse effect profile.
Trial Enrollment Criteria, Design, and Objectives
To be eligible for enrollment in the phase 1 trial individuals must be at least 12 years of age or older with a histologically confirmed malignancy that is unresectable or metastatic and for which standard curative or palliative interventions do not exist or are ineffective.2 Patients could have received any number of prior lines of therapy in the metastatic setting, including prior BET inhibitor therapy and prior CDK4/6 inhibitor therapy. Additionally, any acute effects from prior chemotherapy and/or radiotherapy must have resolved. An ECOG performance status of 2 or below was also required for patients at least 16 years of age and a Lansky score of at least 50% was required for patients under 16 years of age.
Patients with treated brain metastases are eligible if there is no evidence of progression on follow-up brain imaging after central nervous system–directed therapy and disease has been clinically stable for at least 1 month. Notably, patients must be able to swallow oral medications.
Eligible patients received ZEN-3694 once daily on days 1 through 28 or 5 days on and 2 days off, plus oral abemaciclib twice daily on days 1 through 28 of each 28-day cycle. Treatment will continue until disease progression or unacceptable toxicity.
The primary outcome measures include defining the maximum-tolerated dose or recommended phase 2 dose of ZEN-3694, the incidence of AEs, overall response rate, clinical benefit rate, and duration of response. Additional parameters with which investigators are using to define efficacy include time to response, overall survival, and progression-free survival. Secondary objectives include pharmacokinetic and thymidine kinase assessment.
The developer of the agent, Zenith Epigenetics is also seeking orphan drug and breakthrough therapy designations for ZEN-3694 in NUT carcinoma.1
References
- FDA grants Zenith’s ZEN-3694 fast track status. News release. Zenith Epigenetics. July 14, 2025. Accessed July 15, 2025. https://www.zenithepigenetics.com/newsroom/news-releases?article=63
- Testing the safety and efficacy of the combination of two anti-cancer drugs, ZEN003694 and abemaciclib, for adult and pediatric patients (12-17 years) with metastatic or unresectable NUT carcinoma, breast cancer and other solid tumors. ClinicalTrials.gov. Updated April 9, 2025. Accessed July 15, 2025. https://clinicaltrials.gov/study/NCT05372640?term=bromodomain%20inhibitor&viewType=Table&rank=7