Clinical trial NCT02232386: Phase 2 Study to Assess Activity & Safety of Front-line Ibrutinib + Rituximab in Unfit Chronic Lymphocytic Leukemia
Official title: A Phase 2 Multicenter Study to Assess the Activity and the Safety of Front-line Ibrutinib Plus Rituximab (IR) in Unfit Patients With Chronic Lymphocytic Leukemia (CLL).
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Lymphocyte Leukemia
Adult Patients
Keywords: Chronic lymphocyte leukemia
Adults
Ibrutinib
Lead sponsor: Gruppo Italiano Malattie EMatologiche dell'Adulto
Sponsor class: OTHER
First posted: 2014-09-05
Enrollment: 156
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The present study aims at evaluating whether treatment with two different drugs, Ibrutinib and Rituximab is both efficient and safe for newly diagnosed patients with chronic lymphocytic leukemia.

Detailed description: Given that:

* Ibrutinib as single agent has been associated with a high response rate and PFS in previously treated patients, and in patients with poor prognosis clinical and biologic features.
* Ibrutinib as single agent has proven activity and is associated with a good safety profile in elderly patients with CLL.
* The Ibrutinib plus Rituximab combination has been associated with a high response rate and PFS in previously treated patients, and in patients with poor prognosis clinical and biologic features.
* The combined administration of Ibrutinib and Rituximab could be an effective and safe front-line treatment schedule for unfit patients with CLL.
* The current study is designed to evaluate whether first line treatment with Ibrutinib and Rituximab results in a significant improvement in PFS at 12 months as compared with chlorambucil plus rituximab in patients unfit for fludarabine- or bendamustine-based treatments.

Eligibility criteria: Inclusion Criteria:

1. 18 years of age or older.
2. Diagnosis of CLL meeting IWCLL criteria.
3. The diagnosis of CLL requires a history of lymphocytosis with a B-lymphocyte count ≥5,000/μL. Prolymphocytes may comprise no more than 55% of blood lymphocytes.
4. Active disease meeting at least 1 of the following IWCLL 2008 criteria for requiring treatment:

   1. Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia or thrombocytopenia.
   2. Massive (ie, at least 6 cm below the left costal margin), progressive, or symptomatic splenomegaly.
   3. Massive nodes (ie, at least 10 cm in longest diameter), progressive, or symptomatic lymphadenopathy.
   4. Progressive lymphocytosis with an increase of more than 50% over a 2-month period or a lymphocyte doubling time (LDT) of less than 6 months (which may be extrapolated). Lymphocyte doubling time can be obtained by linear regression extrapolation of ALCs obtained at intervals of 2 weeks over an observation period of 2 to 3 months. For patients with initial blood lymphocyte counts of less than 30 x 109/L (30,000/μL), LDT should not be used as a single parameter to define indication for treatment. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (eg, infections) should be excluded.
   5. Constitutional symptoms, defined as 1 or more of the following disease-related symptoms or signs:

      * Unintentional weight loss \>10% within the previous 6 months prior to screening
      * Significant fatigue (inability to work or perform usual activities)
      * Fevers higher than 38.0°C for 2 or more weeks without evidence of infection; or
      * Night sweats for more than 1 month without evidence of infection
      * Measurable nodal disease by computed tomography (CT). Measurable nodal disease is defined as at least one lymph node \>1.5 cm in longest diameter in a site that has not been previously irradiated. An irradiated lesion may be assessed for measurable disease only if there has been documented progression in that lesion since radiotherapy has ended.
5. No prior treatment.
6. Total CIRS \>6 and/or creatinine clearance \<70 ml/min \[Cockcroft-Gault\]).
7. Hematology values within the following limits: Absolute neutrophil count (ANC) ≥1 x 109/L (ie, ≥1000/μL) independent of growth factor support. Platelets ≥50,000/mm3 if bone marrow involvement independent of transfusion support
8. Biochemical values within the following limits:

   1. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 x upper limit of normal (ULN)
   2. Total bilirubin ≤1.5 x ULN unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin
   3. Serum creatinine ≤2 x ULN or estimated Glomerular Filtration Rate (Cockroft Gault) ≥40 mL/min
9. 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 not to donate sperm during and after the study. For females, these restrictions apply for 1 month after the last dose of study drug. For males, these restrictions apply for 3 months after the last dose of study drug.
10. Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin \[β-hCG\]) or urine pregnancy test at Screening. Women who are pregnant or breastfeeding are ineligible for this study.
11. A signed (or signed by their legally-acceptable representatives) informed consent document indicating that they understand the purpose of and procedures required for the study, including biomarkers, and are willing to participate in the study.

