Phase 2 Study to Assess Activity & Safety of Front-line Ibrutinib + Rituximab in Unfit Chronic Lymphocytic Leukemia (LLC1114)

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).

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Adult Patients; Chronic Lymphocyte Leukemia
• Intervention / Treatment: Drug: Ibrutinib; Drug: Rituximab

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.

• Study Type: Interventional
• Enrollment (Actual): 156
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Alessandria, Italy
    • S.O.C. di Ematologia - Azienda Ospedaliera - SS. Antonio e Biagio e Cesare Arrigo
  • Ascoli Piceno, Italy
    • U.O.C. Ematologia e Terapia Cellulare - Ospedale "C. e G. Mazzoni" di Ascoli Piceno
  • Asti, Italy
    • S.O.C. di Medicina Interna B - Ospedale - Cardinal Massaia di Asti
  • Bari, Italy
    • UO Ematologia con trapianto-Università degli Studi di Bari Aldo Moro
  • Bologna, Italy
    • Istituto di Ematologia "Lorenzo e A. Seragnoli" - Università degli Studi di Bologna - Policlinico S. Orsola - Malpighi
  • Cagliari, Italy
    • ASL N.8 - Ospedale "A. Businco" - Struttura Complessa di Ematologia e CTMO
  • Campobasso, Italy
    • U.O.C. di Onco-Ematologia - Centro di Ricerca e Formazione ad Alta tecnologia nelle Scienze Biomediche
  • Catania, Italy
    • Unità di Onco-Ematologia - Azienda Ospedaliera - Garibaldi
  • Catanzaro, Italy
    • Azienda Ospedaliera Pugliese Ciaccio - Presidio Ospedaliero A.Pugliese - Unità Operativa di Ematologia
  • Cona, Italy
    • Azienda Ospedaliero Universitaria Arcispedale Sant'Anna Dipartimento di Scienze Mediche Sezione di Ematologia e Fisiopatologia dell'Emostasi
  • Cosenza, Italy
    • U.O. Ematologia - P.O. Annunziata - A.O. di Cosenza
  • Foggia, Italy
    • Struttura Complessa di Ematologia Ospedali Riuniti Foggia - Azienda Ospedaliero-Universitaria
  • Genova, Italy
    • IRCCS_AOU San Martino-IST-Ematologia 1-Monoblocco 11°piano- lato ponente
  • Lecce, Italy
    • ASL Le/1 P.O. Vito Fazzi - U.O. di Ematologia ed UTIE
  • Meldola, Italy
    • Istituto Scientifico Romagnoli per lo Studio e la Cura dei Tumori- IRST
  • Messina, Italy
    • Azienda Ospedaliera Universitaria - Policlinico G. Martino Dipartimento di Medicina Interna - U.O. Messina
  • Messina, Italy
    • Divisione di Ematologia - Azienda Ospedaliera Ospedali Riuniti "Papardo Piemonte"
  • Milano, Italy
    • Ospedale Niguarda " Ca Granda" - SC Ematologia Blocco SUD, Ponti Est, Scala E, 4° piano
  • Modena, Italy
    • UO Ematologia - AOU Policlinico di Modena
  • Novara, Italy
    • .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
  • Padova, Italy
    • Università degli Studi di Padova - Ematologia ed Immunologia Clinica
  • Pagani, Italy
    • U.O. di Oncoematologia di Nocera Inferiore-plesso ospedaliero "A. Tortora" di Pagani del DEA Nocera-Pagani
  • Parma, Italy
    • Cattedra di Ematologia CTMO Università degli Studi di Parma
  • Pavia, Italy
    • S.C. Ematologia - Fondazione IRCCS Policlinico S. Matteo
  • Perugia, Italy
    • Sezione di Ematologia ed Immunologia Clinica - Ospedale S.Maria della Misericordia
  • Pescara, Italy
    • U.O. Ematologia Clinica - Azienda USL di Pescara
  • Ravenna, Italy
    • Dipartimento Oncologico - Ospedale S.Maria delle Croci
  • Reggio Calabria, Italy
    • Dipartimento Emato-Oncologia A.O."Bianchi-Melacrino-Morelli"
  • Reggio Emilia, Italy
    • Unità Operativa Complessa di Ematologia - Arcispedale S. Maria Nuova
  • Rimini, Italy
    • Ospedale "Infermi"
  • Roma, Italy
    • Università Cattolica del Sacro Cuore - Policlinico A. Gemelli
  • Roma, Italy
    • Dipartimento di Biotecnologie Cellulari ed Ematologia - Università degli Studi "Sapienza" di Roma
  • Siena, Italy
    • U.O.C. Ematologia e Trapianti - A.O. Senese - Policlinico " Le Scotte"
  • Terni, Italy
    • A.O. Santa Maria - Terni S.C Oncoematologia
  • Torino, Italy
    • Dipartimento di Oncologia ed Ematologia S.C. Ematologia 2 A.O. Città della Salute e della Scienza di Torino San Giovanni Battista
  • Torino, Italy
    • Divisione di Ematologia dell' Università degli Studi di Torino - "Città della Salute e della Scienza di Torino"

