ZEN-3694 / Zenith Capital Corp, Newsoara Biopharma - LARVOL DELTA

Dysregulating transcription and epigenetic remodeling using dual BRD4 and CDK9 inhibition in pancreatic ductal adenocarcinoma (AACR 2025) - "Here, we show preclinical evidence that combination treatment of VIP152 and ZEN3694 synergistically dysregulates PDAC transcription and remodels the epigenomic landscape. Future directions will include exploring Myc amplified subtype specific selectivity and in vivo validation of toxicity and efficacy."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • BRD4 • MYC

Anti-tumor effects following BET inhibition in preclinical models of pediatric and AYA osteosarcoma (AACR 2025) - "Effect of BETi (AZD5153, BMS-986378, ZEN-3694) in clinical trials for pediatric and adult solid tumors were investigated...To interrogate mechanisms of action, RNA-seq analysis of BET/BRD4 inhibition via AZD5153, PROTAC (ARV-825), and BRD4 siRNA in OS cell lines revealed distinct and overlapping patterns of alterations in gene expression...At the transcript level, increased DHRS2 was evident with no changes in TMPRSS9. These data sets reveal the promise of BETi for treatment of OS PDX derived from treatment naïve patients some of which go on to relapse, and in OS PDX derived from metastatic sites."

Preclinical • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • BRD2 • BRD4 • DHRS2 • H2AX

A randomized, open-label, phase 2b study of the BET bromodomain inhibitor (BETi) ZEN-3694 plus enzalutamide vs. enzalutamide in patients with metastatic castration resistant prostate cancer (mCRPC). (ASCO 2025) - P2 | "Clinical Trial Registration Number: NCT04986423 The abstract will be released to the public on May 22, 2025 at 5:00 PM EDT"

Clinical • Metastases • P2b data • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

NCI-2021-11793: Testing the Combination of the Anticancer Drugs ZEN003694 and Binimetinib in Patients With Advanced/Metastatic or Unresectable Solid Tumors With RAS Alterations and Triple Negative Breast Cancer (clinicaltrials.gov) - P1 | N=42 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Mar 2025 ➔ Mar 2027 | Trial primary completion date: Mar 2025 ➔ Mar 2027 | Suspended ➔ Recruiting

Enrollment open • Trial completion date • Trial primary completion date • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRAF • ER • HER-2 • HRAS • KRAS • NF1 • NRAS • PGR

The COSMYC Trial (COmbined Suppression of MYC) (clinicaltrials.gov) - P2 | N=50 | Not yet recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

New P2 trial • Castration-Resistant Prostate Cancer • CNS Disorders • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Continuation Protocol for ZEN003694 in Patients Experiencing Clinical Benefit While Enrolled in a ZEN003694 Protocol (clinicaltrials.gov) - P1/2 | N=40 | Enrolling by invitation | Sponsor: Zenith Epigenetics | Trial completion date: Dec 2024 ➔ Dec 2026 | Trial primary completion date: Dec 2024 ➔ Dec 2026

Trial completion date • Trial primary completion date • Castration-Resistant Prostate Cancer • Prostate Cancer

ZEN003694 and Enzalutamide Versus Enzalutamide Monotherapy in Metastatic Castration-Resistant Prostate Cancer (clinicaltrials.gov) - P2 | N=200 | Recruiting | Sponsor: Zenith Epigenetics | Trial completion date: Jun 2025 ➔ Jun 2026 | Trial primary completion date: Dec 2024 ➔ Dec 2025

Monotherapy • Trial completion date • Trial primary completion date • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Testing the Addition of Anti-Cancer Drug, ZEN003694 (ZEN-3694) and PD-1 Inhibitor (Pembrolizumab), to Standard Chemotherapy (Nab-Paclitaxel) Treatment in Patients With Advanced Triple-Negative Breast Cancer (clinicaltrials.gov) - P1 | N=57 | Recruiting | Sponsor: National Cancer Institute (NCI) | Suspended ➔ Recruiting

Enrollment open • Breast Cancer • HER2 Negative Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2 • PD-L1 • PGR

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) - P1/2 | N=55 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Dec 2024 ➔ Dec 2025 | Trial primary completion date: Dec 2024 ➔ Dec 2025

Combination therapy • Trial completion date • Trial primary completion date • NUT Midline Carcinoma • Oncology • Pediatrics • BRD4 • NUTM1

