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Chronic Lymphocyte LeukemiaPhase 2LLC1114NCT02232386

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

A Phase 2 study testing Ibrutinib and Rituximab in people with Chronic Lymphocyte Leukemia and Adult Patients, run by Gruppo Italiano Malattie EMatologiche dell'Adulto at 36 sites in Italy.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Chronic Lymphocyte Leukemia, Adult Patients
What is being tested?
Ibrutinib and Rituximab
Could I receive a placebo?
No, everyone receives an active treatment
How many people
156 participants
Where
36 sitesItaly
Study dates
2 Mar 2015to 16 Apr 2024
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 18 years of age or older.
  • Diagnosis of CLL meeting IWCLL criteria.
  • 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.
  • Active disease meeting at least 1 of the following IWCLL 2008 criteria for requiring treatment:
  • Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia or thrombocytopenia.
  • Massive (ie, at least 6 cm below the left costal margin), progressive, or symptomatic splenomegaly.
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  • Massive nodes (ie, at least 10 cm in longest diameter), progressive, or symptomatic lymphadenopathy.
  • 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.
  • 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.
  • No prior treatment.
  • Total CIRS >6 and/or creatinine clearance <70 ml/min [Cockcroft-Gault]).
  • 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
  • Biochemical values within the following limits:
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 x upper limit of normal (ULN)
  • Total bilirubin ≤1.5 x ULN unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin
  • Serum creatinine ≤2 x ULN or estimated Glomerular Filtration Rate (Cockroft Gault) ≥40 mL/min
  • 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.
  • 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.
  • 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.

Who cannot join

  • 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.
  • Pregnant or lactating females
  • Known presence of alcohol and/or drug abuse.
  • Any potential subject who meets any of the following criteria will be excluded from participating in the study.
  • Major surgery within 4weeks of randomization.
  • Uncontrolled autoimmune hemolytic anemia or thrombocytopenia.
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  • Known central nervous system lymphoma.
  • 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.
  • Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) in any moment of the study.
  • Requires treatment with strong CYP3A inhibitors.
  • 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
  • Vaccinated with live, attenuated vaccines within 4 weeks of randomization.
  • 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.
  • 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.

Trial locations and contacts

36 sites in 1 country.

36 sites in 1 country

Italy36 sites

  • S.O.C. di Ematologia - Azienda Ospedaliera - SS. Antonio e Biagio e Cesare Arrigo

    Alessandria

  • U.O.C. Ematologia e Terapia Cellulare - Ospedale "C. e G. Mazzoni" di Ascoli Piceno

    Ascoli Piceno

  • S.O.C. di Medicina Interna B - Ospedale - Cardinal Massaia di Asti

    Asti

  • UO Ematologia con trapianto-Università degli Studi di Bari Aldo Moro

    Bari

  • Istituto di Ematologia "Lorenzo e A. Seragnoli" - Università degli Studi di Bologna - Policlinico S. Orsola - Malpighi

    Bologna

  • ASL N.8 - Ospedale "A. Businco" - Struttura Complessa di Ematologia e CTMO

    Cagliari

  • U.O.C. di Onco-Ematologia - Centro di Ricerca e Formazione ad Alta tecnologia nelle Scienze Biomediche

    Campobasso

  • Unità di Onco-Ematologia - Azienda Ospedaliera - Garibaldi

    Catania

  • Azienda Ospedaliera Pugliese Ciaccio - Presidio Ospedaliero A.Pugliese - Unità Operativa di Ematologia

    Catanzaro

  • Azienda Ospedaliero Universitaria Arcispedale Sant'Anna Dipartimento di Scienze Mediche Sezione di Ematologia e Fisiopatologia dell'Emostasi

    Cona

  • U.O. Ematologia - P.O. Annunziata - A.O. di Cosenza

    Cosenza

  • Struttura Complessa di Ematologia Ospedali Riuniti Foggia - Azienda Ospedaliero-Universitaria

    Foggia

  • IRCCS_AOU San Martino-IST-Ematologia 1-Monoblocco 11°piano- lato ponente

    Genova

  • ASL Le/1 P.O. Vito Fazzi - U.O. di Ematologia ed UTIE

    Lecce

  • Istituto Scientifico Romagnoli per lo Studio e la Cura dei Tumori- IRST

    Meldola

  • Azienda Ospedaliera Universitaria - Policlinico G. Martino Dipartimento di Medicina Interna - U.O. Messina

    Messina

  • Divisione di Ematologia - Azienda Ospedaliera Ospedali Riuniti "Papardo Piemonte"

    Messina

  • Ospedale Niguarda " Ca Granda" - SC Ematologia Blocco SUD, Ponti Est, Scala E, 4° piano

    Milan

  • UO Ematologia - AOU Policlinico di Modena

    Modena

  • .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

    Novara

  • Università degli Studi di Padova - Ematologia ed Immunologia Clinica

    Padova

  • U.O. di Oncoematologia di Nocera Inferiore-plesso ospedaliero "A. Tortora" di Pagani del DEA Nocera-Pagani

