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: PHASE2
Conditions: Diffuse Large B-cell Lymphoma Refractory, Diffuse Large B-cell Lymphoma Recurrent
Sponsor: Fondazione Italiana Linfomi - ETS

 
 
 
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“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.” 
STUDY DRUG Bortezomib 
Study ID FIL_VERAL12 
Version 4.0 del 11/11/2019 
EUDRACT: 2012-000924-16 
 
STUDY CONTACT INFORMATION 
 
 
SPONSOR 
Fondazione Italiana Linfomi Onlus (FIL) 
Secretary: c/o Uffici PACTO 
Address: Spalto Marengo 44, , 15121 Alessandria, Italy 
Phone no.: +39 0131033151- Fax no.: +39-0131-263455 - Email: segreteria@filinf.it 
 
PRINCIPAL INVESTIGATOR 
Barbara Botto, MD 
Address: SCDO Ematologia AOU Città della Salute e della Scienza, Torino, Italy 
Phone no.: +39-011-6336177- 6334553 - Fax no.: +39-011-6335611- Email: bbotto@cittadellasalute.to.it 
 
SCIENTIFIC DIRECTOR 
Umberto Vitolo, MD 
Address: SCDO Ematologia AOU Città della Salute e della Scienza, Torino, Italy 
Phone no.: +39-011-6335937-6335550 - Fax no.: +39-011-6335611 - Email: uvitolo@cittadellasalute.to.it  
 
CO-Investigators 
Monica Balzarotti, MD 
Address: Oncologia Medica ed Ematologia ,  Humanitas Cancer Center ,  Rozzano (Milano)  
Phone no.: +39- 02 8224 4536  - Fax no.: +39- 02-8224 4590 - Email: monica.balzarotti@humanitas.it  
Annalisa Chiappella, MD 
Address: SCDO Ematologia AOU Città della Salute e della Scienza, Torino, Italy 

 
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Phone no.: +39-011-6335937-6335550 - Fax no.: +39-011-6335611 
Email: achiappella@cittadellasalute.to.it  
 
 

 
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WRITING COMMITTEE AND SCIENTIFIC SUPPORT 
Umberto Vitolo, MD, SCDO Ematologia AOU Città della Salute e della Scienza, Torino, Italy 
Annalisa Chiappella, MD, SCDO Ematologia AOU Città della Salute e della Scienza, Torino, Italy 
Monica Balzarotti, MD, UO Ematologia, Humanitas Cancer Center, Rozzano 
Maria Giuseppina Cabras, MD, UO Ematologia, Ospedale Oncologico Businco, Cagliari 
Francesco Merli, MD, UO Ematologia, Arcispedale Santa Maria Nuova, Reggio Emilia  
Enrico Maria Pogliani, MD, Clinica Ematologica e Unità di Trapianto midollo osseo, Ospedale San Gerardo 
Monza 
Francesco Zaja, MD, SC Ematologia, Azienda sanitaria-universitaria integrata Trieste (ASUITS)  
 
BIOMETRY 
Responsible: Giovannino Ciccone, MD  
Address: SCDU Epidemiologia dei Tumori –AOU Città della Salute e della Scienza, Torino, Italy 
Phone no.: +39-011-6336857 - Fax no.: +39-011-6706692 
 
PHARMACOVIGILANCE 
Responsible: Ufficio Farmacovigilanza, Uffici Studi FIL, Fondazione Italiana Linfomi Onlus  
Address: c/o Uffici PACTO, Spalto Marengo 44, 15121 Alessandria 
Phone no.: +39 0131033156 - Fax no.: +39 0131263455 - E-mail: drugvigilance@filinf.it 
REFERENCE LABORATORY FOR MOLECULAR BIOLOGY 
Responsible: Gaidano Gianluca, MD 
Biological study committee: 
Marco Ladetto, MD 
Davide Rossi, MD 
 
HISTOPATOLOGY 
Responsible: Stefano Pileri, MD 
Histopathology Committee:  
Fabio Facchetti, MD 
Domenico Novero, MD 
Marco Paulli, MD 
Stefano Ascani, MD 
 
 

 
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1 
INVESTIGATOR AGREEMENT  
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will 
conduct the study as outlined herein and will complete the study within the time designated. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who 
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully informed 
regarding the study drug and the conduct of the study. 
 
