Ibrutinib + R-CHOP Followed by Ibrutinib Maintenance

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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DLBCL

Intervention / Treatment
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* Drug: Ibrutinib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Ibrutinib in combination to rituximab-CHOP followed by ibrutinib maintenance
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ibrutinib+R-CHOP<br>Screening phase for selection of Activated-B-Cell (ABC)-DLBCL Induction phase: R-CHOP21 x 5 cycles in combination with ibrutinib Maintenance phase: maintenance with Ibrutinib for 18 months for patients responding to the induction phase (CR or PR) | Drug: Ibrutinib<br>* Ibrutinib in combination to rituximab-CHOP followed by ibrutinib maintenance<br>* Other names: IMBRUVICA (commercial name);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) (1st time point of assessment) | PFS of the high/high-intermediate risk patients from date of enrolment | Time between the date of enrolment and the date of disease progression, relapse or death from any cause (24 months) | 
| Progression-free survival (PFS) (2nd time point of assessment) | PFS of the high/high-intermediate risk patients from date of enrolment | Time between the date of enrolment and the date of disease progression, relapse or death from any cause (36 months) | 
| Progression-free survival (PFS) (3dr time point of assessment) | PFS of the high/high-intermediate risk patients from date of enrolment | Time between the date of enrolment and the date of disease progression, relapse or death from any cause (48 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall Survival | Time between the date of enrolment and the date of death from any cause (24, 36 and 48 months). | 
| Complete response and Overall Response (CR+PR) rate at the end of induction | Complete response and Overall Response | End of induction (EOI) (4 months) | 
| Duration of response (DOR) | Duration of response | 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) | 
| Complete remission (CRR) after ibrutinib maintenance | Complete remission after ibrutinib maintenance | End of treatment (EOT) (up to 24 months) | 
| Event Free Survival (EFS) | Event Free Survival | 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DLBCL, Activated-B-Cell DLBCL, Ibrutinib, Phase II