CClinicalTrials.gg
Sign In
CompletedNCT02692248Updated Oct 10, 2024Results posted

Ibrutinib in Patients With Refractory/Relapsed Non-GCB Diffuse Large B-cell Lymphoma Non-candidates to ASCT

A Phase 2 interventional study of Ibrutinib and Rituximab in Diffuse Large B-Cell Lymphoma, sponsored by Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea. Completed at 17 sites in Spain. Open to participants aged 18 Years to 99 Years. Per ClinicalTrials.gov, last updated 2024-10-10.

Sponsored by Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea · Phase 2, Interventional, and Treatment

Phase
Phase 2
Study type
Interventional
Enrollment
64
Allocation
Not applicable
Ages
18 Years to 99 Years
Sex
All
01

Study summary

Multicentric phase II trial to evaluate efficacy and safety of ibrutinib in combination with rituximab, gemcitabine, oxaliplatin and dexamethasone followed by Ibrutinib maintenance 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.

Read the 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.

02

Conditions studied

  • Diffuse Large B-Cell Lymphoma
03

Who can participate

Ages eligible
18 Years to 99 Years
Sexes eligible
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).

    -A central review will be performed for confirmation of the germinal center B-cell-like, however even when negative results are reported, the patient will still be part of the study if clinical benefit after cycle 4 is documented (stable disease, partial response and complete response).

  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

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.

    • Young patients with more than a previous line and refractory could be considered as not suitable for autologous stem cell transplant and, therefore, are eligible for this study.
  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
04

Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrollment
64 participants (actual)

Study arms

  • 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/m2 IV on day 1 or 2 (at investigator discretion). * Oxaliplatine 100 mg/m2 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 · Drug: Rituximab · Drug: Gemcitabine · Drug: Oxaliplatin · Drug: Dexamethasone

Interventions

  • DrugIbrutinib

    Ibrutinib 560 mg daily for 14 days during induction cycles. Maintenance phase: Continuous cycles until disease progression or unacceptable toxicity (maximum of 2 years).

  • DrugRituximab

    Rituximab 375 mg/m2 IV day 1 during 4 cycles.

  • DrugGemcitabine

    Gemcitabine 1000 mg/m2 IV (30-minute infusion) on day 1 or 2, 4 cycles every 14 days.

  • DrugOxaliplatin

    Oxaliplatin 100 mg/m2 (3-hour infusion) on day 1 or 2, after Gemcitabine infusion, 4 cycles every 14 days.

  • DrugDexamethasone

    Dexamethasone 20 mg orally or IV on day 1 and orally on days 2-3, 4 cycles every 14 days.

05

What researchers measure

Primary outcomes

  1. Overall Response (OR) Rate

    Overall Response (OR) rate (complete remission + partial response) measured by PET(Positron Emission Tomography)/CT image scan. OR will be assessed by Lugano Classification: Revised Criteria for Response Assessment.

    Time frame: Treatment responses will be evaluated 30 days after end of study treatment which can be occurred after 2 years and 4 months

Secondary outcomes

  1. CR Rate During Induction and Maintenance Phases.

    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

    Time frame: Complete treatment responses will be evaluated 30 days after end of study treatment which can be occurred after 2 years and 4 months

  2. Response Duration

    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.

    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.

  3. Progression Free Survival

    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. Progression is defined using Lugano Classification for response assessment for Non-Hodgkin Lymphoma, defined as Score of 4 or 5 with an increase in uptake intensity over baseline period for Individual lymph nodes/target lymph node masses; New areas of FDG avidity consistent with lymphoma at mid- or end-of-treatment assessment for Extranodal injuries; new injuries; New or recurrent areas of FDG avidity in bone marrow.

    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

  4. Event-free Survival

    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

    Time frame: 2 years and 4 months.

  5. Overall Survival

    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.

    Time frame: 2 years

  6. Percentage of Participants That Present Treatment-Related Adverse Events Oxaliplatin and Dexamethasone

    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

    Time frame: 2 years and 4 months

06

Results

Posted Oct 10, 2024
Limitations and caveats
The main limitation of the IBDCL trial was the lack of randomization and a parallel control group, that precluded comparison of outcome measures with other existing therapeutic approaches.

Participant flow

64 patients from 15 different hospitals were registered.

Participant flow — Overall Study
MilestoneIbrutinib -R-GEMOX-Dexa
Started64
Completed64
Not completed0

Outcome measures

PrimaryOverall Response (OR) Rate

Overall Response (OR) rate (complete remission + partial response) measured by PET(Positron Emission Tomography)/CT image scan. OR will be assessed by Lugano Classification: Revised Criteria for Response Assessment.

Time frame:
Treatment responses will be evaluated 30 days after end of study treatment which can be occurred after 2 years and 4 months
Reported as:
Count of participants · Participants
Overall Response (OR) Rate
ParticipantsIbrutinib -R-GEMOX-Dexa
Overall Response (OR) Rate36
SecondaryCR Rate During Induction and Maintenance Phases.

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

Time frame:
Complete treatment responses will be evaluated 30 days after end of study treatment which can be occurred after 2 years and 4 months
Reported as:
Count of participants · Participants
CR Rate During Induction and Maintenance Phases.
ParticipantsIbrutinib -R-GEMOX-Dexa
CR Rate During Induction and Maintenance Phases.25
SecondaryResponse Duration

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.

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.
Reported as:
Median · months
Response Duration
monthsIbrutinib -R-GEMOX-Dexa
Response Duration6.5 (0.0 to 38.3)
SecondaryProgression Free Survival

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. Progression is defined using Lugano Classification for response assessment for Non-Hodgkin Lymphoma, defined as Score of 4 or 5 with an increase in uptake intensity over baseline period for Individual lymph nodes/target lymph node masses; New areas of FDG avidity consistent with lymphoma at mid- or end-of-treatment assessment for Extranodal injuries; new injuries; New or recurrent areas of FDG avidity in bone marrow.

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
Reported as:
Median · months
Progression Free Survival
monthsIbrutinib -R-GEMOX-Dexa
Progression Free Survival4.1 (2.2 to 6.1)
SecondaryEvent-free Survival

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

Time frame:
2 years and 4 months.
Reported as:
Median · months
Event-free Survival
monthsIbrutinib -R-GEMOX-Dexa
Event-free Survival4.03 (2.5 to 5.6)
SecondaryOverall Survival

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.

Time frame:
2 years
Reported as:
Median · months
Overall Survival
monthsIbrutinib -R-GEMOX-Dexa
Overall Survival11.67 (7 to 16.3)
SecondaryPercentage of Participants That Present Treatment-Related Adverse Events Oxaliplatin and Dexamethasone

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

Time frame:
2 years and 4 months
Reported as:
Count of participants · Participants
Percentage of Participants That Present Treatment-Related Adverse Events Oxaliplatin and Dexamethasone
ParticipantsIbrutinib -R-GEMOX-Dexa
Percentage of Participants That Present Treatment-Related Adverse Events Oxaliplatin and Dexamethasone55

Adverse events

Collected over 2 years and 4 months. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Ibrutinib -R-GEMOX-Dexa46/64 (71.9%)33/64 (51.6%)63/64 (98.4%)
Most frequent serious events
Showing 10 of 47
Most frequent serious events
EventIbrutinib -R-GEMOX-Dexa
Diarrhoea - Grade 3Gastrointestinal disorders2/64
Fever - Grade 3General disorders2/64
Fracture - Grade 3Injury, poisoning and procedural complications2/64
Respiratory failure - Grade 3Respiratory, thoracic and mediastinal disorders2/64
Abdominal pain - Grade 3Gastrointestinal disorders1/64
Akathisia - Grade 3Nervous system disorders1/64
Anemia - Grade 3Blood and lymphatic system disorders1/64
Back Pain - Grade 3Musculoskeletal and connective tissue disorders1/64
Confusion - Grade 3Nervous system disorders1/64
Diarrhoea - Grade 2Gastrointestinal disorders1/64
Most frequent other events
Most frequent other events
EventIbrutinib -R-GEMOX-Dexa
Platelet count decreasedBlood and lymphatic system disorders39/64
Neutrophil count decreasedBlood and lymphatic system disorders22/64
DiarrhoeaGastrointestinal disorders20/64
AnemiaBlood and lymphatic system disorders14/64
NauseaGeneral disorders14/64
Lymphocyte count decreaseBlood and lymphatic system disorders10/64
ParesthesiaNervous system disorders8/64
FatigueGeneral disorders7/64
VomitingGastrointestinal disorders6/64
HypomagnesemiaBlood and lymphatic system disorders4/64

