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

• Progression-free survival [ Time Frame: From study entry until disease progression, death or date of last contact, up to 10 years ] [ Designated as safety issue: No ]
  Progression free survival will be estimated and graphed using the Kaplan-Meier product-limit method.
• Overall survival [ Time Frame: From entry into the study to death or the date of last contact, up to 10 years ] [ Designated as safety issue: No ]
  Overall survival will be estimated and graphed using the Kaplan-Meier product-limit method.
• Frequency and severity of adverse effects assessed by Common Terminology Criteria for Adverse Events version 3.0 [ Time Frame: Up to 10 years ] [ Designated as safety issue: Yes ]

• Progression-free survival
• Overall survival
• Toxicity as assessed by CTCAE version 3.0
• Relationship of tumor response rate with DNA isolation and sequencing of BRAF and ras mutation analysis
• Levels of BRAF and ras mutation in the tumor
• Protein levels of p-ERK/ERKERK
• Pharmacokinetic profile of AZD6244

This phase II trial is studying the side effects and how well selumetinib works in treating patients with recurrent low-grade ovarian cancer. Selumetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth

PRIMARY OBJECTIVES:

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

II. To examine the acute toxicity of AZD6244 (NSC #748727) during the first course of treatment using CTCAE version 3.0.

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).

TERTIARY OBJECTIVES:

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

OUTLINE: This is a multicenter study.

Patients receive selumetinib orally (PO) twice a day on days 1-28. Courses 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 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.

• Borderline Ovarian Surface Epithelial-stromal Tumor
• Ovarian Serous Cystadenocarcinoma
• Primary Peritoneal Cavity Cancer
• Recurrent Borderline Ovarian Surface Epithelial-stromal Tumor

• Drug: selumetinib
  Given PO
  Other Names:

  • ARRY-142886
  • AZD6244
• Genetic: mutation analysis
  Correlative studies
• Genetic: protein expression analysis
  Correlative studies
• Other: immunohistochemistry staining method
  Correlative studies
  Other Name: immunohistochemistry
• Other: pharmacological study
  Correlative studies
  Other Name: pharmacological studies

Inclusion Criteria:

• Meeting 1 of the following diagnosis:

  • Low-grade ovarian carcinoma that recurred as low-grade serous carcinoma (invasive micropapillary serous carcinoma or invasive grade I serous carcinomas as defined by GOG, FIGO WHO, or S. G. Silverberg) or peritoneal carcinoma
  • Serous borderline ovarian carcinoma that recurred as low-grade serous carcinoma (invasive micropapillary serous carcinoma or invasive grade I serous carcinomas as defined by GOG, FIGO WHO, or S. G. Silverberg) or peritoneal carcinoma
• Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques including palpation, plain x-ray, CT scan, or MRI scan, OR ≥ 10 mm by spiral CT scan
• Patients whose primary tumor was serous borderline ovarian carcinoma, low-grade serous ovarian carcinoma, 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)
• No known brain metastases
• GOG performance status 0-1
• Platelet count ≥ 100,000/mm³
• ANC count ≥ 1,500/mm³
• Bilirubin < 1.5 times upper limit of normal (ULN)
• Creatinine < 1.5 times ULN
• Transaminases < 2.5 times ULN
• Neuropathy ≤ grade 1
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception prior to, during, and for 4 weeks after completion of study therapy

• QTc interval ≤ 450 msec and no factors that increase the risk of QT prolongation or arrhythmic events including, but not limited to, any of the following:

  • Heart failure
  • Hypokalemia
  • Family history of long QT interval syndrome
  • NYHA class III-IV heart failure
• No history of allergic reactions attributed to compounds of similar chemical or biological composition to AZD6244 or its excipient Captisol
• No refractory nausea and vomiting, chronic gastrointestinal diseases (e.g., inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption
• No uncontrolled intercurrent illness including ongoing or active infection, psychiatric illness, or social situations that would limit compliance with study requirements
• More than 4 weeks since prior chemotherapy or radiotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered
• No prior AZD6244
• No prior MEK inhibitor
• No HIV-positive patients on combination antiretroviral therapy
• No concurrent medications with the potential to prolong the QT interval
• No concurrent drugs known to affect or with the potential to affect selected CYP450 isoenzymes
• No concurrent grapefruit or grapefruit juice during AZD6244 administration
• No other concurrent investigational or commercial agents for this cancer