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    EudraCT Number:2015-005317-68
    Sponsor's Protocol Code Number:ACE-CL-208
    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:2016-02-09
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2015-005317-68
    A.3Full title of the trial
    A Phase 2 Study of the Efficacy and Safety of ACP-196 in Subjects with Relapsed/Refractory CLL and Intolerant of Ibrutinib Therapy
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 2 Study of the Efficacy and Safety of ACP-196 in Subjects with Relapsed/Refractory CLL and Intolerant of Ibrutinib Therapy
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberACE-CL-208
    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 B.V.
    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
    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-208 Clinical Team
    B.5.3 Address:
    B.5.3.1Street AddressKloosterstraat 9, 5349
    B.5.3.2Town/ cityAB OS
    B.5.3.3Post codeCA 64065
    B.5.4Telephone number001650 591 2800
    B.5.5Fax number0016505912816
    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 Yes
    D. name Calquence
    D. of the Marketing Authorisation holderAstraZeneca
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEMA/OD/198/15
    D.3 Description of the IMP
    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.3.9.1CAS number 1420477-60-6
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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
    High Risk Chronic Lymphocytic Leukemia
    E.1.1.1Medical condition in easily understood language
    High Risk Chronic Lymphocytic Leukemia
    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 10008976
    E.1.2Term Chronic lymphocytic leukemia
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of acalabrutinib in subjects with relapsed/refractory CLL who are intolerant of ibrutinib therapy
    E.2.2Secondary objectives of the trial
    To evaluate the safety and tolerability of acalabrutinib in subjects with relapsed/refractory CLL who are intolerant of ibrutinib therapy
    - To determine the effect of acalabrutinib on peripheral blood B cells, T cells, NK cells, and MDSCs.
    - To evaluate potential predictive biomarkers and mechanisms of resistance for the disease.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Men and women ≥ 18 years of age.

    2. Prior diagnosis of CLL that meets published diagnostic criteria as follows:

    a. Monoclonal B-cells (either kappa or lambda light chain restricted) that are clonally co-expressing ≥ 1 B-cell marker (CD19, CD20, or CD23) and CD5.

    b. Prolymphocytes may comprise ≤ 55% of blood lymphocytes.

    c. No evidence of cyclin D1 rearrangement or BCL-1 over expression.

    d. Presence of ≥ 5 x 109 B lymphocytes/L (5000 μL) in the peripheral blood (at any point since diagnosis).

    3. Must have received ≥ 1 prior therapy for CLL and not be appropriate for treatment or retreatment with purine analogue-based therapy as defined by ≥ 1 of the following criteria:

    a. Failure to respond (stable disease [SD] or disease progression on treatment) or progression-free interval of < 3 years from treatment with a purine analogue-based therapy and anti-CD20 antibody-containing chemoimmunotherapy regimen after ≥ 2 cycles.

    b. Age ≥ 70 years

    c. Age ≥65 years with the presence of 1 of the following comorbidities that might place the subject at an unacceptable risk for treatment-related toxicity with purine analogue-based therapy, provided they have received ≥1 prior treatment including ≥2 cycles of an alkylating-agent based (or purine analogue-based) anti-CD20 antibody-containing chemoimmunotherapy regimen:

    i. Cumulative Illness Rating Scale - Geriatric (CIRS-G) ≥6.

    ii. Creatine clearance (CrCL) <70 mL/min.

    d. History of purine analogue-associated autoimmune anemia, neutropenia, or autoimmune thrombocytopenia.

    e. Fluorescent in situ hybridization (FISH) showing 17p deletion mutation or p53 mutation (by central laboratory).

    4. Intolerant of ibrutinib, defined as:

    a. The subject has discontinued ibrutinib therapy due to Grade 3 or 4 AEs that persisted in spite of optimal supportive care measures OR

    b. Subjects who had Grade 2 AEs related to ibrutinib therapy, in spite of optimal supportive care measures that persisted for ≥ 2 weeks or that recurred ≥ 2 times whether dose was reduced or discontinued.

    5. Measurable nodal disease by CT, defined as ≥ 1 lymph node > 1.5 cm as measured in the longest diameter in a site that has not been previously irradiated. An irradiated lesion may be assessed for measurable disease only if there has been documented progression in that lesion since radiotherapy has ended.

    6. Documented disease progression after stopping ibrutinib therapy as defined by the IWCLL 2008 criteria.

    7. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.

    8. 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.

