UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
——————————————
FORM 8-K
——————————————
CURRENT REPORT
Pursuant to Section 13 or 15(d)
of the Securities Exchange Act of 1934
Date of report (Date of earliest event reported): June 5, 2023
——————————————
(Exact name of registrant as specified in its charter)
——————————————
(State or other jurisdiction of incorporation or organization) | (Commission File Number) | (I.R.S. Employer Identification No.) | ||||||||||||
(Address of principal executive offices) (Zip Code)
(212 ) 433-3791
(Registrant’s telephone number, include area code)
N/A
(Former name or former address, if changed since last report)
——————————————
Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:
| Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425) | |||||
| Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12) | |||||
| Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b)) | |||||
| Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c)) | |||||
Securities registered pursuant to Section 12(b) of the Act:
| Title of each class | Trading Symbol(s) | Name of each exchange on which registered | ||||||
Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).
Emerging growth company ☐
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐
Item 7.01 Regulation FD Disclosure.
On June 5, 2023, Zentalis Pharmaceuticals, Inc. (the “Company”) presented a poster titled “A Phase 1/2 Dose Escalation Study of the BCL-2 Inhibitor ZN-d5 and the WEE1 Inhibitor Azenosertib (ZN-c3) in Patients (Pts) With Acute Myeloid Leukemia (AML)” (the “ZN-d5 Poster”) at the 2023 American Society of Clinical Oncology Annual Meeting (“ASCO”). A copy of the ZN-d5 Poster is furnished as Exhibit 99.1 to this Current Report on Form 8-K (this “Current Report”) and incorporated herein by reference.
The information contained in Item 7.01 of this Current Report (including Exhibit 99.1 attached hereto) shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference in any filing under the Securities Act of 1933, as amended, or the Exchange Act, whether made before or after the date hereof, except as expressly provided by specific reference in such a filing.
Item 8.01 Other Events.
On June 5, 2023, the Company presented at ASCO a poster titled “Correlation of Cyclin E1 Expression and Clinical Outcomes in a Phase 1b Dose-Escalation Study of Azenosertib (ZN-c3), a WEE1 inhibitor, in Combination with Chemotherapy (CT) in Patients (pts) with Platinum-Resistant or Refractory (R/R) Epithelial Ovarian, Peritoneal, or Fallopian Tube Cancer (EOC)” (the “Azenosertib Poster”). A copy of the Azenosertib Poster is filed as Exhibit 99.2 to this Current Report and incorporated herein by reference.
Item 9.01 Financial Statements and Exhibits.
(d) Exhibits
The following Exhibit 99.1 relating to Item 7.01 shall be deemed to be furnished, and not filed:
Exhibit No. | Description | |||||||
| 104 | Cover Page Interactive Data File (embedded within the inline XBRL document) | |||||||
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| ZENTALIS PHARMACEUTICALS, INC. | ||||||||||||||
| Date: June 5, 2023 | By: | /s/ Melissa Epperly | ||||||||||||
| Melissa Epperly | ||||||||||||||
| Chief Financial Officer | ||||||||||||||