TRβ Agonism Enhances Tumor Suppression by BETi in an Anaplastic Thyroid Cancer Model (ATA 2024) - "Cell-based assays were used to determine the effects of GC-1 and BETi (JQ-1 and ZEN-3694) on 8505C ATC cell phenotype alone and in combination. PPIN analysis revealed TRβ and bromodomain and extra-terminal domain (BET) family proteins interaction nodes including BRD4. GC-1 and BETi have an additive effect in inhibiting the aggressive ATC phenotype in vitro, significantly reducing cell viability and other tumorigenic parameters. ZEN-3694 was shown, for the first time, to inhibit the aggressive ATC phenotype and reduce cellular viability both alone and in combination with GC-1."

Late-breaking abstract • Preclinical • Endocrine Cancer • Oncology • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma • BRD4

ZEN003694 Combined With Niraparib in Patients With Metastatic or Recurrent Solid Tumors (clinicaltrials.gov) - P1 | N=0 | Withdrawn | Sponsor: Haider Mahdi | N=26 ➔ 0 | Recruiting ➔ Withdrawn

Enrollment change • Metastases • Trial withdrawal • Oncology • Ovarian Cancer • Solid Tumor • BRCA

NCI-2021-11793: Testing the Combination of the Anticancer Drugs ZEN003694 and Binimetinib in Patients With Advanced/Metastatic or Unresectable Solid Tumors With RAS Alterations and Triple Negative Breast Cancer (clinicaltrials.gov) - P1 | N=42 | Suspended | Sponsor: National Cancer Institute (NCI) | Recruiting ➔ Suspended

Combination therapy • Metastases • Trial suspension • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRAF • ER • HER-2 • HRAS • KRAS • NF1 • NRAS • PGR

Testing the Addition of Anti-cancer Drug, ZEN003694, to the Usual Chemotherapy Treatment, Cetuximab Plus Encorafenib, for Colorectal Cancer (clinicaltrials.gov) - P1 | N=30 | Recruiting | Sponsor: National Cancer Institute (NCI) | Initiation date: Nov 2024 ➔ Jun 2024

Combination therapy • Metastases • Trial initiation date • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF

A phase 1 study of the BET inhibitor ZEN003694 in combination with the MEK1/2 inhibitor binimetinib in solid tumors with RAS pathway alterations and triple-negative breast cancer (NCI number 10449). (ASCO 2024) - "Prior therapy with BET, RAF, MEK, or ERK inhibitor is not permitted. This study is currently ongoing in dose escalation."

Combination therapy • P1 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRAF • ER • HER-2 • HRAS • KRAS • NF1 • NRAS • PGR

A Study of ZEN003694 and Talazoparib in Patients With Triple Negative Breast Cancer (clinicaltrials.gov) - P2 | N=115 | Terminated | Sponsor: Zenith Epigenetics | Trial completion date: Dec 2024 ➔ Mar 2024 | Active, not recruiting ➔ Terminated; Parts 1 and 2 and Expansion Cohort C were completed. Expansion Cohorts A and B were discontinued based on results from an interim futility analysis and not due to safety concerns.

Combination therapy • Trial completion date • Trial termination • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2 • PGR

ZEN-3694, Enzalutamide, and Pembrolizumab for the Treatment of Metastatic Castration-Resistant Prostate Cancer (clinicaltrials.gov) - P2 | N=54 | Recruiting | Sponsor: Rahul Aggarwal | Trial completion date: Dec 2025 ➔ Apr 2027 | Trial primary completion date: Dec 2025 ➔ Apr 2027

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor • PD-L1 • RB1

Testing the Addition of Anti-Cancer Drug, ZEN003694 (ZEN-3694) and PD-1 Inhibitor (Pembrolizumab), to Standard Chemotherapy (Nab-Paclitaxel) Treatment in Patients With Advanced Triple-Negative Breast Cancer (clinicaltrials.gov) - P1 | N=57 | Suspended | Sponsor: National Cancer Institute (NCI) | Recruiting ➔ Suspended

Metastases • Trial suspension • Breast Cancer • HER2 Negative Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2 • PD-L1 • PGR

Continuation Protocol for ZEN003694 in Patients Experiencing Clinical Benefit While Enrolled in a ZEN003694 Protocol (clinicaltrials.gov) - P1/2 | N=40 | Enrolling by invitation | Sponsor: Zenith Epigenetics | Trial completion date: Dec 2023 ➔ Dec 2024 | Trial primary completion date: Dec 2023 ➔ Dec 2024

