Phase II Randomized Study With R-DHAP +/- Bortezomib as Induction Therapy in Relapsed/Refractory Diffuse Large B-cell Lymphoma (DLBCL) Patients Eligible to Transplantation. BR-DHAP Versus R-DHAP.

NCT01805557 | Completed Phase 2

• 1 other identifier: FIL_VERAL12
• Study Type: interventional
• Target: 108
• Locations: 1 country
• Sites: 24

Brief 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.

Conditions

Diffuse Large B-cell Lymphoma Refractory; Diffuse Large B-cell Lymphoma Recurrent

Keywords

Diffuse Large B-cell Lymphoma (DLBCL); Bortezomib

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (5)

• Overall Response Rate (ORR)

  At the end of the induction phase (6 months)

• Overall Survival (OS)

  36 months

• Number of Patients With Treatment-Related Adverse Events (AEs)/Serious Adverse Events (SAEs) as a Measure of Safety

  12 months

• Mobilizing potential

  6 months

• Number of Patients completing ASCT

  12 months

Study Arms (2)

R-DHAP

ACTIVE COMPARATOR

R-DHAP x 2, restaging, mobilization and harvest of peripheral stem cell + R-DHAP x 2, restaging with PET evaluation

Drug: R-DHAP

BR-DHAP

EXPERIMENTAL

Bortezomib + R-DHAP x 2, restaging, mobilization and harvest of peripheral stem cell + Bortezomib + R-DHAP x 2, restaging with PET evaluation

Drug: R-DHAP; Drug: BR-DHAP

Interventions

R-DHAP DRUG

* 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; R-DHAP

BR-DHAP DRUG

* 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.

BR-DHAP

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18-65
• Relapsed/refractory disease after receiving one line of standard chemoimmunotherapy (R-CHOP, GA-CHOP, R-CHOP like)
• 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.
• No prior Bortezomib therapy
• Measurable and/or evaluable disease
• Any Ann Arbor stage and IPI group at relapse
• Performance status \< 2 according to ECOG scale unless due to lymphoma
• No Central Nervous System (CNS) disease (meningeal and/or brain involvement by lymphoma)
• 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
• HIV negativity, HCV negativity, HBV negativity or patients with HBcAb +, HBsAg -, HBs Ab+/- with HBV-DNA negativity (in these patients Lamivudine prophylaxis is mandatory)
• Normal liver function (ALP, AST, ALT, GGT, conjugated bilirubin total \< 2 x ULN) if not related to lymphoma
• Normal kidney function (creatinine clearance \> 45 ml/min)
• Cardiac ejection fraction \> 50% (MUGA scan or echocardiography)
• Normal lung function
• Absence of active opportunistic infections

You may not qualify if:

• Diagnosis of Lymphoblastic Lymphoma, Burkitt Lymphoma, Non Hodgkin Lymphoma CD20 negative, Mantle Cell Lymphoma, Follicular Lymphoma g I-II-IIIa-IIIb, Primary Mediastinal Lymphoma
• Age \> 65 years
• Patients ineligible to high-dose chemotherapy
• Performance status \> 2 according to ECOG scale if not due to lymphoma
• Patient has known or suspected hypersensitivity or intolerance to Rituximab
• 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.
• CNS disease (meningeal and/or brain involvement by lymphoma)
• History of clinically relevant liver or renal insufficiency; significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, rheumatologic, hematologic, psychiatric, or metabolic disturbances
• Uncontrolled diabetes (if receiving antidiabetic agents, subjects must be on a stable dose for at least 3 months before first dose of study drug
• 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
• Cardiac ejection fraction \< 50% (MUGA scan or echocardiography)
• Creatinine clearance \< 45 ml/min
• Presence of major neurological disorders
• HIV positivity, HCV positivity, HBV positivity with the exception of patients with HBcAb +, HbsAg -, HBs Ab+/- with HBV-DNA negative
• Active opportunistic infection

Sponsors & Collaborators

• Fondazione Italiana Linfomi - ETS: lead
• Janssen Pharmaceutica: collaborator
• Janssen-Cilag Ltd.: collaborator
• Centro di Riferimento per l'Epidemiologia e la Prev. Oncologica Piemonte: collaborator

Study Sites (24)

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori-Ematologia

Meldola, Forlì-Cesena, 47014, Italy

Location

Clinica Humanitas

Rozzano, Milano, 20089, Italy

Location

ASST Grande Ospedale Metropolitano Niguarda - SC Ematologia

Milan, MI, 20162, Italy

Location

CRO Aviano

Aviano, Pordenone, 33081, Italy

Location

ASST Valle Olona

Gallarate, Varese, Italy

Location

A.O. SS. Antonio e Biagio e C. Arrigo

Alessandria, 15121, Italy

Location

Clinica di ematologia AOU Umberto I Ospedali Riuniti

Ancona, 60100, Italy

Location

ASST Spedali Civili di Brescia - Ematologia

Brescia, 25123, Italy

Location

Ospedale Businco - SC Ematologia e CTMO

Cagliari, 09121, Italy

Location

Ematologia 1 Ospedale S. Martino

Genova, 16132, Italy

Location

SC Ematologia - Trapianto di midollo osseo Fond. IRCCS Istituto Nazionale Tumori

Milan, 20133, Italy

Location

SCDU Ematologia - Università del Piemonte Orientale

Novara, 28100, Italy

Location

Ospedale S. Antonio

Padua, 35128, Italy

Location

U.O. Complessa di Ematologia Ospedale di Parma

Parma, 43100, Italy

Location

Ospedale Civile Guglielmo da Saliceto

Piacenza, 29121, Italy

Location

Osp. S. Maria delle Croci

Ravenna, 48121, Italy

Location

Grande Ospedale Metropolitano Bianchi Melacrino Morelli - Ematologia

Reggio Calabria, 89124, Italy

Location

AO Arcispedale S.Maria Nuova Ematologia

Reggio Emilia, 42123, Italy

Location

Osp. degli Infermi Divisione di Oncologia

Rimini, 47923, Italy

Location

A.O. Universitaria S. Andrea

Roma, 00189, Italy

Location

SC Oncoematologia con autotrapianto AO Santa Maria

Terni, 05100, Italy

Location

AOU Citta della Salute e della Scienza di Torino - Ematologia Universitaria

Torino, 10126, Italy

Location

AOU Citta della Salute e della Scienza di Torino-SC Ematologia

Torino, 10126, Italy

Location

Azienda Ospedaliero - Universitaria di Udine

Udine, 33100, Italy

Location

MeSH Terms

Conditions

Lymphoma, Large B-Cell, Diffuse

Condition Hierarchy (Ancestors)

Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Study Officials

• Umberto Vitolo, MD

  SC Ematologia 2-AO Città della Salute e della Sienza-Molinette

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 5, 2013
• First Posted: March 6, 2013
• Study Start: February 4, 2013
• Primary Completion: March 12, 2019
• Study Completion: November 20, 2020
• Last Updated: June 8, 2022

Record last verified: 2022-06

Locations

IT (24)