 
 
 
Investigator’s Signature Date 
 
 
 
 
 
 
 
 
Name of Investigator (Typed or Printed) 
 
 
 
 
 
 
 
 
 
 
Institution, Address* 
 
 
 
 
 
 
 
Phone Number* 
 
 
 
 
 
 
 
Investigator-Sponsor Signature* 
Date (where required) 
 
 
 
 
 
 
 
Name of Coordinating Investigator (Typed or Printed) 
 
 
 
 
 
 
 
Institution 
 
 
 
 
 
 
 

 
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2 
* If the address or phone number of the investigator changes during the course of the study, written 
notification will be provided by the investigator to the sponsor and will not require protocol 
amendment(s)INDEX  
Sommario 
1 
INVESTIGATOR AGREEMENT ........................................................................................................... 4 
2 
INDEX ............................................................................................................................................ 5 
3 
FLOW CHART ................................................................................................................................. 8 
4 
BACKGROUND AND INTRODUCTION ............................................................................................... 9 
4.1 
Diffuse large B cell Lymphoma .................................................................................................... 9 
4.2 
Relapsed /refractory DLBCL ........................................................................................................ 9 
4.3 
Bortezomib .............................................................................................................................. 10 
5 
RATIONALE OF THE STUDY ........................................................................................................... 11 
6 
OBJECTIVES OF THE STUDY ........................................................................................................... 11 
6.1 
General objectives ................................................................................................................... 11 
6.2 
End-points ............................................................................................................................... 11 
6.2.1 
Primary endpoint ........................................................................................................................... 11 
6.2.2 
Secondary endpoints ...................................................................................................................... 11 
7 
PATIENT SELECTION CRITERIA ....................................................................................................... 12 
7.1 
Inclusion criteria ...................................................................................................................... 12 
7.2 
Exclusion criteria ...................................................................................................................... 13 
8 
STUDY DESIGN ............................................................................................................................. 15 
8.1 
Rationale for the Study Design ................................................................................................. 16 
9 
STATISTICAL CONSIDERATIONS ..................................................................................................... 16 
9.1 
Statistical design ...................................................................................................................... 16 
9.1.1 
Sample size ..................................................................................................................................... 16 

 
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9.1.2 
Stratification and randomization ................................................................................................... 17 
9.1.3 
Statistical analysis .......................................................................................................................... 17 
9.1.4 
Study duration ................................................................................................................................ 18 
10 
PATHOLOGICAL REVIEW AND BIOLOGIC STUDIES .......................................................................... 18 
11 
STUDY TREATMENT ...................................................................................................................... 18 
11.1 
Initial dose and schedule .......................................................................................................... 18 
11.2 
Mobilization and apheresis ...................................................................................................... 19 
11.3 
Dose Modification and Delay .................................................................................................... 19 
11.3.1 
Dose-adjustment for Bortezomib .............................................................................................. 19 
11.3.2 
Dose- adjustment for Rituximab ................................................................................................ 21 
11.3.3 
Dose- adjustment for DHAP ....................................................................................................... 21 
11.4 
General information ................................................................................................................. 21 
11.5 
Drug supply ............................................................................................................................. 21 
11.6 
Packaging, dispensing and storage ............................................................................................ 21 
11.7 
Known Anticipated Risks of VELCADE ....................................................................................... 22 
11.7.1 
Consolidated Known Anticipated Risks of VELCADE .................................................................. 22 
11.7.2 
Table 1 - Known Anticipated Risks of VELCADE by MedDRA System Organ Class, Observed 
Incidence, and Preferred Term ................................................................................................................... 23 
12 
WITHDRAWAL AND UNBLINDING CRITERIA .................................................................................. 30 
13 
CONCOMITANT TREATMENT ........................................................................................................ 30 
13.1 
Recommended concomitant treatments ................................................................................... 30 
13.2 
Permitted concomitant therapy................................................................................................ 30 
13.3 
Prohibited concomitant therapy ............................................................................................... 31 
14 
CLINICAL EVALUATION, LABORATORY TESTS AND FOLLOW-UP ...................................................... 31 
14.1 
Staging evaluation, baseline ..................................................................................................... 31 
14.2 
Evaluation at each R-DHAP and BR-DHAP courses ..................................................................... 31 

 
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14.3 
Intermediate response evaluation ............................................................................................ 32 
14.3.1 
Pre-transplantation  evaluation - end of study .......................................................................... 32 
14.3.2 
Follow-up ................................................................................................................................... 32 
15 
FORMS AND PROCEDURES FOR COLLECTING DATA AND DATA MANAGING ................................... 33 
16 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS ............................................................................... 33 
16.1 
Definitions ............................................................................................................................... 33 
16.1.1 
Adverse Event ............................................................................................................................ 33 
16.1.2 
Serious Adverse Event ............................................................................................................... 33 
16.1.3 
Unlisted (Unexpected) Adverse Event ....................................................................................... 34 
16.1.4 
Associated with the Use of the Drug ......................................................................................... 34 
16.1.5 
Product Quality Complaint ........................................................................................................ 34 
16.2 
Attribution Definitions ............................................................................................................. 34 
16.2.1 
Intensity (Severity) Reporting and Attribution .......................................................................... 34 
16.2.2 
Special Reporting Situations ...................................................................................................... 35 
16.2.3 
Reporting Procedures ................................................................................................................ 36 
17 
ETHICAL CONSIDERATIONS ........................................................................................................... 38 
17.1 
Patient protection .................................................................................................................... 38 
18 
SUBJECT IDENTIFICATION PERSONAL DATA PROTECTION .............................................................. 38 
18.1 
Informed consent ..................................................................................................................... 39 
19 
CONFLICT OF INTEREST ................................................................................................................. 39 
20 
DATA OWNERSHIP ....................................................................................................................... 39 
21 
PUBLICATION POLICY ................................................................................................................... 40 
22 
STUDY INSURANCE ....................................................................................................................... 40 
23 
REFERENCES ................................................................................................................................. 41 
24 
APPENDIXES ................................................................................................................................ 44 

