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    Summary
    EudraCT Number:2014-003212-36
    Sponsor's Protocol Code Number:ACE-WM-001
    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:2014-11-14
    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 number2014-003212-36
    A.3Full title of the trial
    An Open-label, Phase 2 Study of ACP-196 in Subjects
    with Waldenström Macroglobulinemia
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An Open-label, Phase 1b/2 Study of ACP-196 in Subjects
    with Waldenström Macroglobulinemia
    A.3.2Name or abbreviated title of the trial where available
    ACE-WM-001
    A.4.1Sponsor's protocol code numberACE-WM-001
    A.5.4Other Identifiers
    Name:IND NumberNumber:118717
    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 SponsorAcerta Pharma BV
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAcerta Pharma BV
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAcerta Pharma BV
    B.5.2Functional name of contact pointACE-WM-001 Clincial Team
    B.5.3 Address:
    B.5.3.1Street AddressKloosterstraat 9
    B.5.3.2Town/ cityOss
    B.5.3.3Post code5349 AB
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+16505912800
    B.5.6E-mailace-wm-001@acerta-pharma.com
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/16/1626
    D.3 Description of the IMP
    D.3.1Product nameacalabrutinib
    D.3.2Product code ACP-196
    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 INNacalabrutinib
    D.3.9.2Current sponsor codeACP-196
    D.3.9.3Other descriptive nameACP-196
    D.3.9.4EV Substance CodeSUB166233
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Waldenström Macroglobulinemia
    E.1.1.1Medical condition in easily understood language
    blood 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 10047804
    E.1.2Term Waldenstrom's macroglobulinaemia recurrent
    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 10047805
    E.1.2Term Waldenstrom's macroglobulinaemia refractory
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the ORR of acalabrutinib in subjects with WM as measured by investigators.
    E.2.2Secondary objectives of the trial
    • To determine the ORR of acalabrutinib by Independent Review
    Committee (IRC)
    • To determine the duration of overall response (DOR) of acalabrutinib by investigator and by IRC, respectively
    • To determine the progression-free survival (PFS) of acalabrutinib by investigator and by IRC, respectively
    • To determine the overall survival (OS) of acalabrutinib
    • To characterize the PK profile of acalabrutinib
    • To characterize the safety of acalabrutinib
    • To evaluate the effect of acalabrutinib in health-related quality of life

    Exploratory Objective
    • To evaluate the PD effects of acalabrutinib
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Men and women ≥ 18 years of age.
    2. Previously treated cohort only: A confirmed diagnosis of WM, which has relapsed after, or been refractory to ≥ 1 prior therapy for WM and which requires treatment
    3. Previously untreated cohort only: A confirmed diagnosis of previously untreated WM in subjects who require treatment and do not want to receive chemoimmunotherapy or have comorbidities that would preclude chemoimmunotherapy such as:
    • Symptomatic hyperviscosity with an IgM ≥ 5,000 mg/dL
    • Disease-related neuropathy
    4. Serum concentration of IgM, as measured by serum protein electrophoresis (SPEP) and immunofixation electrophoresis (IFE), that exceeds the upper limits of normal or measurable nodal WM (defined as the presence of ≥1 lymph node that measures ≥ 2.0 cm in the longest diameter and ≥ 1.0 cm in the longest perpendicular diameter).
    5. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
    6. Women who are sexually active and can bear children must agree to use highly effective forms of contraception during the study and for 2 days after the last dose of acalabrutinib. Highly effective forms of contraception are defined in the protocol.
    7. This criterion was removed as of Protocol Amendment 7.
    8. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty.
    9. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local patientprivacy regulations).
    E.4Principal exclusion criteria
    1. Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the subject has been disease free for ≥ 2 years or which will not limit survival to < 2 years. Note: These cases must be discussed with the Medical Monitor.
    2. A life-threatening illness, medical condition or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of acalabrutinib, or put the study outcomes at undue risk.
    3. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or left ventricular ejection fraction (LVEF) ≤ 40%, or QTc > 480 msec.
    4. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or
    complete bowel obstruction.
    5. Any immunotherapy within 4 weeks of first dose of study drug.
    6. For subjects with recent chemotherapy or experimental therapy the first dose of study drug must occur after 5 times the half-life of the agent(s).
    7. Prior exposure to a BCR inhibitor (eg, Btk, phosphoinositide-3 kinase [PI3K]]], or Syk inhibitors) or BCL-2 inhibitors (eg, ABT-199).
    8. Ongoing immunosuppressive therapy, including systemic or enteric corticosteroids for treatment of WM or other conditions. Note: Subjects may use topical or inhaled corticosteroids or low-dose steroids (≤ 10 mg of prednisone or equivalent per day) as therapy for comorbid conditions. During study participation, subjects may also receive systemic or enteric corticosteroids as needed for treatment-emergent comorbid conditions.
    9. Grade ≥ 2 toxicity (other than alopecia) continuing from prior anticancer therapy including radiation.
    10. Known history of human immunodeficiency virus (HIV) or active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) or any uncontrolled active systemic infection.
    11. Major surgery within 4 weeks before first dose of study drug.
    12. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura.
    13. History of a bleeding diathesis (eg, hemophilia, von Willebrand disease).
    14. History of stroke or intracranial hemorrhage within 6 months before the first dose of acalabrutinib.
    15. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) within 28 days of first dose of study drug.
    16. Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole).
    17. Absolute neutrophil count (ANC) < 0.75 x 10^9/L or platelet count <50 x 10^9/L. For subjects with disease involvement in the bone marrow, ANC < 0.50 x 10^9/L or platelet count < 30 x 10^9/L.
    18. Creatinine > 2.5 x institutional upper limit of normal (ULN); total bilirubin > 2.5 x ULN; or aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3.0 x ULN
    19. Lactating or pregnant.
    20. Concurrent participation in another therapeutic clinical trial.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint of the study is the overall response rate, defined as a subject achieving a minor response or better according to the Response Assessment Criteria for WM as assessed by investigators.

    ORR, defined as a subject achieving a MR or better according to the
    response assessment criteria defined by Modified 3rd IWWM workshop criteria, as assessed by investigators.
    E.5.1.1Timepoint(s) of evaluation of this end point
    after 30 days after stop study treatment
    E.5.2Secondary end point(s)
    Efficacy:
    • Overall Response Rate (ORR), defined by Modified 3rd IWWM
    workshop criteria, as assessed by IRC
    • Duration of overall response (DOR) by investigator, assessed using
    Response Assessment Criteria for WM and Modified 3rd IWWM workshop criteria
    • DOR by IRC, assessed using the Modified 3rd IWWM workshop criteria
    • Progression-free survival (PFS) by investigator, assessed using
    Response Assessment Criteria for WM and Modified 3rd IWWM workshop criteria
    • PFS by IRC, assessed using the Modified 3rd IWWM workshop criteria
    • Overall survival (OS)
    • Effect of acalabrutinib on peripheral T/B/natural killer (NK) cell counts
    • Effect of acalabrutinib on serum immunoglobulin levels

    Safety:
    • Frequency, severity, and relatedness of adverse events (AEs)
    • Frequency of AEs requiring discontinuation of study drug or dose
    reductions

    Pharmacokinetics
    • Plasma pharmacokinetics of acalabrutinib

    Patient Reported Outcomes:
    • Health-related quality of life

    Exploratory Endpoints
    Pharmacodynamics:
    • BTK occupancy and biologic markers of B-cell function
    E.5.2.1Timepoint(s) of evaluation of this end point
    after 30 days after stop study 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
    Safety and Efficacy Profile
    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 Yes
    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.8.2.4Number of treatment arms in the trial1
    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 concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA11
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    France
    Greece
    Italy
    Netherlands
    United Kingdom
    United States
    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
    End of study is defined as 48 cycles after enrolment of the last subject.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    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 years3
    E.8.9.2In all countries concerned by the trial months6
    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: 18
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 70
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 70
    F.4.2.2In the whole clinical trial 88
    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)
    none
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-01-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-04-24
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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