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    Summary
    EudraCT Number:2014-002061-30
    Sponsor's Protocol Code Number:4.0
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2016-03-17
    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 number2014-002061-30
    A.3Full title of the trial
    Therapeutic HPV vaccine trial +/- anti-CD40 in HPV-driven squamous cell carcinoma.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    HPV Vaccine Trial
    A.3.2Name or abbreviated title of the trial where available
    HARE-40
    A.4.1Sponsor's protocol code number4.0
    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 SponsorUniversity Hospital Southampton 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 supportEuropean Commission FP7 Framework Programme
    B.4.2CountryEuropean Union
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSouthampton Clinical Trials Unit
    B.5.2Functional name of contact pointKerry-Ann Lee
    B.5.3 Address:
    B.5.3.1Street AddressSouthampton Clinical Trials Unit
    B.5.3.2Town/ cityMP131 Southampton General Hospital
    B.5.3.3Post codeSO166YD
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number02381205154
    B.5.5Fax number0844 7740621
    B.5.6E-mailHARE-40@soton.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 nameRBLO15.1(LIP)/RBLO16.1(LIP)
    D.3.2Product code N/A
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRBL015.1 (LIP)
    D.3.9.1CAS number N/A
    D.3.9.2Current sponsor codeRBL015.1 (LIP)
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number3.6 to 36.4
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRBL016.1 (LIP)
    D.3.9.1CAS number N/A
    D.3.9.2Current sponsor codeRBL016.1 (LIP)
    D.3.9.4EV Substance CodeAS2
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number3.6 to 36.4
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    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) Yes
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product Yes
    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) Yes
    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 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 nameRBLO15.1(RIN)/RBLO16.1(RIN)
    D.3.2Product code N/A
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntradermal use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRBL015.1(RIN)
    D.3.9.1CAS number N/A
    D.3.9.3Other descriptive nameDTH control re-agent 15.1
    D.3.9.4EV Substance CodeAS3
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number32
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRBL016.1(RIN)
    D.3.9.1CAS number N/A
    D.3.9.3Other descriptive nameDTH control re-agent 16.1
    D.3.9.4EV Substance CodeAS4
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number32
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    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) Yes
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product Yes
    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) Yes
    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
    HPV induced cancers such as Head and Neck Squamous Cell Carcinoma (HNSCC), Anogenital Cancer, Cervical Cancer, Penile Cancer
    E.1.1.1Medical condition in easily understood language
    Head and Neck Cancer(HNSCC), or any other cancer induced by the HPV virus
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10067821
    E.1.2Term Head and neck cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10008229
    E.1.2Term Cervical cancer
    E.1.2System Organ Class 100000020977
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10061424
    E.1.2Term Anal cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10034299
    E.1.2Term Penile cancer
    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
    Phase I objective:
    To establish a safe and tolerable dose of HPV mRNA vaccine (Arm 1A).

    Phase II objectives:
    • To assess if there is evidence of clinical effect (according to irRECIST 1.1 criteria) [Arm 1B].
    • To assess if there is evidence of clinical effect in terms of a significant increase of immune cells following E6 and E7 HPV mRNA vaccine [Arm 1B].


    E.2.2Secondary objectives of the trial
    • To establish the immunogenicity of the HPV mRNA vaccine and to characterise the immune responses (cellular and humoral) [Arms 1A and 1B].
    • To evaluate and to characterise immune events in blood and tumour following administration of E6 and E7 HPV mRNA vaccine [Arm 1B] and to assess their linkage to immune events in the blood and tissue of the skin [Arm 1B ].
    • To demonstrate that the tumour microenvironment can be manipulated by E6 and E7 HPV mRNA vaccine in advanced disease patients [Arms 1B]. This will be assessed by measuring immune cell numbers after intervention compared to baseline where two tissue samples can be collected.
    • To evaluate whether E6 and E7 HPV mRNA vaccine has detectable clinical effects in advanced HPV16-driven cancers and to assess if these clinical effects are linked with immune effects (blood; tissue where accessible) [Arm 1B].
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Arm 1A:
    • Previous HPV16+ head and neck squamous cell carcinoma.
    • At least 12 months after completion of treatment.
    • Within 5 years of treatment completion.
    • Currently no clinical evidence of disease.
    • ECOG performance status 0 or 1.
    • Able to provide written informed consent.

