A Phase I Trial of Oral Metronomic Topotecan in Combination With Oral Pazopanib Utilizing a Daily Dosing Schedule to Treat Recurrent or Persistent Gynecologic Tumors

Inclusion Criteria:

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

- Female patients, greater than 18 years of age with recurrent or persistent
gynecologic tumor including ovarian, primary peritoneal, fallopian tube, cervical
cancer, and any other appropriate gynecologic tumor

- 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

- GOG performance status of 0,1,or 2

- Must have a life expectancy of at least six months

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

- Hemoglobin > 9.0 g/dL.

- ANC ≥ 1.5 x 10^9/L.

- Platelet count ≥ 100 x 10^9/L.

- PT or INR < 1.2 x ULN.

- PTT < 1.2 x ULN.

- Total bilirubin ≤ 1.5 x ULN.

- ALT and 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 UPC < 1.0. If dipstick > 2+ or UPC > 1, then
a 24-hour urine protein must be assessed. Subjects must have a 24-hour urine
protein value < 1 g to be eligible.

- A female is eligible to enter and participate in this study if she is of:
Non-childbearing potential OR is post-menopausal.

Exclusion Criteria:

- 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.

- Whole pelvic or extended field radiation therapy within 45 days of first dose of
study treatment and/or concurrent radiotherapy treatment during study participation.

- 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 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 suspected bleeding

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

- Presence of uncontrolled infection.

- Prolongation of QTc > 480 msecs.

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

- Cardiac angioplasty or stenting

- Myocardial infarction

- Unstable angina

- Symptomatic peripheral vascular disease

- Class III or IV congestive heart failure, as defined by the NYHA

- Poorly controlled hypertension (defined as SBP of > 140 mmHg or DBP of > 90 mmHg).
Initiation or adjustment of antihypertensive medication(s) is permitted prior to
study entry. Blood pressure must be re-assessed on two occasions that are separated
by a minimum of 24 hours. The mean SBP/DBP values from each blood pressure assessment
must be <140/90 mmHg in order for a subject to be eligible for the study.

- History of cerebrovascular accident, pulmonary embolism or insufficiently treated 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; however, the
use of therapeutic levels of warfarin must have ended more than 14 days prior to
first dose of study treatment.

- Evidence of active bleeding or bleeding diathesis.

- 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 prior to the first dose of study
treatment(see Section 4.8.2).

- Prior use of any investigational or licensed anti-angiogenic agent, including
topotecan,bevacizumab, thalidomide, and agents that target VEGF, VEGF receptors, or
PDGF.

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

- Known hypersensitivity to topoisomerase I inhibitors or pazopanib.