Clinical trial NCT02670317: Phase II Study About Combination CHOP-21, Obinutuzumab and Ibrutinib in Untreated Young High Risk DLBCL Patients.
Official title: Multicenter Phase II Single Arm Open-label Study on the Feasibility, Safety and Efficacy of Combination of CHOP-21 Supplemented With Obinutuzumab and Ibrutinib in Untreated Young High Risk Diffuse Large B-cell Lymphoma (DLBCL) Patients.
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Lymphoma, B-Cell
Keywords: DLBCL
large B cell lymphoma
NHL
Lead sponsor: Fondazione Italiana Linfomi - ETS
Sponsor class: OTHER
First posted: 2016-02-01
Enrollment: 1
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: The efficacy of G-CHOP-21 in combination with Ibrutinib in terms of 2-yrs PFS (progression-free survival)
timeFrame: 2 years
measure: The safety of G-CHOP-21 in combination with Ibrutinib in terms of proportion of patients experiencing grade 3 or greater extra-hematologic toxicity or treatment interruption for safety reasons or any toxic death during the 6 cycles of treatment
timeFrame: 5 months of treatment
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: 2 years
measure: Complete Remission (CR) Rate
timeFrame: 6 months
measure: Overall Response Rate (ORR)
timeFrame: 6 months
measure: The Duration Of Response (DOR) after the end of treatment
timeFrame: 2 years
Other outcomes:
Locations:
city: Candiolo
country: Italy
facility: IRCCS Candiolo - Fondazione del Piemonte per l'oncologia
state: TO
city: Alessandria
country: Italy
facility: AO SS. Antonio e Biagio e C. Arrigo
city: Bari
country: Italy
facility: AOU Policlinico Consorziale
city: Bergamo
country: Italy
facility: AO Papa Giovanni XXIII
city: Bolzano
country: Italy
facility: Ospedale di Bolzano
city: Cagliari
country: Italy
facility: Ospedale Businco
city: Cosenza
country: Italy
facility: AO di Cosenza
city: Firenze
country: Italy
facility: AOU Careggi
city: Lecce
country: Italy
facility: P.O. Vito Fazzi
city: Meldola
country: Italy
facility: IRST Meldola
city: Messina
country: Italy
facility: Ospedale Papardo
city: Milano
country: Italy
facility: Istituto Europeo Oncologico
city: Modena
country: Italy
facility: AOU Policlinico di Modena
city: Monza
country: Italy
facility: Ospedale San Gerardo
city: Napoli
country: Italy
facility: IRCCS Napoli Pascale
city: Novara
country: Italy
facility: Ospedale Maggiore della Carità
city: Palermo
country: Italy
facility: AOOR Villa Sofia Cervello
city: Parma
country: Italy
facility: AOU di Parma
city: Piacenza
country: Italy
facility: Ospedale G. Da Saliceto
city: Potenza
country: Italy
facility: AOR San Carlo
city: Rimini
country: Italy
facility: Ospedale Degli Infermi
city: Roma
country: Italy
facility: Policlinico Gemelli
city: Roma
country: Italy
facility: Policlinico Umberto I
city: Rozzano
country: Italy
facility: Humanitas
city: San Giovanni Rotondo
country: Italy
facility: Casa Sollievo della Sofferenza
city: Torino
country: Italy
facility: AOU Città Della Salute e Della Scienza Ematologia Universitaria
city: Torino
country: Italy
facility: AOU Città Della Salute e Della Scienza SC Ematologia
city: Udine
country: Italy
facility: AOU di Udine
city: Varese
country: Italy
facility: Ospedale di Circolo e Fondazione Macchi
Study officials:
affiliation: Policlinico Umberto I - Università "La Sapienza"
name: Maurizio Martelli, MD
role: PRINCIPAL_INVESTIGATOR
References: