Phase II Study About Combination CHOP-21, Obinutuzumab and Ibrutinib in Untreated Young High Risk DLBCL Patients.
Phase II Study About Combination CHOP-21, Obinutuzumab and Ibrutinib in Untreated Young High Risk DLBCL Patients.
This is a prospective, multicenter, single arm, phase II trial in young patients (18-60
 years) with poor-prognosis (aaIPI 2 or 3) newly diagnosed Diffuse Large B-cell Lymphoma
 (DLBCL).

 Aim of the study is to assess the efficacy and the safety of G-CHOP in combination with
 ibrutinib.
This is a prospective, multicenter, single arm, phase II trial in young patients (18-60
 years) with poor-prognosis (age-adjusted International Prognostic Index, aaIPI, 2 or 3) newly
 diagnosed Diffuse Large B-cell Lymphoma (DLBCL).

 Patient will receive 6 courses of G-CHOP21 (Obimutizumab- cyclophosphamide,
 hydroxydaunomycin, Oncovin, and prednisone) followed by 2 doses of Obinutuzumab supplemented
 with Ibrutinib. Duration of treatment will be 5 months plus 4-5 weeks for response
 evaluation.

 During the study, disease status will be evaluated after the 4th cycle by computed tomography
 (CT) scan, and after end of treatment by imaging test (18FDG-PET [positron emission
 tomography] and CT scan).

 Patients will be recruited over 2 years and followed for a minimum of 2 years after the end
 of the treatment phase.
Inclusion Criteria:

 -  Histologically confirmed Diffuse Large B-Cell Lymphoma (DLBCL) not otherwise specified
 (NOS)

 -  Previously untreated disease

 -  Age 18-60

 -  Age adjusted IPI=2-3

 -  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 × 109/L independent
 of growth factor support, platelet count ≥ 100,000/mm3 or ≥50,000/mm3 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/1.73m2, 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 nonhepatic
 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

 -  Non peripheral neuropathy or active neurological non neoplastic disease of CNS

 -  Non major surgical intervention prior 3 months to enrolment if not due to lymphoma
 and/or not 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.

 -  Patients with any other malignancy that has been treated with surgery alone with
 curative intent and the malignancy has been 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. Men must agree to not donate sperm during and after
 the study. For females, these restrictions apply for 6 months after the last dose of
 study drug. For males, these restrictions apply for 6 months after the last dose of
 study drug.

 -  Women of childbearing potential must have a negative serum (betahuman chorionic
 gonadotropin [β-hCG]) or urine pregnancy test at Screening. Women who are pregnant or
 breastfeeding are ineligible for this study.

 -  Life expectancy > 6 months

 -  Sign (or their legally-acceptable representatives must sign) an informed consent
 document indicating that they understand the purpose of and procedures required for
 the study and are willing to participate in the study.

 Exclusion Criteria:

 -  Any Other histologies than Diffuse Large B- Cell Lymphoma (DLBCL): composite or
 transformed disease and patients with follicular lymphoma IIIB

 -  Primary mediastinal lymphoma (PMBL)

 -  Known central nervous system 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.

 -  Vaccinated with live, attenuated vaccines within 4 weeks of enrollment

 -  Presence of major neurological disorders

 -  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 coexisting medical or psychological condition that would preclude
 participation in the study or compromise 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