ZN-c3 for the Treatment of Metastatic Triple-Negative Breast Cancer and Advanced Ovarian Cancer

An Early Phase I Study of the Pharmacodynamics of WEE1 Inhibitor, ZN-c3, in Metastatic Solid Tumors

This early phase I trial tests the safety and side effects of ZN-c3 in treating patients with triple-negative breast cancer or ovarian cancer that have spread to other parts of the body (metastatic or advanced). ZN-c3 is an enzyme inhibitor that may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Study Overview

• Status: Withdrawn
• Conditions: Anatomic Stage IV Breast Cancer AJCC v8; Metastatic Triple-Negative Breast Carcinoma; Stage III Fallopian Tube Cancer AJCC v8; Stage III Ovarian Cancer AJCC v8; Stage III Primary Peritoneal Cancer AJCC v8; Stage IV Fallopian Tube Cancer AJCC v8; Stage IV Ovarian Cancer AJCC v8; Stage IV Primary Peritoneal Cancer AJCC v8; Advanced Fallopian Tube Carcinoma; Advanced Ovarian Carcinoma; Advanced Primary Peritoneal Carcinoma
• Intervention / Treatment: Drug: Wee1 Inhibitor ZN-c3

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the primary pharmacodynamic effect of wee1 inhibitor ZN-c3 (ZN-c3) in tumor biopsies from patients with advanced triple-negative breast cancer (TNBC) and ovarian cancer.

II. To assess safety and tolerability of the proposed therapy.

SECONDARY OBJECTIVES:

I. To assess clinical benefit of TNBC and ovarian cancer patient from the proposed therapy.

II. To determine time to disease progression. III. To assess participant survival on study.

EXPLORATORY OBJECTIVES:

I. To evaluate ZN-c3 pharmacokinetics (PK). II. To identify predictive biomarkers of sensitivity to therapy. III. To identify emerging mechanisms of resistance to therapy.

OUTLINE:

Patients receive Wee1 inhibitor ZN-c3 orally (PO) once daily (QD) on days 1-21. Treatment repeats every 21 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for to 1 year.

• Study Type: Interventional
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Oregon
    • Portland, Oregon, United States, 97239
      • OHSU Knight Cancer Institute
      • Contact: Evthokia (Evie) Hobbs, M.D.; Phone Number: 503-494-6594; Email: hobbev@ohsu.edu
      • Principal Investigator: Evthokia Hobbs, M.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Participant must provide written informed consent before any study-specific procedures or interventions are performed
• Participants aged >= 18 years

• Participants with biopsy proven metastatic TNBC defined as:

  • Estrogen receptor (ER) < 10%, progesterone receptor (PR) < 10%
  • HER2 non-amplified by College of American Pathologists (CAP) guidelines
• Participants with biopsy proven advanced ovarian cancer (including primary peritoneal and fallopian tube cancers)
• Prior PARP inhibitor therapy allowed
• Participants must have at least one measurable site of disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 that is amendable to biopsy
• Participants must have received at least one standard of care line of therapy in the recurrent setting
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) =< 2
• Prior treatment related toxicities resolved to =< grade 1 (except neuropathy, alopecia or skin pigmentation)
• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L; excluding measurements obtained within 7 days after daily administration of filgrastim/sargramostim or within 3 weeks after administration of pegfilgrastim
• Platelet count >= 100 x 10^9/L; excluding measurements obtained within 3 days after transfusion of platelets
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 × upper limit of normal (ULN). If liver function abnormalities are due to underlying liver metastases, AST and ALT =< 5 x ULN
• Total serum bilirubin =< 1.5 x ULN or =< 3 x ULN in the case of Gilbert's disease
• Serum creatinine =< 1.5 x ULN or creatinine clearance (CrCl) >= 60 mL/min
• Participants of childbearing potential must have a negative serum beta human chorionic gonadotropin (beta-hCG) test
• Participants of childbearing potential must agree to use an effective method of contraception per institutional standard prior to the first dose and for 90 days after the last dose of ZN-c3
• Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study procedures, including pretreatment and on-treatment biopsies
• Willingness to practice adequate sun protection (use of sunscreen or sun-protective clothing or limitation of sun exposure)

Exclusion Criteria:

• Prior Wee-1 inhibitor exposure

• Any of the following treatment interventions within the specified time frame prior to cycle 1 day 1:

  • Major surgery within 28 days (the surgical incision should be fully healed prior to study drug administration)
  • Radiation therapy within 21 days; however, if the radiation portal covered =< 5% of the bone marrow reserve, the subject is eligible irrespective of the end date of radiotherapy
  • Autologous or allogeneic stem cell transplant within 3 months
  • Current use of an investigational agent that is not expected to be cleared by the first dosing of study drug or that has demonstrated to have prolonged side effects
  • Prescription, non-prescription drugs or food known as moderate to strong inducers of CYP3A within 2 weeks

• A serious illness or medical condition(s) including, but not limited to, the following:

