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

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.