Brief Title
ZN-c3 for the Treatment of Metastatic Triple-Negative Breast Cancer and Advanced Ovarian Cancer
Official Title
An Early Phase I Study of the Pharmacodynamics of WEE1 Inhibitor, ZN-c3, in Metastatic Solid Tumors
Brief Summary
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.
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 Phase
Early Phase 1
Study Type
Interventional
Primary Outcome
Percent decrease of phosphorylated CDK1 and/or Ki67, or p-HH3, or p-CHK1 in tumor cells
Secondary Outcome
Clinical benefit rate (CBR)
Condition
Advanced Fallopian Tube Carcinoma
Intervention
Wee1 Inhibitor ZN-c3
Study Arms / Comparison Groups
Treatment (wee1 inhibitor ZN-c3)
Description: 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.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
14
Start Date
July 30, 2023
Completion Date
July 31, 2025
Primary Completion Date
September 30, 2024
Eligibility Criteria
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
Gender
All
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Evthokia Hobbs, M.D., ,
Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT05368506
Organization ID
STUDY00022229
Secondary IDs
NCI-2022-03599
Responsible Party
Principal Investigator
Study Sponsor
OHSU Knight Cancer Institute
Collaborators
Oregon Health and Science University
Study Sponsor
Evthokia Hobbs, M.D., Principal Investigator, OHSU Knight Cancer Institute
Verification Date
January 2023