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    The EU Clinical Trials Register currently displays   43719   clinical trials with a EudraCT protocol, of which   7255   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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    EudraCT Number:2015-003213-18
    Sponsor's Protocol Code Number:RHMCAN1129
    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:2016-12-07
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2015-003213-18
    A.3Full title of the trial
    A Phase Ib/II combination trial of acalabrutinib with rituximab, cyclophosphamide, doxorubicin,vincristine and prednisolone (R-CHOP) for patients with diffuse large B-cell lymphoma (DLBCL)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A phase Ib/II combination trial of acalabrutinib with standard R-CHOP chemotherapy in patients with diffuse large B-cell lymphoma
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberRHMCAN1129
    A.5.4Other Identifiers
    Name:CR UK Trial NumberNumber:CRUKDE/16/006
    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 support
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Hospital Southampton NHS Foundation Trust
    B.5.2Functional name of contact pointAilsa Duckworth
    B.5.3 Address:
    B.5.3.1Street AddressR&D office, E level, Southampton Centre for Biomedical Research
    B.5.3.2Town/ citySouthampton General Hospital, Tremona Road
    B.5.3.3Post codeSO16 6YD
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number023 8120 5131
    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.3.4Pharmaceutical 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 (Org 300196-0; SCH 900850)
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number100 to 200
    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
    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
    Diffuse large B-cell lymphomas (most common type of non-Hodgkins lymphoma)
    E.1.1.1Medical condition in easily understood language
    Diffuse large B-cell lymphomas (most common type of non-Hodgkins lymphoma)
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.1
    E.1.2Level PT
    E.1.2Classification code 10012818
    E.1.2Term Diffuse large B-cell lymphoma
    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
    The primary objective at Stage 1 is to:
    1. Examine the safety and toxicity profile of acalabrutinib in combination with R-CHOP and define the dose limiting toxicity (DLT) or maximum administered dose (MAD).

    The primary objective at Stage 2 is to:
    2. To document the anti-tumour activity of acalabrutinib in combination with R-CHOP in patients with previously untreated CD20 positive DLBCL.
    3. To determine additional safety information on acalabrutinib in combination with R-CHOP.

    E.2.2Secondary objectives of the trial
    Secondary and Tertiary objectives

    Secondary Objectives

    1. To determine the pharmacokinetic (PK) profile of acalabrutinib when given in combination with R-CHOP in patients with DLBCL.

    2. To evaluate the effect of acalabrutinib in combination with R-CHOP on outcomes according to cell of origin.

    3. To measure the duration of response to acalabrutinib in combination with R-CHOP over a follow-up period of 2 years.

    Tertiary Objectives

    4. To determine BTK occupancy by acalabrutinib in peripheral blood mononuclear cells when given in combination with R-CHOP.

    5. To determine BTK occupancy by acalabrutinib in tumour material taken 8 days after initiation of therapy when acalabrutinib is given in combination with R-CHOP (optional).

    6. To determine the impact of the addition of acalabrutinib on R-CHOP mediated antibody dependent cellular cytotoxicity (ADCC).

    7. To determine evidence of B-cell receptor activation (BCR) in patients before and after treatment with R-CHOP and acalabrutinib.

    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Histologically confirmed DLBCL, expressing CD20. Sufficient diagnostic material should be available to forward to a central laboratory for gene expression profiling and pathology review
    2. Measurable disease of at least 15mm
    3. Not previously treated for lymphoma and fit enough to receive combination chemoimmunotherapy with curative intent
    4. Stage IAX (bulk defined as lymph node diameter >10cm) to stage IV disease and deemed to require a full course of chemotherapy. Patients with non-bulky IE disease are not eligible
    5. ECOG performance status 0-2 or 3 if this is directly attributable to lymphoma
    6. Adequate bone marrow function with platelets > 100x109/L; neutrophils > 1.0x109/L at study entry, unless lower figures are attributable to lymphoma
    7. Measured or calculated creatinine clearance > 30mls/min, (calculated using the formula of Cockcroft and Gault [(140-Age) x Mass (kg)x(1.04 (for women)or 1.23 (for men))/Serum Creatinine (umolL)]
    8. Serum bilirubin < 35╬╝mol/L and transaminases < 2.5x upper limit of normal at time of study entry
    9. Cardiac function sufficient to tolerate 300mg/m2 of doxorubicin. A pre-treatment echocardiogram or MUGA is required to establish baseline LVEF equal to or greater than 55%
    10. No concurrent uncontrolled medical condition
    11. Life expectancy > 3 months
    12. Aged 16 years or above
    13. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty
    14. Ability to understand the purpose and risks of the study and provide signed and dated informed consent
    E.4Principal exclusion criteria
    1. Previous history of treated or untreated indolent lymphoma. However newly diagnosed patients with DLBCL who are found to also have small cell infiltration of the bone marrow or other diagnostic material (discordant lymphoma) will be eligible
    2. Patients who have received immunisation with a live vaccine within four weeks prior to enrolment will be ineligible
    3. Diagnosis of primary mediastinal lymphoma
    4. Diagnosis of primary Central Nervous System lymphoma.
    5. History of stroke or intracranial haemorrhage in preceding 6 months
    6. History of bleeding diathesis (eg. haemophilia, von Willebrand disease)
    7. Requires or receiving anticoagulation with warfarin or equivalent antagonists (eg. phenprocoumon) within 7 days of first dose of acalabrutinib. However patients using therapeutic low molecule weight heparin or low dose aspirin will be eligible
    8. Prior exposure to a BCR inhibitor(eg. BtK inhibitors, phosphoinositide-3 kinase (PI3K), or SyK inhibitors) or BCL-2 inhibitor (eg. ABT-199)
    9. Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer
    10. Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Patients receiving proton pump inhibitors who switch to short-acting H2-receptor antagonists or antacids are eligible for enrolment into this study.
    11. Uncontrolled systemic infection
    12. Major surgery in the preceding 4 weeks of first dose of study drug. 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
    13. 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.
    14. Serological positivity for Hepatitis B, C, or known HIV infection. As per standard of care, prior to initiation of immunochemotherapy, the results of hepatitis serology should be known prior to commencement of therapy.
    - Positive test results for chronic HBV infection (defined as positive HBsAg serology) will not be eligible. Patients with occult or prior HBV infection (defined as negative HBsAg and positive total HBcAb) will not be eligible. Patients who have protective titres of hepatitis B surface antibody (HBsAb) after vaccination will be eligible.
    - Positive test results for hepatitis C virus (HCV) antibody serology will not be eligible.
    15. Women who are sexually active and can bear children must agree to use highly effective forms of contraception during the study and for 90 days after the last dose of acalabrutinib. Highly effective forms of contraception are defined in Section 4.7
    16. Breastfeeding or pregnant
    17. Men who are sexually active and can potentially father children must agree to use highly effective forms of contraception during the study and for 90 days after the last dose of acalabrutinib. Highly effective forms of contraception are defined in Section 4.7
    18. Men must agree to refrain from sperm donation during the study and for 90 days after the last dose of study drug.
    19. Serious medical or psychiatric illness likely to affect participation or that may compromise the ability to give informed consent
    20. Prior malignancy (other than DLBCL), 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 SCTU
    21. Malabsorption syndrome, disease significantly affecting gastrointestinal function, resection of the stomach or small bowel, gastric bypass, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction or gastric restrictions and bariatric surgery, such as gastric bypass
    22. Any immunotherapy within 4 weeks of 1st dose of the study
    23. Concurrent participation in another therapeutic clinical trial
    E.5 End points
    E.5.1Primary end point(s)
    1. Dose limiting toxicity of acalabrutinib combined to R-CHOP