Exclusion Criteria:

1. Any significant concurrent, uncontrolled medical condition or organ system dysfunction and/or laboratory abnormality or psychiatric disease 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 or prevent the subject from signing the informed consent form.
2. Pregnant or lactating females
3. Known presence of alcohol and/or drug abuse.
4. Any potential subject who meets any of the following criteria will be excluded from participating in the study.
5. Major surgery within 4weeks of randomization.
6. Uncontrolled autoimmune hemolytic anemia or thrombocytopenia.
7. Known central nervous system lymphoma.
8. History of stroke or intracranial hemorrhage within 6 months prior to randomization, or of a significant cerebrovascular disease in the past 6 months or ongoing event with active symptoms or sequelae.
9. Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) in any moment of the study.
10. Requires treatment with strong CYP3A inhibitors.
11. 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
12. Vaccinated with live, attenuated vaccines within 4 weeks of randomization.
13. Known history of human immunodeficiency virus (HIV) positive serology for HIV; active Hepatitis B Virus infection or positive serology for Hepatitis B (HBV) defined as a positive test for HBsAg and HBV-DNA; active Hepatitis C or HCV-RNA positive; any uncontrolled active systemic infection requiring intravenous (IV) antibiotics, antifungal, or antiviral treatment such as, but not limited to, chronic renal infection, chronic chest infection; history of tuberculosis within the last five years or recent exposure to tuberculosis equal to or less than 6 months.
14. Richter's syndrome (RS), concomitant or past malignancy. Subjects who have been free of malignancy for at least 5 years, or have a history of completely resected non-melanoma skin cancer, or successfully treated in situ carcinoma are eligible.

