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    Summary
    EudraCT Number:2014-004388-20
    Sponsor's Protocol Code Number:CRUKD/15/004
    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:2015-05-05
    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 number2014-004388-20
    A.3Full title of the trial
    A Cancer Research UK randomised, double-blind, placebo-controlled Phase IIa trial of AMG 319 given orally as a neoadjuvant therapy in patients with human papillomavirus (HPV) positive and negative head and neck squamous cell carcinoma (HNSCC)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase IIa trial of neoadjuvant AMG 319 in human papillomavirus (HPV) positive and negative head and neck squamous cell carcinoma (HNSCC).
    A.4.1Sponsor's protocol code numberCRUKD/15/004
    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 SponsorCancer Research UK
    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 Research UK
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportAmgen Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCancer Research UK
    B.5.2Functional name of contact pointCentre for Drug Development
    B.5.3 Address:
    B.5.3.1Street AddressAngel Building, 407 St John Street
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeEC1V 4AD
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+4402072420200
    B.5.5Fax number+4402030147633
    B.5.6E-mailregulatory@cancer.org.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 nameAMG 319
    D.3.2Product code AMG 319
    D.3.4Pharmaceutical form Capsule
    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 INNAMG 319
    D.3.9.2Current sponsor codeAMG 319 hydrate
    D.3.9.3Other descriptive nameAMG 319
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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
    D.8.3Pharmaceutical form of the placeboCapsule
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    human papillomavirus (HPV) positive and negative head and neck squamous cell carcinoma (HNSCC)
    E.1.1.1Medical condition in easily understood language
    human papillomavirus (HPV) positive and negative head and neck cancer
    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 10060121
    E.1.2Term Squamous cell carcinoma of head and neck
    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 assess changes in immune infiltration in tumour before and after treatment with AMG 319.
    To assess the safety and toxicity profile of AMG 319 in HNSCC.
    E.2.2Secondary objectives of the trial
    To investigate the pharmacokinetic behaviour of AMG 319.
    To document possible tumour response to neoadjuvant AMG 319.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) Histologically proven HNSCC of the hypopharynx, oropharynx, oral cavity ,supraglottis or larynx (except T1 glottic tumours) for whom surgery with curative intent ± post-operative radiotherapy or chemoradiotherapy is considered the primary treatment of choice. Surgery should be scheduled to take place no sooner than 21 days and no later than 30 days post first dose of AMG 319 or placebo.

    Patients presenting with recurrence can be considered for inclusion, as long as their previous treatment did not include radiotherapy ± chemotherapy or any other anti-cancer therapy i.e. treated with surgery alone and this did not take place within 6 months prior to trial entry.
    Patients presenting with a second primary HNSCC can be considered for inclusion, as long as any previous radiotherapy, chemotherapy or any other anti-cancer therapy was completed more than 5 years prior to trial entry.
    2) Patients considered fit to undergo curative resection surgery.
    3) Haematological and biochemical indices within the ranges shown below. These measurements must be performed within eight days prior to the patient receiving the first dose of AMG 319 or placebo.

    Laboratory Test Value required
    •Haemoglobin (Hb) ≥ 100 g/L
    •Absolute neutrophil count ≥ 1.5 x 10^9/L
    •Platelet count ≥ 100 x 10^9/L
    •Bilirubin ≤ 1.5 x upper limit of normal ULN
    •Alanine aminotransferase (ALT)
    and/or aspartate aminotransferase (AST) ≤ 2.5 x ULN
    •Alkaline Phosphatase (alk phos/ALP) ≤ 2.5 x ULN
    •Amylase ≤ 2 x ULN
    •Calculated creatinine clearance (using
    the Wright or Cockcroft-Gault formula) ≥ 50 mL/min

    4) 18 years or over at the time informed consent is given.
    5) Written (signed and dated) informed consent and capable of co-operating with treatment and follow-up.

