Cediranib Maleate in Treating Patients With Recurrent or Persistent Endometrial Cancer

PRIMARY OBJECTIVES:

I. To assess the activity of cediranib (cediranib maleate) in patients with either
persistent or recurrent endometrial carcinoma.

II. To determine the frequency and degree of toxicity of cediranib as assessed by the Common
Terminology Criteria for Adverse Events (CTCAE) version (v.)4.0 in this cohort of patients.

SECONDARY OBJECTIVES:

I. To determine the duration of progression-free survival and overall survival. II. To
estimate the probability of response without restriction on the duration of response
documentation since study enrollment.

TERTIARY OBJECTIVES:

I. To determine if the response to cediranib correlates with high-expression of its receptor
targets (e.g., vascular endothelial growth factor receptor [VEGFR] [1, 2, 3] and platelet
derived growth factor receptor [PDGFR]).

II. To determine if the response to cediranib correlates with high endogenous circulating
plasma levels of VEGFA, low-levels of its endogenous inhibitor, soluble fms-related tyrosine
kinase 3 (sFlt-1) (the truncated, circulating portion of VEGFR-1), or circulating tissue
factor (TF) or circulating prostate apoptosis response-4 (Par-4), both potential markers of
tumor progression.

III. To determine if a high-expression of VEGFA on pre-treatment tumor specimens correlates
with response to cediranib.

IV. To determine if expression of phosphorylated mitogen activated protein kinase (ERK) 1
and 2, c-Jun, signal transducer and activator of transcription 3 (Stat3), protein kinase C
(PKC), and phosphorylated ribosomal protein S6 (p70S6) kinase correlates with resistance or
sensitivity to cediranib.

OUTLINE:

Patients receive cediranib maleate orally (PO) daily. Courses repeat every 28 days in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and
then every 6 months for 3 years.

Inclusion Criteria:

- Patients must have recurrent or persistent endometrial carcinoma, which is refractory
to curative therapy or established treatments; histologic confirmation of the
original primary tumor is required

- Patients with the following histologic epithelial cell types are eligible:
endometrioid adenocarcinoma, serous adenocarcinoma, undifferentiated carcinoma,
clear cell adenocarcinoma, mixed epithelial carcinoma, adenocarcinoma not
otherwise specified (N.O.S.), mucinous adenocarcinoma, squamous cell carcinoma,
and transitional cell carcinoma

- All patients must have measurable disease; measurable disease is defined by Response
Evaluation Criteria in Solid Tumors (RECIST) (version 1.1); measurable disease is
defined as at least one lesion that can be accurately measured in at least one
dimension (longest diameter to be recorded); each lesion must be >= 10 mm when
measured by computed tomography (CT), magnetic resonance imaging (MRI) or caliper
measurement by clinical exam; or >= 20 mm when measured by chest x-ray; lymph nodes
must be >= 15 mm in short axis when measured by CT or MRI

- Patients must have at least one "target lesion" to be used to assess response on this
protocol as defined by RECIST version 1.1; tumors within a previously irradiated
field will be designated as "non-target" lesions unless progression is documented or
a biopsy is obtained to confirm persistence at least 90 days following completion of
radiation therapy

- Patients must not be eligible for a higher priority Gynecologic Oncology Group (GOG)
protocol, if one exists; in general, this would refer to any active GOG Phase III
protocol or Rare Tumor protocol for the same patient population

- Patients who have received one prior regimen must have a GOG performance status of 0,
1, or 2; patients who have received two prior regimens must have a GOG performance
status of 0 or 1

- Recovery from effects of recent surgery, radiotherapy, or chemotherapy

- Patients should be free of active infection requiring antibiotics (with the
exception of uncomplicated urinary tract infection [UTI])

- Any hormonal therapy directed at the malignant tumor must be discontinued at
least one week prior to registration

- Any other prior therapy directed at the malignant tumor must be discontinued at
least three weeks prior to registration

- Patients must have had one prior chemotherapeutic regimen for management of
endometrial carcinoma; initial treatment may include chemotherapy, chemotherapy and
radiation therapy, and/or consolidation/maintenance therapy; chemotherapy
administered in conjunction with primary radiation as a radio-sensitizer WILL be
counted as a systemic chemotherapy regimen

- Patients are allowed to receive, but are not required to receive, one additional
cytotoxic regimen for management of recurrent or persistent disease according to the
following definition: cytotoxic regimens include any agent that targets the genetic
and/or mitotic apparatus of dividing cells, resulting in dose-limiting toxicity to
the bone marrow and/or gastrointestinal mucosa

