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    Summary
    EudraCT Number:2017-004401-40
    Sponsor's Protocol Code Number:RG_17-194
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-11-06
    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 number2017-004401-40
    A.3Full title of the trial
    STELLAR: A phase II, randomiSed study of CHOP-R in combination with acalabruTinib comparEd to CHOP-R in patients with newLy diagnosed Richter’s Syndrome (RS) and a pLAtfoRm for initial investigations into activity of novel treatments in relapsed/refractory and newly diagnosed RS.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A trial of CHOP-R therapy with or without acalabrutinib in patients with newly diagnosed Richter's Syndrome
    A.3.2Name or abbreviated title of the trial where available
    STELLAR
    A.4.1Sponsor's protocol code numberRG_17-194
    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 of Birmingham
    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 supportBloodwise
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportAcerta
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity of Birmingham
    B.5.2Functional name of contact pointDr Francesca Yates
    B.5.3 Address:
    B.5.3.1Street AddressCentre for Clinical Haematology
    B.5.3.2Town/ cityQueen Elizabeth Hospital Birmingham
    B.5.3.3Post codeB15 2TT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01213717867
    B.5.5Fax number01213717878
    B.5.6E-mailstellar@trials.bham.ac.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 Information not present in EudraCT
    D.2.1.1.1Trade name Cyclophosphamide
    D.2.1.1.2Name of the Marketing Authorisation holderSandoz Limited
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation numberEU/3/16/1625
    D.3 Description of the IMP
    D.3.1Product nameCyclophosphamide
    D.3.4Pharmaceutical form Powder and solvent for solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous bolus use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCyclophosphamide
    D.3.9.1CAS number 6055-19-2
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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.IMP: 2
    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.2.1.1.1Trade name Acalabrutinib
    D.2.1.1.2Name of the Marketing Authorisation holderAcerta Pharma BV
    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 No
    D.2.5.1Orphan drug designation numberEU/3/16/1624
    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.3.9.1CAS number 1420477-60-6
    D.3.9.3Other descriptive nameCalquence
    D.3.9.4EV Substance CodeAS9
    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.IMP: 3
    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 Information not present in EudraCT
    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 nameDoxorubicin
    D.3.4Pharmaceutical form Concentrate and solvent for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous bolus use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNdoxorubicin hydrochloride
    D.3.9.1CAS number 25316-40-9
    D.3.9.3Other descriptive nameCaelyx
    D.3.9.4EV Substance CodeAS3
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.0
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNdoxorubicin hydrochloride
    D.3.9.1CAS number 25316-40-9
    D.3.9.3Other descriptive nameMyocet
    D.3.9.4EV Substance CodeAS4
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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.IMP: 4
    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 Information not present in EudraCT
    D.2.1.1.1Trade name Vincristine
    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 nameVincristine
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNVincristine sulphate
    D.3.9.1CAS number 2068-78-2
    D.3.9.3Other descriptive nameLeurocristine sulfate
    D.3.9.4EV Substance CodeAS6
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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.IMP: 5
    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 Information not present in EudraCT
    D.2.1.1.1Trade name Prednisolone
    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 namePrednisolone
    D.3.4Pharmaceutical form Tablet
    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 INNprednisolone
    D.3.9.1CAS number 50-24-8
    D.3.9.4EV Substance CodeAS7
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number1 to 30
    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.IMP: 6
    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 Information not present in EudraCT
    D.2.1.1.1Trade name Rituximab
    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 nameRituximab
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous drip use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRituximab
    D.3.9.1CAS number 174722-31-7
    D.3.9.3Other descriptive nameMabThera, Rixathon, Truxima
    D.3.9.4EV Substance CodeAS8
    D.3.10 Strength
    D.3.10.1Concentration unit mg/l milligram(s)/litre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Richter's Syndrome
    E.1.1.1Medical condition in easily understood language
    A rare type of non-hodgkin lymphoma
    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 10058728
    E.1.2Term Richter's syndrome
    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
    1A) Randomised Question (main randomised component of the trial):
    To compare the rate of progression free survival (PFS)* of participants with Richter's Syndrome (RS) who are given CHOP-R alone (chemo-immunotherapy, standard of care) against participants with RS who are given CHOP-R plus acalabrutinib (the investigational drug).

    1B)Platform Study Questions:
    Cohort 1: to assess the overall response rate (ORR)** at 6 months of participants who take acalabrutinib alone after relapse with RS or if their disease progressed whilst or after having CHOP-R therapy.
    Cohort 2: to assess the overall response rate (ORR) of participants after 6 cycles of CHOP-R plus acalabrutinib.

    *PFS - the length of time during and after the treatment that a patient lives with the disease but it does not get worse

    **ORR - how well the participant's disease responds to treatment e.g. reaching partial or complete remission
    E.2.2Secondary objectives of the trial
    To evaluate:
    2a) Overall survival (OS) - how long each of the participants live from day one of the trial.

