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    Summary
    EudraCT Number:2015-005220-26
    Sponsor's Protocol Code Number:ACE-LY-308
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2017-03-23
    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 ConcernedGermany - BfArM
    A.2EudraCT number2015-005220-26
    A.3Full title of the trial
    A Phase 3, Randomized, Double blind, Placebo controlled, Multicenter Study of Bendamustine and Rituximab (BR) alone Versus in Combination with Acalabrutinib (ACP 196) in Subjects with Previously Untreated Mantle Cell Lymphoma
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 3, Randomized, Double blind, Placebo controlled, Multicenter Study of Bendamustine and Rituximab (BR) alone Versus in Combination with Acalabrutinib (ACP 196) in Subjects with Previously Untreated Mantle Cell Lymphoma
    A.4.1Sponsor's protocol code numberACE-LY-308
    A.5.4Other Identifiers
    Name:IND Number: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-LY-308 Clinical 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 number1650591-2800
    B.5.5Fax number1650591-2816
    B.5.6E-mailace-ly-308@acerta-pharma.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEMA/OD/231/15
    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.3.9.2Current sponsor codeACP-196
    D.3.9.3Other descriptive nameACP-196
    D.3.9.4EV Substance CodeSUB166233
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    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.2.1.1.1Trade name Levact
    D.2.1.1.2Name of the Marketing Authorisation holderAstellas Pharma GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 nameLevact
    D.3.4Pharmaceutical form Powder for concentrate for solution for infusion
    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 INNBENDAMUSTINE
    D.3.9.1CAS number 16506-27-7
    D.3.9.4EV Substance CodeSUB05707MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    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 RoleComparator
    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.2.1.1.1Trade name MabThera
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameMabThera
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    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 INNRITUXIMAB
    D.3.9.1CAS number 174722-31-7
    D.3.9.4EV Substance CodeSUB12570MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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.IMP: 4
    D.1.2 and D.1.3IMP RoleComparator
    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.2.1.1.1Trade name Bendamustine hydrochloride Accord
    D.2.1.1.2Name of the Marketing Authorisation holderAccord Healthcare Ld.
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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.3.4Pharmaceutical form Powder for concentrate for solution for infusion
    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 INNBENDAMUSTINE
    D.3.9.1CAS number 16506-27-7
    D.3.9.4EV Substance CodeSUB05707MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    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 RoleComparator
    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.2.1.1.1Trade name Bendamustine hydrochloride
    D.2.1.1.2Name of the Marketing Authorisation holderDr. Reddy’s Laboratories (UK) Ltd.
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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.3.4Pharmaceutical form Powder for concentrate for solution for infusion
    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 INNBENDAMUSTINE
    D.3.9.1CAS number 16506-27-7
    D.3.9.4EV Substance CodeSUB05707MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Mantle Cell Lymphoma
    E.1.1.1Medical condition in easily understood language
    Mantle Cell 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 HLT
    E.1.2Classification code 10026798
    E.1.2Term Mantle cell lymphomas
    E.1.2System Organ Class 100000004851
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of acalabrutinib (ACP-196) in combination with bendamustine and rituximab (BR) compared with placebo in combination with BR based on Independent Review Committee (IRC) assessment of progression-free survival (PFS) per the Lugano Classification for Non Hodgkin Lymphoma (NHL) (Cheson 2014) in subjects with previously untreated mantle cell lymphoma (MCL).
    E.2.2Secondary objectives of the trial
    To evaluate acalabrutinib (ACP-196) in combination with BR compared with placebo in combination with BR in terms of:
    • Investigator-assessed PFS per the Lugano Classification for NHL
    • Investigator-assessed ORR per the Lugano Classification for NHL
    • IRC-assessed overall response rate (ORR), defined as a subject achieving either a partial response (PR) or complete response (CR) per the Lugano Classification for NHL.
    • Overall survival (OS)
    • IRC-assessed duration of response (DOR) per the Lugano Classification for NHL
    • IRC-assessed time to response (TTR) per the Lugano Classification for NHL
    • IRC-assessed ORR (CR + PR) per Revised Response Criteria for Malignant Lymphoma (Cheson 2007)
    • PRO by Functional Assessment of Cancer Therapy Lymphoma (FACT-Lym) scale score
    • PRO by the EuroQol (EQ-5D-5L) index score
    • PRO by the EORTC QLQ-C30 score
    • Medical Ressource utilization (MRU)
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Pharmacokinetic Sub-study
    Patient demographic, pathophysiologic, and therapeutic features, such as body weight, excretory and metabolic functions, and other therapies, can alter dose-concentration relationships. The collection of relevant PK information in patients who are representative of the target population enables an assessment of these features on drug concentrations (Food and Drug Administration [FDA] 1999). Due to a short half-life, trough concentrations of acalabrutinib are generally not measurable.
