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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT01805557
Other study ID # FIL_VERAL12
Secondary ID
Status Completed
Phase Phase 2/Phase 3
First received
Last updated
Start date February 4, 2013
Est. completion date November 20, 2020

Study information

Verified date June 2022
Source Fondazione Italiana Linfomi ONLUS
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

The probability to achieve CR with R-chemotherapy in patients failing a rituximab containing first line regimen is quite low, in particular in cases with non GCB profile. The bioCORAL trial suggest that ABC subset have a dismal outcome whichever the induction treatment. Thus it can be argued the addition of new molecule to the RDHAP regimen could be of value. Bortezomib appears the best candidate in this setting as ABC subtypes constitutively express NFkb, which is the target of bortezomib itself. Data from the literature suggest an encouraging activity of R-chemo+ bortezomib in non GCB-derived DLBCL, although in small series. Thus, the addition of bortezomib is here justified by the need to circumvent constitutional resistance to chemotherapy. Published experience of the association between bortezomib and cytarabine are also encouraging with acceptable cumulative toxicity.


Description:

This is a prospective, multicenter, two-arm randomized phase II screening trial34 in young patients (18-65 years) affected by relapsed/refractory Diffuse Large B-cell Lymphoma (DLBCL) at diagnosis, eligible to high-dose therapy. Aim of the study is to to assess whether the addition of Bortezomib to R-DHAP is more promising than standard R-DHAP, as induction therapy before high dose chemotherapy with ASCT with respect to response and safety. Patients will be randomized at first relapse between: a) the standard salvage therapy Rituximab in association to DHAP every 28 days (R-DHAP) for 4 cycles and b) Bortezomib in association to the same regimen (BR-DHAP). In both arms the induction therapy is followed by autologous stem cell transplantation or, if indicated, by allogeneic stem cell transplant. A patient is considered evaluable if it is possible to assess response by PET after 4 cycle or, if a patient withdraws from the study for PD, before completion of study treatment. After providing written informed consent, patients will be evaluated for eligibility during a 21-day screening period. If they continue to meet eligibility criteria, they will be randomized to receive the first dose of BR-DHAP or R-DHAP .


