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    Summary
    EudraCT Number:2010-021613-23
    Sponsor's Protocol Code Number:
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2010-08-18
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2010-021613-23
    A.3Full title of the trial
    HYPAZ: An open-label investigation into hypertension induced by pazopanib therapy
    A.3.2Name or abbreviated title of the trial where available
    HYPAZ: Hypertension induced by pazopanib
    A.4.1Sponsor's protocol code number
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorCambridge University Hospitals NHS Foundation Trust and University of Cambridge
    B.1.3.4Country
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Votrient 400 mg
    D.2.1.1.2Name of the Marketing Authorisation holderGlaxo Group Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namePazopanib (Votrient) 400mg
    D.3.2Product code GW786034
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNpazopanib hydrochloride
    D.3.9.1CAS number 635702-64-6
    D.3.9.2Current sponsor codeGW786034
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number400
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Votrient 200 mg
    D.2.1.1.2Name of the Marketing Authorisation holderGlaxo Group Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namePazopanib (Votrient) 200mg
    D.3.2Product code GW786034
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNpazopanib hydrochloride
    D.3.9.1CAS number 635702-64-6
    D.3.9.2Current sponsor codeGW786034
    D.3.9.4EV Substance CodeAS2
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Hypertension induced by pazopanib treatment of various cancer types
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level PT
    E.1.2Classification code 10037400
    E.1.2Term Pulmonary hypertension
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    What causes high blood pressure in some patients taking pazopanib as a treatment for cancer?
    E.2.2Secondary objectives of the trial
    Most of the secondary objectives are about examining changes in the way that blood vessels work during pazopanib treatment, and whether these changes might explain how and why high blood pressure is caused.

    Does pazopanib cause changes in the way that blood vessel walls work? (Different tests will be done to investigate this, some at the clinic, and some during normal daily activities)

    Does pazopanib cause changes in blood circulation in the small vessels of the eye?

    Does pazopanib cause changes in blood vessels within tumours, and is there a relationship between any such changes and blood pressure changes, and also how well the drug works?

    What changes in levels of chemicals in the blood and urine are seen when pazopanib is taken?

    Is there a relationship between the concentration of pazopanib in the blood and how blood pressure is affected?

    Are there any genetic (inherited) factors which explain blood pressure changes caused by the drug?
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Patients 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

    2.Patients with the following tumour types where VEGF inhibition would be appropriate therapy will be included in the study:
    • Renal cell carcinoma
    • Ovarian carcinoma with a rising CA-125, 2nd or subsequent lines
    • Ovarian carcinoma with residual disease after chemotherapy in the absence of rising CA-125, 2nd or subsequent lines
    • Cervical cancer, metastatic or recurrent, and progressing after conventional chemotherapy
    • Glioblastoma, progressing after conventional chemotherapy
    • Advanced or metastatic soft tissue sarcoma, residual disease post chemotherapy in the absence of progression, 2nd or subsequent lines
    • Advanced or metastatic soft tissue sarcoma progressing post conventional chemotherapy, 3rd or subsequent lines
    • Non-small cell lung cancer, 1st or subsequent lines
    • ErbB2 positive, advanced or metastatic breast cancer, 2nd or subsequent lines
    • Gemcitabine-refractory pancreatic cancer, 2nd or subsequent lines
    • Non-cutaneous (ocular or mucosal) melanoma and cutaneous melanoma any line
    • GI tract 2nd line residual disease or subsequent lines
    • Small Cell Lung cancer 3rd line
    • Other solid tumours in which anti-VEGF therapy is judged by the CI to be of possible clinical benefit

    3.Must have measurable disease as per RECIST 1.1. A measurable lesion is defined as a lesion that can be accurately measured in at least one dimension with the longest diameter ≥ 20mm using conventional techniques. Patients with ovarian cancer or prostate cancer, where validated tumour markers (CA125 and PSA) are used clinically to monitor response, do not require measurable disease as per RECIST 1.1

