azenosertib (ZN-c3) / Zentalis Pharma - LARVOL DELTA

Testing the Combination of the Anticancer Drugs Trastuzumab Deruxtecan (DS-8201a) and Azenosertib (ZN-c3) in Patients With Stomach or Other Solid Tumors (clinicaltrials.gov) - P1 | N=48 | Not yet recruiting | Sponsor: National Cancer Institute (NCI) | Initiation date: Apr 2024 ➔ Aug 2024

Combination therapy • Trial initiation date • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor

Targeting replication stress in pancreatic cancer: A phase II trial investigating azenosertib in combination with gemcitabine in second-line advanced pancreatic cancer. (ASCO 2024) - P2 | "Clinical Trial Registration Number: NCT06015659"

Clinical • Combination therapy • Metastases • P2 data • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor

Phase 1 results of the WEE1 inhibitor, azenosertib, in combination with gemcitabine (gem) in adult and pediatric patients (pts) with relapsed or refractory (R/R) osteosarcoma. (ASCO 2024) - P1/2 | "Clinical Trial Registration Number: NCT04833582"

Clinical • Combination therapy • P1 data • Oncology • Osteosarcoma • Pediatrics • Sarcoma • Solid Tumor

Zentalis Pharmaceuticals Reports First Quarter 2024 Financial Results and Operational Progress (GlobeNewswire) - "1H 2025: Topline data from registration-enabling Phase 2 DENALI study (ZN-c3-005) of azenosertib monotherapy in platinum resistant high-grade serous ovarian cancer. 2H 2025: Topline data from registration-enabling Phase 2 TETON study (ZN-c3-004) of azenosertib monotherapy in recurrent or persistent USC. 2025: Initiate registration-enabling trial of azenosertib in PSOC in the 1L maintenance setting. 2026: First NDA for azenosertib in a gynecologic malignancy."

NDA • New trial • P2 data • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • Uterine Cancer

Zentalis Pharmaceuticals Reports First Quarter 2024 Financial Results and Operational Progress (GlobeNewswire) - "Anticipated Upcoming Milestones: 1H 2024 - Presentation of final results of Phase 1 (ZN-c3-003) azenosertib + chemotherapy (gemcitabine) trial in R/R osteosarcoma at 2024 ASCO Annual Meeting; 2H 2024 - Presentation of final results of Phase 1b (ZN-c3-001) azenosertib monotherapy trial in solid tumors; Topline data from Phase 1/2 MAMMOTH (ZN-c3-006) azenosertib + PARP inhibitor (niraparib) and azenosertib monotherapy trial in platinum resistant ovarian cancer in partnership with GSK; Presentation of initial data from Phase 1 (ZN-c3-016) azenosertib + BEACON regimen (encorafenib + cetuximab) trial in BRAF mutant metastatic colorectal cancer in partnership with Pfizer; Initial data from Phase 1 (ZN-d5-004C) azenosertib + ZN-d5 trial in R/R AML; Additional details on design of planned registration-enabling trial of azenosertib in PSOC in the 1L maintenance setting."

Clinical protocol • P1 data • P1/2 data • Acute Myelogenous Leukemia • Colorectal Cancer • Gastrointestinal Cancer • Gynecologic Cancers • Hematological Malignancies • Leukemia • Oncology • Osteosarcoma • Ovarian Cancer • Sarcoma • Solid Tumor

Testing the Combination of the Anticancer Drugs Trastuzumab Deruxtecan (DS-8201a) and Azenosertib (ZN-c3) in Patients With Stomach or Other Solid Tumors (clinicaltrials.gov) - P1 | N=48 | Not yet recruiting | Sponsor: National Cancer Institute (NCI)

Combination therapy • New P1 trial • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor

Azenosertib in Uterine Serous Carcinoma: Biomarker Study (clinicaltrials.gov) - P2 | N=25 | Not yet recruiting | Sponsor: Joyce Liu, MD

