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.
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.
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.
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 .
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.