A Phase 2 Study of the Wee1 inhibitor Adavosertib (AZD1775) in women with recurrent or persistent uterine serous carcinoma or uterine carcinosarcoma

Protocol # :
Uterine Cancer
Disease Sites
Corpus Uteri
Principal Investigator
Liu, Joyce, F
Site Investigator
Castro, Cesar, Martin
Penson, Richard, Thomas
Site Research Nurses
Belavusava, Vera
Bowes, Brittany, N.
Doherty, Kelsie
Hindenach, Sarah
Hurley-Whalen, Christin
Keis, Rylee
Morrissey, Stephanie, C.
Neals, Allison
Thistle, Katrina, M.

Trial Description

This research study is studying an investigational drug as a possible treatment for uterine

The drug involved in this study is:


Eligibility Requirements

Inclusion Criteria:

- Participants in Parts A and C 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 in Part B must have histologically or cytologically confirmed recurrent
uterine carcinosarcoma. Additionally, the following features must also be present:

- Presence of a p53 alteration (by either IHC or next generation sequencing)

- Metastatic or extra-uterine component must be confirmed on pathology to be from
the carcinoma component of the disease

- Patients without confirmation that the metastatic or extrauterine component of
disease is of carcinoma histology may be considered after discussion with the PI

- Participants must have measurable disease, defined as at least one lesion that can be
accurately measured per RECIST 1.1 criteria. See Section 11 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 or uterine
carcinosarcoma. 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.

- Age 18 years or older.

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

- Participants must have normal organ and marrow function as defined below:

- absolute neutrophil count ≥1,500/mcL

- hemoglobin ≥9 g/dL

- platelets ≥100,000/mcL

- total bilirubin ≤ 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 × ULN or ≤5 × ULN in patients with liver metastases

- creatinine ≤1.5 × ULN OR

- creatinine clearance ≥45 mL/min/1.73 m2 as calculated by the Cockroft-Gault
method for participants with creatinine levels above institutional normal.

- Willingness to release archival tissue for research purposes.

- Participants in Part C must have biopsiable disease (in a lesion that is not being
utilized as the target lesion for RECIST assessment) and be willing to undergo pre-
and on-treatment biopsies. Participants in Part B with biopsiable disease must be
willing to undergo pre- and on-treatment biopsies.

- The effects of AZD1775 on the developing human fetus are unknown. For this reason,
women of child-bearing potential must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) from 2 weeks prior to study entry and for
1 month after study drug discontinuation. Please see Appendix C for "Definition Women
of Childbearing Potential and Acceptable Contraceptive Methods." Patients of
child-bearing potential should not be breastfeeding, and must have a negative serum or
urine pregnancy test within 3 days prior to the start of study treatment. Should a
woman become pregnant or suspect she is pregnant while she 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
AZD1775, or those who have not recovered to Grade 1 from adverse events (excluding
alopecia or anorexia) due to agents administered more than 3 weeks earlier.
Participants may not have had hormonal therapy within 2 weeks of the first dose of

- Participants who are receiving any other investigational agents.

- Participants who have MSI-high or MMR-deficient tumors will not be eligible unless
they have already received prior therapy with pembrolizumab or another PD1/PD-L1
immune checkpoint inhibitor or are deemed not to be a candidate for immune checkpoint

- Participants with known brain metastases or other CNS disease should be excluded from
this clinical trial because of their poor prognosis and because they often develop
progressive neurologic dysfunction that would confound the evaluation of neurologic
and other adverse events. Participants with treated brain metastases that have no
evidence of progression or hemorrhage for at least 2 weeks after treatment will be
allowed on study.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to AZD1775.

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

- Participants receiving any medications or substances that are sensitive CYP3A4
substrates or are CYP3A4 substrates with a narrow therapeutic index, or which are
moderate to strong inhibitors/inducers of CYP3A4 which cannot be discontinued two
weeks prior to Day 1 of dosing and withheld through the study until 2 weeks after the
last dose of study drug. Co-administration of aprepitant or fosaprepitant during this
study is prohibited.

- Transporter studies (in vitro) have shown that AZD1775 is an inhibitor of breast
cancer resistance protein (BRCP). Please see Appendix B for additional details
regarding prohibited drugs and drugs to be used with caution, including drugs affected
by CYP3A4 or BRCP. Because the lists of these agents are constantly changing, it is
important to also regularly consult a frequently-updated list such as
http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as
the Physicians' Desk Reference may also provide this information.

- 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 a percutaneous
endoscopic gastrostomy (PEG) tube, be receiving total parenteral nutrition (TPN), or
be dependent on IV fluid support.

- Participants with any of the following cardiac diseases currently or within the last 6
months as defined by the New York Heart Association (NYHA) ≥ Class 2 will not be

- Unstable angina pectoris

- Congestive heart failure

- Acute myocardial infarction

- Conduction abnormality not controlled with pacemaker or medication

- Significant ventricular or supraventricular arrhythmias (patients with chronic
rate-controlled atrial fibrillation in the absence of other cardiac abnormalities
are eligible).

- Participants with a mean resting corrected QT interval (QTc) ≥ 480msec at study entry,
as calculated by the Frederica formula (QTcF) by institutional standards obtained from
an electrocardiogram (ECG) or congenital long QT syndrome. (Note: if one ECG
demonstrates a QTcF >480 msec, then a mean QTcF of ≤ 480 msec obtained from 3 ECGs 2-5
minutes apart is required at study entry.

- Participants with any concomitant or prior invasive malignancies are ineligible with
the following exceptions:

- Treated limited-stage basal cell or squamous cell carcinoma of the skin

- Carcinoma in situ of the breast or cervix

- Prior cancer treated with curative intent with no evidence of recurrent disease 3
years following diagnosis and judged by the investigator to be at low risk of

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Pregnant women are excluded from this study because AZD1775 is an agent with an
unknown 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 AZD1775, breastfeeding should be discontinued if the
mother is treated with AZD1775.

- Known HIV-positive participants are ineligible because of the potential for
pharmacokinetic interactions of antiretroviral medications with AZD1775 and the
potential for an increased risk of lethal infections for these participants when
treated with marrow-suppressive therapy.

- 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 [m huang],
ginkgo biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, and ginseng).
Participants should stop herbal medications at least 7 days prior to first dose of