A Phase 1/2 Dose Escalation Study of the BCL-2 Inhibitor ZN-d5 and the WEE1 Inhibitor Azenosertib (ZN-c3) in Patients (Pts) With Acute Myeloid Leukemia (AML) Catherine Smith1, Pankit Vachhani2, Guillermo Garcia Manero3, Nicole Grieselhuber4, Guru Subramanian Guru Murthy5, Astha Bhatia6, Jatinder Arora6, Hooman Izadi7, Anthony Fiorino7, Raajit Rampal8 1Division of Hematology/Oncology, Department of Medicine, Helen Diller family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA; 2Division of Hematology and Oncology, Heersink School of Medicine, University of Alabama Birming- ham, Birmingham, AL; 3Department of Leukemia, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX; 4The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH; 5Cancer Center - Froedtert Hospital, Medical College of Wisconsin, Milwaukee, WI; 6Zentalis Pharmaceuticals, New York, NY; 7Formerly Zentalis Pharmaceuticals, New York, NY; 8Memorial Sloan Kettering Cancer Center, New York, NY BACKGROUND • B-cell lymphoma 2 (BCL-2) is an anti-apoptotic protein and pathway inhibition combined with chemotherapy and/or targeted therapeutics has led to significant clinical benefit in pts with AML1 • Disruption of cell cycle regulation may complement BCL-2 inhibition as many malignant cells are dependent on proteins that regulate cell cycle progression2 • The cell cycle checkpoint protein, WEE1, is highly expressed in genomically unstable malignancies and inhibition of WEE1 induces tumor cell apoptosis3,4 • It has been previously reported that the combination of ZN-d5 (an oral, selective BCL-2 inhibitor) and azenosertib (an oral, highly potent WEE1 inhibitor) synergistically enhance killing of AML cells both in vitro and in vivo, as well as in TP53-mutated models5 • Based on this strong pre-clinical rationale, a Phase 1/2 study was designed to evaluate the novel combination of ZN-d5 and azenosertib in pts with relapsed/refractory (R/R) AML METHODS Azenosertib (ZN-c3): A Novel, Selective, and Orally Bioavailable WEE1 Inhibitor • WEE1 is a protein kinase that inhibits the activity of both CDK1 and CDK2 kinases and is involved in the regulation of G1/S, G2/M, and M phase cell cycle checkpoints4 (Figure 1A) – WEE1 plays an important role during normal cell cycle progression but also in response to DNA damage and interacts with DNA damage response pathways4 • WEE1 inhibition causes cancer cells to proceed into mitosis without being able to repair damaged DNA, resulting in premature mitotic entry and apoptosis4 (Figure 1B) – WEE1 inhibition also increases replication stress by inducing aberrant firing of replication origins and depletion of nucleotide pools3 Figure 1: WEE1 Inhibition by Azenosertib Forces Cancer Cells to Proceed Into Mitosis, Resulting in Apoptosis ZN-d5: A Potent BCL-2 Inhibitor Designed With Improved Selectivity for BCL-2 • The intrinsic apoptotic pathway is controlled by the BCL-2 protein family on the mitochondrial outer membrane6,7 • BCL-2 inhibitors may restore the normal apoptosis process, making it an important target for cancer treatments (Figure 2) • BH3 mimetics bind to BCL-2 proteins and displace pro-apoptotic factors to trigger apoptosis • ZN-d5 is highly selective for BCL-2 over BCL-xL, resulting in reduced platelet toxicity in vitro Figure 2: BCL-2 Inhibition and Apoptosis Figure 1A: WEE1 Activity in Cell Cycle Progression Figure 1B: WEE1 Inhibition by Azenosertib Resulting in Cancer Cell Death Poster# TPS7077 ACKNOWLEDGMENTS We would like to thank all the patients, families, and caregivers as well as the investigators and study site staff for their invaluable contributions to this study. This study is funded by Zentalis Pharmaceuticals. Study Design • This phase 1/2 open-label study (ZN-d5-004C, NCT05682170) is determining the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), pharmacokinetics (PK), and clinical activity of ZN-d5 + azenosertib in pts with AML (Figure 3) • The phase 1 dose-escalation stage is based on a Bayesian Optimal Interval design • Phase 2 is an open-label expansion to be conducted if supported by safety and efficacy data from the