    4. ECOG performance status 0 or 1

    5. Age ≥18 years

    6. Adequate organ system function (meeting detailed criteria)

    7. A female is eligible to enter and participate in this study if she is of non-childbearing potential or is taking specified contraceptive measures. A male is eligible to participate if any female partner is of non-childbearing potential or if he is taking specified contraceptive measures.
    E.4Principal exclusion criteria
    1. Known hypertension (blood pressure > 150/90 (± 2 mmHg, at investigator’s discretion)) at baseline

    2. On anti-hypertensive therapy indicated for hypertension.

    3. History of any one or more of the following cardiovascular conditions within the last 6 months: Cardiac angioplasty or stenting, Myocardial infarction, Unstable angina, Coronary artery bypass graft surgery,Peripheral vascular disease or Raynaud’s phenomenon, Cerebrovascular accident (CVA) including transient ischaemic attack (TIA), Class III or IV congestive heart failure as defined by the New York Heart Association (NYHA)

    4. Hypersensitivity to agents used in forearm blood flow studies (acetylcholine, sodium nitroprusside, L-NMMA)

    5. Difficult upper limb arterial access (as assessed by an easily palpable brachial artery)

    6. Anticoagulant therapy (warfarin). (Subcutaneous heparin is allowed but will need to be omitted on visits V2, V3 and VHyp)

    7. Pregnant or lactating female

    8. History or clinical evidence of central nervous system (CNS) metastases

    9. Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding

    10. Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product

    11. Presence of uncontrolled infection

    12. Corrected QT interval (QTc) > 480 msecs using Bazett’s formula

    13. History of pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months

    14. Prior major surgery or trauma within 28 days prior to first dose of study drug and/or presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement not considered to be major)

    15. Evidence of active bleeding or bleeding diathesis

    16. Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that increase the risk of pulmonary hemorrhage

    17. Significant haemoptysis within 8 weeks prior to first dose of pazopanib

    18. Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with patient’s safety, provision of informed consent, or compliance to study procedures

    19. Unable or unwilling to discontinue use of prohibited medications list for at least 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of pazopanib and for the duration of the study

    20. Treatment with any of the following anti-cancer therapies:
    • radiation therapy (single fraction of radiotherapy for pain control is allowed in this period and when on study), surgery or tumour embolization within 14 days prior to the first dose of pazopanib OR
    • chemotherapy, immunotherapy, biologic therapy, investigational therapy within 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of pazopanib
    • pazopanib or other antiangiogenic treatment (e.g. bevacizumab) within the past 12 weeks

    21. Administration of any non-oncologic investigational drug within 30 days or 5 half-lives whichever is longer prior to receiving the first dose of study treatment

    22. Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 and/or that is progressing in severity, except alopecia

    23. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to pazopanib

    MRI Exclusions
    Patients with any of the following contraindications to MRI scanning (as assessed by local MRI safety questionnaire), will not participate in MRI assessments, but may participate in the study.
    1. Intracranial aneurysm clips (except Sugita) with an appropriate operative conformation
    2. History of intra-orbital metal fragments that have not been removed
    3. Pacemaker or non-MR-compatible heart valves
    4. Inner ear implants
    5. History of claustrophobia in MR
    6. Contraindications to contrast agent
    E.5 End points
    E.5.1Primary end point(s)
    Change in forearm blood flow ratio (of infused vs. control arm) or absolute flow (infused arm only) in response to intra-arterial acetylcholine infusion (and also expressed as a percentage change from baseline). [Endothelium-dependent]
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    For the purposes of analysis "study completion" relates to the cardiovascular research aspects of the study, and occurs when the last of the agreed number of patients (determined after the interim analysis) completes the VHyp visit.

    The trial as a whole will conclude when the last patient in the Treatment Continuation phase completes the post-treatment follow-up or withdraws.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months4
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 0
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 0
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state52
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 52
    F.4.2.2In the whole clinical trial 52
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Ongoing pazopanib therapy will be available to patients completing the main study (12 weeks of treatment) where this is felt appropriate by the investigator, until disease progression, death or at the investigator's discretion.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2010-09-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-11-24
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2014-09-25
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