- Note: Patients on this non-cytotoxic study are allowed to receive one additional
cytotoxic chemotherapy regimen for management of recurrent or persistent
disease, as defined above; however, due to the novel nature of biologic
compounds, patients are encouraged to enroll on second-line non-cytotoxic
studies prior to receiving additional cytotoxic therapy

- Patients must have NOT received any non-cytotoxic chemotherapy for management of
recurrent or persistent disease; prior hormonal therapy is allowed

- Absolute neutrophil count (ANC) greater than or equal to 1,500/mcl

- Platelets greater than or equal to 100,000/mcl

- Creatinine less than or equal to 1.5 x institutional upper limit normal (ULN) or
creatinine (Cr) clearance >= 60 ml/min

- Bilirubin less than or equal to 1.5 x upper limit of normal (ULN)

- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST])
less than or equal to 2.5 x ULN

- Alkaline phosphatase less than or equal to 2.5 x ULN

- Neuropathy (sensory and motor) less than or equal to grade 1

- Urine protein creatinine (UPC) ratio must be < 1.0 gm

- If UPC ratio >= 1, collection of 24-hour urine measurement of urine protein is
recommended

- Prothrombin time (PT) such that international normalized ratio (INR) is =< 1.5 x ULN
(or an in-range INR, usually between 2 and 3, if a patient is on a stable dose of
therapeutic warfarin) and a partial thromboplastin time (PTT) =< 1.5 x ULN

- Patients must have an amylase and lipase =< ULN

- Patients must have a thyroid stimulating hormone (TSH) level and a free thyroxine
(free T4) level within the institutional normal limits

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

- Patients must meet pre-entry requirements as specified

- Patients of childbearing potential must have a negative serum pregnancy test prior to
the study entry and be practicing an effective form of contraception

Exclusion Criteria:

- Patients who have had prior therapy with cediranib (AZD 2171) or other VEGF
pathway-targeted therapy

- Patient with a history of other invasive malignancies, with the exception of
non-melanoma skin cancer and other specific malignancies as noted, are excluded if
there is any evidence of other malignancy being present within the last three years;
patients are also excluded if their previous cancer treatment contraindicates this
protocol therapy

- Patients who have received prior radiotherapy to any portion of the abdominal cavity
or pelvis OTHER THAN for the treatment of endometrial cancer within the last three
years are excluded; prior radiation for localized cancer of the breast, head and
neck, or skin is permitted, provided that it was completed more than three years
prior to registration, and the patient remains free of recurrent or metastatic
disease

- Patients who have received prior chemotherapy for any abdominal or pelvic tumor OTHER
THAN for the treatment of endometrial cancer within the last three years are
excluded; patients may have received prior adjuvant chemotherapy for localized breast
cancer, provided that it was completed more than three years prior to registration,
and that the patient remains free of recurrent or metastatic disease

- Patients with serious, non-healing wound, ulcer, or bone fracture; this includes
history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess
within 28 days prior to the first date of cediranib (AZD 2171) therapy

- Patients with active bleeding or pathologic conditions that carry high risk of
bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major
vessels

- Patients with history or evidence upon physical examination of central nervous system
(CNS) disease, including primary brain tumor, seizures not controlled with standard
medical therapy or any brain metastases

- Patients with clinically significant cardiovascular disease; this includes:

- Uncontrolled hypertension defined as systolic > 150 mmHg or diastolic > 100 mmHg
despite optimized antihypertensive therapy

- Myocardial infarction or unstable angina within 6 months of the first date of
cediranib (AZD 2171) therapy

- New York Heart Association (NYHA) grade II or greater congestive heart failure
or serious cardiac arrhythmia requiring medication; women who have received
prior treatment with an anthracycline (including doxorubicin and/or liposomal
doxorubicin) and have an ejection fraction < institutional lower limit of normal
(LLN) will be excluded from the study

- CTCAE grade 2 or greater peripheral vascular disease

- History of cerebrovascular accident (CVA, stroke), transient ischemic attack
(TIA) or subarachnoid hemorrhage within six months of the first date of
cediranib (AZD 2171) therapy

- Mean corrected QT interval (QTc) > 500 msec or history of familial long QT
syndrome

- Patients with known hypersensitivity to Chinese hamster ovary cell products or other
recombinant human or humanized antibodies

- Patients undergoing invasive procedures as defined below:

- Major surgical procedure, open biopsy or significant traumatic injury within 28
days prior to the first date of cediranib (AZD 2171) therapy

- Major surgical procedure anticipated during the course of the study

- Minor surgical procedures, fine needle aspirates, or core biopsies within 7 days
prior to the first date of cediranib (AZD2171) therapy

- Patients who are pregnant or nursing