Adavosertib in Treating Patients With SETD2-Deficient Locally Advanced or Metastatic Solid Tumors

PRIMARY OBJECTIVES:

I. To determine the objective response rate by Response Evaluation Criteria in Solid Tumors
(RECIST) 1.1 criteria of adavosertib (AZD1775) in advanced solid tumor malignancies other
than clear cell renal cell carcinoma with evidence of biallelic loss of SETD2 using
next-generation sequencing panel.

II. To determine the objective response rate by RECIST 1.1 criteria of AZD1775 in clear cell
renal cell carcinoma with evidence of loss of SETD2 using next-generation sequencing panel.

SECONDARY OBJECTIVES:

I. To determine the clinical benefit rate and duration of response of AZD1775 in
SETD2-deficient tumors other than clear cell renal cell carcinoma.

II. To determine the clinical benefit rate and duration of response of AZD1775 in
SETD2-deficient clear cell renal cell carcinoma subgroup.

III. To characterize the safety profile of AZD1775. IV. To determine whether H3K36me3
expression by immunohistochemical assay is associated with clinical outcomes.

OUTLINE:

Patients receive adavosertib 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 30 days.

Inclusion Criteria:

- Cohort A: Histologically confirmed locally advanced or metastatic solid tumor
malignancy other than clear cell renal cell carcinoma with progression on at least one
prior systemic therapy and presence of biallelic loss of SETD2 detected in tumor
tissue detected using a Clinical Laboratory Improvement Act (CLIA)-certified next
generation sequencing panel (e.g. UCSF500, FoundationOne); biallelic loss will be
defined by one or more of the following:

- Pathogenic or likely pathogenic loss-of-function SETD2 mutation with mutant
allele frequency (MAF) > 50%

- Pathogenic or likely pathogenic loss-of-function SETD2 mutation with MAF > 2
times the MAF of other oncogenic mutations detected in the tumor sample

- Pathogenic or likely pathogenic loss-of-function SETD2 mutation with concomitant
loss of chromosome 3p

- Pathogenic or likely pathogenic loss-of-function SETD2 mutation with copy-neutral
loss of heterozygosity

- Cohort B: Patients with histologically confirmed locally advanced or metastatic clear
cell renal cell caricnoma (with clear cell component on pathology), who have been
treated with at least one prior systemic therapy for locally advanced or metastatic
disease, including either tyrosine kinase inhibitor and/or immune checkpoint
inhibitor, with evidence of SETD2 mutation on CLIA-certified next generation
sequencing panel

- All next generation sequencing (NGS) sequencing reports including information
pertaining to mutant allele frequency and chromosome 3p loss will be reviewed by
the University of California at San Francisco (UCSF) Molecular Tumor Board to
verify bi-allelic loss of SETD2

- Measurable disease by RECIST 1.1 criteria

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Hemoglobin >= 9 g/dL

- Total bilirubin within normal institutional limits (WLN) or =< 1.5 x upper limit of
normal (ULN) in patients with liver metastases; or total bilirubin =< 3 x ULN with
direct bilirubin WLN in patients with well documented Gilbert's syndrome

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =<
3.0 x institutional upper limit of normal (=< 5 x ULN if known liver metastases)

- Serum creatinine =< 1.5 x ULN, OR

- Creatinine clearance >= 45 ml/min (24 hour urine creatinine clearance or calculated by
Cockcroft-Gault equation)

- 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

- 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

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

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 study treatment, 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
enrollment; patients with known brain metastases 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

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

- 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 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)

- AZD1775 should not be given to patients who have a history of Torsades de pointes
unless all risk factors that contributed to Torsades have been corrected; AZD1775
has not been studied in patients with ventricular arrhythmias or recent
myocardial infarction

- Mean resting corrected QT (QTc) interval using the Fridericia formula (QTcF) > 450 ms
(i.e., grade 1 or higher) for males and > 470 ms for females on electrocardiogram
(ECG) prior to initiation of study treatment obtained from 3 electrocardiograms (ECGs)
obtained 2-5 minutes apart at study entry, or history of congential long QT syndrome

- If baseline QTc on screening ECG is > 450 ms for males or > 470 ms for females:

- Check potassium and magnesium serum levels

- Correct any identified hypokalemia and/or hypomagnesemia and repeat ECG to
confirm QTcF interval

- For patients with baseline heart rate (HR) < 60 bpm or > 100 bpm, manual
measurement of QT interval by cardiologist is required, with Fridericia
correction applied to that manual measurement to determine the QTc for
eligibility consideration

- Note: For patients with HR 60-100 bpm, manual measurement of QTc interval is NOT
required

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant or breastfeeding women; pregnant women are excluded from this study;
breastfeeding should be discontinued if the mother is treated with AZD1775

- Prior treatment with WEE1 inhibitor