Primary outcomes:
measure: Number of patients on progression-free survival
timeFrame: At 12 months from treatment start
Secondary outcomes:
measure: Number of patients in complete response (CR) or partial response (OR)
timeFrame: At the end of induction therapy, that is, 7 months from treatment start
measure: Number of patients in CR
timeFrame: At the end of induction therapy, that is, at 7 months from treatment start
measure: Number of negative minimal residual disease CRs
timeFrame: At the end of induction therapy, that is, at 7 months from treatment start
measure: Number of days from treatment discontinuation to new treatment restart.
timeFrame: At the end of the study, that is, 90 months from treatment start
measure: Number of patients in event-free survival
timeFrame: At 36 months from treatment start
measure: Number of patients in overall survival (OS)
timeFrame: At 36 months from treatment start
measure: Number of patients in which there is a hematological improvement
timeFrame: At the end of the study, that is, at 90 months from treatment start
measure: Number of patients with improvement in the immunoglobulin levels
timeFrame: At 90 months from treatment start
measure: Number of adverse events and serious adverse events
timeFrame: At 90 months from study start
measure: Number of patients requiring hospitalization
timeFrame: At 90 months from study entry
measure: Number of patients in which clinical and biological features can be linked
timeFrame: At 90 months from study entry
measure: Number of leukemic subpopulations
timeFrame: At 90 months from start
measure: Number of patients with RS identified by FDG-PET/CT
timeFrame: At 90 months from study start
Other outcomes:
Locations:
city: Alessandria
country: Italy
facility: S.O.C. di Ematologia - Azienda Ospedaliera - SS. Antonio e Biagio e Cesare Arrigo
city: Ascoli Piceno
country: Italy
facility: U.O.C. Ematologia e Terapia Cellulare - Ospedale "C. e G. Mazzoni" di Ascoli Piceno
city: Asti
country: Italy
facility: S.O.C. di Medicina Interna B - Ospedale - Cardinal Massaia di Asti
city: Bari
country: Italy
facility: UO Ematologia con trapianto-Università degli Studi di Bari Aldo Moro
city: Bologna
country: Italy
facility: Istituto di Ematologia "Lorenzo e A. Seragnoli" - Università degli Studi di Bologna - Policlinico S. Orsola - Malpighi
city: Cagliari
country: Italy
facility: ASL N.8 - Ospedale "A. Businco" - Struttura Complessa di Ematologia e CTMO
city: Campobasso
country: Italy
facility: U.O.C. di Onco-Ematologia - Centro di Ricerca e Formazione ad Alta tecnologia nelle Scienze Biomediche
city: Catania
country: Italy
facility: Unità di Onco-Ematologia - Azienda Ospedaliera - Garibaldi
city: Catanzaro
country: Italy
facility: Azienda Ospedaliera Pugliese Ciaccio - Presidio Ospedaliero A.Pugliese - Unità Operativa di Ematologia
city: Cona
country: Italy
facility: Azienda Ospedaliero Universitaria Arcispedale Sant'Anna Dipartimento di Scienze Mediche Sezione di Ematologia e Fisiopatologia dell'Emostasi
city: Cosenza
country: Italy
facility: U.O. Ematologia - P.O. Annunziata - A.O. di Cosenza
city: Foggia
country: Italy
facility: Struttura Complessa di Ematologia Ospedali Riuniti Foggia - Azienda Ospedaliero-Universitaria
city: Genova
country: Italy
facility: IRCCS_AOU San Martino-IST-Ematologia 1-Monoblocco 11°piano- lato ponente
city: Lecce
country: Italy
facility: ASL Le/1 P.O. Vito Fazzi - U.O. di Ematologia ed UTIE
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnoli per lo Studio e la Cura dei Tumori- IRST
city: Messina
country: Italy
facility: Azienda Ospedaliera Universitaria - Policlinico G. Martino Dipartimento di Medicina Interna - U.O. Messina
city: Messina
country: Italy
facility: Divisione di Ematologia - Azienda Ospedaliera Ospedali Riuniti "Papardo Piemonte"
city: Milano
country: Italy
facility: Ospedale Niguarda " Ca Granda" - SC Ematologia Blocco SUD, Ponti Est, Scala E, 4° piano
city: Modena
country: Italy
facility: UO Ematologia - AOU Policlinico di Modena
city: Novara
country: Italy
facility: .C.D.U. Ematologia - DIMECS e Dipartimento Oncologico - Università del Piemonte Orientale Amedeo Avogadro Gianluca Gaidano S.C.D.U. Ematologia - DIMECS e Dipartimento Oncologico - Università del Piemonte Orientale Amedeo Avogadro Novara Davide Rossi S
city: Padova
country: Italy
facility: Università degli Studi di Padova - Ematologia ed Immunologia Clinica
city: Pagani
country: Italy
facility: U.O. di Oncoematologia di Nocera Inferiore-plesso ospedaliero "A. Tortora" di Pagani del DEA Nocera-Pagani
city: Parma
country: Italy
facility: Cattedra di Ematologia CTMO Università degli Studi di Parma
city: Pavia
country: Italy
facility: S.C. Ematologia - Fondazione IRCCS Policlinico S. Matteo
city: Perugia
country: Italy
facility: Sezione di Ematologia ed Immunologia Clinica - Ospedale S.Maria della Misericordia
city: Pescara
country: Italy
facility: U.O. Ematologia Clinica - Azienda USL di Pescara
city: Ravenna
country: Italy
facility: Dipartimento Oncologico - Ospedale S.Maria delle Croci
city: Reggio Calabria
country: Italy
facility: Dipartimento Emato-Oncologia A.O."Bianchi-Melacrino-Morelli"
city: Reggio Emilia
country: Italy
facility: Unità Operativa Complessa di Ematologia - Arcispedale S. Maria Nuova
city: Rimini
country: Italy
facility: Ospedale "Infermi"
city: Roma
country: Italy
facility: Dipartimento di Biotecnologie Cellulari ed Ematologia - Università degli Studi "Sapienza" di Roma
city: Roma
country: Italy
facility: Università Cattolica del Sacro Cuore - Policlinico A. Gemelli
city: Siena
country: Italy
facility: U.O.C. Ematologia e Trapianti - A.O. Senese - Policlinico " Le Scotte"
city: Terni
country: Italy
facility: A.O. Santa Maria - Terni S.C Oncoematologia
city: Torino
country: Italy
facility: Dipartimento di Oncologia ed Ematologia S.C. Ematologia 2 A.O. Città della Salute e della Scienza di Torino San Giovanni Battista
city: Torino
country: Italy
facility: Divisione di Ematologia dell' Università degli Studi di Torino - "Città della Salute e della Scienza di Torino"
Study officials:
affiliation: Policlinico Umberto I di Roma
name: Francesca Mauro
role: PRINCIPAL_INVESTIGATOR
References: