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.

NCT ID: NCT01805557

Last Updated: 2022-06-08

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 108 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-02-04
• Study Completion Date: 2020-11-20

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.

Detailed 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 .

Conditions

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

R-DHAP

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

Group Type: ACTIVE_COMPARATOR

R-DHAP

Intervention Type: 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

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

Group Type: EXPERIMENTAL

R-DHAP

Intervention Type: 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

Intervention Type: 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.

Interventions

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

Intervention Type: DRUG

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.

Intervention Type: DRUG

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Janssen Pharmaceutica

INDUSTRY

Sponsor Role: collaborator

Janssen-Cilag Ltd.

INDUSTRY

Sponsor Role: collaborator

Centro di Riferimento per l'Epidemiologia e la Prev. Oncologica Piemonte

OTHER

Sponsor Role: collaborator

Fondazione Italiana Linfomi - ETS

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Umberto Vitolo, MD

Role: STUDY_DIRECTOR

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

Locations

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

Meldola, Forlì-Cesena, Italy

Clinica Humanitas

Rozzano, Milano, Italy

ASST Grande Ospedale Metropolitano Niguarda - SC Ematologia

Milan, MI, Italy

CRO Aviano

Aviano, Pordenone, Italy

ASST Valle Olona

Gallarate, Varese, Italy

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

Alessandria, , Italy

Clinica di ematologia AOU Umberto I Ospedali Riuniti

Ancona, , Italy

ASST Spedali Civili di Brescia - Ematologia

Brescia, , Italy

Ospedale Businco - SC Ematologia e CTMO

Cagliari, , Italy

Ematologia 1 Ospedale S. Martino

Genova, , Italy

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

Milan, , Italy

SCDU Ematologia - Università del Piemonte Orientale

Novara, , Italy

Ospedale S. Antonio

Padua, , 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

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, , Italy

Countries

Italy

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

FIL_VERAL12

Identifier Type: -

Identifier Source: org_study_id