    Arm 1B:
    • HPV16+ head and neck, cervical, anogenital and penile carcinoma patients with recurrent disease.
    • Intention to treat is palliative.
    • Patient willing to have repeated tumour biopsies and re-biopsy deemed safe and feasible clinically.
    • Tissue samples available confirming HPV16+ disease to send to Central Laboratory.
    E.4Principal exclusion criteria
    Arm 1A and 1B:
    • Patients unable to consent.
    • Any patient who has been previously vaccinated in any Arm of the trial.
    • <18 years
    • Systemic steroids (prednisolone >10 mg/day or equivalent) or other drugs with a likely effect on immune competence are forbidden during the trial. The predictable need of their use will preclude the patient from trial entry. Replacement steroids for adrenal insufficiency/failure are allowed.
    • Major surgery in the preceding three to four weeks, which the patient has not yet recovered from.
    • Patients who are of high medical risk because of non-malignant systemic disease, as well as those with active uncontrolled infection.
    • Patients with clinically relevant autoimmune disease will be excluded.
    • Patient with a history of anaphylactic reactions or severe allergies are excluded.
    • Patients with any other condition which in the Investigator’s opinion would not make the patient a good candidate for the clinical trial, such as concurrent congestive heart failure or prior history of New York Heart Association (NYHA) class III/IV cardiac disease.
    • Current malignancies at other sites, with the exception of adequately treated basal or squamous cell carcinoma of the skin. Cancer survivors, who have undergone potentially curative therapy for a prior malignancy, have no evidence of that disease for five years and are deemed at low risk for recurrence, are eligible for the study.
    • Patients who are serologically positive for or are known to suffer from Hepatitis B, C, Syphilis or HIV. Counselling will be offered to all patients prior to testing.
    • Patients who have a positive pregnancy test or who are breast feeding.
    • Fertile males or females who are unable or unwilling to use an effective method of birth control (eg. condom with spermicide, diaphragm with spermicide, birth control pills, injections, patches, intrauterine device, or intrauterine hormone-releasing system) during study treatment and until 28 days after patients finish the study end of treatment.
    • Elevated Liver Function Tests – ALT >3.0 x ULN, AST >3.0 x ULN, Bilirubin >3.0 x ULN.
    • Any other investigational drug within 28 days or 5 half-lives depending on what gives the longer range before the first treatment of this study
    E.5 End points
    E.5.1Primary end point(s)
    Arm 1A: safety and Toxicity

    Arm 1B: Response according to irRECIST
    E.5.1.1Timepoint(s) of evaluation of this end point
    Arm 1A: Following cohort SRC meetings

    Arm 1B: End of Treatment
    E.5.2Secondary end point(s)
    Arm 1A:
    • Adverse event rate according to CTCAE v4.03.
    • Systemic levels of induced HPV16‐specific T‐cell and B-cell immune responses.
    • Duration of detectable vaccine‐induced immune responses (if appropriate).


    Arm 1B:
    • Adverse event rate according to CTCAE v4.03.
    • Systemic levels of induced HPV16‐specific T‐cell and B-cell immune responses.
    • Duration of detectable vaccine‐induced immune responses (if appropriate).
    • Percentage change in densities of immune cells in tumour tissue (where paired samples can be collected).
    • Change in numbers of immune cells from screening to the end of treatment as assessed by immunohistochemistry or flow cytometry.
    • Clinical response according to irRECIST 1.1 at Day 85, and at months 6 and 9.
    • Disease control rate according to irRECIST 1.1 at months 6 and 9.
    • Best overall response (irRECIST 1.1).
    • Intra-tumoural levels of HPV16‐specific immune responses (where paired tumour samples can be collected).
    • Safety/tolerability of HPV mRNA vaccine in terms of the adverse event rate according to CTCAE v4.03 at Day 85.
    • Grade 3 or above vaccine administration-related toxicity (within 90 days after the last administration of study drugs).
    • Progression-Free Survival (PFS).
    • Overall Survival (OS).
    • Disease Specific Interval (DSI).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Arm 1A
    End of Treatment
    End of Treatment
    End of Treatment

    Arm 1B
    End of Treatment
    End of Treatment
    End of Treatment
    End of Treatment
    End of Treatment, 6 and 9 months
    Day 85,6&9 months
    6&9 months
    Month 24
    End of Treatment
    End of Treatment
    End of Treatment - within 90 days after the last administration of study drugs
    End of Treatment
    End of Treatment
    End of 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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    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 Yes
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Dose escalation study
    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) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA1
    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
    The trial will end when all patient visits have taken place and all data has been accurately submitted.
    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 months5
    E.8.9.1In the Member State concerned days29
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months5
    E.8.9.2In all countries concerned by the trial days29
    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: 123
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 30
    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 state153
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 153
    F.4.2.2In the whole clinical trial 153
    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)
    There will be no continued provision of the study drugs after completion of the course of administration. Patients will receive up to 8 doses of the vaccine and if in part 2 of the study, up to 4 doses of the antibody.
    Following completion of the patient's follow up they will continue with standard of care which includes ongoing regular surveillance.
    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 Decision2016-05-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-07-18
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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