    2b) Randomised question only: overall response rate (ORR) - how many of the participants achieve (for example) a partial or complete remission at the end of CHOP-R treatment.

    2c) Cohorts 1 and 2: Progression free survival (PFS)- the length of time during and after the extension study acalabrutinib treatment that the patient lives with the disease but it doesn't get worse.

    2d) Quality of Life (QoL) assessed using the Eastern Cooperative Oncology Group (ECOG) performance status and the CLL17 and NHL-HG29 questionnaires - this is an assessment of the participants' general well-being and ability to carry out activities in their daily life.

    2e) Toxicity - the types, severity, and frequency of side effects that the participants might have while on the trial.

    2f) Proportion of patients proceeding to stem cell transplantation - the number of patients who reach a point where they can
    E.2.3Trial contains a sub-study Information not present in EudraCT
    E.3Principal inclusion criteria
    Inclusion criteria for the Randomised Trial
    -Suitable for anthracycline-containing chemo-immunotherapy.
    -Patients with CLL and newly diagnosed biopsy proven DLBCL-type RS.
    -ECOG performance status of 0, 1, 2 or 3.
    -Age 16 years and over.
    -Signed written informed consent prior to performing any study-specific procedures

    Inclusion criteria Cohort 1 (progressive RS following chemo-immunotherapy)
    -Patients with relapsed/refractory RS who received anthracycline based chemotherapy with anti-CD20 monoclonal antibody.
    -ECOG performance status of 0, 1, 2 or 3.
    -Age 16 years and over.
    -Signed written informed consent prior to performing any study-specific procedures

    Inclusion criteria Cohort 2 (anthracycline-naïve RS patients, diagnosed while on ibrutinib)
    -Ibrutinib-exposed CLL patients who have developed biopsy-proven DLBCL-type RS within four weeks of last dose of ibrutinib.
    -No previous anthracycline treatment and suitable for anthracycline-containing chemo-immunotherapy.
    -Patients with CLL and newly diagnosed biopsy proven DLBCL-type RS.
    -ECOG performance status of 0, 1, 2 or 3.
    -Age 16 years and over.
    -Signed written informed consent prior to performing any study-specific procedures

    E.4Principal exclusion criteria
    Exclusion criteria ALL
    -Known central nervous system (CNS) involvement of CLL or DLBCL.
    -Any other active malignancy that requires active treatment, with the exception of basal cell carcinoma, in-situ cervical cancer, and non-invasive squamous cell carcinoma of the skin.
    -Chronic or ongoing active infectious disease
    -Positive serology for Hepatitis B (HBKnown human immunodeficiency virus (HIV) positive.
    -Patients with active bleeding or history of bleeding diathesis (e.g. haemophilia, von Willebrand disease).
    -Patients receiving therapeutic anticoagulation with warfarin or equivalent (e.g. phenoprocoumon).
    -Uncorrected prolonged prothrombin time (PT) or an activated partial thromboplastin time (APTT) > 2 x the upper limit of normal (ULN).
    -Major surgery within 30 days prior to randomisation and/or inadequate recovery from any prior major surgery, toxicity or complications.
    -Patients with malabsorption syndrome or medical conditions significantly affecting gastrointestinal function.
    -Clinically significant cardiac disease including unstable angina, uncontrolled congestive heart failure, and unstable arrhythmias requiring therapy, with the exception of extra systoles or minor conduction abnormalities.
    -Significant concurrent, uncontrolled severe medical condition including, but not limited to, renal, hepatic, haematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease.
    -History of significant cerebrovascular disease in the 6 months prior to randomisation, including intracranial haemorrhage.
    -Known or suspected hypersensitivity to components of the investigational products
    -Patients who have received treatment with any non-marketed drug substance or experimental therapy within 4 weeks prior to proposed start of treatment
    -Current participation in any other interventional clinical study.
    -Patients known or suspected of not being able to comply with a study
    -Breast feeding women or women with a positive pregnancy test at screening.
    -Women of childbearing potential and men not willing to use highly effective contraception during study and for 12 months after last dose of study therapy

    Additional exclusion criteria for the Randomised Trial
    -Prior therapy with CHOP or any anthracycline containing treatment at any time prior to randomisation.
    -Ibrutinib-exposed CLL patients who have been newly diagnosed with RS within four weeks of their last dose of ibrutinib. (Ibrutinib-exposed CLL patients who discontinue ibrutinib due to toxicity or progressive CLL and later (more than four weeks) develop RS are not excluded from the randomised trial component).
    -Previous acalabrutinib exposure.

    Additional exclusion criteria for Cohort 1 (progressive RS following chemo-immunotherapy)
    -Previous acalabrutinib exposure.

