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    Summary
    EudraCT Number:2020-003876-42
    Sponsor's Protocol Code Number:SAKK38/19
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2022-01-26
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2020-003876-42
    A.3Full title of the trial
    Assessing a ctDNA and PET-oriented therapy in patients with DLBCL. A multicenter, open-label, phase II trial
    Assessing a ctDNA and PET-oriented therapy in patients with DLBCL. A multicenter, open-label, phase II trial
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Assessing a ctDNA and PET-oriented therapy in patients with DLBCL
    Aggiustamento terapeutico basato su PET/TAC e DNA tumorale circolante in pazienti con linfoma diffuso a grandi cellule B
    A.3.2Name or abbreviated title of the trial where available
    SAKK 38/19
    SAKK 38/19
    A.4.1Sponsor's protocol code numberSAKK38/19
    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 SponsorSAKK
    B.1.3.4CountrySwitzerland
    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 supportAstraZeneca
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSAKK - Gruppo Svizzero di Ricerca Clinica sul Cancro
    B.5.2Functional name of contact point-
    B.5.3 Address:
    B.5.3.1Street AddressEffingerstrasse 33
    B.5.3.2Town/ cityBerna
    B.5.3.3Post codeCH-3008
    B.5.3.4CountrySwitzerland
    B.5.6E-mailandrea.fuhrer@sakk.ch
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAcalabrutinib
    D.3.2Product code [ACP-196]
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAcalabrutinib
    D.3.9.1CAS number 1420477-60-6
    D.3.9.2Current sponsor codeACP-196
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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
    Disseminated large B cell lymphoma
    Linfoma diffuso a grandi cellule B
    E.1.1.1Medical condition in easily understood language
    Disseminated large B cell lymphoma
    Linfoma diffuso a grandi cellule B
    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 10060580
    E.1.2Term Diffuse large cell lymphoma (Adult T-cell lymphoma/leukemia) (Working Formulation)
    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
    - Efficacy of acalabrutinib-R-CHOP in DLBCL harboring MYD88 L265P and/or CD79A/B mutations (cohort A)
    - Activity of treatment escalation to acalabrutinib-R-CHOP followed by acalabrutinib monotherapy in double positive patients: PET/CT positive (Deauville score 4) and no molecular response (<2log10 fold reduction) after two courses of R-CHOP (cohort B)
    - Feasibility of treatment de-escalation to 4 total R-CHOP courses plus 2 infusions of single agent rituximab in patients lacking both MYD88 L265P and CD79A/B mutations and quickly obtaining both negative PET/CT (Deauville score 1-3) and molecular response (>2log10 reduction of ctDNA) after 2 cycles of R-CHOP [...] (cohort C)
    - Clinical implications of negative PET/CT (Deauville score 1-3) but no molecular response (<2log10 reduction of ctDNA) vs a positive PET/CT (Deauville score 4) but molecular response (>2log10 reduction of ctDNA) after two R-CHOP courses (cohort D)
    -Efficacia di acalabrutinib-R-CHOP in DLBCL che presentano mutazioni di MYD88 L265P e/o CD79A/B (coorte A)
    -Attività dell’escalation del trattamento ad acalabrutinib-R-CHOP seguito da acalabrutinib in monoterapia in pazienti con DLBCL doppiamente positivi: positività alla PET/TC (score Deauville pari a 4) e assenza di risposta molecolare (riduzione <2log10) dopo 2 cicli di R-CHOP (coorte B)
    -Fattibilità della de-escalation del trattamento a 4 cicli totali di R-CHOP più 2 infusioni di rituximab in monoterapia in pazienti senza mutazioni di MYD88 L265P e di CD79A/B e nei quali si ottengono rapidamente sia una negatività alla PET/TC (score Deauville 1-3) sia la risposta molecolare (riduzione ctDNA >2log10) dopo 2 cicli R-CHOP [...] (coorte C)
    -Implicazioni cliniche di una situazione di negatività alla PET/TC (score Deauville 1-3) ma in assenza di risposta molecolare (riduzione ctDNA <2log10) rispetto a una situazione di positività alla PET/TC (score Deauville pari a 4) [...] (coorte D)
    E.2.2Secondary objectives of the trial
    - Safety and tolerability of acalabrutinib-R-CHOP
    - Assessment of prognostic value of baseline PET radiomics indexes, alone or in association with other parameters
    - Sicurezza e tollerabilità di acalabrutinib-R-CHOP
    - Valutazione del valore prognostico degli indici di radiomica PET al basale, da soli o in associazione con altri parametri
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Written informed consent according to ICH GCP E6(R2) regulations before registration and prior to any trial specific procedures.
