WEE1 Inhibitor AZD1775 in Treating Patients With Advanced Refractory Solid Tumors With CCNE1 Amplification

PRIMARY OBJECTIVES:

I. To evaluate the proportion of patients with the objective response rate (ORR) to WEE1
inhibitor AZD1775 (AZD1775) in patients with advanced refractory cancers with CCNE1
amplification.

SECONDARY OBJECTIVES:

I. To evaluate the proportion of patients alive and progression free at 6 months of treatment
with AZD1775 in patients with advanced refractory cancers with CCNE1 amplification.

II. To evaluate proportion of patients with extended time to progression (time to progression
on AZD1775/ time to progression on last line of therapy >= 1.3).

III. To evaluate time until death or disease progression. IV. To identify potential
predictive biomarkers beyond the genomic alteration by which treatment is assigned or
resistance mechanisms using additional genomic, ribonucleic acid (RNA), protein and
imaging-based assessment platforms.

OUTLINE:

Patients receive WEE1 inhibitor AZD1775 orally (PO) once daily (QD) on days 1-5 and 8-12.
Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 weeks.

Inclusion Criteria:

- Patients must have one of the histologically advanced solid tumors harboring CCNE1
amplification: their diseases are refractory to, or do not have, standard-of-care
therapy; or they declined standard-of-care therapy; patients with triple negative
breast cancer or small cell lung cancer are not eligible since there is an ongoing
phase Ib study of AZD1775 as a single agent targeting these patients; CCNE1
amplification is defined in a Clinical Laboratory Improvement Amendments
(CLIA)-certified laboratory: CCNE1 amplification > 7 based on targeted custom Ampliseq
panel on the Ion Torrent PGM; or CCNE1 amplification on alternate CLIA platforms such
as Foundation One, UW-OncoPlex - Cancer Gene Panel, Memorial Sloan
Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT),
Solid Tumor Genomic Assay (Life Technologies), etc. will also be eligible to be
treated after principle investigator (PI) approval; patients with known CCNE1
amplification on local or commercial platforms can start treatment after planned
biopsy or submission of recent archival sample; central next-generation sequencing
(NGS) CCNE1 and fluorescence in situ hybridization (FISH) testing will be performed to
confirm the result

- Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version
1.1

- Has read and understands the informed consent form (ICF) and has given written ICF
prior to any study procedures

- Any prior radiation must have been completed at least 7 days prior to the start of
study drugs, and patients must have recovered from any acute adverse effects prior to
the start of study treatment

- Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1

- Absolute neutrophil count (ANC) >= 1500/uL

- Hemoglobin (HgB) >= 9 g/dL for mono-therapy

- Platelets >= 100,000/uL

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x upper limit
of normal (ULN) or =< 5 x ULN if known hepatic metastases

- Serum bilirubin within normal limits (WNL) or =< 1.5 x ULN in patients with liver
metastases; or total bilirubin =< 3.0 x ULN with direct bilirubin WNL in patients with
well documented Gilbert's syndrome

- Serum creatinine =< 1.5 x ULN, or measured creatinine clearance (CrCl) >= 45 mL/min as
calculated by the Cockcroft-Gault method or 24-hour measured urine CrCl >= 45 mL/min

- Female patients who are not of child-bearing potential and fertile females of
childbearing potential who agree to use adequate contraceptive measures from 2 weeks
prior to the study and until 1 month after study treatment discontinuation, who are
not breastfeeding, and who have a negative serum or urine pregnancy test within 3 days
prior to the start of study treatment; male patients willing to abstain or use barrier
contraception (i.e. condoms) for the duration of the study and for 3 months after
treatment stops

- Willingness and ability to comply with study and follow-up procedures

- Ability to take oral medications without medical history of malabsorption or other
chronic gastrointestinal disease, or other conditions that may hamper compliance
and/or absorption of the study agent

- No prior treatment with wee1 kinase inhibition

- Provision of an archival tissue block, or 10 formalin-fixed paraffin-embedded (FFPE)
slides, if available, and if not available having biopsiable disease and agreeing to
pre-treatment biopsies

Exclusion Criteria:

- Use of anti-cancer treatment drug =< 21 days or 5 half-lives (whichever is shorter)
prior to the first dose of AZD1775; for drugs for which 5 half-lives is =< 21 days, a
minimum of 10 days between termination of the prior treatment and administration of
AZD1775 treatment is required

- Previous radiation therapy completed =< 7 days prior to the start of study drugs

- Major surgical procedures =< 28 days of beginning AZD1775, or minor surgical
procedures =< 7 days; no waiting period required following port-a-cath or other
central venous access placement

- Grade > 1 toxicity from prior therapy (except alopecia or anorexia)

- Patient has an inability to swallow oral medications; Note: Patient may not have a
percutaneous endoscopic gastrostomy (PEG) tube or be receiving total parenteral
nutrition (TPN)

- No other anticancer-therapy (chemotherapy, immunotherapy, hormonal anti-cancer
therapy, radiotherapy [except for palliative local radiotherapy]), biological therapy
or other novel agent is to be permitted while the patient is receiving study
medication; patients on luteinizing hormone-releasing hormone (LHRH) analogue
treatment for more than 6 months are allowed entry into the study and may continue at
the discretion of the investigator

- Known malignant central nervous system (CNS) disease other than neurologically stable,
treated brain metastases - defined as metastasis having no evidence of progression or
hemorrhage for at least 2 weeks after treatment; must be off any systemic
corticosteroids for the treatment of brain metastases for at least 14 days prior to
enrolment

- Patient has had prescription or non-prescription drugs or other products known to be
sensitive to CYP3A4 substrates or CYP3A4 substrates with a narrow therapeutic index,
or to be moderate to strong inhibitors/inducers of CYP3A4 which cannot be discontinued
2 weeks prior to day 1 of dosing and withheld throughout the study until 2 weeks after
the last dose of study drug; co-administration of aprepitant or fosaprepitant during
this study is prohibited; the use of sensitive substrates of CYP3A4, such as
atorvastatin, simvastatin and lovastatin, is also prohibited in this study

- Transporter studies (in vitro) have shown that AZD1775 is an inhibitor of breast
cancer resistance protein (BCRP)

- Herbal preparations are not allowed throughout the study; these herbal medications
include but are not limited to: St. John's wort, kava, ephedra (ma hung), gingko
biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto and ginseng; patients
should stop using these herbal medications 7 days prior to first dose of study
treatment

- Any known hypersensitivity or contraindication to the components of the study drug
AZD1775

- Any of the following cardiac diseases currently or within the last 6 months as defined
by New York Heart Association (NYHA) >= class 2

- 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)

- Mean resting corrected QTc interval using the Fridericia formula (QTcF) > 450
msec/male and > 470 msec/female (as calculated per institutional standards) obtained
from 3 electrocardiograms (ECGs) 2-5 minutes apart at study entry, or congenital long
QT syndrome

- Pregnant or breastfeeding women

- Serious active infection at the time of study entry, or another serious underlying
medical condition that would impair the ability of the patient to receive study
treatment

- Symptomatic and uncontrolled metastasis in the central nervous system or
leptomeningeal or lymphangitic carcinomatosis

- Presence of other active invasive cancers that do not harbor CCNE1 amplification

- Grade 2 or higher peripheral neuropathy

- Known positive test result for human immunodeficiency virus or active hepatitis B or C
virus infection