dose-escalation stage • Prior to initiating dose-escalation for the ZN-d5 + azenosertib combination, an azenosertib monotherapy cohort is being enrolled, as it has not been previously administered to pts with hematologic malignancies. Figure 3: ZN-d5-004C – Inhibition of BCL-2 and WEE1 in R/R AML: Study Endpoints Objectives Endpoints Primary Assess the safety and tolerability of ZN-d5 and azenosertib in combination and azenosertib monotherapy Incidence, severity, and relatedness of AEs Determine the MTD and RP2D for ZN-d5 and azenosertib in combination Observed DLTs Secondary Assess the clinical activity of ZN-d5 and azenosertib in combination and azenosertib monotherapy Rate of and duration of remission (ELN 2017 criteria), relapse rate, time to relapse Characterize the PK of ZN-d5 and azenosertib in combination and the PK of azenosertib when administered as a monotherapy Plasma PK parameters for ZN-d5 and azenosertib Patient Population Study Sites • This study is open and enrolling at 7 sites in the United States (Figure 4) Figure 4: Currently Enrolling Study Site Treatment Period ZN-d5 Ramp-Up (2-4 days) Combination Dose Escalation BOIN design; N≈40 Up to 15 possible cohorts (<10 expected) ZN-d5 (up to 1000 mg QD); Azenosertib (up to 400 mg QD on a 5D on, 2D off schedule) Phase 1: Dose Escalation Phase 2: Expansion RP2D Screening (-21 days) 28-day Treatment Cycles (until disease progression, etc.) DLT Assessment Period (Ramp-Up + Cycle 1) Post-Treatment Follow-up 7-Day Safety Follow-up 30-Day EOT Visit A Phase 1/2 Dose Escalation Study of the BCL-2 Inhibitor ZN-d5 and the WEE1 Inhibitor Azenosertib (ZN-c3) in Subjects with Relapsed or Refractory Acute Myeloid Leukemia Azenosertib Monotherapy Cohort N=3-15 Azenosertib (up to 400 mg QD or alternative dosing schedule) Study will be expanded after identification of the RP2D REFERENCES 1. Konopleva M, et al. Cancer Discov. 2016;6:1106-1117. 2. de Jong MRW, et al. Cancers. 2019;11:1743. 3. Kok YP, et al. Oncogenesis. 2020;9:88. 4. Matheson CJ, et al. Trends Pharmacol Sci. 2016;37:872-881. 5. Izadi H, et al. AACR 2022. Poster Presentation. Konopleva M and Letai A. Blood. 2018;132:1007-1012. 6. Bhola PD and Letai A. Mol Cell. 2016;61:695-704. 7. Pinchman JR, et al. ESMO. 2021. Poster 528P. 8. Dohner H, et al. Blood. 2017;140:1345-1377. Mechanism of Action of BCL-2 Inhibitors 1 • BCL-2 is an anti-apoptotic protein involved in tumor survival and chemo resistance1 The intrinsic apoptotic pathway is controlled by the BCL-2 protein family on the mitochondrial outer membrane2, 3 BCL-2 inhibitors may restore the normal apoptosis process, making it an important target for cancer treatments • • Presented at the ASCO Annual Meeting, Chicago, IL. June 2-6 University of California San Francisco, CA Ohio State University The James Cancer Hospital Columbus, OH Dana Farber Cancer Institute Boston, MA University of Texas MD Anderson Cancer Center Houston, TX New York University Langone Health New York, NY University of Alabama Birmigham, AL Sloan Kettering Cancer Center New York, NY Key Inclusion Criteria • Adults ≥ 18 years of age • Histologically or cytologically confirmed AML, as defined by World Health Organization (WHO) 2016 revised criteria8, including secondary and therapy-related AML • Subjects must be relapsed from or refractory to ≥1 prior lines of therapy which can include venetoclax-based regimens, induction chemotherapy, stem cell transplant, or salvage therapy • Adequate organ function: – ALT and AST ≤3 × ULN (≤5 × ULN if leukemic disease in the liver) – Alkaline phosphatase ≤5 × ULN – Total bilirubin ≤1.5 × ULN (≤3 × ULN if Gilbert syndrome or if leukemic disease in the liver) – eGFR (CKD-EPI) ≥60 mL/min and adjusted for body surface area • Use of an acceptable form of contraception Key Exclusion Criteria • Prohibited treatments or procedures from the specified time frame prior to the initiation of treatment until EOT: – Systemic anti-neoplastic agents within 5 half-lives – Hematopoietic stem cell transplant within 60 days ■ If no GVHD ≥ Grade 2 or that has required treatment with immunosuppressive agents within 28 days – Radiation therapy within 14 days • Presence of a clinically significant non-hematologic toxicity related to prior AML therapy (other than alopecia, neuropathy, or skin pigmentation) that has not returned to baseline or resolved to Grade ≤2 • Active CNS involvement • Diagnosis of acute PML • Peripheral WBC count of >25 × 109 /L (cytoreduction permitted during screening) • Significant cardiovascular disease
Correlation of Cyclin E1 Expression and Clinical Outcomes in a Phase 1b Dose-Escalation Study of Azenosertib (ZN-c3), a WEE1 inhibitor, in Combination with Chemotherapy (CT) in Patients (pts) with Platinum-Resistant or Refractory (R/R) Epithelial Ovarian, Peritoneal, or Fallopian Tube Cancer (EOC) Joyce Liu1, Siqing Fu2, Gary Richardson3, Zivko Vranjes4, Tarek Meniawy5, Catherine Shannon6, Erika P. Hamilton7, Stephanie Blank8, Cara Mathews9, Jasmina Alidzanovic10, Rossitza Krasteva11, Qing Shi12, Olivier Harismendy12, Mieke Ptaszynski13, Shannon N. Westin2, Funda Meric-Bernstam2, Premal H. Thaker14 1Dana Farber Cancer Institute, Boston, MA; 2The University of Texas MD Anderson Cancer Center, Houston, TX; 3Cabrini Hospital, Malvern, Australia; 4University Clinical Center of Republic of Srpska, Bosnia and Herzegovina; 5Linear Cancer Research, University of Western Australia, Perth, Australia; 6Mater Hospital, Brisbane, Australia; 7Tennessee Oncology, Sarah Cannon Research Institute, Nashville, TN; 8Icahn School of Medicine at Mount Sinai, New York City, NY; 9Women & Infants Hospital of Rhode Island, Providence, RI; 10University Clinical Center Tuzla, Bosnia and Herzegovina; 11Uni Hospital, Panagyurishte, Bulgaria; 12Zentalis Pharmaceuticals, New York, NY; 13Formerly Zentalis Pharmaceuticals, New York, NY; 14Siteman Cancer Center, Washington University, St Louis, MO INTRODUCTION • Azenosertib is an oral, highly specific, potent inhibitor of WEE1 kinase. Preclinical and clinical data have shown it to be highly synergistic with multiple chemotherapies (Figure 1). • Cyclin E1 positivity accelerates the G1/S transition, resulting in replication stress and rendering cells even more sensitive to WEE1 inhibition (Figure 2). • Cyclin E1 positivity is also strongly correlated with platinum resistance and worse ovarian cancer outcomes (Figure 3). • Zentalis 002 was a Phase 1b dose escalation study to define the recommended Phase 2 dose and early clinical activity of azenosertib in combination with chemotherapy. • The purpose of this analysis was to describe the results of Zentalis 002 to date and determine if Cyclin E1 status was associated with benefit from azenosertib. RESULTS Figure 1: Multiple Chemotherapeutic Agents Induce DNA or Mitotic Machinery Damage, with Mechanistic Potential to Synergize with Azenosertib Figure 2: Synergy between Azenosertib and Chemotherapy in Non-Clinical CCNE1 Amplified Ovarian Cancer Models Ma J, et al. Cancer Res 2023;83(7_Supplement):2153. Figure 3: Ovarian Cancer Patients with CCNE1 Amplified and/or Cyclin E1 Positive Cancers have a Worse Outcome Following Platinum-Based Chemotherapy Treatment Stronach et al. Mol Cancer Res 2018;16:1103-11. Pils et al. Eur J Cancer 2014;50:99-110. Peterson et al. Gynecol Oncol 2020;157:405-10. Nakayama et al. Cancer 2010;116:2621-34. Kang et al. Cancer 2023;129:697-713. Chan et al. J Pathol Clin Res 2020;6:252-62. Ayahn et al. Mod Pathol 2017;30:297-303 Carboplatin creates cross-linking DNA adducts, Gemcitabine causes DNA chain termination and fragmentation. In response to chemotherapy-induced DNA damage, intact WEE1 arrests the cell cycle allowing for adequate DNA repair. Azenosertib inhibits WEE1 and allows the cell cycle to proceed despite unrepaired chemotherapy-induced DNA damage, leading to cell death. Paclitaxel stops microtubules from disassembling in M phase causing mitotic catastrophe and cell death. Azenosertib inhibits WEE1 and drives the cell cycle through G2/M thereby sensitizing cells to paclitaxel. Gemcitabine, Carboplatin Paclitaxel WEE1 CDK/Cyclin Cell death S G2 M G1 citabine, arboplatin clitaxel E1 K/Cyclin el death Azenosertib Cyclin E1 positive OVCAR3 cells show greater synergistic effects in all chemotherapy and azenosertib combinations than Cyclin E1 Low OV90 and TYK-nu cells. The drug combination effect was evaluated by measurement of cell viability and 4 calculation methods (ZIP, Bliss, Loewe and HSA) following a Synergy Finder instruction (https://synergyfinder.org). NOD/SCID mice bearing OVCAR3 tumors were treated with azenosertib orally every day and paclitaxel intraperitoneally as a single agent or in combination as indicated. All treatments were well tolerated. 68% TGI 74% TGI Regression OVCAR3 OV90 TYK-nu A Cyclin E1 Positive Tumor Model is Sensitive to Combination Treatment of Azenosertib and Paclitaxel Increased Synergy between Azenosertib and Chemotherapy is Observed in Cyclin E1 Positive Ovarian Cancer Cell Lines 1 2 4 53 Ayahn (2017) [OS] Cyclin E1 Alteration Chan (2020) [OS] Kang (2023) [OS] Nakayama (2010) [OS] Petersen (2020) [OS] Petersen (2020) [PFS] Pils (2014) [OS] Stonach (2018) [OS] Stronach (2018) [PFS] N Hazard Ratio 500 100 1000 Amplification Amplification+ Overexpression Presented at the ASCO Annual Meeting, Chicago, IL. June 2-6 Abstract # 5513 Poster Bd # 208 GOG-3072 CONCLUSIONS • Azenosertib is active with chemotherapy and can be safely combined. RP2Ds are: – Paclitaxel 80 mg/m2 on D1, D8, D15 (28-day cycles) + Azenosertib 300 mg QD 5:2 – Carboplatin AUC 5 mg/mL*min on D1 (21-day cycles) + Azenosertib 200 mg QD 5:2 – PLD 40 mg/m2 D1 (28-day cycles) + Azenosertib 400 mg QD 5:2 – Gemcitabine + Azenosertib has exciting and durable activity, a MTD has not been determined, further dose cohorts are ongoing • Azenosertib-chemotherapy doublet combinations have a longer ORR, mDOR, and mPFS compared to historic control data for single-agent chemotherapy • Cyclin E1 status predicts the benefit from the addition of azenosertib to single-agent chemotherapy suggesting that azenosertib restores chemotherapy sensitivity in heavily pre-treated platinum-resistant ovarian cancer • Azenosertib + chemotherapy has a high level of clinical activity and safety, supporting a randomized study comparing this combination to carboplatin-doublet chemotherapy in platinum sensitive ovarian cancer Abbreviations: 5:2, 5-days of treatment followed by 2-days off treatment; mDOR, median duration of response; mPFS, median progression-free survival; MTD, maximum tolerated dose; ORR, objective response rate; PLD, pegylated liposomal doxorubicin; RP2D, recommended phase 2 dose. Figure 4: Zentalis 002/GOG-3072 Trial Schema Abbreviations: 5:2, 5-days of treatment followed by 2-days off treatment; A, azenosertib; AUC, area under the time-concentration curve; CRM, continuous reassessment model; DOR, duration of response; ECOG, Eastern Cooperative Oncology Group; G, gemcitabine; MTD, maximum tolerated dose; ORR, objective