Biomarker • New P2 trial • Endometrial Serous Adenocarcinoma • Oncology • Solid Tumor • Uterine Cancer

Pharmacokinetics assessment of intranasal NEO100 treatment on blood-brain barrier disruption and brain penetration of drugs in rodent brain (AACR 2024) - "Co-administration of IN NEO100 with ZN-c3, everolimus, and infigratinib increases their brain and plasma exposure. As a result, no significant increase in brain-to-plasma partition was registered for any of the three drugs tested in this study. IN NEO100-mediated increase in brain drug concentration was independent of BBB disruption"

PK/PD data • Preclinical • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

The novel WEE1i, APR-1051, is a potentially well tolerated and effective treatment for cyclin E-overexpressing cancers (AACR 2024) - "One challenge for two of the leading WEE1i, AZD1775 and ZN-c3, has been the observed off-targeting of PLK family members, namely, PLK1, PLK2 and PLK3. APR-1051 is now progressing through IND-enabling studies. Together, these findings underscore the potential of APR-1051 as a novel WEE1i for the treatment of Cyclin E-overexpressing cancers."

Oncology • Ovarian Cancer • Solid Tumor • CCNE1 • PLK2

The selective WEE1 inhibitor azenosertib shows synergistic anti-tumor activity with KRASG12C inhibitors in multiple KRASG12C models (AACR 2024) - "Similarly, treatment of a KRASG12C inhibitor-resistant patient-derived xenograft (PDX) model of CRC resulted in synergistic TGI in the combination arm (61%) relative to monotherapy azenosertib (17%) or adagrasib (2%). Finally, analysis of biomarkers from both in vitro and in vivo tumor samples demonstrated synergistic increases in protein markers of RS, DNA damage, and apoptosis with combination therapy.Taken together, our results suggest that the combination of azenosertib with KRASG12C inhibitors enhances tumor growth inhibition over single agent therapy and may be an effective treatment option for patients with KRASG12C tumors."

Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

ACR-2316: A potentially first-in-class, potent, selective WEE1/PKMYT1 inhibitor rationally designed for superior single agent activity through synergistic disruption of cell cycle checkpoints (AACR 2024) - "ACR-2316 is more selective than adavosertib, azenosertib, and lunresertib based on >200 kinases profiled by AP3 and 468 kinases assessed by KINOMEscan...In conclusion, ACR-2316 is a potent, selective dual WEE1/PKMYT1 inhibitor with superior single-agent activity compared to clinical WEE1 or PKMYT1 inhibitors. ACR-2316 is progressing through IND-enabling studies in preparation for clinical monotherapy development."

Oncology • Ovarian Cancer • Solid Tumor • CDK1 • CDK2 • CHEK1 • PKMYT1 • PLK1

Dr Westin on Early Findings With Azenosertib in High-Grade Serous Ovarian Cancer (OncLive) - P1/2 | N=90 | DENALI (NCT05128825) | Sponsor K-Group, Beta, Inc. | "Shannon N. Westin...discusses the potential implications of the phase 2 DENALI trial (NCT05128825) of azenosertib (ZN-c3) in patients with high-grade serous ovarian, fallopian tube, or primary peritoneal cancer....During the phase 1 portion, early efficacy signals with the agent were also observed in patients with ovarian cancer, as well as those with uterine cancer and other solid tumors, Westin adds."

