Phase I Trial of Oral Metronomic Topotecan and Oral Pazopanib to Treat Recurrent/Persistent Gynecologic Tumors

This is a Phase 1, dose-escalation study in female patients with recurrent or persistent
gynecologic tumors. The study will include a Screening Phase, a Treatment Phase and a
Followup Phase. In the Screening Phase the subject's eligibility for study participation
will be determined; this phase can last up to 28 days. The Treatment Phase will begin when
the subject starts study treatment and will continue until the subject is removed from study
treatment. The Follow-up Phase will last for 30 days after the subject ends study treatment.
The study will be conducted at approximately 1 site and will include approximately 41
evaluable patients. Treatment cycle length is 28 days. Radiologic imaging will be repeated
after every 2 cycles of treatment.

Inclusion Criteria:

- Subjects must provide written informed consent prior to the performance of study
specific procedures, and must be willing to comply with treatment and follow-up.

- Female patients, greater than 18 years of age with a histologically confirmed
recurrent/persistent gynecologic malignancy.

- For patients with recurrent/persistent epithelial ovarian, fallopian tube, or primary
peritoneal carcinoma: persistent disease = progression during primary platinum
therapy; recurrent disease = disease that recurs ≤ 12 months after discontinuing
primary platinum therapy; if disease recurrence occurs > 12 months after
discontinuing primary platinum therapy, there must be progression either during a 2nd
platinum therapy or < 6 months after discontinuing the 2nd platinum therapy.

- For patients with other gynecologic malignancies:

- Malignancy is metastatic or unresectable and no curative or palliative measures
exist or are no longer effective.

- Maximum of two total prior treatments (this includes neoadjuvant, adjuvant, and
metastatic settings) for the recurrent or persistent gynecologic tumors
including chemotherapy, hormonal therapy, investigational therapy, radiation
therapy, etc.)

- Disease may be measurable or non-measurable according to RECIST version 1.0

- Gynecologic Oncology Group (GOG) performance status of 0,1,or 2

- Must have a life expectancy of at least six months

- Adequate bone marrow, liver, renal, and cardiac function at study entry as assessed
by the following:

- Hemoglobin > 9.0 g/dL.

- Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L.

- Platelet count ≥ 100 x 10^9/L.

- Prothrombin time (PT) or international normalized ratio (INR) < 1.2 x upper
limit of normal (ULN).

- Partial thromboplastin time (PTT) < 1.2 x ULN.

- Total bilirubin ≤ 1.5 x ULN.

- Alanine transaminase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN.

- Creatinine ≤ 1.5 mg/dL or if serum creatinine is greater than 1.5 mg/dL,
calculated creatinine clearance must be > 50 mL/min

- Urine dipstick for protein < 2+ or urine protein creatinine (UPC) ratio < 1.0.

- Left ventricular ejection fraction (LVEF) ≥ 50% or the institutional lower limit
of normal (LLN)

- Patients must be physiologically incapable of becoming pregnant, be postmenopausal,
or have a negative pregnancy test and agree to use adequate contraception.

Exclusion Criteria:

- Treatment naive patients.

- Repetitive or prolonged neutropenia or thrombocytopenia during previous therapy.

- Concurrent malignancy other than malignancies under study. Subjects who have had
another malignancy and have been disease free for 3 years, or subjects with a history
of completely resected non-melanomatous skin carcinoma or successfully treated in
situ carcinoma are eligible.

- Prior radiation therapy.

- Myelosuppressive chemotherapy within the past 28 days or has not recovered from the
myelosuppressive effects of recent chemotherapy.

- Use of an investigational agent, including an investigational anti-cancer agent,
immunotherapy, biological therapy, or hormonal therapy within 28 days prior to the
first dose of study treatment.

- Prior major surgery or trauma within 28 days prior to the first dose of study
treatment and/or presence of any non-healing wound, fracture, or ulcer.

- History or clinical evidence of central nervous system (CNS) metastases or
leptomeningeal carcinomatosis.

- Inability to swallow a capsule or clinically significant gastrointestinal
abnormalities including, but not limited to:

- Malabsorption syndrome

- Major resection of the stomach or small bowel that could affect the absorption
of study treatment

- Active peptic ulcer disease

- Inflammatory bowel disease

- Ulcerative colitis, or other gastrointestinal conditions with increased risk of
perforation

- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 28 days prior to beginning study treatment.

- Unresolved bowel obstruction or diarrhea ≥ Grade 1

- Known intraluminal metastatic lesion(s) with risk of bleeding

- Known endobronchial lesions or involvement of large pulmonary vessels by tumor.

- Presence of uncontrolled infection.

- Prolongation of corrected QT interval > 480 milliseconds.

- History of any one or more of the following cardiovascular conditions within the past
6 months:

- Cardiac angioplasty or stenting

- Myocardial infarction

- Unstable angina

- Coronary artery bypass graft

- Symptomatic peripheral vascular disease

- Class III or IV congestive heart failure, as defined by the New York Heart
Association (NYHA)

- Poorly controlled hypertension (defined as systolic blood pressure of > 140 mmHg or
diastolic blood pressure of > 90 mmHg). Initiation or adjustment of antihypertensive
medication(s) is permitted prior to study entry.

- History of cerebrovascular accident, transient ischemic attack, pulmonary embolism,
or insufficiently treated deep vein thrombosis (DVT) within the past 6 months.
Subjects with recent DVT who have been treated with therapeutic anti-coagulating
agents for at least 6 weeks are eligible

- Evidence of active bleeding or bleeding diathesis.

- Recent hemoptysis in excess of 2.5 mL within 8 weeks of 1st dose of study treatment.

- Any serious and/or unstable pre-existing medical, psychiatric, or other condition
that could interfere with subject's safety, provision of informed consent, or
compliance to study procedures.

- Use of any prohibited medication within 14 days or 5 half-lives of the drug
(whichever is longer) prior to the first dose of study treatment and during the
study.

- Prior use of any investigational or licensed anti-angiogenic agent, including
topotecan, bevacizumab, thalidomide, and agents that target vascular endothelial
growth factor (VEGF), VEGF receptors, or platelet-derived growth factor (PDGF).

- Any ongoing toxicity from prior anti-cancer therapy that is > Grade 1 and/or that is
progressing in severity, except alopecia.

- Known hypersensitivity to topoisomerase I inhibitors or pazopanib.

- Administration of any non-oncologic investigational drug within 30 days or five
half-lives of a drug (whichever is longer) prior to the first dose of study
treatment.