    Intensive PK samples will be collected for acalabrutinib, bendamustine and bendamustine metabolite from approximately 40 subjects in the PK substudy per Table 11 1 predose/before the start of the bendamustine infusion and postdose/after the start of infusion. For this subset of subjects, acalabrutinib or placebo administration for Cycle 1 Day 2, Cycle 1 Day 8, and Cycle 2 Day 2 must occur at the site. PK samples should be collected after the morning dose of acalabrutinib. The PK sampling site must be on the opposite arm from the site of bendamustine infusion. The predose samples can be taken up to 30 minutes before acalabrutinib or placebo administration. When acalabrutinib or placebo and bendamustine are administered on the same day (PK on Day 2 of Cycles 1 and 2), the 30 minute bendamustine infusion should be started immediately (within 5 minutes) after the morning dose of acalabrutinib or placebo is administered. The times of the dose administration of acalabrutinib and bendamustine and times of each PK sample will be recorded in the CRF.

    Biomarker Evaluation
    Peripheral blood mononuclear cells (PBMC) and tumor samples will be used for biomarker evaluations. To determine the temporal effect of study drugs on the phenotype of malignant cells in subjects, blood samples will be collected and analyzed centrally per the Schedule of Assessments.
    The term “biomarker PBMC” refers to samples where PBMC will be isolated and frozen as viable cells. The PBMC may be analyzed at a future date for changes in cell surface marker expression and modulation of intracellular signaling pathways, including BTK phosphorylation. The plasma fraction from the PBMC isolation will be frozen and preserved for future measurements of soluble analytes (ie, cytokines), and/or circulating tumor DNA (ctDNA) for mutational analysis. Biomarker PBMC samples will be collected from approximately 100 subjects. Samples will be collected before treatment on the following days: Cycle 1 Day 1, Cycle 2 Day 1, and Cycle 7 Day 1 (or after completion of BR therapy). A sample will also be collected within 7 days of a suspected CR or disease progression, or discontinuation of treatment, and at the SFU visit.
    Archival or fresh tumor biopsy samples will be evaluated from all subjects to evaluate potential biomarkers related to response to therapy and/or to investigate potential mechanisms of primary resistance. Analysis of proteins, gene expression and/or mutations may be used to support this exploratory endpoint. These samples will be collected during screening only. Assays will be conducted only if subject is enrolled in study and has provided consent.
    E.3Principal inclusion criteria
    1. Men and women, ≥ 65 years of age.
    2. Pathologically confirmed MCL, with documentation of chromosome translocation t(11;14)(q13;q32) and/or overexpression of cyclin D1 in
    association with other relevant markers (eg, CD5, CD19, CD20, PAX5).
    3. MCL requiring treatment and for which no prior systemic anticancer therapies have been received.
    4. Presence of radiologically measurable lymphadenopathy and/or extranodal lymphoid malignancy.
    5. ECOG performance status of ≤ 2.
    6. Men who are sexually active and can beget children must agree to use highly effective forms of contraception during the study and for 6 months after the last dose of bendamustine, or 12 months after the last dose of rituximab, whichever is longest. Highly effective forms of contraception are defined in Section 9.2.2.
    7. Men must agree to refrain from sperm donation during the study and for 6 months after the last dose of bendamustine, or 12 months after the last dose of rituximab, whichever is longest.
    8. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty.
    9. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local patient privacy regulations).
    E.4Principal exclusion criteria
    1.History of prior malignancy except for the following:
    a.Malignancy treated with curative intent and with no evidence of active disease present for more than 2 yrs before screening and felt to be at low risk for recurrence by treating physician
    b.Adequately treated lentigo maligna melanoma without current evidence of disease or adequately controlled nonmelanomatous skin cancer
    c.Adequately treated carcinoma in situ without current evidence of disease
    2.Subjects for whom the goal of therapy is tumor debulking before stem cell transplant
    3.Any history of CNS lymphoma or leptomeningeal disease
    4.Uncontrolled AIHA or ITP
    5.Major surgical procedure within 28 days before 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
    6.Significant cardiovascular disease such as uncontrolled or untreated symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of first dose of study drug, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or QTc > 480 msec (calculated using Friderica’s formula: QT/RR0.33) at screening. Exception: Subjects with controlled, asymptomatic atrial fibrillation during screening are allowed to enroll on study
    7.ANC < 1.0 x 109/L or platelet count < 75 x 109/L; for subjects with disease involvement in the bone marrow, ANC < 0.75 x 109/L or platelet count < 50 x 109/L. Subjects will only be considered eligible if peripheral blood counts can be maintained independent of growth factors or transfusions during the screening period
    8.Total bilirubin > 1.5 x ULN; or AST or ALT > 2.5 x ULN
    9.Estimated creatinine clearance of < 50 mL/min, calculated using the formula of Cockcroft and Gault [(140-age)•mass (kg)/(72•creatinine mg/dL)•multiply by 0.85 if female.]
