Phase II Study of Clinical Activity of Pegaspargase in Women With Relapsed or Refractory Epithelial Ovarian Cancer, Fallopian Tube Cancer, and/or Primary Peritoneal Cancer

Background:

- The bacterial enzyme L-asparaginase (L-ASP) catalyzes hydrolysis of asparagine to
aspartate and is used to treat acute lymphoblastic leukemia (ALL).Studies demonstrated
in vitro cytotoxic activity against solid tumor types including ovarian cancer.

- Our laboratory demonstrated L-ASP inhibits vascular remodeling and modulates
heterotypic adhesion interactions between ovarian cancer cells and endothelial cells.
Results indicate L-ASP has the ability to modify the local tumor microenvironment.

- Epithelial ovarian cancer requires neovascularization for growth and metastasis.
Anti-angiogenesis agents show promise in treatment of recurrent disease.

- The pegylated form of L-ASP, pegaspargase, (Sigma Tau ONCASPAR (Trademark)) is shown to
deplete serum levels of asparagine and is approved for ALL. ONCASPAR is in clinical
trial with gemcitabine for pancreatic cancer and other solid tumors.

- Recommended dose of pegaspargase in ALL is 2,500 IU/m^2 every two weeks intramuscular
(IM)/intravenous (IV). IM dosing of 2,000 IU/m^2 every two weeks has been studied in a
phase I protocol with various solid tumors.

- Demonstration of safety and anti-angiogenic activity will lead to combination studies.

Primary Objectives:

- To preliminarily evaluate the anti-tumor activity of pegaspargase, 2,000 IU/ m^2 every
two weeks intravenous (IV) (or intramuscular (IM)) and explore associations with
toxicity and clinical outcome.

- To evaluate the safety of pegaspargase in patients with recurrent or refractory
ovarian, fallopian tube, and/or primary peritoneal cancer.

Secondary Objectives:

- To explore changes in circulating angiogenic cytokines after treatment with
pegaspargase.

- To measure apoptosis and proliferation in tumor (or malignant effusion) by protein
array before and during therapy.

- To evaluate changes in tumor vascularity using dynamic contrast enhanced (DCE) magnetic
resonance imaging (MRI).

Eligibility:

- Women with epithelial ovarian cancer, fallopian tube cancer, and/or primary peritoneal
cancer that is persistent, relapsed and/or refractory to prior therapy.

- There is no limit to number of prior treatment regimens. Patients may not have
previously received L-ASP.

- Women must have disease amenable to biopsy or malignant effusions (pleural effusion or
ascites) that may be serially tapped.

- Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, 2.

- Evidence of adequate end organ function and normal coagulation parameters (prothrombin
time (PT), activated partial thromboplastin time (aPTT)).

Design:

- Women will receive 2,000 IU/m^2 of pegaspargase intravenously every two weeks in 28-day
cycles until disease progression, excessive toxicity, or withdrawal from study.

- Biopsy of tumor and dynamic contrast-enhanced-magnetic resonance imaging (MRI) will be
performed prior to starting pegaspargase (mandatory) and after 6 weeks of treatment
(optional).

- Clinical outcome will be measured and correlated with biological endpoints.

- Research blood samples will be taken to assess changes in serum vascular endothelial
growth factor (VEGF), interleukin-6 (IL6), and interleukin-8 (IL8).

- Blood will be collected to evaluate circulating endothelial cells.

- Patients will be seen in clinic every 4 weeks and outcome measured every other cycle.

- INCLUSION CRITERIA:

- All patients 18 years and older with epithelial ovarian, fallopian tube, or primary
peritoneal cancer that is persistent, relapsed or refractory to prior standard
platinum and taxane-based therapy will be eligible. Tumor histology must be reviewed
and confirmed by the National Cancer Institute (NCI) Laboratory of Pathology.
Recurrent ovarian cancer is not a curable tumor. Patients who are platinum-sensitive
and who, upon detailed informed consent, wish to consider this experimental regimen,
will be considered.