response rate; PFS, progression-free survival; PLD, pegylated liposomal doxorubicin; PROC, platinum-resistant ovarian cancer; RECIST, response evaluation criteria in solid tumors; RP2D, recommended Phase 2 dose. Table 1: Baseline Characteristics Characteristic Azenosertib + Paclitaxel (N=26) Azenosertib + Carboplatin (N=36) Azenosertib + Gemcitabine (N=18) Azenosertib + PLD (N=35) Total (N=115) Age Median (Range) 61.5 (45-83) 61.0 (48-77) 62.5 (47-77) 56.0 (34-75) 61.0 (34-83) Race and Ethnicity, n (%) White 24 (92.3) 34 (94.4) 16 (88.9) 34 (97.1) 108 (93.9) Black or African- American 0 0 0 0 0 Asian 1 (3.8) 1 (2.8) 1 (5.6) 1 (2.9) 4 (3.5) Other / NR 1 (3.8) 1 (2.8) 1 (5.6) 0 3 (2.6) Hispanic (Yes/No/NR) 1/25/0 (3.8/96.2/0) 0/34/2 (0/94.4/5.6) 1/17/0 (5.6/94.4/0) 1/33/1 (2.9/94.3/2.9) 3/109/3 (2.6/94.8/2.6) ECOG Performance Status, n (%) 0 21 (80.8) 21 (58.3) 12 (66.7) 24 (68.6) 78 (67.8) 1 5 (19.2) 15 (41.7) 6 (33.3) 11 (31.4) 37 (32.2) Geographic Region, n (%) US 6 (23.1) 10 (27.8) 10 (55.6) 5 (14.3) 31 (27.0) Europe 10 (38.5) 10 (27.8) 6 (33.3) 27 (77.1) 53 (46.1) Australia 9 (34.6) 15 (41.7) 1 (5.6) 3 (8.6) 28 (24.3) Korea 1 (3.8) 1 (2.8) 1 (5.6) 0 3 (2.6) Platinum Status Refractory, n (%) 5 (19.2) 9 (25.0) 3 (16.7) 7 (20.0) 24 (20.9) Prior Lines of Therapy 1-2, n (%) 22 (84.6) 30 (83.3) 18 (100) 33 (94.3) 103 (89.6) 3-4, n (%) 4 (15.4) 6 (16.7) – 2 (5.7) 12 (10.4) Prior PARP Inhibitor n (%) 8 (30.8) 10 (27.8) 5 (27.8) 5 (14.3) 28 (24.3) Abbreviations: ECOG, Eastern Cooperative Oncology Group; NR, not reported; PLD, pegylated liposomal doxorubicin. Table 2: Treatment-Related Adverse Events ≥20% Treatment-Related Adverse Event, n (%) Azenosertib + Paclitaxel (Continuous, N=7; Intermittent, N=19) Azenosertib + Carboplatin (Continuous, N=22; Intermittent, N=14) Azenosertib + Carboplatin (Continuous, N=14; Intermittent, N=8) Azenosertib + Gemcitabine (Continuous N=8; Intermittent, N=10) Azenosertib + PLD (Continuous N=27; Intermittent, N=8) Total (Continuous, N=64; Intermittent, N=51) All Doses* All Doses Doses ≤ MTD All Doses** All Doses* Grade All Gr Gr ≥3 All Gr Gr ≥3 All Gr Gr ≥3 All Gr Gr ≥3 All Gr Gr ≥3 All Gr Gr ≥3 Hematologic Neutropenia C 5 (71.4) 5 (71.4) 9 (40.9) 7 (31.8) 4 (28.6) 3 (21.4) 7 (87.5) 6 (75.0) 19 (70.4) 17 (63.0) 40 (62.5) 35 (54.7) I 11 (57.9) 5 (26.3) 7 (50.0) 1 (7.1) 4 (50.0) - 7 (70.0) 4 (40.0) 3 (37.5) 3 (37.5) 28 (54.9) 13 (25.5) Thrombo- cytopenia C 4 (57.1) 2 (28.6) 16 (72.7) 11 (50.0) 11 (78.6) 6 (42.9) 8 (100.0) 5 (62.5) 9 (33.3) 2 (7.4) 37 (57.8) 20 (31.3) I 4 (21.1) - 9 (64.3) 5 (35.7) 4 (50.0) 2 (25.0) 8 (80.0) 6 (60.0)* 3 (37.5) 3 (37.5) 24 (47.1) 14 (27.5) Anemia C 5 (71.4) - 10 (45.5) 3 (13.6) 5 (35.7) 1 (7.1) 6 (75.0) 2 (25.0) 11 (40.7) 4 (14.8) 32 (50.0) 9 (14.1) I 8 (42.1) 1 (5.3) 10 (71.4) 4 (28.6) 4 (50.0) 1 (12.5) 5 (50.0) 2 (20.0) 2 (25.0) 1 (12.5) 25 (49.0) 8 (15.7) Gastro- intestinal Nausea C 4 (57.1) - 15 (68.2) 1 (4.5) 10 (71.4) 1 (7.1) 5 (62.5) - 16 (59.3) 2 (7.4) 40 (62.5) 3 (4.7) I 7 (36.8) 1 (5.3) 6 (42.9) – 3 (37.5) - 5 (50.0) – 4 (50.0) 1 (12.5) 22 (43.1) 2 (3.9) Vomiting C 3 (42.9) 1 (14.3) 8 (36.4) – 6 (42.9) - 1 (12.5) – 11 (40.7) 2 (7.4) 23 (35.9) 3 (4.7) I 2 (10.5) 1 (5.3) 2 (14.3) – 2 (25.0) - 1 (10.0) – 4 (50.0) 1 (12.5) 9 (17.6) 2 (3.9) Diarrhea C 4 (57.1) 1 (14.3) 4 (18.2) – 1 (7.1) - 1 (12.5) – 8 (29.6) – 17 (26.6) 1 (1.6) I 6 (31.6) 1 (5.3) 5 (35.7) – 3 (37.5) - 6 (60.0) – 2 (25.0) – 19 (37.3) 1 (2.0) Other Fatigue C 6 (85.7) 1 (14.3) 8 (36.4) – 3 (21.4) - 3 (37.5) 1 (12.5) 8 (29.6) 3 (11.1) 25 (39.1) 5 (7.8) I 8 (42.1) 2 (10.5) 5 (35.7) 1 (7.1) 4 (50.0) - 6 (60.0) 2 (20.0) 2 (25.0) – 21 (41.2) 5 (9.8) Abbreviations: C, Continuous azenosertib