Clinical trial NCT03731234: Ibrutinib + R-CHOP Followed by Ibrutinib Maintenance
Official title: Phase II Multicenter Single Arm Study to Evaluate the Efficacy and Safety of Ibrutinib in Combination to Rituximab-CHOP Followed by Ibrutinib Maintenance in Untreated Patients With Activated-B-Cell (ABC)-DLBCL at Intermediate-high and High Risk (IPI ≥2)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: DLBCL
Keywords: DLBCL
Activated-B-Cell DLBCL
Ibrutinib
Phase II
Lead sponsor: Fondazione Italiana Linfomi - ETS
Sponsor class: OTHER
Collaborators: name: Janssen-Cilag S.p.A.
First posted: 2018-11-06
Enrollment: 75
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Ibrutinib in combination to rituximab-CHOP followed by ibrutinib maintenance
Primary purpose: TREATMENT

Brief summary: This is a prospective, multicenter, single arm, phase II trial in patients with ≥ 18 and \<65 years with poor-prognosis (IPI ≥ 2) and newly diagnosed ABC-DLBCL.

Aim of the study is to assess the efficacy and the safety of R-CHOP in combination with ibrutinib for 6 cycles followed by ibrutinib maintenance for 18 months in ABC-DLBCL patients achieving at least a PR after the induction phase

Detailed description: Step 1 - Screening phase If central review will confirm and define the diagnosis of ABC-DLBCL according the COO, eligible patients will have to sign an additional informed consent prior to receive the study subsequent treatment.

Step 2 - study treatment phases Induction phase: 5 courses of R-CHOP every 21 days combined with ibrutinib (560 mg/day, continuously).

Maintenance phase: patients achieving a CR or a PR after 5 courses of RI-CHOP21 will enter the maintenance phase with ibrutinib (560 mg/day, continuously) for 18 months.

Radiotherapy could be delivered as consolidation treatment at the end of R-chemotherapy, according to Institution local clinical practice, in patients with focal PET positive residual disease and to bone extranodal lesions or scrotum, if testicular involvement irrespective of initial tumor diameter.

Eligibility criteria: INCLUSION CRITERIA

* Histologically confirmed DLBCL not otherwise specified (NOS). Patients with follicular lymphoma IIIB and large B-cell lymphoma with IRF4 rearrangement can be also included.
* ABC type defined by Lymph2Cx on the NanoString platform. Note: A formalin fixed paraffin embedded lymph node or tumor biopsy specimen must be submitted to Central Pathology for review during the Screening Period. The specimen must have been acquired by a surgical incision or excision biopsy or from a core needle biopsy
* Previously untreated disease
* Age ≥ 18 and \< 65 years
* IPI score ≥ 2
* Ann Arbor stage II-IV disease
* Measurable disease ≥ 1.5 cm in longest diameter, and measurable in 2 perpendicular dimensions
* Normal blood count as defined as: absolute neutrophil count ≥1.0 × 10 9 /L independent of growth factor support, platelet count ≥ 100,000/mm 3 or ≥ 50,000/mm 3 if bone marrow (BM) involvement independent of transfusion support in either situation Normal organ functions defined as: creatinine ≤2 times the upper limit of normal (ULN) or estimated Glomerular Filtration Rate (Cockroft-Gault) ≥40 ml/min/1.73m 2 , aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤3× the ULN; total bilirubin ≤ 1.5 × the ULN unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin: patients with documented Gilbert disease may be enrolled if total bilirubin is ≤ 3.0 × the ULN; International normalized ratio (INR) \< 1.5 × the ULN in the absence of therapeutic anticoagulation; partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) \< 1.5 × the ULN in the absence of a lupus anticoagulant
* Patients with occult or prior hepatitis B infection (defined as HBsAg negative, anti-HBs positive and /or anti-HBc positive) may be included if hepatitis B virus (HBV) DNA is undetectable. These patients must be willing to undergo bi-monthly DNA testing and they should receive prophylaxis with Lamivudine
* No active hepatitis C virus (HCV) infection
* Known availability of biopsy material
* No Central Nervous System (CNS) disease (meningeal and/or brain involvement by lymphoma)
* Absence of active infections
* No peripheral neuropathy or active neurological non-neoplastic disease of CNS
* No major surgical intervention prior 3 months to enrolment if not due to lymphoma and/or no other disease life-threatening that can compromise chemotherapy treatment
* Patient with a history of curatively treated basal or squamous cell carcinoma or melanoma of the skin or in situ carcinoma of the cervix at any time prior to the study.
* No previous malignancies or patient with a history of curatively treated basal or squamous cell carcinoma or melanoma of the skin or in situ carcinoma of the cervix at any time prior to the study or patients with any other malignancy in remission without treatment for at least 5 years prior to enrolment
* Women of childbearing potential and men who are sexually active must be practicing a highly effective method of birth control during and after the study consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials. - Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin \[Beta-hCG\]) or urine pregnancy test at Screening. Women who are pregnant or breastfeeding are ineligible for this study.
* Life expectancy \> 6 months
* Written informed consent from the patient stating understanding of the purpose and procedures required by the study and willingness to take part in the study

