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
- 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
- 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
- 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.
- 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
- 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
- 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
- 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.