dosing; I, Intermittent azenosertib dosing; MTD, maximum tolerated dose; PLD, pegylated liposomal doxorubicin. *All doses were at or below the MTD **A MTD for Gemcitabine + Azenosertib has not been determined, further dose cohorts are ongoing. Table 3: Clinical Activity of Azenosertib Doublets Endpoint Azenosertib + Paclitaxel (N=26) Azenosertib + Carboplatin (N=36) Azenosertib + Gemcitabine (N=18) Azenosertib + PLD (N=35) Total (N=115) Response-Evaluable (N) 22 28 13 31 94 ORR (confirmed), N (%) 11 (50.0) 10 (35.7) 5 (38.5) 6 (19.4) 32 (34.0) Median DOR (95% CI) in months 5.6 (3.8-NE) 11.4 (8.3-NE) 6.2 (NE) 7.3 (1.5-NE) 8.3 (5.6-12.4) Clinical Benefit Rate (CR + PR + SD for ≥ 16 weeks), N (%) 18 (81.8) 16 (57.1) 6 (46.2) 24 (77.4) 64 (68.1) Median PFS (95% CI) in months 7.4 (5.5-NE) 10.4 (3.3-14.5) 8.3 (3.3-NE) 6.3 (3.7-11.0) 9.0 (5.8-13.7) Response evaluable subjects are treated subjects with baseline measurable disease per RECIST version 1.1 and at least one post-baseline assessment. All objective responses were confirmed per RECIST v 1.1. Abbreviations: CR, complete response; DOR, duration of response; NE, non-evaluable; ORR, objective response rate; PFS, progression-free survival; PLD, pegylated liposomal doxorubicin; PR, partial response; SD, stable disease. Figure 5: Waterfall Plots Abbreviations: CR, complete response; NE, non-evaluable; PD, progressive disease; PR, partial response; SD, stable disease; uCR, unconfirmed complete response; uPR, unconfirmed partial response. Figure 6: Kaplan-Meier Curves of Progression-Free Survival Abbreviations: PLD, pegylated liposomal doxorubicin 0 0.0 0.2 0.4 0.6 0.8 1.0 5 10 15 20 25 Time (months) Patients at risk Pr og re ss io n- Fr ee S ur vi va l Pr ob ab ili ty 35 36 26 18 18 8 11 4 7 4 1 1 4 1 0 0 0 1 Median (months) Azenosertib combined with Paclitaxel PLD Carboplatin Gemcitabine 6.28 PLD (N=35) Paclitaxel (N=26) 7.36 Gemcitabine (N=18) 8.31 Carboplatin (N=36) 10.35 Figure 7: Cyclin E1 Immunohistochemistry (IHC) *H-scores calculated by using the percentage of cells (0 to 100%) with intensity of Cyclin E1 expression (0 to 3) Table 4: Objective Responses by Cyclin E1 IHC-Status Endpoints Azenosertib + Paclitaxel Azenosertib + Carboplatin Azenosertib + Gemcitabine Azenosertib + PLD Total Response Evaluable with IHC (N) * 19 22 13 28 82 Overall Response Rate, n (%) 10 (52.6) 8 (36.4) 5 (38.5) 6 (21.4) 29 (35.4) Response Evaluable IHC H-Score >50 (N) 19 18 11 22 70 Overall Response Rate, n (%) 10 (52.6) 8 (44.4) 5 (45.5) 5 (22.7) 28 (40.0) Response Evaluable IHC H-Score ≤50 (N) 0 4 2 6 12 Overall Response Rate, n (%) NA 0 0 1 (16.7) 1 (8.3) Response evaluable subjects are treated subjects with baseline measurable disease per RECIST version 1.1 and at least one post-baseline assessment. The ORRs for subjects with available IHC data appear to be consistent across cohorts with the overall population.Abbreviations: IHC, immunohistochemistry; PLD, pegylated liposomal doxorubicin. Figure 8: Kaplan-Meier Curve of Progression-Free Survival by Cyclin E1 IHC-Status Abbreviations: CI, confidence interval; IHC, immunohistochemistry 0 0.0 0.2 0.4 0.6 0.8 5 10 15 20 25 1.0 Time (months) Patients at risk Su rv iv al P ro ba bi lit y 78 12 36 2 12 1 4 1 1 0 Median (months) 3.25 IHC ≤50 (N=12) IHC >50 IHC ≤50 IHC >50 (N=78) 9.86 Hazard Ratio (95% CI) 0.37 (0.18 – 0.79) Log-rank p-value 0.0078 Figure 9: Proposed Randomized Phase 3 Trial Design of Azenosertib + Chemo- therapy in Cyclin E1+ Recurrent Platinum-Sensitive Ovarian Cancer *Paclitaxel or Carboplatin **Paclitaxel or Pegylated Liposomal Doxorubicin ***Azenosertib, 400 mg QD 5:2 Abbreviations: 5:2, 5-days of treatment followed by 2-days off