EXCLUSION CRITERIA

* DLBCL including High grade B-cell Lymphomas, both with double hit and NOS according to the 2017 Revised WHO Classification of Tumour of Haematopoietic and Lymphoid Tissues
* GCB-DLBCL after centralized COO profiling
* Any other histologies than DLBCL: composite or transformed disease.
* Primary mediastinal lymphoma (PMBL)
* Known central nervous system lymphoma
* Primary testicular lymphoma
* Any prior lymphoma therapy
* Contraindication to any drug in the chemotherapy regimen
* Left ventricular ejection fraction (LVEF) \< 50%
* Neuropathy ≥ grade 2
* Seropositive for or active viral infection with HBV
* HBsAg positive
* HBsAg negative, anti-HBs positive and/or anti-HBc positive with detectable viral DNA
* Known seropositive active HCV
* Human immunodeficiency virus (HIV) infection
* Any of the following abnormal laboratory values (unless any of these abnormalities are due to underlying lymphoma): creatinine ≥ 2 times the ULN (unless creatinine clearance normal, or calculated creatinine clearance \< 40 mL/min (using the Cockcroft-Gault formula); AST or ALT ≥3 × the ULN; total bilirubin \>1.5 × the ULN: patients with documented Gilbert disease may be enrolled if total bilirubin is ≤ 3.0 × the ULN; INR \> 1.5 × the ULN in the absence of therapeutic anticoagulation; PTT or aPTT \> 1.5 × the ULN in the absence of a lupus anticoagulant"
* History of stroke or intracranial hemorrhage within the past 6 months.
* Requires anticoagulation with warfarin or equivalent vitamin K antagonists
* Requires treatment with strong CYP3A inhibitors
* History of clinically relevant liver or renal insufficiency; significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, rheumatologic, hematologic, psychiatric, or metabolic disturbances
* Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification.
* Any uncontrolled active systemic infection requiring intravenous (IV) antibiotics
* Major surgical intervention prior 4 weeks to enrollment if not due to lymphoma and/or other disease life-threatening that can compromise chemotherapy treatment
* Prior malignancies other than lymphoma in the last 5 years with exception of currently treated basal or squamous cell carcinoma or melanoma of the skin or in situ carcinoma of the cervix
* Any other medical or psychological condition that might preclude participation in the study or impair the patient's ability to give informed consent.
* Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk.
* If female, the patient is pregnant or breast-feeding

