FDA Awards Orphan Drug Designation to ZEN-3694 for NUT Carcinoma

The FDA has granted orphan drug designation to ZEN-3964 for treatment for patients with NUT carcinoma, according to an announcement from Zenith Epigenetics.1

NUT carcinoma is a rare and aggressive form of cancer with no currently approved treatments. ZEN-3694 is a once daily, oral BET bromodomain inhibitor that interferes with the NUTM1 gene fusing with transcriptional regulator, helping disrupt the root activity of NUT carcinoma. During early clinical studies, more than 550 patients have been dosed with ZEN-3694, which has produced strong evidence of clinical efficacy, on-target safety, and combinability with other approved targeted therapies.

“Orphan drug status underscores the unmet need for novel treatment options in [ NUT carcinoma], where patients face poor prognoses and currently have no approved targeted therapies,” Donald McCaffery, president and chief executive officer of Zenith Epigenetics, stated in a news release. “We believe ZEN-3694, through its epigenetic mechanism and combinatorial approach, has the potential to significantly improve outcomes and survival for people with NUT carcinoma. Orphan drug designation and the recently announced fast track designation help us advance this program with the goal of making ZEN-3694 available to those who may benefit from it.”

How are the studies of ZEN-3694 for NUT carcinoma designed?

ZEN-3694 is currently being investigated in NUT carcinoma in two ongoing clinical trials. The first of which is a phase 1/2 trial (NCT05019716) that is evaluating ZEN-3694 combined with cisplatin and etoposide as treatment for patients 12 years of age or older with metastatic and unresectable NUT carcinoma, including patients who have undergone prior surgery.2 Patients in this trial are required to be diagnosed with NUT carcinoma, based on standard criteria including ectopic expression of NUT protein per World Health Organization (WHO) criteria; or NUT gene translocation detection as determined by DNA/RNA sequencing or fluorescence in situ hybridization testing.

Patients are receiving ZEN-3694 orally once or twice daily on days 1 to 14 or days 1 to 21 of each cycle, depending on the dosage assignment of patients. Within cycles, patients are receiving cisplatin on day 1 and etoposide on days 1 to 3 intravenously (IV) for cycles 1 to 4 or up to 8 cycles.

Phase 1 of this trial is determining the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ZEN-3694 given in combination with etoposide and cisplatin. Phase 2 of this trial is evaluating overall response rate (ORR) with the combination of ZEN-3694, cisplatin, and etoposide.

ZEN-3694 is also being investigated in a phase 1 trial (NCT05372640) evaluating the proper dosage of the drug when combined with abemaciclib (Verzenio) as a treatment for patients with NUT carcinoma, breast cancer, and other metastatic, unresectable solid tumors.3 Participants in this trial are required to have a histologically confirmed malignancy that is both unresectable and metastatic without any effective or existing standard curative or palliative measures. A dose-expansion cohort is enrolling patients specifically with NUT carcinoma per standard diagnostic criteria.

In this trial, patients are receiving ZEN-3694 orally once daily on days 1 to 28 or on a 5-days-on, 2-days-off schedule, in combination with abemaciclib orally twice per day in 28-day cycles.

The trial’s primary objective is to determine the MTD as well as the RP2D for ZEN-3694 and abemaciclib. Researchers are also evaluating preliminary rates of antitumor activity, including progression-free survival, overall survival, ORR, time to response, and duration of response as a secondary objective.

References

1. Zenith Epigenetics’ ZEN-3694 receives orphan drug designation from FDA. News Release. Zenith Epigenetics. October 27, 2025. Accessed November 14, 2025. https://www.zenithepigenetics.com/newsroom/news-releases?article=64
2. Testing the safety and efficacy of the addition of a new anti-cancer drug, ZEN003694, to chemotherapy treatment (etoposide and cisplatin) for adult and pediatric patients (12-17 years) with NUT carcinoma. ClinicalTrials.gov. Updated September 3, 2025. Accessed November 14, 2025. https://clinicaltrials.gov/study/NCT05019716
3. 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 September 19, 2023. Accessed November 14, 2025. https://clinicaltrials.gov/study/NCT05372640