    • Age = 18 years
    • EGOG performance status 0-2 (or 3 if due to disease)
    • Histologically confirmed, treatment-naïve DLBCL, NOS that fulfill all the following:
    - Patient eligible for 6 cycles of R-CHOP
    - Ann Arbor stage I-IV
    - Metabolically active measurable disease by 18FDG PET-CT
    - No previous treatment with systemic chemotherapy or radiotherapy (a pre-phase treatment with steroids for 10 days is allowed after PET/CT and baseline liquid biopsy have been collected)
    - At least 1 measurable site of disease according to Revised Response Criteria for Malignant Lymphoma. The site of disease must be greater than 1.5 cm in the long axis regardless of short axis measurement or greater than 1.0 cm in the short axis regardless of long axis measurement, and clearly measurable in 2 perpendicular dimensions.
    - Quantifiable and qualifiable circulating tumor DNA
    • Patients with a prior malignancy and treated with curative intention are eligible if all treatment of that malignancy was completed at least 2 years before registration and the patient has no evidence of disease at registration. Less than 2 years is acceptable for malignancies with low risk of recurrence and/or no late recurrence.
    • Adequate bone marrow, hepatic renal, cardiac and coagulation function
    • Consenso informato scritto secondo i regolamenti ICH GCP E6(R2) prima della registrazione e prima di qualsiasi procedura studio specifica.
    • Età = 18 anni
    • Performance status EGOG 0-2 (o 3 se dovuto a malattia)
    • DLBCL non altrimenti specificato (NOS) confermato istologicamente, naïve al trattamento, a condizione che siano soddisfatti tutti seguenti criteri:
    - Pazienti idonei a ricevere 6 cicli di R-CHOP
    - Stadio Ann Arbor I-IV
    - Malattia metabolicamente attiva misurabile mediante PET-TC con 18FDG
    - Pazienti non precedentemente trattati con chemioterapia o radioterapia sistemica (è consentito un trattamento con steroidi per 10 giorni come pre-fase successivamente a PET/TC e al prelievo basale di biopsia liquida).
    - Almeno 1 sede di malattia misurabile secondo i criteri di risposta aggiornati per i linfomi maligni. La sede di malattia deve misurare più di 1,5 cm nel diametro maggiore, indipendentemente dalla misura del diametro minore oppure misurare più di 1,0 cm nel diametro minore, indipendentemente dalla misura del diametro maggiore ed essere chiaramente misurabile in 2 dimensioni perpendicolari.
    - DNA tumorale circolante quantificabile e qualificabile.
    • I pazienti con neoplasia maligna precedente e trattati con intento curativo sono idonei se tutte le terapie per tale neoplasia maligna sono state portate a termine almeno 2 anni prima dell’inclusione e il paziente non mostra evidenze di malattia all’inclusione. Un periodo inferiore a 2 anni è accettabile per neoplasie maligne con basso rischio di recidiva e/o non caratterizzate da recidiva tardiva.
    • Funzionalità del midollo osseo, epatica, renale e cardiaca, e coagulazione adeguate.
    E.4Principal exclusion criteria
    • CNS lymphoma involvement.
    • Stage I disease that has been completely surgically excised (not measurable).
    • Concomitant treatment with any other experimental drug.
    • Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV), unstable angina pectoris, history of myocardial infarction within the last six months, serious arrhythmias requiring medication (with exception of asymptomatic or rate controlled atrial fibrillation or paroxysmal supraventricular tachycardia), significant QTprolongation, uncontrolled hypertension.
    • Uncontrolled systemic infection.
    • History of cerebrovascular accident or intracranial hemorrhage within 6 months prior to registration.
    • Specific diagnostic categories of large B-cell lymphoma such as high grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, primary central nervous system lymphoma, T-cell/histiocyte-rich large B- cell lymphoma, intravascular large B-cell lymphoma, plasmablastic lymphoma, lymphomatoid granulomatosis, primary effusion lymphoma etc.
    • Requires or receiving anticoagulation with warfarin or equivalent antagonists (eg, phenprocoumon), ‘dual’ antiplatelet therapy (DAPT), such as aspirin and clopidogrel. However, use of therapeutic low molecule weight heparin, direct oral anticoagulants, or low dose anti- platelet agents is allowed.