    E.4Principal exclusion criteria
    1) Prior radiotherapy, immunotherapy, chemotherapy or other anti-cancer therapy (excluding surgery) for current HNSCC.
    2) Patients should be excluded from the trial if they have active or previous malignancies of other types which in the investigator's opinion would mean they are not a good candidate for the clinical trial.
    3) Female patients who are able to become pregnant (or are already pregnant or lactating). However, those patients who have a negative serum or urine pregnancy test before enrolment and agree to use two forms of contraception (one effective form plus a barrier method) [oral, injected or implanted hormonal contraception and condom; intra-uterine device and condom; diaphragm with spermicidal gel and condom] or agree to sexual abstinence*, effective from the first administration of AMG 319 throughout the trial and for six months afterwards are considered eligible.
    4) Male patients with partners of child-bearing potential (unless they agree to take measures not to father children by using a barrier method of contraception [condom plus spermicide] or to sexual abstinence* effective from the first administration of AMG 319, throughout the trial and for six months afterwards. Men with partners of child-bearing potential must also be willing to ensure that their partner uses an effective method of contraception for the same duration for example, hormonal contraception, intrauterine device, diaphragm with spermicidal gel or sexual abstinence). Men with pregnant or lactating partners must be advised to use barrier method contraception (for example, condom plus spermicidal gel) to prevent exposure of the foetus or neonate.
    5) Patients unable to swallow oral medications (trial medication must not be chewed, crushed, dissolved or divided).
    6) Major thoracic or abdominal surgery from which the patient has not yet recovered.
    7) At high medical risk because of non-malignant systemic disease including active uncontrolled infection.
    8) Active or uncontrolled auto-immune disease which may require systemic immunomodulator therapy during the trial treatment period. Exceptions to this are atopic dermatitis and psoriasis not requiring systemic treatment.
    9) Long term use of systemic corticosteroids with the exception of replacement treatment. Discontinuation of steroid use within seven days prior to receiving the first dose of AMG 319 or placebo would be acceptable. Inhaled and topical steroids are permitted.
    10) Known to be serologically positive for hepatitis B, hepatitis C or human immunodeficiency
    virus (HIV). If there is clinical suspicion of infection this must be ruled out by appropriate serological and PCR testing.
    11) QTc > 470 msec (Friderica [QTc F] correction) or a history or family history of QT prolongation.
    12) Regular and/or prolonged treatment with medications known to cause QTc interval prolongation within seven days prior to receiving the first dose of AMG 319 or placebo.
    13) Is a participant or plans to participate in another interventional clinical trial, whilst taking part in this Phase IIa trial of AMG 319. Participation in an observational trial or interventional clinical trial which does not involve administration of an IMP would be acceptable
    14) Any other condition which in the Investigator’s opinion would not make the patient a good candidate for the clinical trial.

    * Abstinence is only considered to be an acceptable method of contraception when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
    E.5 End points
    E.5.1Primary end point(s)
    • Detection of a greater than 2-fold increase in CD8+ effector T cell numbers in tumour tissue after treatment with AMG 319 as assessed by immunohistochemistry.

    • Determining causality of each adverse event to AMG 319 and grading severity according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.02.
    E.5.1.1Timepoint(s) of evaluation of this end point
    • CD8+ effector T cell numbers in tumour tissue: Pre and post treatment biopsies
    • Determining causality of each adverse event to AMG 319: continually reviewed
    E.5.2Secondary end point(s)
    • Determining the steady state concentration of AMG 319 in blood.
    • Re-assessment of tumour size immediately prior to resection surgery with Magnetic Resonance Imaging (MRI) or Computerised Tomography (CT) using Immune-Related Response Criteria (irRC).
    E.5.2.1Timepoint(s) of evaluation of this end point
    • Concentration of AMG 319 in blood: Blood samples for PK analysis to be collected pre-dose on Day 8 (± 1 day), Day 15 (± 1 day) and Day 22
    • Re-assessment of tumour size immediately prior to resection surgery (- 3 days)
    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 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) 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 Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    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 Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 concerned9
    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 the date when the last patient has completed their survival follow-up or all patients have died (whichever is first).
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months0
    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.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 42
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 12
    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 Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    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 state54
    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)
    Standard treatment - participation in this trial will not affect or delay standard treatment for patients recruited to the trial.
    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 Decision2015-06-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-06-08
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2018-05-03
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