    Additional exclusion criteria for Cohort 2 (anthracycline-naïve RS patients, diagnosed while on ibrutinib)
    -Prior therapy with CHOP or any anthracycline containing treatment at any time prior to randomisation.
    -Previous acalabrutinib exposure.
    E.5 End points
    E.5.1Primary end point(s)
    Randomised component:
    Progression free survival (PFS) defined as the time from randomisation to the date of progression or death from any cause. Progression will be defined by the modified Cheson criteria. Patients who are alive and progression free at the time of analysis will be censored at date last seen. Any participants who withdraw or are lost to follow-up will also be censored at date last seen.

    Single-arm Cohort 1 (progressive RS following chemo-immunotherapy):
    Overall response after 24 weeks of treatment based on the modified Cheson criteria. Complete response (CR) and partial response (PR) are considered to be positive responses for assessment of this outcome. Participants who withdraw prior to the 6 month assessment or do not have the 6 month assessment will be considered non-responders.

    Single-arm Cohort 2 (anthracycline-naïve RS patients, diagnosed while on ibrutinib):
    Overall response after 6 cycles of treatment, defined by the modified Cheson criteria. CR and PR are considered to be positive responses for assessment of this outcome. Participants who withdraw prior to the post-cycle-6 assessment or do not have the post-cycle-6 assessment will be considered non-responders.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Randomised component: 2 years

    Single-arm Cohort 1: 24 weeks

    Single-arm Cohort 2: 6 cycles of CHOP-R (18 weeks)
    E.5.2Secondary end point(s)
    (1) Overall survival (OS) defined as time from date of randomisation (for randomised trial) or registration (to the relevant cohort for single-arm cohorts) to date of death from any cause. Participants who are alive at the time of analysis will be censored at date last seen. (Note that participants randomised to receive CHOP-R, who progress on the standard of care arm and are eligible for cohort 1, may enter single-arm Cohort 1 to receive acalabrutinib monotherapy. Their survival time for analysis of the randomised component will be from date of randomisation, and that used for analysis of Cohort 1 will be from date of registration to Cohort 1.)

    (2) Overall response (ORR) (randomised component only) after cycle 6, defined by the modified Cheson criteria (Appendix 1). CR and PR are considered to be positive responses for assessment of this outcome. Participants who withdraw prior to the post-cycle-6 assessment or do not have the post-cycle-6 assessment will be considered non-responders.

    (3) Overall response (cohort 1 only) after 12 weeks, defined by the modified Cheson criteria (Appendix 1). CR and PR are considered to be positive responses for assessment of this outcome. Participants who withdraw prior to the 12-week assessment or do not have the 12-week assessment will be considered non-responders.

    (4) Progression free survival (PFS) (single-arm cohorts only) defined as the time from date of registration to date of progression or death from any cause. Progression will be defined by the modified Cheson criteria (Appendix 1). Participants who are alive and progression free at the time of analysis will be censored at date last seen. Any patients who withdraw or are lost to follow-up will also be censored at date last seen.

    (5) Quality of Life (QoL), (assessed using ECOG performance status), and the CLL17 and NHL-HG29 questionnaires (Appendix 2)) at the end of cycles 4 and 6 for participants receiving CHOP-R as part of their treatment (randomised cohorts and Cohort 2), and at 12 and 24 weeks for participants receiving acalabrutinib monotherapy (Cohort 1).

    (6) Toxicity defined as the number of participants who experience one or more adverse event grade 3 or higher or serious adverse event of any grade.

    (7) Proportion of participants proceeding to allogeneic or autologous stem cell transplantation
    E.5.2.1Timepoint(s) of evaluation of this end point
    (1) OS (all cohorts): 2 years
    (2) ORR randomised component: 6 cycles of CHOP-R (18-weeks)
    (3) ORR Cohort 1: 12 weeks
    (4) PFS (cohorts 1 and 2): 2 years
    (5) QoL randomised cohorts and Cohort 2: end of cycles 4 (12 weeks) and 6 (18 weeks); Cohort 1: 12 and 24 weeks
    (6) Toxicity (all cohorts): 2 years
    (7) Toxicity (all cohorts): 2 years
    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 No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    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 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
    Platform arms are registration only.
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    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 concerned16
    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
    LPLV last patient, last visit.
    The Trials Office will notify the MHRA and main REC that the trial has ended at the appropriate time and will provide them with a summary of the clinical trial report within 12 months of the end of trial.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    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.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 45
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 60
    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 state105
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 105
    F.4.2.2In the whole clinical trial 105
    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)
    All patients will remain on therapy per the protocol until they discontinue due to disease progression, toxicity, or patient choice. All drugs will be provided to all patients per protocol until the final patient ceases treatment. At this point the study will then close.
    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 Decision2018-12-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-01-31
    P. End of Trial
    P.End of Trial StatusOngoing
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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