Primary outcomes:
measure: Progression-free survival (PFS) (1st time point of assessment)
timeFrame: Time between the date of enrolment and the date of disease progression, relapse or death from any cause (24 months)
measure: Progression-free survival (PFS) (2nd time point of assessment)
timeFrame: Time between the date of enrolment and the date of disease progression, relapse or death from any cause (36 months)
measure: Progression-free survival (PFS) (3dr time point of assessment)
timeFrame: Time between the date of enrolment and the date of disease progression, relapse or death from any cause (48 months)
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: Time between the date of enrolment and the date of death from any cause (24, 36 and 48 months).
measure: Complete response and Overall Response (CR+PR) rate at the end of induction
timeFrame: End of induction (EOI) (4 months)
measure: Duration of response (DOR)
timeFrame: From the date when criteria for response are met (CR or PR) until the date of progression or relapse. Patients without relapse or progression or death from other causes will be censored at their last assessment date (24 months from response date)
measure: Complete remission (CRR) after ibrutinib maintenance
timeFrame: End of treatment (EOT) (up to 24 months)
measure: Event Free Survival (EFS)
timeFrame: From the date of enrolment to the date of disease progression, relapse from CR, initiation of subsequent systemic anti-lymphoma therapy after the least 6 cycles of RI-CHOP (each cycle is 21 days), or death whichever occurs first (24, 36 and 48 months)
Other outcomes:
Locations:
city: Castelfranco Veneto
country: Italy
facility: Ospedale di Castelfranco Veneto - Oncoematologia IOV
state: Treviso
city: Alessandria
country: Italy
facility: A.O. SS. Antonio e Biagio e Cesare Arrigo - S.C. Ematologia
city: Ancona
country: Italy
facility: Università Politecnica delle Marche- Clinica di Ematologia
city: Avellino
country: Italy
facility: Azienda Ospedaliera S.Giuseppe Moscati - S.C. Ematologia e Trapianto emopoietico
city: Aviano
country: Italy
facility: Centro Riferimento Oncologico- S.O.C. Oncologia Medica A
city: Bari
country: Italy
facility: IRCCS Istituto Tumori Giovanni Paolo II - U.O.C Ematologia
city: Brescia
country: Italy
facility: ASST Spedali Civili di Brescia - Ematologia
city: Cagliari
country: Italy
facility: Ospedale Businco - SC Ematologia e CTMO
city: Catania
country: Italy
facility: Arnas Nuovo Ospedale Garibaldi Nesima - U.O.C. Ematologia
city: Firenze
country: Italy
facility: Azienda Ospedaliera Universitaria Careggi - Unità funzionale di Ematologia
city: Genova
country: Italy
facility: Ospedale Policlinico San Martino S.S.R.L- IRCCS per l'Oncologia - Ematologia
city: Messina
country: Italy
facility: Azienda Ospedali Riuniti Papardo-Piemonte - S.C. Ematologia
city: Milano
country: Italy
facility: Istituto Scientifico San Raffaele - Unità Linfomi - Dipartimento Oncoematologia
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori di Milano - Ematologia
city: Milano
country: Italy
facility: IEO Istitito Europeo di Oncologia - Divisione Ematoncologia
city: Milano
country: Italy
facility: ASST Grande Ospedale Metropolitano Niguarda - SC Ematologia
city: Modena
country: Italy
facility: Azienda Ospedaliero-Universitaria Policlinico di Modena - Ematologia
city: Monza
country: Italy
facility: Monza - Fondazione IRCCS San Gerardo dei Tintori - Ematologia
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori - IRCCS Fondazione G. Pascale - UOC Ematologia Oncologica
city: Novara
country: Italy
facility: AOU Maggiore della Carità di Novara - SCDU Ematologia
city: Padova
country: Italy
facility: I.R.C.C.S. Istituto Oncologico Veneto - Oncologia 1
city: Pavia
country: Italy
facility: IRCCS Policlinico S. Matteo di Pavia - Div. di Ematologia
city: Pescara
country: Italy
facility: P.O. Spirito Santo di Pescara - UOS Dipartimentale - Centro di diagnosi e Terapia dei linfomi
city: Piacenza
country: Italy
facility: Ospedale Guglielmo da Saliceto - U.O.Ematologia
city: Pisa
country: Italy
facility: AOU Pisana - U.O. Ematologia
city: Potenza
country: Italy
facility: A.O.R. "San Carlo" - U.O. Ematologia
city: Ravenna
country: Italy
facility: Ospedale delle Croci - Ematologia
city: Reggio Emilia
country: Italy
facility: Azienda Unità Sanitaria Locale-IRCCS - Arcispedale Santa Maria Nuova - Ematologia -
city: Rimini
country: Italy
facility: Ospedale degli Infermi di Rimini - U.O. di Ematologia
city: Roma
country: Italy
facility: Dipartimento di Medicina Traslazionale e di Precisione, Università 'La Sapienza'
city: Roma
country: Italy
facility: Università Cattolica S. Cuore - Ematologia
city: San Giovanni Rotondo
country: Italy
facility: Casa Sollievo della Sofferenza - UO Ematologia
city: Terni
country: Italy
facility: A.O. S. Maria di Terni - S.C. Oncoematologia
city: Torino
country: Italy
facility: A.O.U. Citta della Salute e della Scienza di Torino - Centro Ematologia Universitaria
city: Torino
country: Italy
facility: A.O.U. Citta della Salute e della Scienza di Torino - S.C.Ematologia
city: Tricase
country: Italy
facility: A.O. C. Panico - U.O.C Ematologia e Trapianto
city: Trieste
country: Italy
facility: Azienda Sanitaria Universitaria Integrata Trieste (ASUITS) SC Ematologia
city: Udine
country: Italy
facility: Ospedale Azienda Sanitaria Universitaria Integrata di Udine (A.S.U.I. Udine)-SOC Clinica Ematologica
city: Varese
country: Italy
facility: Ospedale di Circolo U.O.C Ematologia
Study officials:
affiliation: Dipartimento di Medicina Traslazionale e di Precisione, Università 'La Sapienza'
name: Maurizio Martelli, Prof.
role: PRINCIPAL_INVESTIGATOR
References: