Selumetinib Sulfate in Treating Woman With Recurrent Low-Grade Ovarian Cancer or Peritoneum Cancer

PRIMARY OBJECTIVES:

I. To examine the tumor response rate of patients on AZD6244 (selumetinib sulfate) (NSC
#748727).

II. To examine the acute toxicity of AZD6244 (NSC #748727) during the first course of
treatment using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

III. To define the pharmacokinetic profile for AZD6244, 100 mg administered orally twice
daily.

SECONDARY OBJECTIVES:

I. To examine the toxicity of AZD6244 (NSC #748727) using the 21 major categories of the
CTCAE version 3.0.

II. To examine the dose and number of courses of AZD6244 (NSC #748727) given. III. To
estimate the progression free survival, and overall survival of women receiving AZD6244 (NSC
#748727).

TRANSLATIONAL RESEARCH OBJECTIVES:

I. To examine deoxyribonucleic acid (DNA) isolation with sequencing of braf, and ras mutation
analysis and to explore their relationship with tumor response with AZD6244 (NSC #748727).

II. To examine protein levels of phosphorylated (p)-ERK/ERKERK) and explore their
relationship with tumor response in patients treated with AZD6244 (NSC #748727).

OUTLINE:

Patients receive selumetinib sulfate orally (PO) twice a day (BID) on days 1-28. Cycles
repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients undergo blood sample collection periodically for correlative and pharmacokinetic
studies and to analyze selumetinib sulfate peak concentrations and the corresponding peak
time values. Previously collected archived tumor tissue samples are obtained to determine
protein levels of p-ERK/ERKERK, DNA isolation and sequencing of BRAF and ras mutation
analysis by immunohistochemistry (IHC).

After completion of study treatment, patients are followed every 3 months for 2 years, every
6 months for 3 years, and then once a year for 5 years.

Inclusion Criteria:

- Patients age greater than 18 with the following tumors are included in the study:

- Patients initially diagnosed with low-grade serous ovarian or peritoneal
carcinoma that recur as low grade serous carcinoma (invasive micropapillary
serous carcinoma or invasive grade I serous carcinomas as defined by Gynecologic
Oncology Group [GOG], International Federation of Gynecology and Obstetrics
[FIGO] World Health Organization [WHO] or Silverberg)

- Patients initially diagnosed with serous borderline ovarian or peritoneal
carcinoma that recur as low grade serous carcinoma (invasive micropapillary
serous carcinoma or invasive grade I serous carcinomas as defined by GOG, FIGO
WHO or Silverberg)

- Measurable disease defined as at least one lesion that can be accurately measured in
at least one dimension (longest dimension to be recorded); each "target" lesion must
be >= 20 mm when measured by conventional techniques, including palpation, plain
x-ray, computed tomography (CT), and magnetic resonance imaging (MRI), or >= 10 mm
when measured by spiral CT

- Patient must have documented low grade serous carcinoma (invasive micropapillary
serous); confirmation must occur before patient is considered eligible for the trial

- Patients whose primary tumor was low-grade serous ovarian or peritoneal carcinoma
must have a pretreatment sample of their tumor from their primary or recurrent
tumor that documents low grade serous carcinoma (invasive micropapillary serous)

- Patients whose primary tumor was serous borderline ovarian or peritoneal
carcinoma must have a pretreatment sample of their tumor from their recurrent
tumor that documents low grade serous carcinoma (invasive micropapillary serous)

- Creatinine CTCAE grade 0-1 (< 1.5 x upper limit of normal [ULN])

- Bilirubin CTCAE grade 0-1 (< 1.5 x ULN)

- Transaminases CTCAE grade 0-1 (< 2.5 x ULN)

- Neutrophil CTCAE grade 0-1 (>= 1500/mcl)

- Platelets CTCAE grade 0-1 (>= 100,000/mcl)

- Neuropathy =< CTCAE grade 1

- No restrictions on prior therapy; patients cannot have previously received AZD6244

- Patients of childbearing potential must have a negative pregnancy test and must agree
to practice an effective means of birth control prior to study entry, for the duration
of study participation, and for four weeks after dosing with AZD6244 ceases

- Patients who have met the pre-entry requirements

- Patients must have signed an approved informed consent and authorization permitting
release of personal health information

- Patients must have a GOG performance status of 0 or 1

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier

- Patients may not be receiving any other investigational agents

- Patients with known brain metastases should be excluded from this clinical trial

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to AZD6244 or its excipient Captisol

- Previous mitogen-activated protein kinase (MEK) inhibitor use

- Patients with corrected QT (QTc) interval > 450 msecs or other factors that increase
the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia,
family history of long QT interval syndrome) including heart failure that meets New
York Heart Association (NYHA) class III and IV definitions are excluded

- Required use of a concomitant medication that can prolong the QT interval

- Patients should not receive any drugs known to affect or with the potential to affect
selected CYP450 isoenzymes

- Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g. inflammatory
bowel disease), or significant bowel resection that would preclude adequate absorption

- 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 women are excluded from this study because the effects of AZD6244 on the
developing human fetus at the recommended therapeutic dose are unknown; because there
is an unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother, breastfeeding should be discontinued if the mother is treated
with AZD6244

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible because of the potential for pharmacokinetic interactions with
AZD6244; appropriate studies will be undertaken in patients receiving combination
antiretroviral therapy when indicated