Patient selection
Patients may be included in the study only if they meet all the following 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 as defined
9. Measurable disease according to RECIST criteria
10. Able to swallow and retain oral medication
11. A life expectancy of at least 12 weeks
Excluson criteria
Patients will be excluded from the study for any of the following reasons:
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
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Active peptic ulcer disease
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Known intraluminal metastatic lesion/s with suspected bleeding
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Inflammatory bowel disease
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Ulcerative colitis, or other gastrointestinal conditions with increased risk of perforation
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History of abdominal fistula, gastrointestinal perforation, or intraabdominal abscess within 28 days prior to beginning study treatment
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Malabsorption syndrome
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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:
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Cardiac angioplasty or stenting
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Myocardial infarction
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Unstable angina
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Symptomatic peripheral vascular disease
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Coronary artery by-pass graft surgery
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Class II, III or IV congestive heart failure as defined by the New York Heart Association (NYHA)
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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 anticoagulant 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
Study Medication
Cyclophophamide
Cyclophosphamide is a nitrogen mustard alkylating agent, from the oxazophorines group. Cyclophosphamide mustard forms DNA crosslinks between (interstrand crosslinkages) and within (intrastrand crosslinkages) DNA strands at guanine N-7 positions. This leads to cell death.
Exhibiting cytotoxic effects only after activation in the liver, cyclophosphomid is called a prodrug. Cyclophosphamide is converted by enzymes of the Cytochrome P450 to active metabolites. The main active metabolite is 4-hydroxycyclophosphamide, which exists in equilibrium with its tautomer, aldophosphamide. Most of the aldophosphamide is oxidised by the enzyme aldehyde dehydrogenase (ALDH) to make carboxyphosphamide. Therefore, cells with relatively large concentrations of aldehyde dehydrogenase (ALDH) (e.g. earlyhaematopoetic stem cells and megakaryocytes as well as stemcells of the mucous membranes) are less sensitive to the toxic effects of cyclophoshamid than cells with lower levels of aldehyde dehydrogenase. This difference in metabolism is the reason for the relatively low toxicity of bone marrow (as anaemia, thrombocytopenia and leukopenia) or mucous membranes.
Pazopanib
Pazopanib is an, oral, angiogenesis inhibitor targeting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and c-kit. VEGF and PDGF are growth factors critical to the development and growth of blood vessels - a process known as angiogenesis. Angiogenesis plays a pivotal role in the growth and spread of several tumour types, with VEGF and PDGF overexpression linked to multiple cancers including cancers of the liver, lung, breast, kidney, bladder, ovaries, and colon. By inhibiting VEGFR, PDGFR, and c-kit pazopanib may stop or slow the rate of tumour growth and development. Pazopanib is currently being studied in a number of different tumour types; clinical trials are currently underway in renal cell carcinoma (Phase III), breast cancer, ovarian cancer, STS, NSCLC, cervical cancer and other solid tumours. It is being evaluated as a monotherapy, in combination with targeted therapies and in combination with cytotoxic chemotherapy. More than 2000 patients have been treated to date in clinical trials. Pazopanib (under the tradename Votrient®) has been licensed by the FDA for the treatment of patients with advanced renal cell carcinoma (RCC) on the 19th of Oct 2009 and is on the market in the US. In the EU, pazopanib has been given a positive opion by the committee for proprietary medicinal products (CPMP) at the European Medicines Agency 19th February 2010. Pazopanib (under the tradename Votrient®) has been licensed by EMA in EU on the 14th of June 2010 for the treatment of patients with advanced renal cell carcinoma (RCC).
Investigation schedule
Therapy indication
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.
Pre-therapeutic examinations
Patients eligible for the study will initially be screened for their suitability to take part in the study. Patients not included in the study should be recorded in a screening log, with a statement of the reasons for their non-participation. Informed consent must be obtained prior to performance of any study-specific procedure. If not noted otherwise, the baseline examinations should be performed within 4 weeks before start of treatment:
• Previous history, physical examination including weight control and vital signs, ECG (ECG no more than 21 days old on inclusion in the study), gynaecological examination
• Assessment of general well-being according to ECOG within 7 days prior to start of study drug
• Documentation of measurable and non-measurable tumour lesions. For radiological disease assessments, CTs and MRIs are acceptable and are used interchangeably below; however, for each individual subject the same one method must be used throughout the study.
• CA-125 tumour marker (determined not more than 7 days before start of treatment). Two pretreatment values at least twice the upper limit of normal are required for an evaluation of the response by means of CA-125.
• Blood count, blood chemistry obligatory (within 7 days before inclusion in the study and within 4 weeks before start of treatment): Haematocrit, haemoglobin, white blood cell (WBC) count, red blood cell (RBC) count, lymphocyte count, neutrophil count, platelet count, aPTT and PT-INR, SGOT, SGPT, alkaline phosphatase, bilirubin (total), urea (blood urea nitrogen), creatinine, creatinine clearance (CrCl) calculated using Cockcroft and Gault formula, calcium, potassium, sodium, magnesium, glucose, lactate dehydrogenase (LDH), albumin, amylase, TSH, free T4, urine dipstick for protein
• Women of childbearing potential must have a negative pregnancy test (HCG in urine/serum) not more than 7 days old on start of treatment.
Quality of life (EORTC-QLQ C 30 and Ovar 28)
Assessment of safety
Adverse Events
The investigator is responsible for documenting all adverse events that occur during the study. Adverse events are all harmful, pathological or unintentional changes in anatomical, physiological or metabolic functions observable in the form of physical signs, symptoms and/or changes in laboratory values that occur during any part of the clinical trial, irrespective of whether there is any relationship to a medication. This also includes a deterioration in preexisting diseases or events, diseases that occur in the intervening period, changes of medication or a significant deterioration in the disease studied. Expected daily variations in the disease under study that do not represent a clinically significant deterioration should not be considered an adverse event.
Causal Assessment
The investigator should make every effort to elucidate any adverse event and where necessary to assess its relationship to the study medication. The causal relationship should be assessed on the basis of the following categories: no relationship, relationship unlikely, relationship suspected (justified suspicion) and relationship probable. The degree of certainty of the relationship between adverse event and drug is determined by how well the event can be explained by the following ftors: (1) known pharmacological properties, (2) comparable reactions observed previously with the drug or another member of its class, (3) an event with comparable substances commonly described in the literature as drug-related, (4) a chronological relationship between the event and drug intake, disappearance on withdrawal or recurrence on re-institution of the drug.
Follow-up
Follow-up investigations will be done every 3 months over 24 months with the aim of determining the time of tumour progression.
The following examinations will be performed every 3 months after end of treatment
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Survival status
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Medical history, physical examination
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Assessment of ECOG performance
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Determination of tumour progression
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CA-125 tumour marker
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Further anticancer treatment
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Quality of life (EORTC-QLQ C 30 and Ovar 28)
The follow-up information can be collected by phone.
Monitoring
Study monitoring is undertaken by monitors appointed by ALCEDIS GMBH, Giessen, Germany. The responsible monitor will be allowed, on request, to inspect the various records of the trial (Case Report Forms and other pertinent data). Due to the electronic documentation system checks for range and plausibility are performed during data entry. The monitor gets an access to read the data only. In line with ICH GCP guidelines, monitoring will include verification of data entered in the eCRF against original patient records. This verification will be performed by direct access to the original subject records, and the Sponsor guarantees that patient confidentiality will be respected at all times. Participation in this study will be taken as agreement to permit direct source data verification.