    10.Prothrombin time/INR or aPTT (in the absence of a lupus anticoagulant) > 2.0 x ULN. Exception: Subjects receiving warfarin are excluded; however, those receiving other anticoagulant therapy who have a higher INR/aPTT may be permitted to enroll to this study after discussion with the medical monitor
    11.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
    12.Uncontrolled active systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment), or intravenous anti infective treatment within 2 weeks before first dose of study drug
    13.Known history of infection with HIV
    14.Ongoing immunosuppressive therapy, including systemic (eg, IV or oral) corticosteroids within 2 weeks before the first dose of study drug. Note: Subjects may use topical or inhaled corticosteroids or low dose steroids (≤ 20 mg prednisone equivalent/day for ≤ 2 weeks) as a therapy for comorbid conditions. During study participation, subjects may also receive systemic (eg, IV or oral) corticosteroids as needed for treatment emergent comorbid conditions
    15.Known history of anaphylaxis or hypersensitivity to bendamustine, rituximab, or any of their components
    16.Serologic status reflecting active hepatitis B or C infection
    a.Subjects who are anti-HBc positive and who are surface antigen negative will need to have a negative PCR result before randomization. Those who are 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 randomization. Those who are hepatitis C PCR positive will be excluded
    17.Received a live virus vaccination within 28 days of first dose of study drug
    18.History of stroke or intracranial hemorrhage within 6 months of first dose of study drug
    19.History of bleeding diathesis (eg, hemophilia or von Willebrand disease)
    20.Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before first dose of study drug
    21.Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) within 7 days of first dose of study drug
    22.Requires treatment with a strong CYP3A inhibitor/inducer
    23.Requires treatment with proton pump inhibitors (eg, 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
    24.Concurrent participation in another therapeutic clinical trial
    25.Active CMV infection (active viremia as evidenced by positive PCR result for CMV DNA)
    26.History of confirmed PML
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint of the study is PFS as assessed by IRC per the Lugano Classification for NHL.
    The primary analysis is a comparison of PFS between Arm 1 (acalabrutinib plus BR) and Arm 2 (placebo plus BR).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Response assessments will be based on the Lugano Classification for NHL, which incorporates assessments via PET/CT and CT alone. During treatment, CT scans will be performed for tumor assessments at Week 12 (± 7 days), then every 12 weeks until Week 96 (± 7 days), and then every 24 weeks (± 7 days) thereafter.
    During treatment, PET/CT scans will be performed at Weeks 12 and 24 (± 7 days), and then only to confirm CR thereafter. Subjects with confirmed CR are not required to undergo further PET/CT scans on study unless there is suspicion of disease progression.
    E.5.2Secondary end point(s)
    •Investigator-assessed PFS per the Lugano Classification for NHL
    •Investigator-assessed ORR (CR+PR) per the Lugano Classification for NHL
    •IRC-assessed ORR (CR+PR) per the Lugano Classification for NHL
    •OS
    •IRC-assessed DOR per the Lugano Classification for NHL
    •IRC assessed TTR per the Lugano Classification for NHL
    •IRC-assessed ORR (CR + PR) per Revised Response Criteria for Malignant Lymphoma (Cheson 2007)
    •PRO as measured by change in scores from baseline to each assessment using the FACT-Lym scale
    •PRO as measured by change in scores from baseline to each assessment using the EQ-5D-5L index score
    •PRO by change in scores from baseline to each assessment using the EORTC QLQ-C30 score
    •MRU associated with the study treatment, including the number of hospitalizations, emergency department visits, blood product transfusions, and use of hematopoietic growth factors, that occur after initiation of study drug.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Response assessments will be based on the Lugano Classification for NHL, which incorporates assessments via PET/CT and CT alone. During treatment:
    CT scans will be performed for tumor assessments at Week 12 (± 7 days), then every 12 weeks until Week 96 (± 7 days), and then every 24 weeks (± 7 days) thereafter.
    PET/CT scans will be performed at Weeks 12 and 24 (± 7 days), and then only to confirm CR thereafter. Subjects with confirmed CR are not required to undergo further PET/CT scans on study unless there is suspicion of disease progression

    PRO assessment will be performed at screening, on Day 1 of Cycles 3, 5, and 8, then every 4 cycles until discontinuation of study treatment, and then every 12 weeks thereafter until disease progression or use of alternative anticancer therapy.
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Pharmacodynamics
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over Yes
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA77
    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
    Argentina
    Australia
    Belgium
    Brazil
    Canada
    China
    Czech Republic
    France
    Germany
    Greece
    Hong Kong
    Hungary
    Israel
    Italy
    Japan
    Korea, Republic of
    Mexico
    New Zealand
    Peru
    Poland
    Romania
    Russian Federation
    Spain
    Taiwan
    Ukraine
    United States
    Vietnam
    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
    LVLS
    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 months8
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    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) No
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 546
    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 state16
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 190
    F.4.2.2In the whole clinical trial 546
    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)
    A treatment termination (TT) visit is required for safety assessments for any subjects who permanently discontinue study drug for any reason (except for death, lost to follow up or withdrawal of consent), including disease progression, and should be scheduled within 7 days of the last dose of all study drugs, if possible. In addition to the TT visit, all subjects who discontinue all study drugs will have a safety follow-up (SFU) visit 30 days (+ 7 days) after the last dose of all study drugs.
    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 Decision2017-06-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-06-26
    P. End of Trial
    P.End of Trial StatusOngoing
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