P1 data • Fallopian Tube Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor • Uterine Cancer

A Phase I/II Single-arm Trial of Azenosertib (ZN-c3) Combined With Carboplatin and Pembrolizumab in Patients With Metastatic Triple-negative Breast Cancer (ZAP-IT) (clinicaltrials.gov) - P1/2 | N=78 | Not yet recruiting | Sponsor: Filipa Lynce, MD

Metastases • New P1/2 trial • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Negative Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Zentalis Pharmaceuticals to Highlight Preclinical Data Demonstrating that WEE1 Inhibitor Azenosertib Exerts Synergistic Anti-tumor Activity with KRAS(G12C) Inhibitors at AACR Annual Meeting 2024 (GlobeNewswire) - "The data demonstrated synergistic cell growth inhibition across a panel of KRAS^G12C cell lines in both 2D and 3D assays. Furthermore, administration of azenosertib in KRAS^G12C inhibitor-sensitive and resistant xenograft models, including using non-small cell lung cancer, colorectal cancer, and pancreatic cancer cell lines, demonstrated monotherapy activity as well as synergistic tumor growth inhibition when combined with KRAS^G12C inhibitors. In addition, extended administration of azenosertib combined with KRAS^G12C inhibitors increased the duration of response versus single agent use. Together, these results support continued study of the potential for azenosertib to provide clinical benefit as a combination therapy."

Preclinical • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor

Zentalis Pharmaceuticals Reports Full Year 2023 Financial Results and Operational Updates (GlobeNewswire) - "1H 2024: Final results of Phase 1 azenosertib + chemotherapy (gemcitabine) trial in osteosarcoma (ZN-c3-003). 2H 2024: Final results of Phase 1b azenosertib monotherapy trial in solid tumors (ZN-c3-001); Topline data from Phase 1/2 azenosertib + PARP inhibitor (niraparib) and azenosertib monotherapy trial in platinum resistant ovarian cancer in partnership with GSK (MAMMOTH, ZN-c3-006); Initial data from Phase 1 azenosertib + BEACON regimen (encorafenib + cetuximab) trial in BRAF mutant metastatic colorectal cancer in partnership with Pfizer (ZN-c3-016); Initial data from Phase 1 of azenosertib + ZN-d5 trial in R/R AML (ZN-d5-004C); Additional details on planned clinical trial of azenosertib in PSOC in the 1L maintenance setting."

P1 data • P1/2 data • Acute Myelogenous Leukemia • Colorectal Cancer • Gastrointestinal Cancer • Gynecologic Cancers • Hematological Malignancies • Leukemia • Oncology • Osteosarcoma • Ovarian Cancer • Sarcoma • Solid Tumor

Zentalis Pharmaceuticals Reports Full Year 2023 Financial Results and Operational Updates (GlobeNewswire) - "1H 2025: Topline data from Phase 2 azenosertib monotherapy trial in platinum resistant high-grade serous ovarian cancer (DENALI, ZN-c3-005). 2H 2025: Topline data from Phase 2 azenosertib monotherapy trial in recurrent or persistent USC (TETON, ZN-c3-004). 2025: Initiate clinical trial of azenosertib in PSOC in the 1L maintenance setting. 2026: First NDA for azenosertib in a gynecologic malignancy."

NDA • New trial • P2 data • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • Uterine Cancer

Azenosertib: "Monotherapy Azenosertib results in a 37% confirmed response rate"; Ovarian cancer, Uterine cancer (Zentalis Pharma) - Corporate Presentation: "Median follow up has increased by nearly 5 months and mPFS has increased to 6.5 months"

P1 data • Oncology • Ovarian Cancer • Uterine Cancer

ZN-c3 + Gemcitabine in Pancreatic Cancer (clinicaltrials.gov) - P2 | N=34 | Recruiting | Sponsor: Brandon Huffman | Not yet recruiting ➔ Recruiting

Enrollment open • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

Indicators of Response to the Wee1 Inhibitor Adavosertib in Acute Myeloid Leukemia (ASH 2023) - P1/2 | "Wee1 is a nuclear kinase that regulates cell cycle progression by inhibiting Cdk1, which is essential for G2 to M phase transition. In addition, high CD34 expression in resistant samples suggests that immature stem and progenitor cells may be less susceptible to Wee1i. In summary, targeting of Wee1 in AML – as studied in NCT05682170 azenosertib study - may be effective for a molecularly defined subset of patients."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • AFDN • CD34 • CDK1 • CDK2 • GLI2 • S100A16

