Phase I Trial of Oral Metronomic Topotecan and Oral Pazopanib to Treat Recurrent/Persistent Gynecologic Tumors
Condition: Gynecologic Tumors
MeSH terms: Genital Neoplasms, Female
Intervention: Oral Topotecan; Pazopanib
Intervention description: Starting on Cycle 1 Day 1, each subject will receive the assigned dose of topotecan administered by mouth.; Starting on Cycle 1 Day 1, each subject will receive the assigned dose of pazopanib administered by mouth.
Intervention MeSH terms: Topotecan
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 33.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Gynecologic tumors

Summary:

      This is a Phase 1, dose-escalation study in female patients with recurrent or persistent
      gynecologic tumors.
    

Eligibility criteria:

        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.