Trial completion date • Trial primary completion date • Metastatic Castration-Resistant Prostate Cancer • Prostate Cancer

ZEN003694 and Enzalutamide Versus Enzalutamide Monotherapy in Metastatic Castration-Resistant Prostate Cancer (clinicaltrials.gov) - P2 | N=200 | Recruiting | Sponsor: Zenith Epigenetics | Phase classification: P2b ➔ P2 | Trial completion date: Sep 2024 ➔ Jun 2025 | Trial primary completion date: Mar 2024 ➔ Dec 2024

Combination therapy • Metastases • Monotherapy • Phase classification • Trial completion date • Trial primary completion date • Genito-urinary Cancer • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor

Synergy of ZEN3694 and VIP152 for dual transcriptional targeting of BET and CDK9 in patient derived organoid models of pancreatic cancer (AACR 2024) - "Here, we show the activity of dual transcription targeting with BET and CDK9 inhibition in patient derived pancreatic cancer organoid models. The combination of ZEN3694 and VIP152 has in vitro synergy in PDAC PCO models with on target activity. Ongoing work is validating this combination in animal models to assess toxicity, in vivo activity, and RNA expression profiling to understand transcriptional pathway dependency and therapeutic resistance."

Clinical • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • BCL2L1 • CDK7 • CDK9 • KRAS • RBP1

Targeting BRD4 with BET inhibition synergizes with anti-HER2 therapy and overcomes resistance in HER2-amplified uterine serous cancer (SGO 2024) - " Effects of anti-HER2 therapy with tyrosine kinase inhibitor (neratinib) or antibody drug conjugate (T-DM1), as well as targeting BRD4 with BET inhibition (ZEN-3694) alone and in combination on survival, cell signaling, and apoptosis was investigated in HER2 amplified models of USC (both HER2 naïve and HER2 resistant). Anti-HER2 therapy causes reliance on HER2 and CCND1-CDK6 pathways for survival as compensatory resistance mechanism. Therefore, combined therapy with BET inhibition is more effective in reducing tumor growth and achieving complete remission than anti-HER2 monotherapy in both in-vitro and CDX in-vivo models of HER2 amplified USC."

Endometrial Serous Adenocarcinoma • Oncology • Uterine Cancer • AURKA • BRD4 • CCND1 • CDK6 • EGFR

Testing the Addition of Anti-cancer Drug, ZEN003694, to the Usual Chemotherapy Treatment, Cetuximab Plus Encorafenib, for Colorectal Cancer (clinicaltrials.gov) - P1 | N=30 | Recruiting | Sponsor: National Cancer Institute (NCI) | Not yet recruiting ➔ Recruiting | N=22 ➔ 30 | Trial completion date: Jun 2024 ➔ Jun 2025 | Initiation date: Feb 2024 ➔ Nov 2024 | Trial primary completion date: Jun 2024 ➔ Jun 2025

Combination therapy • Enrollment change • Enrollment open • Metastases • Trial completion date • Trial initiation date • Trial primary completion date • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF

An LC-MS/MS method for determination of the bromodomain inhibitor ZEN-3694 and its metabolite ZEN-3791 in human plasma. (PubMed, Bioanalysis) - P1 | "ZEN-3694 and ZEN-3791 recoveries were between 93 and 105%. This LC-MS/MS assay is an essential tool to study ZEN-3694 in an ongoing clinical trial (NCT04840589)."

Journal

Testing the Combination of the Anticancer Drugs ZEN003694 and Binimetinib in Patients With Advanced/Metastatic or Unresectable Solid Tumors With RAS Alterations and Triple Negative Breast Cancer (clinicaltrials.gov) - P1 | N=42 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Mar 2024 ➔ Mar 2025 | Trial primary completion date: Mar 2024 ➔ Mar 2025

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRAF • ER • HER-2 • HRAS • KRAS • NF1 • NRAS • PGR

ZEN003694 Combined With Niraparib in Patients With Metastatic or Recurrent Solid Tumors (clinicaltrials.gov) - P1 | N=26 | Recruiting | Sponsor: Haider Mahdi | Not yet recruiting ➔ Recruiting

Enrollment open • Oncology • Ovarian Cancer • Solid Tumor • BRCA