Baseline characteristics

Age, Continuous
Age, Continuous(years)Ibrutinib -R-GEMOX-Dexa
Median67.4 (24.5 to 83.7)
Sex: Female, Male
Sex: Female, Male(Participants)Ibrutinib -R-GEMOX-Dexa
Female26
Male38
Race and Ethnicity Not Collected
Race and Ethnicity Not Collected(Participants)Ibrutinib -R-GEMOX-Dexa
Region of Enrollment
Region of Enrollment(participants)Ibrutinib -R-GEMOX-Dexa
Spain64
ECOG-PS
ECOG-PS(Participants)Ibrutinib -R-GEMOX-Dexa
023
131
210
DLBCL type
DLBCL type(Participants)Ibrutinib -R-GEMOX-Dexa
DLBCL without specification60
DLBCL rich in T lymphocytes3
Follicular lymphoma1
Previous lines of treatment
Previous lines of treatment(Previous lines of treatment)Ibrutinib -R-GEMOX-Dexa
Median2 (1 to 5)
International prognostic index (IPI)
International prognostic index (IPI)(Participants)Ibrutinib -R-GEMOX-Dexa
0-16
2-343
4-513
Unk2

2 further baseline measures are reported on the registry.

07

Study locations

17 sites
  • Hospital Universitario Central de Asturias
    Oviedo, Asturias 33011, Spain
  • Hospital Especialidades
    Jerez de la Frontera, Cádiz 11407, Spain
  • Hospital Universitario Donostia
    Donostia San Sebastian, Guipúzcoa 20080, Spain
  • Hospital Universitario Son Espases
    Palma, Islas Baleares 07120, Spain
  • Hospital de Navarra
    Pamplona, Navarra 31008, Spain
  • Complexo Hospitalario Universitario de Vigo
    Vigo, Pontevedra, Spain
  • Hospital Universitario Vall d'Hebron
    Barcelona, 08035, Spain
  • Hospital Clínic de Barcelona
    Barcelona, 08036, Spain
  • Complejo Hospitalario de Jaén
    Jaén, 23007, Spain
  • Hospital Universitario Infanta Leonor
    Madrid, 28031, Spain
  • MD Anderson Cancer Center
    Madrid, 28033, Spain
  • Hospital Universitario 12 de Octubre
    Madrid, 28041, Spain
  • Hospital General Universitario Morales Meseguer
    Murcia, 30008, Spain
  • Hospital Universitario Virgen del Rocío
    Sevilla, 41013, Spain
  • Hospital Clínic Universitari de València
    Valencia, 46010, Spain
  • Hospital Universitario y Politécnico La Fe
    Valencia, 46026, Spain
  • Hospital Clínico Universitario de Valladolid
    Valladolid, 47005, Spain
08

References and documents

Study documents

  • Protocol and informed consent form · Oct 21, 2016
  • Statistical analysis plan · Apr 26, 2021

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No

09

Registry details

Key details

Study ID
NCT02692248
Lead sponsor
Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea
Collaborators
Janssen-Cilag, S.A.
Responsible party
Sponsor
First posted
Feb 26, 2016
Start date
Apr 7, 2016
Primary completion
Nov 8, 2018
Completion
Jan 19, 2021
Results posted
Oct 10, 2024
Last update
Oct 10, 2024

Study contacts

Dolores Caballero, MD
study chair · University of Salamanca

Oversight

Data monitoring committee
No
View the source record on ClinicalTrials.gov ↗

Not currently enrolling

This study is completed, as verified in Oct 2024. You cannot join it, but the record below documents what was studied.

Follow this study

Get an email when the registry record changes — status, dates, results — or when someone posts here.

Sign in to follow

Discussion

Questions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.

Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.

Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.

Other studies in this condition

Lymphoma→

Other studies from this sponsor

Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea

Start the discussion