    Pagani

  • Cattedra di Ematologia CTMO Università degli Studi di Parma

    Parma

  • S.C. Ematologia - Fondazione IRCCS Policlinico S. Matteo

    Pavia

  • Sezione di Ematologia ed Immunologia Clinica - Ospedale S.Maria della Misericordia

    Perugia

  • U.O. Ematologia Clinica - Azienda USL di Pescara

    Pescara

  • Dipartimento Oncologico - Ospedale S.Maria delle Croci

    Ravenna

  • Dipartimento Emato-Oncologia A.O."Bianchi-Melacrino-Morelli"

    Reggio Calabria

  • Unità Operativa Complessa di Ematologia - Arcispedale S. Maria Nuova

    Reggio Emilia

  • Ospedale "Infermi"

    Rimini

  • Dipartimento di Biotecnologie Cellulari ed Ematologia - Università degli Studi "Sapienza" di Roma

    Roma

  • Università Cattolica del Sacro Cuore - Policlinico A. Gemelli

    Roma

  • U.O.C. Ematologia e Trapianti - A.O. Senese - Policlinico " Le Scotte"

    Siena

  • A.O. Santa Maria - Terni S.C Oncoematologia

    Terni

  • Dipartimento di Oncologia ed Ematologia S.C. Ematologia 2 A.O. Città della Salute e della Scienza di Torino San Giovanni Battista

    Torino

  • Divisione di Ematologia dell' Università degli Studi di Torino - "Città della Salute e della Scienza di Torino"

    Torino

Other trials in Italy

About this study

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).

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.

Read the 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.
Being tested
Ibrutinib, Rituximab
Keywords
Chronic lymphocyte leukemia, Adults, Ibrutinib

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • IbrutinibDrug

    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.

  • RituximabDrug

    Rituximab 375 mg/m2 iv. Month 1: day 1 of weeks 1, 2, 3, 4; months 2-6: day 1of week 1.

Study groups in NCT02232386
Study groupRoleWhat they receive
TreatmentExperimentalIbrutinib (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.
Receives: Drug: Ibrutinib; Drug: Rituximab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: At 12 months from treatment start

Secondary outcomes (13)

  1. 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.

    Measured: At the end of induction therapy, that is, 7 months from treatment start

  2. 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.

    Measured: At the end of induction therapy, that is, at 7 months from treatment start

  3. 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.

    Measured: At the end of induction therapy, that is, at 7 months from treatment start

  4. Number of days from treatment discontinuation to new treatment restart.

    Time To Next Treatment (TTNT) after treatment discontinuation.

    Measured: At the end of the study, that is, 90 months from treatment start

  5. Number of patients in event-free survival

    event-Free Survival (PFS) at 36 months.

    Measured: At 36 months from treatment start

  6. Number of patients in overall survival (OS)

    Overall Survival (OS) at 36 months.

    Measured: At 36 months from treatment start

  7. 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.

    Measured: At the end of the study, that is, at 90 months from treatment start

  8. Number of patients with improvement in the immunoglobulin levels

    Rate of patients with improvement in the immunoglobulin levels.

    Measured: At 90 months from treatment start

  9. Number of adverse events and serious adverse events

    Measured: At 90 months from study start

  10. Number of patients requiring hospitalization

    Rate of patients requiring hospitalization, emergency department visits, blood product transfusions and use of hematopoietic growth factors.

    Measured: At 90 months from study entry

  11. 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.

    Measured: At 90 months from study entry

  12. 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.

    Measured: At 90 months from start

  13. Number of patients with RS identified by FDG-PET/CT

    Rate of cases of patients with RS or SM identified by FDG-PET/CT

    Measured: At 90 months from study start

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted5 Sep 2014 (estimated)
  2. Study start2 Mar 2015
  3. Primary completionApr 2018
  4. Study completion16 Apr 2024

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
156 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02232386
Sponsor's protocol ID
LLC1114
Other IDs
2014-002714-23, 2014
Acronym
LLC1114
Status last verified
Jan 2025
First submitted
2 Sep 2014
Last updated
16 Jan 2025
Results posted
No
Data monitoring committee
No
Individual data sharing
No

Publications

  • Peragine N, De Propris MS, Intoppa S, Milani ML, Mauro FR, Cuneo A, Rigolin GM, Del Giudice I, Foa R, Guarini A. Early CD49d downmodulation in chronic lymphocytic leukemia patients treated front-line with ibrutinib plus rituximab predicts long-term response. Leuk Lymphoma. 2022 Dec;63(12):2982-2986. doi: 10.1080/10428194.2022.2105324. Epub 2022 Aug 1. No abstract available.

    PubMed 35913400

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Ibrutinib and Rituximab in people with Chronic Lymphocyte Leukemia and Adult Patients, run by Gruppo Italiano Malattie EMatologiche dell'Adulto at 36 sites in Italy.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 24 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 16 Jan 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 36 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of patients on progression-free survival (time frame: At 12 months from treatment start). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02232386, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Jan 2025.

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