    9. This criterion has been removed as of Protocol Amendment 3.

    10. This criterion has been removed as of Protocol Amendment 3.

    11. Willing and able to participate in all required evaluations and procedures in this study protocol, including swallowing capsules without difficulty.

    12. 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 patient privacy regulations).
    E.4Principal exclusion criteria
    1. Ongoing Grade 3 or 4 AE attributed to ibrutinib therapy. Note: Subjects may be eligible for enrollment once the ibrutinib-related AE improves to Grade ≤ 2.

    2. Treatment with systemic anticancer therapy for CLL is prohibited between discontinuation of ibrutinib and enrollment on this trial.

    3. Prior exposure to a BCL-2 inhibitor (e.g., venetoclax/ABT-199).

    4. Prior malignancy (other than CLL), except for adequately treated basal cell or squamous cell skin cancer, in situ cancer, or other cancer from which the subject has been disease free for ≥ 2 years.

    5. 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 corrected QT interval (QTc) > 480 msec at screening. Exception: Subjects with controlled, asymptomatic atrial fibrillation during screening are allowed to enroll on study.

    6. Malabsorption syndrome, disease significantly affecting gastrointestinal function, resection of the stomach, extensive small bowel resection that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass.

    7. Evidence of active Richter's transformation or any evidence of disease progression on ibrutinib therapy or any BTK inhibitor.

    8. CNS involvement by CLL or related Richter’s transformation.

    9. Known history of HIV, serologic status reflecting active hepatitis B or C infection, or any uncontrolled active systemic infection.

    a) Subjects who are anti-hepatitis B core antibody (anti-HBc) positive and who are surface antigen negative will need to have a negative polymerase chain reaction (PCR) result before enrollment. Those who are hepatitis B surface antigen (HBsAg) positive or hepatitis B PCR positive will be excluded.

    b) Subjects who are hepatitis C antibody positive will need to have a negative PCR result before enrollment. Those who are hepatitis C PCR positive will be excluded.

    10. Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (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 or equivalent for longer than 2 weeks).

    11. History of stroke or intracranial hemorrhage within 2 months before the first dose of study drug.

    12. History of bleeding diathesis (e.g., hemophilia or von Willebrand disease).

    13. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening.

    14. Major surgical procedure within 28 days of first dose of study drug. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug.

    15. Requires treatment with a strong CYP3A inhibitor.

    16. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment to this study.

    17. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon).

    18. Absolute neutrophil count (ANC) < 0.75 x 109/L or platelet count < 50 x 109/L, unless there is bone marrow involvement.

    19. Total bilirubin > 1.5 x upper limit of normal (ULN); or AST or ALT >3.0 x ULN.

    20. Estimated CrCL 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].

    21. Breastfeeding or pregnant.

    22. Concurrent participation in another therapeutic clinical trial.
    E.5 End points
    E.5.1Primary end point(s)
    Efficacy will be evaluated based on the modified International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria (Appendix 2).

    The primary efficacy endpoint is ORR assessed by the investigators.
    E.5.1.1Timepoint(s) of evaluation of this end point
    See section above.
    E.5.2Secondary end point(s)
    The secondary efficacy endpoints are:
    • Duration of response (DOR)
    • PFS
    • Time-to-next treatment (TTNT)
    • OS

    The safety of acalabrutinib will be characterized by laboratory assessments and the type, frequency, severity, and causal attribution of AEs, or AEs leading to discontinuation of study treatment.

    For consistency of interpretation, AEs and laboratory results will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), and the severity of both hematologic and nonhematologic AEs will be graded using the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 or higher. Standard definitions for seriousness will be applied (see Section 6.1).

    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 B cells, NK cells (CD56+), T cells (CD3+, CD4+, CD8+ levels), and MDSCs (HLA-DR- CD14+CD11b+ CD33+ levels) will also be evaluated. Genotyping for BTK, p53, and phospholipase C gamma (PLCγ) mutations will be performed.
    E.5.2.1Timepoint(s) of evaluation of this end point
    See section above.
    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) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. 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 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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA15
    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
    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
    The end of trial is defined as the date of the last subject’s last visit.
    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 months8
    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 months8
    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: 30
    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 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 state2
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 10
    F.4.2.2In the whole clinical trial 60
    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)
    After completing study regimen treatment can continue until the end of the trial for subjects without disease progression and who are tolerating therapy after discussion with the medical monitor.
    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 Decision2016-03-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-05-16
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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