A Study of ZN-c3 in Women With Recurrent or Persistent Uterine Serous Carcinoma (clinicaltrials.gov) - P2 | N=130 | Recruiting | Sponsor: K-Group, Beta, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc | Trial completion date: Dec 2023 ➔ May 2025 | Trial primary completion date: Dec 2022 ➔ Nov 2024

Trial completion date • Trial primary completion date • Endometrial Serous Adenocarcinoma • Oncology • Uterine Cancer

A Study of ZN-c3 in Combination With Gemcitabine in Subjects With Osteosarcoma (clinicaltrials.gov) - P1/2 | N=84 | Active, not recruiting | Sponsor: K-Group, Beta, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Oncology • Osteosarcoma • Pediatrics • Sarcoma • Solid Tumor

Zentalis Pharmaceuticals Reports Third Quarter 2023 Financial Results and Operational Updates (GlobeNewswire) - "Anticipated Upcoming Milestones: 2H 2024: (i) Final results of Phase 1b azenosertib monotherapy trial in solid tumors (ZN-c3-001); (ii) Topline data from Phase 1/2 azenosertib + PARP inhibitor (niraparib) and azenosertib monotherapy trial in platinum resistant ovarian cancer in partnership with GSK (MAMMOTH, ZN-c3-006); (iii) Initial data from Phase 1 azenosertib + BEACON regimen (encorafenib + cetuximab) trial in BRAF mutant metastatic colorectal cancer in partnership with Pfizer (ZN-c3-016); (iv) Initial data from Phase 1 of azenosertib + ZN-d5 trial in R/R AML (ZN-d5-004C)."

P1 data • P1/2 data • Acute Myelogenous Leukemia • Colorectal Cancer • Ovarian Cancer • BRAF

Zentalis Pharmaceuticals Reports Third Quarter 2023 Financial Results and Operational Updates (GlobeNewswire) - "Anticipated Upcoming Milestones: (i) 1H 2024: Final results of Phase 1 azenosertib + chemotherapy (gemcitabine) trial in osteosarcoma (ZN-c3-003); (ii) 1H 2025: Topline data from Phase 2 azenosertib monotherapy trial in platinum resistant high-grade serous ovarian cancer (DENALI, ZN-c3-005); (iii) 2H 2025: Topline data from Phase 2 azenosertib monotherapy trial in recurrent or persistent USC (TETON, ZN-c3-004)."

P1 data • P2 data • Osteosarcoma • Ovarian Cancer • Uterine Cancer

Zentalis Pharmaceuticals Reports Third Quarter 2023 Financial Results and Operational Updates (GlobeNewswire) - P1 | N=146 | NCT04158336 | Sponsor: K-Group Beta | "...The Company announced an updated analysis of the ongoing Phase 1 clinical trial of azenosertib as a monotherapy in solid tumors (ZN-c3-001), which continued to show anti-tumor activity with intermittent dosing. In the same population of 19 platinum resistant or refractory ovarian cancer and uterine serous carcinoma (USC) patients that were included in the data reported on June 6, 2023, the objective response rate (ORR) was 37%. Median follow-up has increased by nearly 5 months and the median progression free survival (mPFS) has increased to 6.5 months....The Company is on track to submit its first New Drug Application (NDA) for azenosertib in a gynecologic malignancy in 2026....The Company...plans to evaluate azenosertib in PSOC in the first-line (1L) maintenance setting in the clinic....The Company plans to provide additional details on this trial in the second half of 2024, and anticipates initiating enrollment in 2025."

NDA • New trial • P1 data • Ovarian Cancer • Uterine Cancer

LB-100 (PP2A Inhibitor) and Azenosertib (WEE1 Inhibitor) in Metastatic Colorectal Cancer Patients (clinicaltrials.gov) - P1 | N=43 | Not yet recruiting | Sponsor: The Netherlands Cancer Institute

Metastases • New P1 trial • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor