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 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.