Recruitment information / eligibility

Status Completed
Enrollment 108
Est. completion date November 20, 2020
Est. primary completion date March 12, 2019
Accepts healthy volunteers No
Gender All
Age group 18 Years to 65 Years
Eligibility Inclusion Criteria: 1. Age 18-65 2. Relapsed/refractory disease after receiving one line of standard chemoimmunotherapy (R-CHOP, GA-CHOP, R-CHOP like) 3. Diffuse Large B-cell Lymphoma at relapse. Patient has to be re-biopsied prior to study entry. If this is harmful for the patient, the patient can be enrolled if archivial tumor sample and block from first diagnosis are available. 4. No prior Bortezomib therapy 5. Measurable and/or evaluable disease 6. Any Ann Arbor stage and IPI group at relapse 7. Performance status < 2 according to ECOG scale unless due to lymphoma 8. No Central Nervous System (CNS) disease (meningeal and/or brain involvement by lymphoma) 9. Adequate hematological counts: ANC > 1.5 x 109/L, Hgb > 9 g/dl (transfusion independent), Platelet count > 75 x 109/L (transfusion independent), with the exception of cytopenia due to lymphoma bone marrow involvement 10. HIV negativity, HCV negativity, HBV negativity or patients with HBcAb +, HBsAg -, HBs Ab+/- with HBV-DNA negativity (in these patients Lamivudine prophylaxis is mandatory) 11. Normal liver function (ALP, AST, ALT, GGT, conjugated bilirubin total < 2 x ULN) if not related to lymphoma 12. Normal kidney function (creatinine clearance > 45 ml/min) 13. Cardiac ejection fraction > 50% (MUGA scan or echocardiography) 14. Normal lung function 15. Absence of active opportunistic infections 16. Non peripheral neuropathy or active neurological non neoplastic disease of CNS 17. Non major surgical intervention prior 3 months to randomization if not due to lymphoma and/or no other disease life-threatening that can compromise chemotherapy treatment 18. Disease free of prior malignancies other than lymphoma for > 3 years with exception of currently treated squamous cell and basal cell carcinoma of the skin or carcinoma in situ of the cervix or breast 19. Life expectancy > 6 months 20. No psychiatric illness that precludes understanding concepts of the trial or signing informed consent 21. Written informed consent 22. Women must be: - postmenopausal for at least 1 year (must not have had a natural menses for at least 12 months) - surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal ligation, or otherwise be incapable of pregnancy), - abstinent (at the discretion of the investigator/per local regulations), or - if sexually active, be practicing a highly effective method of birth control (eg, prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device, double-barrier method (eg, condoms, diaphragm, or cervical cap, with spermicidal foam, cream, or gel, male partner sterilization) as local regulations permit, before entry, and must agree to continue to use the same method of contraception throughout the study. They must also be prepared to continue birth control measures for at least 12 months after terminating treatment. 23. Women of childbearing potential must have a negative serum or urine beta-human chorionic gonadotropin (beta-hCG) pregnancy test at screening 24. Men must agree to use an acceptable method of contraception (for themselves or female partners as listed above) for the duration of the study. Men must agree to use a double barrier method of birth control and to not donate sperm during the study and for 3 months after receiving the last dose of study drug. Exclusion criteria: 1. Diagnosis of Lymphoblastic Lymphoma, Burkitt Lymphoma, Non Hodgkin Lymphoma CD20 negative, Mantle Cell Lymphoma, Follicular Lymphoma g I-II-IIIa-IIIb, Primary Mediastinal Lymphoma 2. Age > 65 years 3. Patients ineligible to high-dose chemotherapy 4. Performance status > 2 according to ECOG scale if not due to lymphoma 5. Patient has known or suspected hypersensitivity or intolerance to Rituximab 6. Patient has received an experimental drug or used an experimental medical device within 4 weeks before the planned start of treatment. Concurrent participation in non-treatment studies is allowed, if it will not interfere with participation in this study. 7. CNS disease (meningeal and/or brain involvement by lymphoma) 8. History of clinically relevant liver or renal insufficiency; significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, rheumatologic, hematologic, psychiatric, or metabolic disturbances 9. Uncontrolled diabetes (if receiving antidiabetic agents, subjects must be on a stable dose for at least 3 months before first dose of study drug 10. Uncontrolled or severe cardiovascular disease including myocardial infarction within six months of enrollment, New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, clinically significant pericardial disease, or cardiac amyloidosis 11. Cardiac ejection fraction < 50% (MUGA scan or echocardiography) 12. Creatinine clearance < 45 ml/min 13. Presence of major neurological disorders 14. HIV positivity, HCV positivity, HBV positivity with the exception of patients with HBcAb +, HbsAg -, HBs Ab+/- with HBV-DNA negative 15. Active opportunistic infection 16. Major surgical intervention prior 3 months to randomization if not due to lymphoma and/or other disease life-threatening that can compromise chemotherapy treatment 17. Prior malignancies other than lymphoma in the last 3 years with exception of currently treated squamous cell and basal cell carcinoma of the skin or carcinoma in situ of the cervix or breast 18. Life expectancy < 6 months 19. Any other coexisting medical or psychological condition that would preclude participation in the study or compromise ability to give informed consent. 20. If female, the patient is pregnant or breast-feeding.

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
R-DHAP
Rituximab 375 mg/sqm iv day 0 or 1 Cisplatin 100 mg/sqm iv day 1 in 6-hours infusion Cytarabine 2000 mg/sqm in 3-hours infusion iv day 2 and day 3 Dexamethasone 40 mg day 1-4 Pegfilgrastim 6 mg sc monodose 24 hours after the end of chemotherapy or G-CSF from day 5 till stem cell harvest during mobilization's course (II o III cycle R-DHAP) Rituximab 375 mg/sqm iv 24 hours before apheresis as purging in vivo during second courses of therapy
BR-DHAP
Rituximab 375 mg/sqm iv day 0 or 1 Bortezomib SC 1.5 mg/sqm day 1, day 4 Cisplatin 100 mg/sqm iv day 1 in 6-hours infusion Cytarabine 2000 mg/sqm in 3-hours infusion iv day 2 and day 3 Dexamethasone 40 mg day 1-4 Pegfilgrastim 6 mg sc monodose 24 hours after the end of chemotherapy or G-CSF from day 5 till stem cell harvest during mobilization's course (II o III cycle R-DHAP) Rituximab 375 mg/sqm iv 24 hours before apheresis as purging in vivo during second courses of therapy Chemotherapy R-DHAP and BR-DHAP will be repeated every 28 days.

