Ibrutinib + R-CHOP Followed by Ibrutinib Maintenance

DLBCL Clinical Trial

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03731234
• Other study ID #: FIL_RI-CHOP
• Status: Recruiting
• Phase: Phase 2
• Start date: July 2, 2019
• Est. completion date: July 2027

Study information

• Verified date: June 2024
• Source: Fondazione Italiana Linfomi - ETS
• Contact: Maurizio Martelli, Prof
• Phone: 00390649974779
• Email: martelli[@]bce.uniroma1.it
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 90
• Est. completion date: July 2027
• Est. primary completion date: June 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 64 Years

Eligibility

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

Related Conditions & MeSH terms

• DLBCL

Intervention

Drug:
• Ibrutinib
Ibrutinib in combination to rituximab-CHOP followed by ibrutinib maintenance

Locations

Country	Name	City	State
Italy	A.O. SS. Antonio e Biagio e Cesare Arrigo - S.C. Ematologia	Alessandria
Italy	Università Politecnica delle Marche- Clinica di Ematologia	Ancona
Italy	Azienda Ospedaliera S.Giuseppe Moscati - S.C. Ematologia e Trapianto emopoietico	Avellino
Italy	Centro Riferimento Oncologico- S.O.C. Oncologia Medica A	Aviano
Italy	IRCCS Istituto Tumori Giovanni Paolo II - U.O.C Ematologia	Bari
Italy	ASST Spedali Civili di Brescia - Ematologia	Brescia
Italy	Ospedale Businco - SC Ematologia e CTMO	Cagliari
Italy	Ospedale di Castelfranco Veneto - Oncoematologia IOV	Castelfranco Veneto	Treviso
Italy	Arnas Nuovo Ospedale Garibaldi Nesima - U.O.C. Ematologia	Catania
Italy	Azienda Ospedaliera Universitaria Careggi - Unità funzionale di Ematologia	Firenze
Italy	Ospedale Policlinico San Martino S.S.R.L- IRCCS per l'Oncologia - Ematologia	Genova
Italy	Azienda Ospedali Riuniti Papardo-Piemonte - S.C. Ematologia	Messina
Italy	ASST Grande Ospedale Metropolitano Niguarda - SC Ematologia	Milano
Italy	Fondazione IRCCS Istituto Nazionale dei Tumori di Milano - Ematologia	Milano
Italy	IEO Istitito Europeo di Oncologia - Divisione Ematoncologia	Milano
Italy	Istituto Scientifico San Raffaele - Unità Linfomi - Dipartimento Oncoematologia	Milano
Italy	Azienda Ospedaliero-Universitaria Policlinico di Modena - Ematologia	Modena
Italy	Monza - Fondazione IRCCS San Gerardo dei Tintori - Ematologia	Monza
Italy	Istituto Nazionale Tumori - IRCCS Fondazione G. Pascale - UOC Ematologia Oncologica	Napoli
Italy	AOU Maggiore della Carità di Novara - SCDU Ematologia	Novara
Italy	I.R.C.C.S. Istituto Oncologico Veneto - Oncologia 1	Padova
Italy	IRCCS Policlinico S. Matteo di Pavia - Div. di Ematologia	Pavia
Italy	P.O. Spirito Santo di Pescara - UOS Dipartimentale - Centro di diagnosi e Terapia dei linfomi	Pescara
Italy	Ospedale Guglielmo da Saliceto - U.O.Ematologia	Piacenza
Italy	AOU Pisana - U.O. Ematologia	Pisa
Italy	A.O.R. "San Carlo" - U.O. Ematologia	Potenza
Italy	Ospedale delle Croci - Ematologia	Ravenna
Italy	Azienda Unità Sanitaria Locale-IRCCS - Arcispedale Santa Maria Nuova - Ematologia -	Reggio Emilia
Italy	Ospedale degli Infermi di Rimini - U.O. di Ematologia	Rimini
Italy	Dipartimento di Medicina Traslazionale e di Precisione, Università 'La Sapienza'	Roma
Italy	Università Cattolica S. Cuore - Ematologia	Roma
Italy	Casa Sollievo della Sofferenza - UO Ematologia	San Giovanni Rotondo
Italy	A.O. S. Maria di Terni - S.C. Oncoematologia	Terni
Italy	A.O.U. Citta della Salute e della Scienza di Torino - Centro Ematologia Universitaria	Torino
Italy	A.O.U. Citta della Salute e della Scienza di Torino - S.C.Ematologia	Torino
Italy	A.O. C. Panico - U.O.C Ematologia e Trapianto	Tricase
Italy	Azienda Sanitaria Universitaria Integrata Trieste (ASUITS) SC Ematologia	Trieste
Italy	Ospedale Azienda Sanitaria Universitaria Integrata di Udine (A.S.U.I. Udine)-SOC Clinica Ematologica	Udine
Italy	Ospedale di Circolo U.O.C Ematologia	Varese

Sponsors (2)

Lead Sponsor	Collaborator
Fondazione Italiana Linfomi - ETS	Janssen-Cilag S.p.A.

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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)
Primary	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	Overall Survival (OS)	Overall Survival	Time between the date of enrolment and the date of death from any cause (24, 36 and 48 months).
Secondary	Complete response and Overall Response (CR+PR) rate at the end of induction	Complete response and Overall Response	End of induction (EOI) (4 months)
Secondary	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)
Secondary	Complete remission (CRR) after ibrutinib maintenance	Complete remission after ibrutinib maintenance	End of treatment (EOT) (up to 24 months)
Secondary	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)