A Phase I/II Study of Pazopanib (GW786034) and Cyclophosphamide in Patients With Platinum-resistant Recurrent, Pre-treated Ovarian Cancer

Inclusion Criteria:

1. Subjects must provide written informed consent prior to performance of study specific procedures or assessments, and must be willing to comply with treatment and follow up assessments and procedures.
2. Female subjects ≥18 years of age
3. Histologically or cytologically confirmed diagnosis of: epithelial ovarian cancer which is platinum resistant (relapse-free interval < 6 months of a platinum-containing primary or secondary platinum therapy) or platinum refractory (progressive disease during primary or secondary platinum therapy), cancer of the fallopian tube, peritoneal cancer Definition of relapse: Demonstration of measurable or non-measurable tumour according to RECIST criteria by an imaging procedure (where applicable before relapse surgery) or increase in the tumour marker CA-125 to twice the upper laboratory value of normal for the hospital
4. Patients must have failed available standard chemotherapy regimen (except if medically contraindicated or refused by the patient)
5. Prior treatment with at least 2 chemotherapy regimens in advanced tumor setting
6. Performance status ECOG 0 2
7. Adequate contraception
8. Adequate organ function
9. Measurable disease according to RECIST criteria.
10. Able to swallow and retain oral medication.
11. A life expectancy of at least 12 weeks.

Exclusion Criteria:

1. Diagnosis of 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
2. 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.

3. Clinically significant gastrointestinal abnormalities which might interfere with oral dosing

   • Active peptic ulcer disease
   • Known intraluminal metastatic lesion/s with suspected bleeding
   • 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
   • Malabsorption syndrome
   • Major resection of the stomach or small bowel
4. Any unstable or serious concurrent condition (e.g., active infection requiring systemic therapy).
5. Prolongation of corrected QT interval (QTc) >480 msecs.

6. 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 Note: Subjects with recent DVT who have been treated with therapeutic anti-coagulant agents (excluding therapeutic warfarin) for at least 6 weeks are eligible
7. Macroscopic hematuria
8. Hemoptysis that is clinically relevant within 4 weeks of first dose of study drug
9. Evidence of active bleeding or bleeding diathesis
10. Known endobronchial lesions or involvement of large pulmonary vessels by tumor
11. 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.
12. Chemotherapy or radiation therapy within 2 weeks prior to the first dose of study drug.
13. Biological therapy, hormonal therapy or treatment with an investigational agent within 28 days or 5 half-lives, whichever is longer prior to the first dose of study drug.
14. Prior antiangiogenic therapy.
15. 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
16. Any ongoing toxicity from prior anti-cancer therapy that is > Grade 1 and/or that is progressing in severity.
17. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to pazopanib
18. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.
19. Pregnancy (for women of childbearing potential absence to be confirmed by ß-hCG test) or lactation period or missing contraception of women of childbearing potential (Pearl-Index < 1, e.g. hormonal contraception including the combined oral contraceptive pill, the transdermal patch, and the contraceptive vaginal ring, intrauterine devices or sterilization) during treatment and for at least 6 months thereafter.
20. More than 3 different chemotherapy regimens in advanced tumor setting
21. Uncontrolled hypertension
22. History of ischemic event (stroke, myocardial infarction, unstable angina, TIA, symptomatic peripheral vascular disease)
23. History or clinical evidence of thrombo-embolic event
24. History of haemoptysis, cerebral, or clinically significant gastrointestinal haemorrhage in the past 6 months
25. Active bleeding
26. Signs/Suspicion of intestinal obstruction