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Ibrutinib in Patients With Refractory/Relapsed Non-GCB Diffuse Large B-cell Lymphoma Non-candidates to Autologous Stem Cell Transplantation

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ClinicalTrials.gov Identifier: NCT02692248
Recruitment Status : Recruiting
First Posted : February 26, 2016
Last Update Posted : June 9, 2017
Janssen-Cilag, S.A.
Information provided by (Responsible Party):
Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea

Brief Summary:
Multicentric phase II trial to evaluate efficacy and safety of ibrutinib in combination with rituximab, gemcitabine, oxaliplatin and dexamethasone followed by Ibrutinib maitenance in patients with refractory/relapsed non-GCB DLBCL non candidates to autologous stem-cell transplantation (ASCT) An extensive biological study will be conducted in order to further characterize this population of DLBCL patients and correlate the response obtained with the biological profile of the tumor.

Condition or disease Intervention/treatment Phase
Diffuse Large B-Cell Lymphoma Drug: Ibrutinib Drug: Rituximab Drug: Gemcitabine Drug: Oxaliplatin Drug: Dexamethasone Phase 2

Detailed Description:

The use of highly effective rituximab-containing therapy for treating diffuse large B-cell lymphoma (DLBCL) makes it more difficult to salvage relapsed or refractory patients. In addition, patients with advanced age or significant comorbidities, who are consequently not candidates for high-dose consolidative therapy, have a very poor prognosis. Prospective studies investigating new salvage regimens are essential.

The combination of rituximab, gemcitabine and oxaliplatin (R-GEMOX) is an effective salvage regimen for patients with relapsing or refractory DLBCL, with a favourable toxicity profile for unfit and/or elderly patients. Ibrutinib, an oral Bruton's tyrosine kinase inhibitor, is a potent killer of ABC DLBCL cell lines in vitro and in xenografts.

It is expected that the combination of ibrutinib with R-GEMOX-Dexa could be effective and well tolerated. Thus, it is proposed an open-label, non-randomized, multicentre, phase II trial, to investigate the safety and efficacy of the combination of ibrutinib with rituximab, gemcitabine, oxaliplatine and dexamethasone followed by ibrutinib maintenance as salvage therapy for patients with relapsed or refractory non-GCB DLBCL non-candidates to stem cell transplant.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 62 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Multicentric Phase II Trial to Evaluate the Efficacy and Safety of Ibrutinib in Combination With Rituximab, Gemcitabine, Oxaliplatin and Dexamethasone Followed by Ibrutinib Maintenance in Patients With Refractory/Relapsed Non-GCB Diffuse Large B-cell Lymphoma Non Candidates to ASCT
Study Start Date : April 2016
Estimated Primary Completion Date : September 2020
Estimated Study Completion Date : September 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma
Drug Information available for: Ibrutinib
U.S. FDA Resources

Arm Intervention/treatment
Experimental: Ibrutinib -R-GEMOX-Dexa

Subjects will receive Ibrutinib with R-GEMOX-Dexa followed by Ibrutinib maintenance according to:

Induction phase:

  • Rituximab 375 mg/m2 IV day 1
  • Gemcitabine 1000 mg/msq IV on day 1 or 2 (at investigator discretion).
  • Oxaliplatine 100 mg/msq on day 1 or 2 (after Gemcitabine administration);
  • Dexamethasone 20 mg orally or IV on day 1 and orally on days 2-3.
  • Ibrutinib 560 mg daily for 14 days.

Responding patients will receive 2 (if CR) or 4 (if PR) additional cycles every 14 days.Patients with SD and ABC profile will receive 4 additional cycles.

Maintenance phase: Responding patients will receive Ibrutinib 560 mg daily - Continuous cycles until a maximum of 2 years, disease progression or unacceptable toxicity.

Drug: Ibrutinib
Ibrutinib 560 mg daily for 14 days during induction cycles. Maintenance phase: Continuous cycles until disease progression or unacceptable toxicity (maximum of 2 years).
Drug: Rituximab
Rituximab 375 mg/m2 IV day 1 during 4 cycles.
Drug: Gemcitabine
Gemcitabine 1000 mg/msq IV (30-minute infusion) on day 1 or 2, 4 cycles every 14 days.
Drug: Oxaliplatin
Oxaliplatin 100 mg/msq (3-hour infusion) on day 1 or 2, after Gemcitabine infusion, 4 cycles every 14 days.
Drug: Dexamethasone
Dexamethasone 20 mg orally or IV on day 1 and orally on days 2-3, 4 cycles every 14 days.

Primary Outcome Measures :
  1. Overall Response (OR) rate (complete remission + partial response) measured by PET(Positron Emission Tomography)/CT imagen scan [ Time Frame: Treatment responses will be evaluated 30 days after end of study treatment wich can be ocurred after 2 years and 4 months ]
    OR will be assessed by Lugano Classification: Revised Criteria for Response Assessment (Cheson et al. 2014)

Secondary Outcome Measures :
  1. CR rate during induction and maintenance phases. [ Time Frame: 2 years ]
    Complete treatment responses evaluation during 21-35 days after initiation of 6 or 8 cycle of study treatment (depend of treatment responses obtained from cycle 4) and 30 days after end of study treatment which can be occurred after 2 years and 4 months

  2. Conversion rate from SD (Stable Disease) or PR to PR or CR by PET/CT imagen scan [ Time Frame: 2 years ]
    Responses conversion rate evaluation after 30 days of the end of the maintenance treatment which can be occurred after 2 years of maintenance study treatment

  3. Response duration [ Time Frame: Response duration will be evaluated at any time during the study when tumor response is documented or after end of study treatment which can be occurred after 2 years and 4 months. ]
    Response duration defined as the time from the documentation of tumor response to disease progression or death, in the event of no documented recurrence, or start of a new anti - lymphoma treatment because of refractory or persistent disease.

  4. Progression free survival [ Time Frame: Progression free survival will be evaluated at any time during the study when first documentation of recurrence, progression, or death or after end of study treatment which can be occurred after 2 years and 4 months ]
    Progression free survival defined as the time between start of treatment and the first documentation of recurrence, progression, or death in the event of no documented recurrence, or start of a new anti - lymphoma treatment, due a refractory or persistent disease

  5. Event-free survival [ Time Frame: 2 years ]
    Event-free survival defined as the time between start of treatment and the first documentation of adverse events and serious adverse events graded according to NCI CTCAE v4.0

  6. Overall survival [ Time Frame: 2 years ]
    Overall survival is defined as the time between the start of treatment and death from any cause. Patients that are withdrawn from the trial or lost of follow-up, will be censored with the date of last contact. Patients who are still alive at the end of the study will be censored at that time.

  7. Safety and tolerability of ibrutinib in combination rituximab, gemcitabine, oxaliplatin and dexamethasone [ Time Frame: 2 years ]
    Safety and tolerability will be assessed during any phase of study treatment and 30 days after end of study treatment which can be occurred after 2 years and 4 months and will be classified according to the Common Toxicity CNC

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Ages Eligible for Study:   18 Years to 99 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Subjects with confirmed histologically diagnosis of diffuse large B-cell lymphoma.
  2. Subjects must be 18 years of age or older.
  3. Non-germinal center B-cell-like (GCB) subtype according to Hans algorithm (local laboratories).
  4. Relapsed or refractory disease after:

    • at least 1 prior line of therapy that includes rituximab in combination with chemotherapy, or,
    • after previous ASCT, or,
    • after reduced intensity conditioning allogeneic transplant, unless patient is receiving immunosuppressive drugs or active graft versus host disease is present at study entry.
  5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
  6. Baseline FDG-PET scan demonstrating positive lesions (Deauville 4 or 5) compatible with CT defined anatomical tumor sites.
  7. Hematology values must be within the following limits:

    1. absolute neutrophil count (ANC) ≥1000/μL independent of growth factor support.
    2. platelets ≥100000/μL or ≥50000/μL if bone marrow involvement independent of transfusion support in either situation.
  8. Biochemical values within the following limits:

    1. alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 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 creatinine clearance (CCr) ≥30 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 to not 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) or urine pregnancy test at Screening. Women who are pregnant or breastfeeding are ineligible for this study.
  11. 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 and able to participate in the study.

Exclusion Criteria:

  1. Prior malignancy other than DLBCL, with the exception of adequately treated basal cell or squamous cell skin tumor, in situ cervical cancer, or other tumor from which the patient has been disease free for at least 2 years or which will not limit survival to < 2 years (Note: these cases must be discussed with the Principal Investigator).
  2. Candidates to autologous stem cell transplant.
  3. Any life-threatening illness, medical condition or organ system dysfunction which, in the investigator's opinion, could compromise the patient's safety,interfere with the absorption or metabolism of ibrutinib, or put the study outcomes at undue risk.
  4. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification.
  5. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis,symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.
  6. Treatment with any immunotherapy, chemotherapy, radiotherapy, or experimental therapy within 3 weeks before first dose of study drug.
  7. Prior treatment with ibrutinib or other BTK inhibitors.
  8. Central nervous system (CNS) involvement by lymphoma.
  9. History of stroke or intracranial hemorrhage within 6 months prior to randomization.
  10. Requires anticoagulation with warfarin or equivalent Vitamin K antagonists.
  11. Requires treatment with strong CYP3A inhibitors.
  12. Grade ≥2 toxicity (other than alopecia) related to prior anticancer therapy including radiation.
  13. Known history of human immunodeficiency virus (HIV), active hepatitis C virus (HCV) (HCV; RNA polymerase chain reaction [PCR]-positive) or active Hepatitis B virus (HBV; DNA PCR-positive) infection or any uncontrolled active systemic infection requiring IV antibiotics. Subjects with PCR-negative HBV are permitted in the study.
  14. Major surgery within 4 weeks before first dose of study drug.
  15. Vaccinated with live, attenuated vaccines within 4 weeks of randomization.
  16. Pregnancy or lactation

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02692248

Contact: Dolores Caballero, MD cabarri@usal.es
Contact: Alejandro Martín García-Sancho, MD amartingar@usal.es

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Contact: Ángel Ramírez Páyer, MD       apayer.angel@gmail.com   
Principal Investigator: Ángel Ramírez Páyer, MD         
Hospital Especialidades Recruiting
Jerez de la Frontera, Cádiz, Spain, 11407
Contact: Mª José Ramírez, MD       mariajoserasa@yahoo.es   
Principal Investigator: Mª José Ramírez, MD         
Hospital Universitario Donostia Recruiting
Donostia San Sebastian, Guipúzcoa, Spain, 20080
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Principal Investigator: Izaskun Ceberio, MD         
Hospital Universitario Son Espases Recruiting
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Contact: Antonio Gutiérrez, MD       antoniom.gutierrez@ssib.es   
Principal Investigator: Antonio Gutiérrez, MD         
Hospital de Navarra Recruiting
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Contact: Mª Cruz Viguria, MD       mc.viguria.alegria@cfnavarra.es   
Principal Investigator: Mª Cruz Viguria, MD         
Complexo Hospitalario Universitario de Vigo Recruiting
Vigo, Pontevedra, Spain
Contact: Ana Margarita Martínez Castro, MD       ana.margarita.martinez.castro@sergas.es   
Principal Investigator: Ana Margarita Martínez Castro, MD         
Hospital Universitario Vall d'Hebron Recruiting
Barcelona, Spain, 08035
Contact: Pau Abrisqueta, MD       pabrisqueta@vhebron.net   
Principal Investigator: Pau Abrisqueta, MD         
Hospital Clínic de Barcelona Recruiting
Barcelona, Spain, 08036
Contact: Eva Giné, MD       EGINE@clinic.ub.es   
Principal Investigator: Eva Giné, MD         
Complejo Hospitalario de Jaén Recruiting
Jaén, Spain, 23007
Contact: Soledad Duran Nieto, MD       soledaduran@hotmail.com   
Principal Investigator: Soledad Durán Nieto, MD         
Hospital Universitario Infanta Leonor Recruiting
Madrid, Spain, 28031
Contact: José Antonio Hernández Rivas, MD       jahr_jahr2006@yahoo.es   
Principal Investigator: Jose Antonio Hernández Rivas, MD         
MD Anderson Cancer Center Recruiting
Madrid, Spain, 28033
Contact: Adolfo de la Fuente, MD       afuente@mdanderson.es   
Principal Investigator: Adolfo de la Fuente, MD         
Hospital Universitario 12 de Octubre Recruiting
Madrid, Spain, 28041
Contact: Carlos Grande, MD       cgrandegar@yahoo.es   
Principal Investigator: Carlos Grande, MD         
Hospital General Universitario Morales Meseguer Recruiting
Murcia, Spain, 30008
Contact: Jose Javier Sánchez Blanco, MD       josej.sanchez3@carm.es   
Principal Investigator: Jose Javier Sánchez Blanco, MD         
Hospital Universitario Virgen del Rocío Recruiting
Sevilla, Spain, 41013
Contact: Fátima de la Cruz, MD       fatimadelacruzv@gmail.com   
Principal Investigator: Fátima de la Cruz, MD         
Hospital Clínic Universitari de València Recruiting
Valencia, Spain, 46010
Contact: Mª José Terol, MD       terol39@mail.ono.es   
Principal Investigator: Mª Jose Terol, MD         
Hospital Universitario y Politécnico La Fe Recruiting
Valencia, Spain, 46026
Contact: Rafael Andreu, MD       randreu69@gmail.com   
Principal Investigator: Rafael Andreu, MD         
Hospital Clínico Universitario de Valladolid Recruiting
Valladolid, Spain, 47005
Contact: Mª Jesús Peñarrubia, MD       mpenarrubiap@gmail.com   
Principal Investigator: Mª Jesús Peñarrubia, MD         
Sponsors and Collaborators
Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea
Janssen-Cilag, S.A.
Study Chair: Dolores Caballero, MD Hospital Universitario de Salamanca

Responsible Party: Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea
ClinicalTrials.gov Identifier: NCT02692248     History of Changes
Other Study ID Numbers: IBDCL-GELTAMO-2015
First Posted: February 26, 2016    Key Record Dates
Last Update Posted: June 9, 2017
Last Verified: June 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Additional relevant MeSH terms:
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Dexamethasone acetate
BB 1101
Anti-Inflammatory Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action