  • Symptomatic brain metastases
  • Leptomeningeal disease that requires or is anticipated to require immediate treatment
  • Myocardial impairment of any cause (e.g., cardiomyopathy, ischemic heart disease, significant valvular dysfunction, hypertensive heart disease, and congestive heart failure) resulting in heart failure by New York Heart Association Criteria (class III or IV)
  • Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the subject inappropriate for entry into this study
  • Significant gastrointestinal abnormalities, including an inability to take oral medication, requirement for intravenous (IV) alimentation, active peptic ulcer, chronic diarrhea or vomiting considered to be clinically significant in the judgment of the Investigator, or prior surgical procedures affecting absorption
  • Active or uncontrolled infection. Subjects with an infection receiving treatment (antibiotic, antifungal or antiviral treatment) may be entered into the study but must be afebrile and hemodynamically stable for >= 72 hours
• Unresolved toxicity of grade > 1 attributed to any prior therapies (excluding grade 2 neuropathy, alopecia or skin pigmentation)
• Known hypersensitivity to any drugs similar to ZN-c3 in class
• Participants that are pregnant or lactating (including the cessation of lactation) or those of childbearing potential who have a positive serum pregnancy test within 14 days prior to cycle 1 day 1
• Participants with active (uncontrolled, metastatic) second malignancies or requiring therapy
• 12-lead electrocardiogram (ECG) demonstrating a corrected QT interval using Fridericia's formula (QTcF) of > 480 msec, except for subjects with atrioventricular pacemakers or other conditions (e.g., right bundle branch block) that render the QT measurement invalid
• Any history or current evidence of congenital long QT syndrome
• Participant requiring any medications that can lead to significant QT prolongation
• Participant requires administration of strong and moderate CYP3A4 inhibitors and inducers as well as strong and moderate P-glycoprotein (P-gp) inhibitors
• Participants with any condition that, in the opinion of the investigator, could jeopardize the participant's safety or adherence to the study protocol
• For TNBC cohort only, participants with tumors showing androgen receptor (AR) >= 80% by immunohistochemistry are excluded

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (wee1 inhibitor ZN-c3); Patients receive Wee1 inhibitor ZN-c3 PO QD on days 1-21. Treatment repeats every 21 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.	Drug: Wee1 Inhibitor ZN-c3; Given PO; Other Names: ZN c3; ZN-c3; ZNc3

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent decrease of phosphorylated CDK1 and/or Ki67, or p-HH3, or p-CHK1 in tumor cells	The point estimate of percentage decrease of either phosphorylated CDK1, or Ki67, or p-HH3, or p-CHK1, or combinations thereof in tumor cells (from baseline) after receiving ZN-c3 will be provided.	Baseline to completion of on-treatment biopsy, up to 21 days
Incidence of adverse events	Incidence of grade >= 3 toxicities will be assessed according to Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0.	Day 1 to 30 days after last dose of study intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical benefit rate (CBR)	CBR is the proportion of all participants that achieve a complete response (CR), partial response (PR) or stable disease (SD) >= 6 months without evidence of radiologic progression to this point (i.e., CR + PR + SD)(per Response Evaluation Criteria in Solid Tumors [RECIST] v 1.1).	Day 1 to end of treatment, approximately 12 months
CBR for ovarian cancer	CBR (i.e., CR + PR + SD) in the ovarian cancer cohort will also be assessed using the Gynecological Cancer Intergroup (GCIG) criteria.	Day 1 to end of treatment, approximately 12 months
Time to disease progression	Measure of the length of time from date of study treatment start until the date of cancer progression.	Day 1 to date of progression, assessed up to 1 year after discontinuing study drug
Progression free survival	Measure of the proportion of participants without disease progression starting from the time from cycle 1 day 1 dose administration to the time of documented disease progression or death from any cause.	Day 1 to date of progression or death from any cause, assessed up to 1 year after discontinuing study drug
Overall survival	Measure of the proportion of participants that are alive starting from the time from cycle 1 day 1 dose administration to the time of death from any cause.	Day 1 to death from any cause, assessed up to 1 year after discontinuing study drug

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
ZN-c3 tumor and plasma concentrations	Measure of tumor and plasma concentrations of ZN-c3.	Baseline to completion of on-treatment biopsy, up to 21 days
Cellular and molecular characteristics	Descriptive measure of molecular characteristics of patients' tumor	Baseline to end of study, up to 1 year after discontinuing study drug.

Collaborators and Investigators

• Sponsor: OHSU Knight Cancer Institute
• Collaborators: Oregon Health and Science University
• Investigators: Principal Investigator: Evthokia Hobbs, M.D., OHSU Knight Cancer Institute

Study record dates

Study Major Dates

• Study Start (Anticipated): July 30, 2023
• Primary Completion (Anticipated): September 30, 2024
• Study Completion (Anticipated): July 31, 2025

Study Registration Dates

• First Submitted: May 5, 2022
• First Submitted That Met QC Criteria: May 5, 2022
• First Posted (Actual): May 10, 2022

Study Record Updates

• Last Update Posted (Estimate): May 4, 2023
• Last Update Submitted That Met QC Criteria: May 2, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Skin Diseases; Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Peritoneal Diseases; Genital Neoplasms, Female; Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Digestive System Neoplasms; Endocrine Gland Neoplasms; Breast Diseases; Fallopian Tube Diseases; Abdominal Neoplasms; Breast Neoplasms; Carcinoma; Ovarian Neoplasms; Fallopian Tube Neoplasms; Peritoneal Neoplasms; Carcinoma, Ovarian Epithelial
• Other Study ID Numbers: STUDY00022229 (Other Identifier: OHSU Knight Cancer Institute); NCI-2022-03599 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No