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    Summary
    EudraCT Number:2011-003099-35
    Sponsor's Protocol Code Number:SA1001
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2011-09-28
    Trial 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 number2011-003099-35
    A.3Full title of the trial
    Phase I/II study of oral MEK inhibitor Selumetinib (AZD6244 Hyd-Sulphate) in Combination with Highly Active Anti-Retroviral Therapy (HAART) in AIDS-associated Kaposi’s sarcoma (KS).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A phase I/II trial of selumetinib in combination with anti-retroviral therapy for AIDS-associated Kaposi's sarcoma
    A.3.2Name or abbreviated title of the trial where available
    A study of selumetinib in patients with Kaposi’s sarcoma
    A.4.1Sponsor's protocol code numberSA1001
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorSheffield Teaching Hospitals NHS Foundation Trust
    B.1.3.4CountryUnited Kingdom
    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 supportCancer Reseach UK
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportAstraZeneca
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCRCTU University of Birmingham
    B.5.2Functional name of contact pointDr. Gillian L McNab
    B.5.3 Address:
    B.5.3.1Street AddressCRCTU School of Cancer Sciences
    B.5.3.2Town/ cityUniversity of Birmingham
    B.5.3.3Post codeB15 2TT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01214146788
    B.5.5Fax number01214143529
    B.5.6E-mailscart@contacts.bham.ac.uk
    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 No
    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 nameSelumetinib
    D.3.2Product code AZD6244
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    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
    AIDS-associated Kaposi's sarcoma
    E.1.1.1Medical condition in easily understood language
    Skin cancer most commonly found in patients with HIV
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level PT
    E.1.2Classification code 10023286
    E.1.2Term Kaposi's sarcoma AIDS related
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To establish the safety and dose of selumetinib in combination with HAART and to establish evidence of whether AIDS-associated KS lesions respond to (i.e. get smaller with) selumetinib in combination with HAART.
    E.2.2Secondary objectives of the trial
    To investigate how selumetinib in combination with HAART moves around the body (pharmacokinetics - drug levels of selumetinib, HAART, and HIV viral load and CD4 counts).

    To assess the toxicity of selumetinib in combination with HAART.

    To monitor any effects that selumetinib has on the body (pharmoacodynamics - serum levels of angiogenic biomarkers, levels of pERK in tumour tissue, changes in peripheral blood mononuclear cells).

    To measure progression free survival at 6 months from commencing treatment.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Patients recruited in Sheffield, Manchester and Leicester will be asked to provide blood for additional laboratory analysis of peripheral blood mononuclear cells (PBMCs). This will explore the effects of pERK inhibition on PBMCs in detail including effects on accessory pathways. This analysis requires blood samples collected freshly and hence is limited to recruiting centres geographically neighbouring Sheffield.
    E.3Principal inclusion criteria
    •HIV positive and established on a HAART regimen for ≥ 3 months.
    •Histologically confirmed KS.
    •Measurable disease according to ACTG criteria.
    •Evidence of disease progression in the past 6 months.
    •Progressive cutaneous or nodal KS not requiring chemotherapy OR progressive KS following cytotoxic chemotherapy.
    •Adequate haematological function:
    o Haemoglobin ≥ 9 g/dL
    o Absolute neutrophil count ≥ 1.5 x 10 9/L
    o Platelets ≥ 100 x 10 9/L
    •Adequate hepatic function:
    o Serum bilirubin ≤ 1.5 x upper limit of normal (ULN), except if the patient is established on the anti-retroviral drug atazanavir (no upper limit) and has AST and ALT levels ≤ 2.5 x ULN
    o ALT ≤ 2.5 x ULN
    o AST ≤ 2.5 x ULN
    •Adequate renal function:
    o Serum creatinine clearance > 50 ml/min (Cockcroft-Gault formula or 24 hour urine collection).
    •Left ventricular function >50% normal
    •Age ≥ 18 years.
    •World Health Organisation (WHO0 performance status ≤ 2.
    •For selumetinib, women of child bearing age and child bearing potential MUST have a negative pregnancy test prior to study entry AND be using an adequate contraception method, which must be continued while on treatment and for at least 4 weeks after the study treatment has ended.
    •Male patients must agree to use an effective contraception method while on treatment and for at least 16 weeks after the study treatment has ended
    (barrier contraception is recommended for all individuals living with HIV).
    •Written informed consent
    E.4Principal exclusion criteria
    •HIV viral load > 200 copies/ml.
    •Active opportunistic infections.
    •Active hepatitis B, hepatitis C.
    Any prior exposure to MEK, Ras, or Raf inhibitors or history of hypersensitivity to selumetinib, or any excipient agents.
    • Any unresolved toxicity > CTCAE Grade 2 from previous anti-cancer therapy, except for alopecia
    • Cardiac conditions as follows:
    o Uncontrolled hypertension (BP ≥150/95 mmHg despite medical therapy)
    o Left ventricular ejection fraction <55% measured by echocardiography
    o Atrial fibrillation with a ventricular rate >100 bpm on ECG at rest
    o Symptomatic heart failure (NYHA grade II-IV)
    o Prior or current cardiomyopathy
    o Severe valvular heart disease
    o Uncontrolled angina (Canadian Cardiovascular Society grade II-IV despite medical therapy)
    o Acute coronary syndrome within 6 months prior to starting treatment
    •Major surgery within 4 weeks prior to starting selumetinib.
    •Evidence of any psychological, familial, sociological or geographical condition potentially hampering protocol compliance.
    •Clinical judgement by the Investigator that the patient should not participate in the study.
    •Refractory nausea, vomiting, chronic gastrointestinal diseases (e.g. inflammatory bowel disease) or significant bowel resection that would preclude adequate absorption.
    Ophthalmological conditions as follows:
    o Intra-ocular pressure >21 mmHg, or uncontrolled glaucoma (irrespective of intra-ocular pressure)
    o Current or past history of central serous retinopathy or retinal vein occlusion
    •Treatment with any investigational product within 28 days of registration
    •Pregnant or breast-feeding women.

