A Biomarker Study of the Wee1 inhibitor Azenosertib (ZN-c3) in women with recurrent or persistent uterine serous carcinoma

This research study is being done to investigate how Azenosertib affects tumor cells of
persistent or recurrent uterine serous carcinoma.

The name of the study drug involved in this study is:

-Azenosertib (a type of Wee1 inhibitor)

Inclusion Criteria:

- Participants must have histologically or cytologically confirmed recurrent or
persistent uterine serous carcinoma. For the purposes of this study, uterine
carcinomas (with the exception of carcinosarcomas) that have any component that is
considered serous will be considered a uterine serous carcinoma.

- Participants must have measurable disease, defined as at least one lesion that can
be accurately measured per RECIST 1.1 criteria. See Section 12 for the evaluation of
measurable disease.

- Participants must have had one prior platinum-based chemotherapy regimen for
management of advanced or metastatic uterine serous carcinoma. Participants with
early stage disease who received adjuvant platinum-based chemotherapy are also
eligible if they recur within 12 months of their adjuvant therapy. Chemotherapy
administered only in conjunction with primary RT as a radiosensitizer should not
count as a systemic regimen. There is no restriction on the number of prior lines of
therapy a participant may have previously received. Additionally, participants must
have a known tumor MSI or MMR status and those participants with MSI-high or
MMR-deficient tumors must have already received prior therapy with a PD1 or PD-L1
immune checkpoint inhibitor or be deemed not to be a candidate for immune checkpoint
therapy.

- Age 18 years or older. Because no dosing or adverse event data are currently
available on the use of azenosertib in participants <18 years of age, children are
excluded from this study.

- ECOG performance status 0, 1, or 2 (see Appendix A)

- Participants must meet the following organ and marrow function as defined below:

- absolute neutrophil count ≥1500/mcL

- hemoglobin ≥9 g/dL (must be at least 2 weeks since any blood transfusion)

- platelets ≥100,000/mcL

- total bilirubin ≤ institutional upper limit of normal (ULN) or

≤1.5x ULN in patients with liver metastases or well-documented Gilbert's
Syndrome

- AST(SGOT)/ALT(SGPT) ≤3 × institutional ULN or ≤5 × institutional ULN in
patients with liver metastases

- creatinine ≤ 1.5x institutional ULN or estimated CrCl≥ 60 mL/min

- Willingness to release archival tissue for research purposes.

- Biopsiable disease in a lesion that is not being utilized as the target lesion for
RECIST assessment and willing to undergo pre- and on-treatment biopsies.

- HIV-infected participants on effective anti-retroviral therapy with undetectable
viral load within 6 months are eligible for this trial. However, participants who
are on antiretroviral therapy that includes strong inhibitors or inducers of CYP3A4
are not eligible, given the potential for interaction with azenosertib, which is a
CYP3A4 substrate.

- Participants with treated brain metastases are eligible if follow-up brain imaging
after CNS-directed therapy shows no evidence of progression. Participants with new
or progressive brain metastases (active brain metastases) are eligible only if the
treating physician determines that immediate CNS-specific treatment is not required
and is unlikely to be required during the first two cycles of therapy. Participants
with known leptomeningeal disease are not eligible.

- Participants with a prior or concurrent malignancy whose natural history or
treatment does not have the potential to interfere with the safety or efficacy
assessment of the investigational regimen are eligible for this trial.

- The effects of azenosertib on the developing human fetus are unknown. For this
reason, women of child-bearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to
study entry and for the duration of study participation. Should a woman become
pregnant or suspect she is pregnant while she or her partner is participating in
this study, she should inform her treating physician immediately.

- Ability to understand and the willingness to sign a written informed consent
document.

Exclusion Criteria:

- Participants who have had chemotherapy, radiotherapy, or investigational therapy
within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to first dose of
azenosertib. Participants may not have had hormonal therapy within 2 weeks of the
first dose of azenosertib.

- Participants who have not recovered from adverse events due to prior anti-cancer
therapy administered more than 3 weeks before first dose of azenosertib (e.g.,.,
have residual toxicities > Grade 1) with the exception of alopecia.

- Participants who are receiving any other investigational agents for this condition.

- Participants may not have had prior receipt of a cell cycle checkpoint inhibitor
(e.g., Chek1, Wee1, or ATR inhibition)

- History of allergic reactions attributed to compounds of similar chemical or
biologic composition to azenosertib.

- Participants receiving any medications or substances that are strong inhibitors or
inducers of CYP3A4 are ineligible. Because the lists of these agents are constantly
changing, it is important to regularly consult a frequently-updated medical
reference. As part of the enrollment/informed consent procedures, the participant
will be counseled on the risk of interactions with other agents, and what to do if
new medications need to be prescribed or if the participant is considering a new
over-the-counter medicine.

- Pregnant women are excluded from this study because azenosertib is an DNA damage
repair pathway agent with the potential for teratogenic or abortifacient effects.
Because there is an unknown but potential risk for adverse events in nursing infants
secondary to treatment of the mother with azenosertib, breastfeeding should be
discontinued if the mother is treated with azenosertib.

--Women of childbearing potential (WoCBP) may be included only if acceptable
contraception (see Appendix C) is in place for two weeks before study entry, for the
duration of the treatment with the study drug and for 5x half-lives of ZN-c3 + 6
months after the last dose of ZN-c3. Sexually active female subjects of childbearing
potential must agree to use protocol-recommended method of contraception from the
start of the screening period until 6 months after the last dose of study drug
ZN-c3.

- Participants must not have undergone major surgical procedures within 28 days of
beginning study treatment or minor surgical procedures within 7 days of beginning
study treatment. Port-a-cath placement will be allowed within a 7 day window of
starting study treatment.

- Participants must be able to swallow oral medication and may not have refractory
nausea and vomiting, have a percutaneous endoscopic gastrostomy (PEG) tube, be
receiving total parenteral nutrition (TPN), or be dependent on IV fluid support.

- Because the composition, PK, and metabolism of many herbal supplements are unknown,
the concurrent use of all herbal supplements is prohibited during the study
(including, but not limited to, cannabis, St. John's wort, kava, ephedra [ma huang],
ginkgo biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, and ginseng).
Participants should stop herbal medications at least 7 days prior to first dose of
azenosertib.

- Patients with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
function using the New York Heart Association Functional Classification. To be
eligible for this trial, patients should be class 2B or better.