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
Overview
- Phase
- Phase 2
- Intervention
- Ibrutinib
- Conditions
- Diffuse Large B-Cell Lymphoma
- Sponsor
- Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea
- Enrollment
- 64
- Locations
- 17
- Primary Endpoint
- Overall Response (OR) Rate
- Status
- Completed
- Last Updated
- last year
Overview
Brief 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.
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.
Investigators
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 ≤
- •Baseline FDG-PET scan demonstrating positive lesions (Deauville 4 or 5) compatible with CT defined anatomical tumor sites.
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.
Arms & Interventions
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.
Intervention: Ibrutinib
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.
Intervention: Rituximab
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.
Intervention: Gemcitabine
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.
Intervention: Oxaliplatin
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.
Intervention: Dexamethasone
Outcomes
Primary Outcomes
Overall Response (OR) Rate
Time Frame: Treatment responses will be evaluated 30 days after end of study treatment which can be occurred after 2 years and 4 months
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.
Secondary Outcomes
- CR Rate During Induction and Maintenance Phases.(Complete treatment responses will be evaluated 30 days after end of study treatment which can be occurred after 2 years and 4 months)
- Response Duration(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.)
- Progression Free Survival(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)
- Event-free Survival(2 years and 4 months.)
- Overall Survival(2 years)
- Percentage of Participants That Present Treatment-Related Adverse Events Oxaliplatin and Dexamethasone(2 years and 4 months)