    Due to higher PK exposure, patients of Asian ethnicity may be at a higher risk of adverse events with selumetinib treatment. Selumetinib is not contra-indicated in patients of Asian ethnicity, but the potential increased risk of toxicity should be considered and included as part of the discussion with the patient prior to receiving informed consent
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome in phase I is the safety and appropriate dosage of selumetinib in combination with HAART. For determining Maximum Tolerated Dose (MTD), defined as the highest dose producing one or less dose limiting toxicity (DLT), DLTs will be assessed during Cycle 1 in Phase I only, (i.e. up to the time of Cycle 2 day 1 assessment). This will be assessed by toxicity using CTCAE v 4.0 criteria.

    The primary outcome in phase II is the best tumour response rate with disease assessment based on AIDS Clinical Trials Group Oncology Committee criteria.
    E.5.2Secondary end point(s)
    The secondary endpoints are:
    - Toxicity
    - Progression free survival at 6 months after commencing treatment
    - Percentage inhibition of pERK in tumour tissue
    - Downstream proteins, apoptotic pathways and adaptive changes to other MAPK pathways
    - Percentage changes in serum angiogenic markers
    - Percentage changes in HIV-viral load and CD4 count
    E.5.2.1Timepoint(s) of evaluation of this end point
    Progression free survival will be measured for 6 month afters completion of treatment. Other secondary endpoints will be met during the treatment.
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    First study of selumetinib in combination with HAART.
    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 concerned6
    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 No
    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
    The end of trial is defined as 30 days after the last subject reaches 6 months post study enrolment.
    This definition allows completion of the secondary end-point of progression free survival rate at 6 months.
    Patients will continue to be followed up beyond 6 months with data collected by the CTU at 1 yr for supporting evidence for future trial planning.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days30
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months10
    E.8.9.2In all countries concerned by the trial days30
    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: 40
    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 state37
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 37
    F.4.2.2In the whole clinical trial 37
    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)
    If the patient is displaying clinical benefit after 18 weeks treatment selumetinib can be continued up to 1 year. Beyond 1 year, if there has been no disease progression, continued treatment will be at the discretion of the Chief Investigator, AZ and the treating physicican.

    Patients remaining on selumetinib would continue to come in for a consultation every 21 days.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation South Yorkshire CLRN
    G.4.3.4Network Country United Kingdom
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2011-11-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-11-10
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-06-30
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