- All patients must have measurable disease by Response Evaluation Criteria in Solid
Tumors (RECIST) criteria. A sentinel lesion adequate for core biopsy through
percutaneous route is ideal but not mandatory. Patients with a malignant pleural
effusion or malignant ascites will be allowed to undergo a paracentesis or
thoracentesis rather than core needle biopsy if the procedure may be performed
safely.

- Patients must have a performance status of Eastern Cooperative Oncology Group (ECOG)
= 0, 1, 2

- Patients must have adequate end organ function:

- Absolute neutrophil count (ANC) greater than or equal to 1500/ mm^3

- Platelets greater than or equal to 100,000/ mm^3

- Serum creatinine less than or equal to 1.5 mg/dL, or if low, creatinine
clearance greater than or equal to 60 mL/min

- Total bilirubin less than or equal to 1.5 times the ULN (upper limit of normal)
unless a history of Gilbert's disease.

- Lipase and amylase less than or equal to 1.5 times the ULN

- Transaminases (aspartate aminotransferase (AST), alanine aminotransferase (ALT))
less than or equal to 2.5 times the ULN

- Fibrinogen greater than or equal to 0.75 times the LLN

- Prothrombin time (PT), partial thromboplastin time (PTT), and International
Normalized Ratio (INR) less than or equal to 1.5 times the ULN. Coagulation
parameters must be drawn peripherally.

- Patients must be at least 4 weeks from previous therapy (chemotherapy, hormonal
therapy, and radiation therapy, alternative therapy, investigational agents, or a
major surgical procedure). Patients must be 6 weeks from carboplatin- or mitomycin
C-containing therapy. Exceptions: Raloxifene will be allowed for bone health and
bisphosphonate therapy will be allowed for the rare situation of bone metastasis.

- There is no limit to the number of prior regimens patients may have received for the
treatment of ovarian cancer.

- Patients must have recovered from any toxicity related to prior cancer therapy to
Common Terminology Criteria for Adverse Events (CTCAE) grade 1, except for stable
peripheral neuropathy, which must have recovered to grade 2 or better, and grade 2
total white blood cell count when ANC is greater than or equal to 1500 (alopecia and
hypertension exempted).

- Women of childbearing potential must agree to use adequate barrier contraception
(interaction with oral contraceptives is unknown) prior to study entry, during
therapy and for 3 months after completion of therapy and must have a negative
pregnancy test.

- Patients must be able to give written informed consent.

EXCLUSION CRITERIA:

- Evidence of severe or uncontrolled systemic disease or any concurrent condition which
in the Investigator's opinion makes it unsafe for the patient to participate in the
trial or which would jeopardize compliance with the protocol.

- Evidence of central nervous system (CNS) involvement. Patients with abnormal clinical
exam or history will require a head computed tomography (CT) or magnetic resonance
imaging (MRI).

- History of clinically symptomatic pancreatitis within the six months prior to
enrollment.

- History of prior exposure to any formulation of L-asparaginase.

- Patients with a history of deep venous thrombosis or pulmonary embolism within the
past 3 months, or pulmonary embolism within the past 6 months, history of recurrent
clot or pulmonary embolism (PE), or those patients requiring ongoing full dose
anticoagulation will be ineligible. Line prophylaxis with 1 mg warfarin daily will be
allowed.

- Patients with active infection will not be eligible, but may become eligible once
infection has resolved and they are at least 7 days from completion of antibiotics.

- Women who are pregnant and women actively breast-feeding will be excluded.

- Previous or current malignancies within the last 5 years, with the exception of
cervical carcinoma in situ curatively treated, ductal or lobular carcinoma in situ
curatively treated and without ongoing therapeutic intervention, and nonmelanomatous
skin cancers curatively treated.

- No concomitant use of complementary or alternative medication or other agents
(investigational or anti-cancer agents) will be allowed without approval of a
principal investigator (PI) or associate investigator (AI). Every effort will be made
to maximize patient safety and minimize changes in chronic medications.