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment; Ibrutinib (PCI-32765) 420 mg (3 x 140 mg capsules) will be administered orally once daily. The first dose will be delivered in the clinic on Day 1, after which subsequent dosing is typically on an outpatient basis. Treatment duration with Ibrutinib will be based on what comes first of the following three options: Treatment until progression or toxicity; Treatment until MRD negativity for 6 months; Treatment for 6 years. Rituximab 375 mg/m2 iv. Month 1: day 1 of weeks 1, 2, 3, 4; months 2-6: day 1of week 1.

Drug: Ibrutinib; Ibrutinib (PCI-32765) 420 mg (3 x 140 mg capsules) will be administered orally once daily. The first dose will be delivered in the clinic on Day 1, after which subsequent dosing is typically on an outpatient basis.; Drug: Rituximab; Rituximab 375 mg/m2 iv. Month 1: day 1 of weeks 1, 2, 3, 4; months 2-6: day 1of week 1.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients on progression-free survival	To estimate Progression-Free Survival (PFS) at 12 months in patients treated with Ibrutinib plus Rituximab combination in unfit patients with CLL.	At 12 months from treatment start

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients in complete response (CR) or partial response (OR)	Rate of Overall Response Rate (ORR) measured in terms of number of patients in CR/PR at the end of induction therapy.	At the end of induction therapy, that is, 7 months from treatment start
Number of patients in CR	Rate of Complete Responses (CR) measured in terms of number of patients in CR at the end of induction therapy.	At the end of induction therapy, that is, at 7 months from treatment start
Number of negative minimal residual disease CRs	Minimal Residual Disease (MRD) in terms of rate of MRD-negative CRs at the end of induction therapy.	At the end of induction therapy, that is, at 7 months from treatment start
Number of days from treatment discontinuation to new treatment restart.	Time To Next Treatment (TTNT) after treatment discontinuation.	At the end of the study, that is, 90 months from treatment start
Number of patients in overall survival (OS)	Overall Survival (OS) at 36 months.	At 36 months from treatment start
Number of patients in which there is a hematological improvement	Rate of hematological improvement in patients with baseline anemia, neutropenia and thrombocytopenia defined by hemoglobin >11 g/dL or increase ≥50% over baseline, granulocyte >1500 mm3 or platelet count >100,000/mm3, respectively.	At the end of the study, that is, at 90 months from treatment start
Number of patients with improvement in the immunoglobulin levels	Rate of patients with improvement in the immunoglobulin levels.	At 90 months from treatment start
Number of adverse events and serious adverse events		At 90 months from study start
Number of patients requiring hospitalization	Rate of patients requiring hospitalization, emergency department visits, blood product transfusions and use of hematopoietic growth factors.	At 90 months from study entry
Number of patients in which clinical and biological features can be linked	Rate of ORR, CR, PFS, EFS, TTNT and OS according to clinical and biologic variables: age, size of nodes, CIRS score, stage, ß2-microglobulin, lymphocyte count, stage, CD38, CD49d, ZAP-70, IGVH mutation status, FISH profile (11q del; 17p del; trisomy 12; 13q del; no aberrations) and mutations of TP53, NOTCH1, SF3B1 and BIRC3.	At 90 months from study entry
Number of leukemic subpopulations	Proportion of leukemic and of normal lymphocyte subpopulations, including evaluation of cytokine receptors/adhesion molecules on peripheral blood lymphocytes at week +2 from the start of treatment.	At 90 months from start
Number of patients with RS identified by FDG-PET/CT	Rate of cases of patients with RS or SM identified by FDG-PET/CT	At 90 months from study start
Number of patients in event-free survival	event-Free Survival (PFS) at 36 months.	At 36 months from treatment start

Collaborators and Investigators

• Sponsor: Gruppo Italiano Malattie EMatologiche dell'Adulto
• Investigators: Principal Investigator: Francesca Mauro, Policlinico Umberto I Di Roma

Study record dates

Study Major Dates

• Study Start (Actual): March 2, 2015
• Primary Completion (Actual): April 1, 2018
• Study Completion (Estimated): April 1, 2024

Study Registration Dates

• First Submitted: September 2, 2014
• First Submitted That Met QC Criteria: September 2, 2014
• First Posted (Estimated): September 5, 2014

Study Record Updates

• Last Update Posted (Actual): November 28, 2023
• Last Update Submitted That Met QC Criteria: November 22, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Adults; Ibrutinib; Chronic lymphocyte leukemia
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Leukemia, B-Cell; Chronic Disease; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Rituximab
• Other Study ID Numbers: LLC1114; 2014-002714-23 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO