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    The EU Clinical Trials Register currently displays   43851   clinical trials with a EudraCT protocol, of which   7283   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    Summary
    EudraCT Number:2014-000440-15
    Sponsor's Protocol Code Number:ACE-CL-001
    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:2014-03-27
    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 number2014-000440-15
    A.3Full title of the trial
    A Phase 1/2, Multicenter, Open-label, and Dose-escalation Study of ACP-196 in Subjects with Chronic Lymphocytic Leukemia, Richter's Syndrome or Prolymphocytic Leukemia
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A trial to see the effects of increased doses of ACP-196 (the test drug) in subjects with Leukemia
    A.4.1Sponsor's protocol code numberACE-CL-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-CL-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-cl-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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameacalabrutinib
    D.3.2Product code ACP-196
    D.3.4Pharmaceutical form Capsule, hard
    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.3.10 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
    • Chronic Lymphocytic Leukemia
    • Richter's Syndrome
    • Prolymphocytic Leukemia
    E.1.1.1Medical condition in easily understood language
    • Leukemia
    • Cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10036889
    E.1.2Term Prolymphocytic leukemia
    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 21.0
    E.1.2Level LLT
    E.1.2Classification code 10008976
    E.1.2Term Chronic lymphocytic leukemia
    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 10058728
    E.1.2Term Richter's syndrome
    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
    • Establish the safety and the MTD of orally administered acalabrutinib in subjects with CLL/SLL
    • Determine the PK of orally administered acalabrutinib and identification of its major metabolite
    E.2.2Secondary objectives of the trial
    Secondary Objective
    • Evaluate tumor response by ORR, DOR and PFS.

    Exploratory Objective
    • Measure PD parameters including drug occupancy of BTK, the target enzyme, and effect on biologic markers of B-cell function
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Men and women ≥ 18 years of age with a confirmed diagnosis of CLL/SLL, which has relapsed after, or been refractory to, ≥ 2 previous treatments for CLL/SLL.
    2. Must have measurable CLL/SLL defined as ≥ 1 lymph node ≥ 2 cm as measured in the longest diameter.
    3. Active disease meeting ≥ 1 of the following IWCLL 2008 criteria for requiring treatment:
    o Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (hemoglobin < 10 g/dL) and/or thrombocytopenia (platelets < 100,000/μL).
    o Massive (ie, ≥ 6 cm below the left costal margin), progressive, or symptomatic splenomegaly.
    o Massive nodes (ie, ≥ 10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy.
    o Progressive lymphocytosis with an increase of > 50% over a 2-month period or a lymphocyte doubling time (LDT) of < 6 months. LDT may be obtained by linear regression extrapolation of absolute lymphocyte counts (ALC) obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In subjects with initial blood lymphocyte counts of <30 X 109/L (30,000/μL), LDT should not be used as a single parameter to define indication for treatment. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (eg, infections) should be excluded.
    o Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy.
    o Constitutional symptoms documented in the subject's chart with supportive objective measures, as appropriate, defined as ≥ 1 of the following disease-related symptoms or signs:
    - Unintentional weight loss ≥ 10% within the previous 6 months before Screening.
     - Fevers higher than 100.5°F or 38.0°C for 2 or more weeks before Screening without evidence of infection.
     - Night sweats for > 1 month before screening without evidence of infection.
    4. ECOG performance status of ≤ 2.
    5. Agreement to use highly effective methods of contraception
    during the study and for 2 days after the last dose of study
    drug if sexually active and able to bear or beget children.
    6. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty.
    7. 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 subject privacy
    regulations).