Locations

Country Name City State
Italy A.O. SS. Antonio e Biagio e C. Arrigo Alessandria
Italy Clinica di ematologia AOU Umberto I Ospedali Riuniti Ancona
Italy CRO Aviano Aviano Pordenone
Italy ASST Spedali Civili di Brescia - Ematologia Brescia
Italy Ospedale Businco - SC Ematologia e CTMO Cagliari
Italy ASST Valle Olona Gallarate Varese
Italy Ematologia 1 Ospedale S. Martino Genova
Italy Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori-Ematologia Meldola Forlì-Cesena
Italy ASST Grande Ospedale Metropolitano Niguarda - SC Ematologia Milano MI
Italy SC Ematologia - Trapianto di midollo osseo Fond. IRCCS Istituto Nazionale Tumori Milano
Italy SCDU Ematologia - Università del Piemonte Orientale Novara
Italy Ospedale S. Antonio Padova
Italy U.O. Complessa di Ematologia Ospedale di Parma Parma
Italy Ospedale Civile Guglielmo da Saliceto Piacenza
Italy Osp. S. Maria delle Croci Ravenna
Italy Grande Ospedale Metropolitano Bianchi Melacrino Morelli - Ematologia Reggio Calabria
Italy AO Arcispedale S.Maria Nuova Ematologia Reggio Emilia
Italy Osp. degli Infermi Divisione di Oncologia Rimini
Italy A.O. Universitaria S. Andrea Roma
Italy Clinica Humanitas Rozzano Milano
Italy SC Oncoematologia con autotrapianto AO Santa Maria Terni
Italy AOU Citta della Salute e della Scienza di Torino - Ematologia Universitaria Torino
Italy AOU Citta della Salute e della Scienza di Torino-SC Ematologia Torino
Italy Azienda Ospedaliero - Universitaria di Udine Udine

Sponsors (4)

Lead Sponsor Collaborator
Fondazione Italiana Linfomi ONLUS Centro di Riferimento per l'Epidemiologia e la Prev. Oncologica Piemonte, Janssen Pharmaceutica, Janssen-Cilag Ltd.

Country where clinical trial is conducted

Italy, 

Outcome

Type Measure Description Time frame Safety issue
Primary Complete Response (CR) Rate Proportion of CR according to the Cheson 2007 response criteria, evaluated by PET scan At the end of the induction phase (6 months)
Secondary Overall Response Rate (ORR) ORR at the end of the induction treatment is defined as Complete Response (CR) or Partial Response according to the Cheson 2007 response criteria, evaluated by PET scan At the end of the induction phase (6 months)
Secondary Overall Survival (OS) OS will be defined as the time between the date of randomization and the date of death from any cause 36 months
Secondary Number of Patients With Treatment-Related Adverse Events (AEs)/Serious Adverse Events (SAEs) as a Measure of Safety Incidence of grade 3 or higher Toxicity measured by CTCAE v.4 during therapy 12 months
Secondary Mobilizing potential Amount of CD34+ stem cell collected/Kg 6 months
Secondary Number of Patients completing ASCT Proportion of randomized patients successfully completing ASCT 12 months
See also
  Status Clinical Trial Phase
Recruiting NCT06033820 - Zanubrutinib+Lenalidomide+R-ICE in Relapsed/Refractory DLBCL Phase 2
Withdrawn NCT05966233 - R-DHAP vs POLA-R-DHAP Followed by Autologous Transplant as First Salvage Treatment in Patient With Relapsed or Refractory Diffuse Large B Cell Lymphoma Phase 2
Recruiting NCT06086197 - A-RGEMOX in the Treatment of Early Relapsed/Refractory DLBCL Phase 2
Recruiting NCT03795571 - Lenalidomide, Rituximab, Gemcitabine, Oxaliplatin and Dexamethasone in Relapse and Refractory DLBCL Phase 1
Completed NCT05169203 - The Use of Biomarkers to Predict CNS Involvement in Diffuse Large B-Cell Lymphoma: a Danish Nationwide Registry Study
Recruiting NCT02955628 - RICE-ibrutinib in Relapsed DLBCL Phase 2
Completed NCT03589469 - Study to Evaluate the Efficacy and Safety of Loncastuximab Tesirine in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma Phase 2