ZEN-3694 / Zenith Epigenetics, Newsoara Biopharma - LARVOL DELTA

Testing the Combination of the Anti-cancer Drugs ZEN003694 (ZEN-3694) and Talazoparib in Patients With Advanced Solid Tumors, The ComBET Trial (clinicaltrials.gov) - P2 | N=88 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Recruiting ➔ Active, not recruiting | Trial completion date: Dec 2027 ➔ Dec 2026

Enrollment closed • Trial completion date • Oncology • Ovarian Cancer • Solid Tumor • BARD1 • BRCA1 • BRCA2 • BRIP1 • FANCA • KRAS • RAD51 • RAD51C • RAD51D

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

SELLAS Life Sciences Presents Preclinical Data Demonstrating SLS009 Activity in Pancreatic Cancer Models at the 2026 AACR Conference on Pancreatic Cancer (The Manila Times) - "SLS009 demonstrated substantially greater single-agent activity than daraxonrasib in the daraxonrasib-resistant model, inducing 17.9% apoptosis versus 2.8% with daraxonrasib and 14.5% necrosis versus 2.7%; The combination of SLS009 and daraxonrasib further increased cancer cell death, inducing 36.5% apoptosis and 30.6% necrosis, compared with 17.9% and 14.5%, respectively, with SLS009 alone and 2.8% and 2.7%, respectively, with daraxonrasib monotherapy; SLS009 combined with ZEN3694 demonstrated synergistic activity, producing greater apoptosis and necrosis than either agent alone; The SLS009/ZEN3694 combination produced sustained suppression of MYC RNA and reduced expression of MYC and MCL-1 proteins, consistent with disruption of transcriptional pathways supporting tumor cell survival."

Preclinical • Pancreatic Ductal Adenocarcinoma

A phase 1b/2 study of the BET inhibitor ZEN-3694 in combination with talazoparib for treatment of patients with TNBC without gBRCA1/2 mutations. (ASCO 2022) - P2 | "Combination of ZEN-3694 and talazoparib demonstrated anti-cancer activity in pretreated mTNBC WT gBRCA1/2 patients. All confirmed responses were observed in TNBC at diagnosis patients, whose tumors are expected to be more sensitive to the combination due to their basal-like properties. The trial is being expanded to Ph."

Clinical • Combination therapy • P1/2 data • Hematological Disorders • HER2 Breast Cancer • HER2 Negative Breast Cancer • Thrombocytopenia • Triple Negative Breast Cancer • BRCA1 • BRCA2 • HER-2 • HRD

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) | Suspended ➔ Recruiting

Enrollment open • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • Solid Tumor • BRAF

Trial of Selumetinib and Bromodomain Inhibitor With Durvalumab for Sarcomas (clinicaltrials.gov) - P2 | N=41 | Recruiting | Sponsor: University of Alabama at Birmingham | Not yet recruiting ➔ Recruiting

Enrollment open • Brain Cancer • Neurofibrosarcoma • Oncology • Sarcoma • Solid Tumor

Testing the Safety and Efficacy of the Addition of a New Anti-cancer Drug, ZEN003694, to Chemotherapy Treatment (Cisplatin and Etoposide or Carboplatin and Paclitaxel) for Adult and Pediatric Patients (12-17 Years) With NUT Carcinoma (clinicaltrials.gov) - P1/2 | N=36 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jun 2026 ➔ Jun 2027 | Trial primary completion date: Jun 2026 ➔ Jun 2027

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

Testing A New Anti-cancer Drug Combination, Entinostat and ZEN003694, for Advanced and Refractory Solid Tumors (clinicaltrials.gov) - P1/2 | N=49 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jul 2026 ➔ Jul 2027 | Trial primary completion date: Jul 2026 ➔ Jul 2027

Trial completion date • Trial primary completion date • Oncology • Pancreatic Cancer • Solid Tumor

Trial of Selumetinib and Bromodomain Inhibitor With Durvalumab for Sarcomas (clinicaltrials.gov) - P2 | N=41 | Not yet recruiting | Sponsor: University of Alabama at Birmingham | Trial completion date: May 2032 ➔ Nov 2032 | Trial primary completion date: May 2031 ➔ Nov 2031

Trial completion date • Trial primary completion date • Brain Cancer • Neurofibrosarcoma • Oncology • Sarcoma • Solid Tumor

ZEN003694 Combined With Talazoparib in Patients With Recurrent Ovarian Cancer (clinicaltrials.gov) - P2 | N=33 | Recruiting | Sponsor: Alexander B Olawaiye, MD | Trial completion date: Mar 2033 ➔ Dec 2034 | Trial primary completion date: Dec 2031 ➔ Nov 2033