    • Concomitant treatment to Acalabrutinib with strong or moderate CYP3A inducers or inhibitors and co-administration with proton pump inhibitors (PPIs).
    • Linfoma che coinvolge il SNC.
    • Malattia in stadio I che è stata completamente asportata chirurgicamente (non misurabile).
    • Trattamento concomitante con qualsiasi altro farmaco sperimentale.
    • Malattia cardiovascolare grave o non controllata (insufficienza cardiaca congestizia NYHA III o IV), angina pectoris instabile, storia di infarto miocardico negli ultimi sei mesi, aritmie gravi che richiedono farmaci (ad eccezione di fibrillazione atriale asintomatica o a frequenza controllata o tachicardia parossistica sopraventricolare), significativo prolungamento dell'intervallo QT, ipertensione non controllata.
    • Infezione sistemica incontrollata.
    • Storia di evento cerebrovascolare o emorragia intracranica entro 6 mesi prima della registrazione.
    • Specifiche categorie diagnostiche di informa a grandi cellule B, quali linfoma a grandi cellule B di alto grado, linfoma primitivo del mediastino a grandi cellule B, linfoma primitivo del sistema nervoso centrale, linfoma a grandi cellule B ricco di cellule T/istiociti, linfoma intravascolare a grandi cellule B, linfoma plasmablastico, granulomatosi linfomatoide, linfoma primitivo effusivo, ecc.
    • Pazienti che richiedono o ricevono terapia anticoagulante con warfarin o antagonisti equivalenti (ad esempio fenprocumone), duplice terapia antipiastrinica (DAPT), come aspirina e clopidogrel. È tuttavia consentito l’uso terapeutico di eparina a basso peso molecolare, anticoagulanti orali diretti o antipiastrinici a basse dosi.
    • Uso concomitante con acalabrutinib di induttori o inibitori forti o moderati del CYP3A e co-somministrazione di inibitori di pompa protonica (PPI).
    E.5 End points
    E.5.1Primary end point(s)
    • Progression free survival according to the Lugano criteria (Cohorts A, C and D)
    • Complete remission rate according to the Lugano criteria (Cohort B)
    • Sopravvivenza libera da progressione secondo i criteri di Lugano (coorti A, C e D)
    • Tasso di remissione completa secondo i criteri di Lugano (coorte B)
    E.5.1.1Timepoint(s) of evaluation of this end point
    The time from registration until the first event of interest:
    - Progressive disease according to the Lugano Classification
    - Death from any cause
    Il tempo dalla registrazione fino al primo evento di interesse:
    - Malattia progressiva secondo la Classificazione di Lugano
    - Decesso per qualsiasi causa
    E.5.2Secondary end point(s)
    • Adverse events type and rate according to CTCAE v5.0 in the cohorts treated with acalabrutinib-R-CHOP
    • Overall survival
    • Progression free survival in cohort B
    • Complete remission rate in cohorts A, C and D
    • Overall response rate (ORR)
    • Duration of response (DoR)
    • Tipo e tasso di eventi avversi secondo CTCAE v5.0 nelle coorti trattate con acalabrutinib-R-CHOP
    • Sopravvivenza globale
    • Sopravvivenza libera da progressione nella coorte B
    • Tasso di remissione completa nelle coorti A, C e D
    • Tasso di risposta globale (ORR)
    • Durata della risposta (DoR)
    E.5.2.1Timepoint(s) of evaluation of this end point
    From registration until death from any cause. Patients not experiencing an event will be censored at the last date they were known to be alive.
    Dalla registrazione fino al decesso per qualsiasi causa. I pazienti che non hanno riscontrato un evento verranno valutati all'ultima data in cui era noto fossero vivi.
    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 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 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 Yes
    E.8.2.3.1Comparator description
    Differenti schemi terapeutici
    Different therapeutical schemes
    E.8.2.4Number of treatment arms in the trial4
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States No
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Italy
    Switzerland
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years10
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years10
    E.8.9.2In all countries concerned by the trial months0
    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: 44
    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 state104
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 104
    F.4.2.2In the whole clinical trial 260
    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 local clinical practice
    I pazienti saranno trattati in accordo alla pratica clinica locale
    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 Decision2022-02-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-04-29
    P. End of Trial
    P.End of Trial StatusOngoing
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