    2. Overall response rate of the combination acalabrutinib and R-CHOP

    3. Safety of the combination acalabrutinib and R-CHOP
    E.5.1.1Timepoint(s) of evaluation of this end point
    For eligible patients AE collection and monitoring commences from the time the patient gives their written consent to participate in the trial and continues for two years after the last administration of acalabrutinib.

    A CT scan (potentially bone marrow) at the end of therapy visit and continued monitoring through follow up will be used to assess overall response.

    Follow up of AEs with a causality of possible, probable or highly probable will continue until the events resolve, stabilise or the patient starts another anticancer therapy.
    E.5.2Secondary end point(s)
    1. Pharmokinetic of acalabrutinib, AUC, Cmax, Tmax, half-life T1/2 and other PK parameter.

    2. Overall response rate of the combination acalabrutinib and R-CHOP according cell of origin

    3. 2-years progression-free survival; 2 years overall survival.

    4. BTK occupancy by acalabrutinib on peripheral blood (PBMC) using fluorescent affinity probe assay.

    5. BTK occupancy by acalabrutinib in repeat tumour core biopsy using a fluorescent affinity probe assay.

    6. Antibody-dependent cell-mediated cytotoxicity (ADCC) of R-CHOP when combined to acalabrutinib, post 1st R-CHOP and at day 8, 2nd cycle acalabrutinib + R-CHOP.

    7. CD86 and CD69 expression as a function of BCR activation by flow cytometry.

    8. Tumour-specific DNA in plasma will be sequenced throughout treatment and compared with lymphoma tissue and clinical course

    9. Apply the following techniques to FFPE tumour material: mutational panel, FISH analysis, immunohistochemical analysis for dual protein expression of Myc and Bcl2 and gene expression
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. PK samples: cycle 2 days 1, 8, 15; cycle 3 day 1;

    2. Gene expression analysis on original biopsy sample.

    3. Disease assessments at baseline, end of therapy visit, then 1 & 2 years post-treatment.

    4. BTK occupancy in PBMCs: cycle 2 days 1 and 8.

    5. Option ultrasound guided needle biopsy or fine needle aspirate at baseline and on cycle 2 day 8.

    6. ADCC assay performed at cycle 2 days 1 and 8.

    7. CD86 and CD69 expression: cycle 2 days 1, 8 and cycle 4 day 1.

    8. Streck Plasma DNA Sample: Baseline, cycle 2 day 1, cycle 3 day 1, end of treatment and follow up visits 3, 6, 9, 12, 16, 20 and 24

    9. Tests on baseline tumour sample.
    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 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 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 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) 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 concerned7
    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 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 the trial is defined as: The patient reaches the final follow up visit, which will be 2 years after receiving the last study treatment.
    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 days3
    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 days3
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F. of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F. of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F. of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F. of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F. of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) Yes
    F. of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 24
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 15
    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 state39
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 39
    F.4.2.2In the whole clinical trial 39
    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)
    Patients will be treated according to standard NHS Guidelines and local policy once they have finished the study. Patients will receive study drug until treatment completion, treatment is discontinued as a result of toxicity, patients withdrawal of consent, or the physicians decision to withdraw the patient from study.
    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 Decision2017-01-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-01-05
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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