Platinum resistant • Platinum sensitive • Trial completion date • Trial primary completion date • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor • BRCA1 • BRCA2

NRG-GY031: Testing Different Amounts of the Combination of Drugs M1774 and ZEN-3694 for the Treatment of Recurrent Ovarian and Endometrial Cancer (clinicaltrials.gov) - P1 | N=65 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Apr 2026 ➔ Jun 2027 | Trial primary completion date: Apr 2026 ➔ Jun 2027

dMMR • MSI-H • Platinum resistant • Trial completion date • Trial primary completion date • Endometrial Adenocarcinoma • Endometrial Cancer • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • ARID1A • MSI

NCI-2022-04099: 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) - P1 | N=45 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jun 2026 ➔ Jun 2027 | Trial primary completion date: Jun 2026 ➔ Jun 2027

Trial completion date • Trial primary completion date • Breast Cancer • NUT Midline Carcinoma • Oncology • Pediatrics • Solid Tumor • NUTM1

Testing the Addition of an Anti-Cancer Drug, ZEN003694, to the Usual Chemotherapy Treatment (Capecitabine) for Metastatic or Unresectable Cancers (clinicaltrials.gov) - P1 | N=30 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jun 2026 ➔ Jun 2027 | Trial primary completion date: Jun 2026 ➔ Jun 2027

Trial completion date • Trial primary completion date • Colorectal Cancer • Oncology • Solid Tumor

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

Trial suspension • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • Solid Tumor • BRAF

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 2026 ➔ Dec 2027 | Trial primary completion date: Dec 2026 ➔ Dec 2027

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 2026 ➔ Jun 2027 | Trial primary completion date: Dec 2025 ➔ Dec 2026

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

CRISPR druggable-genome screen identifies BRD4 as a synergistic vulnerability with the natural product cerberin in pancreatic cancer organoids (AACR 2026) - "Adopting a CRISPR/Cas9 druggable screen in 3D PDAC PDO models, we provide proof-of-concept for synergy between cardiac glycosides and BRD4/BET inhibitors. This work links a PDO-based CRISPR platform with natural-product pharmacology to provide a framework for mechanistic partners to advance the use of cardiac glycosides for clinical translation."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • ANXA2 • BRD4 • ENPP2 • FDX1 • KRAS • NR1I2 • PIK3R1

Activity of dual BET and CDK9 inhibition in murine models of pancreatic ductal adenocarcinoma (AACR 2026) - "Across two independent PDAC PDX models, ZEN3694 and VIP152 yield tumor growth inhibition. All treatments were well tolerated in two independent PDAC models, PDX1and PDX2. Ongoing studies are analyzing early timepoints for a putative mechanism involving transient disruption in the activation of RNA polymerase II."

Preclinical • Oncology • Pancreatic Ductal Adenocarcinoma • CDKN2A • CDKN2B • KRAS • MTAP • PDX1 • SMAD4

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

Testing the Combination of the Anti-cancer Drugs ZEN003694 (ZEN-3694) and Talazoparib in Patients With Advanced Solid Tumors, The ComBET Trial (clinicaltrials.gov) - P2 | N=88 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Dec 2026 ➔ Dec 2027

Trial completion date • Oncology • Ovarian Cancer • Solid Tumor • BARD1 • BRCA1 • BRCA2 • BRIP1 • FANCA • KRAS • RAD51 • RAD51C • RAD51D

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

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

A Study of ZEN003694 in People With Squamous Cell Lung Cancer (clinicaltrials.gov) - P2 | N=13 | Recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Trial completion date: Nov 2026 ➔ Nov 2027 | Trial primary completion date: Nov 2026 ➔ Nov 2027

Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • NSD3

Testing the Combination of ZEN003694 and Nivolumab With or Without Ipilimumab in Solid Tumors (clinicaltrials.gov) - P1 | N=66 | Suspended | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jan 2026 ➔ Sep 2028 | Recruiting ➔ Suspended | Trial primary completion date: Jan 2026 ➔ Sep 2028

IO biomarker • Platinum resistant • Trial completion date • Trial primary completion date • Trial suspension • Oncology • Ovarian Cancer • Refractory Ovarian Cancer • Solid Tumor • PD-L1

Testing the Safety and Efficacy of the Addition of a New Anti-cancer Drug, ZEN003694, to Chemotherapy Treatment (Cisplatin and Etoposide or Carboplatin and Paclitaxel) for Adult and Pediatric Patients (12-17 Years) With NUT Carcinoma (clinicaltrials.gov) - P1/2 | N=36 | Recruiting | Sponsor: National Cancer Institute (NCI) | Phase classification: P1 ➔ P1/2

Phase classification • NUT Midline Carcinoma • Oncology • Pediatrics • BRD4 • NUTM1