Phase I/II Study of Pazopanib and Cyclophosphamide in Patients With Platinum-resistant Recurrent Ovarian Cancer

This study is a prospective open-label, non-randomized multicenter phase I/II trial in order to determine overall response rate of patients with platinum-resistant or refractory recurrent, pretreated epithelial ovarian cancer.

In order to assure adequate toxicity assessment, a phase-I-trial is proponed. Phase II will be performed with MTD.

Inclusion criteria

• Written informed consent
• Female subjects ≥18 years of age
• Histologically or cytologically confirmed diagnosis of: epithelial ovarian cancer which is platinum resistant or platinum refractory,cancer of the fallopian tube, peritoneal cancer
• Patients must have failed available standard chemotherapy regimen
• Prior treatment with at least 2 chemotherapy regimens in advanced tumor setting
• Performance status ECOG 0 - 2
• Adequate contraception
• Adequate organ function
• Measurable disease according to RECIST criteria.
• Able to swallow and retain oral medication.
• Life expectancy of at least 12 weeks.

Exclusion criteria

• Any second malignancy within the last 5 years, with the exception of basal cell or squamous cell skin cancer or in situ carcinoma of the cervix uteri
• 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.
• Clinically significant gastrointestinal abnormalities which might interfere with oral dosing
• Any unstable or serious concurrent condition (e.g., active infection requiring systemic therapy).
• Prolongation of corrected QT interval (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
• Coronary artery by-pass graft surgery
• Class II, III or IV congestive heart failure as defined by the New York Heart Association (NYHA)
• History of cerebrovascular accident, pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months
• Macroscopic hematuria
• Hemoptysis that is clinically relevant within 4 weeks of first dose of study drug
• Evidence of active bleeding or bleeding diathesis
• Known endobronchial lesions or involvement of large pulmonary vessels by tumor
• Prior major surgery or trauma within 14 days prior to first dose of study drug and/or presence of any non-healing wound, fracture, or ulcer.
• Chemotherapy or radiation therapy within 2 weeks prior to the first dose of study drug.
• Biological therapy, hormonal therapy or treatment with an investigational agent within 28 days or 5 half-lives
• Prior antiangiogenic therapy.
• Is unable or unwilling to discontinue predefined prohibited medications listed in the protocol for 14 days or five half-lives of a drug (whichever is longer) prior to Visit 1 and for the duration of the study
• Any ongoing toxicity from prior anti-cancer therapy that is > Grade 1 and/or that is progressing in severity.
• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to pazopanib
• Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.
• Pregnancy
• More than 3 different chemotherapy regimens in advanced tumor setting
• Uncontrolled hypertension
• History of ischemic event (stroke, myocardial infarction, unstable angina, TIA, symptomatic peripheral vascular disease)
• History or clinical evidence of thrombo-embolic event
• History of haemoptysis, cerebral, or clinically significant gastrointestinal haemorrhage in the past 6 months
• Active bleeding
• Signs/Suspicion of intestinal obstruction