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

Primary Purpose

Diffuse Large B-Cell Lymphoma

Status
Unknown status
Phase
Phase 2
Locations
Spain
Study Type
Interventional
Intervention
Ibrutinib
Rituximab
Gemcitabine
Oxaliplatin
Dexamethasone
Sponsored by
Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Diffuse Large B-Cell Lymphoma

Eligibility Criteria

18 Years - 99 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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:

  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

Sites / Locations

  • Hospital Universitario Central de Asturias
  • Hospital Especialidades
  • Hospital Universitario Donostia
  • Hospital Universitario Son Espases
  • Hospital de Navarra
  • Complexo Hospitalario Universitario de Vigo
  • Hospital Universitario Vall d'Hebron
  • Hospital Clínic de Barcelona
  • Complejo Hospitalario de Jaén
  • Hospital Universitario Infanta Leonor
  • MD Anderson Cancer Center
  • Hospital Universitario 12 de Octubre
  • Hospital General Universitario Morales Meseguer
  • Hospital Universitario Virgen del Rocío
  • Hospital Clínic Universitari de València
  • Hospital Universitario y Politécnico La Fe
  • Hospital Clínico Universitario de Valladolid

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Ibrutinib -R-GEMOX-Dexa

Arm Description

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.

Outcomes

Primary Outcome Measures

Overall Response (OR) rate (complete remission + partial response) measured by PET(Positron Emission Tomography)/CT imagen scan
OR will be assessed by Lugano Classification: Revised Criteria for Response Assessment (Cheson et al. 2014)

Secondary Outcome Measures

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
Conversion rate from SD (Stable Disease) or PR to PR or CR by PET/CT imagen scan
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
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.
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
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
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.
Safety and tolerability of ibrutinib in combination rituximab, gemcitabine, 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

Full Information

First Posted
February 17, 2016
Last Updated
August 12, 2020
Sponsor
Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea
Collaborators
Janssen-Cilag, S.A.
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1. Study Identification

Unique Protocol Identification Number
NCT02692248
Brief Title
Ibrutinib in Patients With Refractory/Relapsed Non-GCB Diffuse Large B-cell Lymphoma Non-candidates to Autologous Stem Cell Transplantation
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 Type
Interventional

2. Study Status

Record Verification Date
June 2020
Overall Recruitment Status
Unknown status
Study Start Date
April 7, 2016 (undefined)
Primary Completion Date
September 2020 (Anticipated)
Study Completion Date
September 2020 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea
Collaborators
Janssen-Cilag, S.A.

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diffuse Large B-Cell Lymphoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
62 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Ibrutinib -R-GEMOX-Dexa
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Ibrutinib
Intervention Description
Ibrutinib 560 mg daily for 14 days during induction cycles. Maintenance phase: Continuous cycles until disease progression or unacceptable toxicity (maximum of 2 years).
Intervention Type
Drug
Intervention Name(s)
Rituximab
Intervention Description
Rituximab 375 mg/m2 IV day 1 during 4 cycles.
Intervention Type
Drug
Intervention Name(s)
Gemcitabine
Intervention Description
Gemcitabine 1000 mg/msq IV (30-minute infusion) on day 1 or 2, 4 cycles every 14 days.
Intervention Type
Drug
Intervention Name(s)
Oxaliplatin
Intervention Description
Oxaliplatin 100 mg/msq (3-hour infusion) on day 1 or 2, after Gemcitabine infusion, 4 cycles every 14 days.
Intervention Type
Drug
Intervention Name(s)
Dexamethasone
Intervention Description
Dexamethasone 20 mg orally or IV on day 1 and orally on days 2-3, 4 cycles every 14 days.
Primary Outcome Measure Information:
Title
Overall Response (OR) rate (complete remission + partial response) measured by PET(Positron Emission Tomography)/CT imagen scan
Description
OR will be assessed by Lugano Classification: Revised Criteria for Response Assessment (Cheson et al. 2014)
Time Frame
Treatment responses will be evaluated 30 days after end of study treatment wich can be ocurred after 2 years and 4 months
Secondary Outcome Measure Information:
Title
CR rate during induction and maintenance phases.
Description
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
2 years
Title
Conversion rate from SD (Stable Disease) or PR to PR or CR by PET/CT imagen scan
Description
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
Time Frame
2 years
Title
Response duration
Description
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.
Title
Progression free survival
Description
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
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
Title
Event-free survival
Description
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
Title
Overall survival
Description
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
Title
Safety and tolerability of ibrutinib in combination rituximab, gemcitabine, oxaliplatin and dexamethasone
Description
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
99 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Subjects with confirmed histologically diagnosis of diffuse large B-cell lymphoma. Subjects must be 18 years of age or older. 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). 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. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. Baseline FDG-PET scan demonstrating positive lesions (Deauville 4 or 5) compatible with CT defined anatomical tumor sites. Hematology values must be within the following limits: absolute neutrophil count (ANC) ≥1000/μL independent of growth factor support. platelets ≥100000/μL or ≥50000/μL if bone marrow involvement independent of transfusion support in either situation. Biochemical values within the following limits: alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 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 creatinine clearance (CCr) ≥30 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 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. 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. 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: 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). 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. 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. 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. 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. Treatment with any immunotherapy, chemotherapy, radiotherapy, or experimental therapy within 3 weeks before first dose of study drug. Prior treatment with ibrutinib or other BTK inhibitors. Central nervous system (CNS) involvement by lymphoma. History of stroke or intracranial hemorrhage within 6 months prior to randomization. Requires anticoagulation with warfarin or equivalent Vitamin K antagonists. Requires treatment with strong CYP3A inhibitors. Grade ≥2 toxicity (other than alopecia) related to prior anticancer therapy including radiation. 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. Major surgery within 4 weeks before first dose of study drug. Vaccinated with live, attenuated vaccines within 4 weeks of randomization. Pregnancy or lactation
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Dolores Caballero, MD
Organizational Affiliation
University of Salamanca
Official's Role
Study Chair
Facility Information:
Facility Name
Hospital Universitario Central de Asturias
City
Oviedo
State/Province
Asturias
ZIP/Postal Code
33011
Country
Spain
Facility Name
Hospital Especialidades
City
Jerez de la Frontera
State/Province
Cádiz
ZIP/Postal Code
11407
Country
Spain
Facility Name
Hospital Universitario Donostia
City
Donostia San Sebastian
State/Province
Guipúzcoa
ZIP/Postal Code
20080
Country
Spain
Facility Name
Hospital Universitario Son Espases
City
Palma
State/Province
Islas Baleares
ZIP/Postal Code
07120
Country
Spain
Facility Name
Hospital de Navarra
City
Pamplona
State/Province
Navarra
ZIP/Postal Code
31008
Country
Spain
Facility Name
Complexo Hospitalario Universitario de Vigo
City
Vigo
State/Province
Pontevedra
Country
Spain
Facility Name
Hospital Universitario Vall d'Hebron
City
Barcelona
ZIP/Postal Code
08035
Country
Spain
Facility Name
Hospital Clínic de Barcelona
City
Barcelona
ZIP/Postal Code
08036
Country
Spain
Facility Name
Complejo Hospitalario de Jaén
City
Jaén
ZIP/Postal Code
23007
Country
Spain
Facility Name
Hospital Universitario Infanta Leonor
City
Madrid
ZIP/Postal Code
28031
Country
Spain
Facility Name
MD Anderson Cancer Center
City
Madrid
ZIP/Postal Code
28033
Country
Spain
Facility Name
Hospital Universitario 12 de Octubre
City
Madrid
ZIP/Postal Code
28041
Country
Spain
Facility Name
Hospital General Universitario Morales Meseguer
City
Murcia
ZIP/Postal Code
30008
Country
Spain
Facility Name
Hospital Universitario Virgen del Rocío
City
Sevilla
ZIP/Postal Code
41013
Country
Spain
Facility Name
Hospital Clínic Universitari de València
City
Valencia
ZIP/Postal Code
46010
Country
Spain
Facility Name
Hospital Universitario y Politécnico La Fe
City
Valencia
ZIP/Postal Code
46026
Country
Spain
Facility Name
Hospital Clínico Universitario de Valladolid
City
Valladolid
ZIP/Postal Code
47005
Country
Spain

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

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