treatment; BICR, blinded independent central review; ECOG, Eastern Cooperative Oncology Group; PARPi, PARP-inhibitor. Azenosertib + Paclitaxel 200 mg QD 5:2 2 dose levels 300 mg QD 5:2 Azenosertib + Gemcitabine Azenosertib + PLD 200 mg QD 3 dose levels Cohort assignment by availability and investigator preference Paclitaxel: 80 mg/m2 on D1, D8, D15 (28-day cycles) Objectives Azenosertib + Carboplatin 300 mg QD Gemcitabine : D1, D8 (21-day cycles) 4 dose levels 200 mg QD 5:2 Carboplatin: AUC 5 mg/mL*min on D1 (21-day cycles) G: 1000 mg/m2 A: 200 mg QD 3 dose levels G: 600 mg/m2 A: 200 mg QD 5:2 400 mg QD 5:2 PLD: 40 mg/m2 D1 (28-day cycles) Dose Finding guided by a CRM Key Eligibility: High-Grade Serous Ovarian Cancer; ECOG performance status 0-2; Platinum-resistant/refractory; Up to 3 prior lines of chemotherapy; Measurable disease per RECIST v 1.1 Primary: Safety and Tolerability MTD and/or RP2D Key Secondary: Clinical Activity (Endpoints: ORR, DOR, PFS, CA125) NCT number- NCT04516447 ACKNOWLEDGMENTS We are grateful to all the patients, their families, and the Investigators that participated in this study. We would also like to thank the GOG for extraordinary development and operational support for this study. -100 -80 -60 -40 -20 0 200^ 200 200 250^ 250^ + Study treatment ongoing. ^intermittent dosing. uPR+: unconfirmed PR, subject ongoing without PD. + Study treatment ongoing. ^intermittent dosing. uPR+: unconfirmed PR, subject ongoing without PD. 200^ 300^, + 300^, + 200 200 200 300^, + 300^, + 300^, + 250^ 200 250^ 200^ 250^, + 250^ 250 200 250 200 200 200 250^ 250^250^, +300 200 300 300 200 200 200 200 200 250 200 250, + 250^, + 250 250, + 250^, + 200250, + 250^, + 300^ PR PD PR PD 200 20 40 60 M ax im um C ha ng e (% ) i n Su m o f T ar ge t L es io n Di am et er s M ax im um C ha ng e (% ) i n Su m o f T ar ge t L es io n Di am et er s 100 A) Azenosertib + Paclitaxel B) Azenosertib + Carboplatin -100 -80 -60 -40 -20 0 20 40 60 8080 100 -100 -80 -60 -40 -20 0 + Study treatment ongoing. ^intermittent dosing. uPR+: unconfirmed PR, subject ongoing without PD. PR PD20 40 60 M ax im um C ha ng e (% ) i n Su m o f T ar ge t L es io n Di am et er s 100 80 C) Azenosertib + Gemcitabine 200 200 200 200^ 200 200^ 200, + 200, + 200, + 200^, + 200 200 200^ PD SD uPR+ PR uCRBest Overall Response PD SD uPR+ PR uCRBest Overall Response PD SD uPR+ PR uCRBest Overall Response ≤ 50≤ 150 to > 50> 150H-Score* 005 61525CCNE1 Not Amplified 62116Tissue Not Evaluated for Amplification • Anti-Cyclin E1 mouse monoclonal antibody (Abcam CCNE1/2460) • H-score > 50 includes all CCNE1 amplified tumors • Prevalence of Cyclin E1-IHC positive, H-score ≥ 50 in this data set is 94% CCNE1 Amplified 0 Patients Amplified CCNE1 Status Not amplified Not evaluated for amplification100 200 Cy cl in E 1 IH C H- Sc or e 300 • Anti-Cyclin E1 ouse monoclonal antibody (Abcam CCNE1/2460) • H-score > 50 includes all CCNE1 ampli ed tumors • Prevalence of Cyclin E1-IHC positive, H-score > 50 in this data set is 87% Key Eligibility: High-Grade Serous Ovarian Cancer; ECOG performance status 0-1; ≥1L Prior Line of Platinum-based chemotherapy; Platinum-Sensitive (Platinum-free interval ≥ 6 months); Prior Bevacizumab & PARPi if eligible and per regional standard of care; Cyclin E1+ (either CCNE1 amplified and/or Cyclin E1 IHC-Positive) Physician’s Choice Carboplatin- Doublet** (6 cycles) Endpoints Primary Progression-Free Survival by BICR No Maintenance Stratification Factors • Prior lines of therapy (1 v 2- 3) • Prior PARPi (Yes v No) • CCNE1 amplification (Yes v No) Azenosertib + Chemotherapy* ( 6 cycles) Azenosertib*** Maintenance Key Secondary Overall Survival R 2:1