Gemcitabine Hydrochloride With or Without Pazopanib Hydrochloride in Treating Patients With Persistent or Relapsed Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Inclusion Criteria

• Patients must have recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal carcinoma; histologic documentation of the original primary tumor is required via the pathology report
• Patients must have measurable disease or detectable (non-measurable) disease: * Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded); each lesion must be greater than or equal to 10 mm when measured by computed tomography (CT), magnetic resonance imaging (MRI) or caliper measurement by clinical exam; or greater than or equal to 20 mm when measured by chest x-ray; lymph nodes must be greater than or equal to 15 mm in short axis when measured by CT or MRI * Detectable disease in a patient is defined as one who does not have measurable disease but has baseline value of cancer antigen (CA)-125 at least 2 x upper limit of normal (ULN)
• Patients who have measurable disease must have at least one “target lesion” to be used to assess response on this protocol as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; tumors within a previously irradiated field will be designated as “non-target” lesions unless progression is documented or a biopsy is obtained to confirm persistence at least 90 days following completion of radiation therapy
• Patients who have received one prior regimen must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2; patients who have received two or three prior regimens must have an ECOG performance status of 0 or 1
• Recovery from effects of recent surgery, radiotherapy, or chemotherapy: * Patients should be free of active infection requiring antibiotics (with the exception of uncomplicated urinary tract infection [UTI]) * Any hormonal therapy directed at the malignant tumor must be discontinued at least one week prior to registration * Any other prior therapy directed at the malignant tumor, including chemotherapy, biological/targeted and immunologic agents (including small molecules and murine monoclonal antibodies), must be discontinued at least three weeks prior to registration; chimeric or human or humanized monoclonal antibodies (including bevacizumab) or vascular endothelial growth factor [VEGF] receptor fusion proteins (including VEGF tartrate-resistant acid phosphatase [TRAP]/aflibercept) must be discontinued for at least 8 weeks prior to registration * At least 4 weeks must have elapsed since the patient underwent any major surgery (e.g., major: laparotomy, laparoscopy, thoracotomy, video assisted thorascopic surgery [VATS]; minor: central venous access catheter placement, ureteral stent placement or exchange, paracentesis, thoracentesis)
• Patients must have had one prior platinum-based chemotherapeutic regimen for management of primary disease containing carboplatin, cisplatin, or another organoplatinum compound; this initial treatment may have included intraperitoneal therapy, consolidation, non-cytotoxic agents (biologic/targeted agents, such as bevacizumab) or extended therapy administered after surgical or non-surgical assessment; if patients were treated with paclitaxel for their primary disease, this can have been given weekly or every 3 weeks
• Patients are allowed to receive, but are not required to receive, two additional cytotoxic regimens for management of recurrent or persistent disease
• Patients are allowed to receive, but are not required to receive, non-cytotoxic (biologic/targeted agents, such as bevacizumab) therapy as part of their primary treatment regimen; patients are allowed to receive, but are not required to receive, poly adenosine diphosphate (ADP) ribose polymerase (PARP) inhibitors for management of primary or recurrent/persistent disease (either alone or in combination with cytotoxic chemotherapy); PARP inhibitors will NOT count as a prior regimen when given alone
• Patients who have received only one prior cytotoxic regimen (platinum-based regimen for management of primary disease), must have a platinum-free interval of greater than 6 months
• Absolute neutrophil count (ANC) greater than or equal to 1,500/mcl
• Platelets greater than or equal to 100,000/mcl
• Hemoglobin greater than or equal to 9 g/dL; patients may not have had a transfusion within 7 days of screening assessment
• Prothrombin time (PT) such that international normalized ratio (INR) is less than or equal to 1.2 x ULN (or an in-range INR, usually between 2 and 3, if a patient is on a stable dose of therapeutic warfarin) and a partial thromboplastin time (PTT) less than or equal to 1.2 x ULN; Note: Subjects receiving anticoagulant therapy are eligible if their INR is stable and within the recommended range for the desired level of anticoagulation
• Creatinine less than or equal to 1.5 mg/dL, or if > 1.5 mg/dL, creatinine clearance must be at least 50 ml/min
• Urine protein to urine creatinine ratio (UPC) should be less than 1; if greater than 1, then 24 hour urine protein must be less than 1 g for patient to be eligible
• Bilirubin less than or equal to 1.5 x ULN
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) less than or equal to 2.5 x ULN
• Subjects who have BOTH bilirubin greater than ULN and AST/ALT greater than 1.0 x ULN are not eligible
• Patients should have normal baseline thyroid-stimulating hormone (TSH); patients with elevated TSH level (between 4.5-10 mU/L in the absence of symptoms of hypothyroidism) must have a normal free thyroxine (T4); TSH that is 10 mU/L or higher is exclusionary * A history of hypothyroidism and/or hyperthyroidism is allowed, as long as the patient has stable well-controlled thyroid function for a minimum of 2 months
• Patients of childbearing potential must have a negative pregnancy test prior to the study entry and be practicing an effective form of contraception; pregnant women are excluded from this study
• Patients must have signed an approved informed consent and authorization permitting the release of personal health information
• Patients must meet pre-entry requirements
• Patients must be capable of taking and absorbing oral medications; a patient must be clear of the following: * Any lesion, whether induced by tumor, radiation or other conditions, which makes it difficult to swallow tablets * Prior surgical procedures affecting absorption including, but not limited to major resection of stomach or small bowel * Active peptic ulcer disease * Malabsorption syndrome
• Any concomitant medications that are associated with a risk of corrected QT interval (QTc) prolongation and/or torsades de pointes should be discontinued or replaced with drugs that do not carry these risks, if possible; patients who must take medication with a risk of possible risk of torsades de pointes should be watched carefully for symptoms of QTc prolongation, such as syncope; patients with personal or family history of congenital long QTc syndrome are NOT eligible
• Strong inhibitors of cytochrome P450 3A4 (CYP3A4) are prohibited; grapefruit juice is an inhibitor of CYP450 and should not be taken with pazopanib
• Strong inducers of CYP3A4 are prohibited
• Concomitant use of agents with narrow therapeutic windows that are metabolized by CYP3A4, cytochrome P450 2D6 (CYP2D6), or cytochrome P450 2C8 (CYP2C8) is not recommended
• A female is eligible to enter and participate in this study if she is of: * Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who has had: ** A hysterectomy ** A bilateral oophorectomy ** A bilateral tubal ligation ** Is post-menopausal * Childbearing potential, including any female who has had a negative serum pregnancy test within 2 weeks prior to the first dose of study treatment, preferably as close to the first dose as possible, and agrees to use adequate contraception; GlaxoSmithKline (GSK) acceptable contraceptive methods, when used consistently and in accordance with both the product label and the instructions of the physician, are as follows: ** Complete abstinence from sexual intercourse for 14 days before exposure to investigational product, through the dosing period, and for at least 21 days after the last dose of investigational product ** Oral contraceptive, either combined or progestogen alone ** Injectable progestogen ** Estrogenic vaginal ring ** Percutaneous contraceptive patches ** Intrauterine device (IUD) or intrauterine system (ISU) with a documented failure rate of less than 1% per year ** Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject’s entry into the study, and this male is the sole partner for that subject ** Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository)

Exclusion Criteria

• Patient who have had previous treatment with pazopanib or with weekly gemcitabine for recurrent or persistent disease
• Patients with a history of other invasive malignancies, with the exception of non-melanoma skin cancer and other specific malignancies are excluded if there is any evidence of other malignancy being present within the last two years; patients are also excluded if their previous cancer treatment contraindicates this protocol therapy
• Patients who have received prior radiotherapy to any portion of the abdominal cavity or pelvis within the last three years are excluded; prior vaginal brachytherapy is allowed; prior radiation for localized cancer of the breast, head and neck, or skin is permitted, provided that it was completed more than two years prior to registration, and the patient remains free of recurrent or metastatic disease
• Patients who have received prior chemotherapy for any abdominal or pelvic tumor OTHER THAN for the treatment of ovarian, fallopian tube, or primary peritoneal cancer within the last three years are excluded; patients may have received prior adjuvant chemotherapy for localized breast cancer, provided that it was completed more than three years prior to registration, and the patient remains free of recurrent or metastatic disease
• Patients with clinically significant cardiovascular disease; this includes: * Uncontrolled hypertension, defined as systolic greater than 150 mmHg or diastolic greater than 90 mmHg * Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry * Congenital long QT syndrome or baseline QTc greater than 480 milliseconds * Myocardial infarction or unstable angina within 6 months prior to registration * New York Heart Association (NYHA) class III or greater congestive heart failure * History of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation) or serious cardiac arrhythmia requiring medication; this does not include asymptomatic, atrial fibrillation with controlled ventricular rate * Patients who have received prior treatment with an anthracycline (including doxorubicin, excluding liposomal doxorubicin) must have an echocardiogram or multigated acquisition scan (MUGA) assessment and are excluded if they have an ejection fraction less than 50% * CTCAE v.4.0 grade 2 or greater peripheral vascular disease (at least brief less than 24 hours [hrs]) episodes of ischemia managed non-surgically and without permanent deficit * History of cardiac angioplasty or stenting within 6 months prior to registration; history of coronary artery bypass graft surgery within 6 months prior to registration * Arterial thrombosis within 6 months prior to registration
• Patients with serious non-healing wound, ulcer, or bone fracture; this includes history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 28 days prior to the first date of study treatment; Note: Deliberate surgically created abdominal fistula is acceptable
• Patients with active bleeding or pathologic conditions that carry high risk of bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major vessels
• History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis, except for individuals who have previously-treated CNS metastases, are asymptomatic, and have had no requirement for steroids or anti-seizure medication for 6 months prior to first dose of study drug; screening with CNS imaging studies (computed tomography [CT] or magnetic resonance imaging [MRI]) is required only if clinically indicated or if the subject has a history of CNS metastases
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to pazopanib
• Known human immunodeficiency virus (HIV)-positive subjects on combination antiretroviral therapy are ineligible
• Patients with any condition that may increase the risk of gastrointestinal bleeding or gastrointestinal perforation, including: * Active peptic ulcer disease * Known gastrointestinal intraluminal metastatic lesions (gastrointestinal serosa metastatic lesions are permitted) * Inflammatory bowel disease (e.g., ulcerative colitis, Crohn’s disease) or other gastrointestinal conditions with increased risk of perforation * Patients with clinical symptoms or signs of gastrointestinal obstruction and patients who require parenteral hydration and/or nutrition
• Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product, including but not limited to: * Malabsorption syndrome * Major resection of the stomach or small bowel
• Patients who are pregnant or nursing
• History of hemoptysis in excess of 2.5 mL (1/2 teaspoon) within 8 weeks prior to first dose of pazopanib
• Uncontrolled intercurrent illness including, but not limited to, psychiatric illness/social situations that would limit compliance with study requirements
• Any ongoing toxicity from prior anti-cancer therapy that is greater than grade 1 and/or that is progressing in severity, except alopecia
• Unable or unwilling to discontinue use of prohibited medications for at least 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of study drug and for the duration of the study