    Inclusion Criteria for Treatment Subgroups. Subjects meeting the following criteria will be eligible for the indicated Treatment Subgroups. In addition, Inclusion Criteria 2 to 8 from the previous apply to the Treatment Subgroups as well.
    1. Treatment Naive only: Men and women ≥ 18 years of age with confirmed diagnosis of CLL/SLL, who require treatment per National Cancer Institute or International Working Group guidelines and a) do not want to receive
    chemoimmunotherapy or b) have comorbidities that would preclude chemoimmunotherapy.
    2. Ibrutinib Intolerant only: Men and women ≥ 18 years of age with confirmed diagnosis of CLL/SLL who are not tolerating ibrutinib due to ibrutinib-related AEs.
    3. Richter's Syndrome and Prolymphocytic Leukemia Transformation only: Men and women ≥ 18 years of age with biopsy proven DLBCL Richter's transformation or prolymphocytic leukemia transformation.
    4. Ibrutinib R/R only: Men and women ≥ 18 years of age with confirmed diagnosis of CLL/SLL whose best response after 2 cycles of ibrutinib therapy was SD or nonresponse or who initially responded to ibrutinib therapy and now have signs
    of clinical progression.
    E.4Principal exclusion criteria
    1. Prior malignancy, except for adequately treated basal cell,
    squamous cell skin cancer or in situ cervical cancer.
    Subjects with other prior malignancies from which the
    subject has been disease free for ≥ 2 years may be
    included if approved by 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%.
    4. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass..
    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. Relapsed after, or refractory to, prior BTK inhibitor therapy (Note: Does not apply to Ibrutinib R/R or Richter's Syndrome Group).
    8. Any history of Richter's transformation (Note: Does not apply to Richter's Syndrome Group).
    9. Central nervous system (CNS) involvement by lymphoma.
    10. Grade ≥ 2 toxicity (other than alopecia) continuing from prior anticancer therapy including radiation.
    11. Known history of human immunodeficiency virus (HIV) or serologic status indicating active hepatitis C virus (HCV) or hepatitis B virus (HBV) infection or any uncontrolled active systemic infection. Subjects with hepatitis B core antibody positive who are surface antigen negative or who are hepatitis C antibody positive will need to have a negative polymerase chain reaction (PCR) result before enrollment. Those who are hepatitis B surface antigen positive or hepatitis B PCR positive and those who are hepatitis C PCR positive will be excluded.
    12. Uncontrolled AIHA or ITP defined as declining hemoglobin or platelet count secondary to autoimmune destruction within the screening period or requirement for high doses of steroids (> 20 mg daily of prednisone daily or equivalent).
    13. History of stroke or intracranial hemorrhage within 6 months prior to the first dose of study drug.
    14. Requires treatment with proton-pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole).
    15. Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) within 7 days of first dose of study drug.
    16. Major surgery within 4 weeks before first dose of study drug.
    17. ANC < 0.75 x 109/L or platelet count < 50 x 109/L unless there is bone marrow involvement.
    18. Total bilirubin > 1.5 x ULN (total bilirubin ≤ 2.5 x ULN allowed in subjects with autoimmune hemolytic anemia that is otherwise controlled); AST or ALT > 3.0 x ULN unless disease related.
    19. Serum amylase > 1.5 x ULN or serum lipase > 1.5 x ULN.
    20. Significant screening ECG abnormalities including 2nd degree AV block type II, 3rd degree block, Grade 2 or higher bradycardia, or QTc ≥ 480 ms.
    21. Cardiac troponin I levels above the limit of normal as specified by the manufacturer.
    22. Breast feeding or pregnant.
    23. History of bleeding diathesis (eg hemophilia, von Willebrand disease).
    24. Concurrent participation in another therapeutic clinical trial.
    25. Estimated creatinine clearance of < 30 mL/min, calculated using the formula of Cockcroft and Gault [(140-Age) • Mass (kg)/(72 • creatinine mg/dL); multiply by 0.85 if female].
    26. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening.
    E.5 End points
    E.5.1Primary end point(s)
    Efficacy Parameters
    • Overall response rate
    • Duration of response
    • Progression-free survival (with a subgroup analysis by sex, male vs female for overall response rate, duration of response)

    Safety Parameters
    • DLTs and MTD
    • Frequency, severity, and attribution of adverse events (AEs)

    Pharmacokinetic and Pharmacodynamic Parameters
    The occupancy of BTK by acalabrutinib will be measured in peripheral blood mononuclear cells (PBMCs) with the aid of a biotin-tagged acalabrutinib analogue probe. The effect of acalabrutinib on biologic markers of B-cell function will also be evaluated.
    E.5.1.1Timepoint(s) of evaluation of this end point
    > 28 days until disease progression or an unacceptable drug-related toxicity occurs
    E.5.2Secondary end point(s)
    None defined
    E.5.2.1Timepoint(s) of evaluation of this end point
    N/A
    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 Yes
    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 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 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 Yes
    E.8.1.7.1Other trial design description
    Sequential Dose Escalation
    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 trial11
    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 EEA7
    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
    Italy
    United Kingdom
    United States
    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
    Last visit 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 years7
    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.1.1.1In 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: 143
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 143
    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 state39
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 53
    F.4.2.2In the whole clinical trial 286
    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)
    Any subjects who have not progressed while receiving study drug treatment and are tolerating study drug may continue beyond Cycle 60. Subjects who are still on treatment at the end of the study and deriving
    clinical benefit from acalabrutinib treatment may be eligible to enroll in a separate rollover study of acalabrutinib monotherapy.
    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 Decision2014-05-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-05-14
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2014-07-21
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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