 
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24.1 
Appendix 1: Timing of treatment and investigations ................................................................. 44 
24.2 
Appendix 2: Response Criteria .................................................................................................. 46 
24.3 
Appendix 3: NCI Common toxicity criteria ................................................................................. 47 
24.4 
Appendix 4: Dispensing information for rituximab .................................................................... 48 
24.5 
Appendix 5: Dispensing information for bortezomib ................................................................. 50 
24.6 
Appendix 6: Suggested Body Surface Area Calculation .............................................................. 52 
24.7 
Appendix 7: Creatinine Clearance Calculation ........................................................................... 53 
24.8 
Appendix 8: ECOG performance status scale ............................................................................. 54 
24.9 
Appendix 9: New York Heart Association Classification of Cardiac Disease ................................. 55 
 
3 
FLOW CHART 
 
 

 
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4 
BACKGROUND AND INTRODUCTION 
4.1 Diffuse large B cell Lymphoma  
Diffuse Large B-cell Lymphoma (DLBCL) is the most common lymphoma subtype, accounting for roughly 30-
40% of all non-Hodgkin Lymphoma (NHL)  in adults,  and its  incidence is increasing. Median age at diagnosis 
is 55-60 years.1,2  
The addition of rituximab to first line anthracycline-containing chemotherapy has significantly improved the 
prognosis of DLBCL  patients at any stage and age , and data of original trials have been recently been 
confirmed after longer follow up.3,4,5 Furthermore, dose-dense and dose –intense chemoimmunotherapy is  
supposed to have  added further improvement in DLBCL outcome6 and results of ongoing prospective trials 
are soon expected. 
4.2 Relapsed /refractory DLBCL  
Despite the improvement with first line treatment in the rituximab era, a proportion of DLBCL patients still 
relapse and need further treatment.  
In younger patients,  induction chemotherapy followed by high dose consolidation and autologous stem cell 
support (ASCT) represents the gold standard since the publication of the PARMA trial.7 Approximately 50% 
of all relapsed patients can be cured  by this strategy, with main prognostic factors being represented by 
duration of first response,8-9 International Prognostic Index at relapse (secondary IPI, sIPI),10-11 and 
chemosensitivity to 2nd line induction therapy  before transplantation.  
More recently, the achievement of complete remission /CR) defined by   PET negativity as per Cheson 2007 
criteria12 has emerged as  a strong discriminant  at transplantation.13-15 Thus, further efforts to increase PET 
negative rate at transplantation are highly  needed.  
The addition of rituximab to second line chemotherapy significantly improves the outcome of patients non-
pretreated with rituximab during first line treatment.16 Otherwise, recent retrospective17 as well as a 
randomized prospective (CORAL)18 trials have pointed out   the lower likelihood  of obtaining an objective 
response with second-line chemotherapy in patients failing first line rituximab-containing regimens. The 
CORAL18 trial randomly compared R-DHAP and R-ICE as induction regimens before transplantation overall 
response rate (ORR) was 83% in patients without as compared to 51% in those with prior exposure to 
rituximab, and CR rate was as low as 30% in cases previously treated with rituximab (C. Gisselbrecht, personal 
communication). Both 3-year event-free survival (EFS, 47 vs 21%) and overall survival (OS, 66% vs 40%) were 
also significantly affected by previous treatment with rituximab. As virtually all patients with relapsed DLBCL 
are actually pretreated with rituximab, strategies to improve ORR through the addition of other active 
compound to R-chemotherapy in the induction phase are warranted.  
Molecular classification of DLBCL has allowed the description of two main subgroups with different 
prognosis: the germinal center B cell like (GCB) and the activated B cell like.19 These two entities are 
distinguishable even through  immunohistochemistry techniques20-22 and show different long term prognosis 
with ABC subtype showing significantly worse survival.  
More recently, the results  of the  so-called bio-CORAL trial   have been published, concerning  the biological 
aspect of the CORAL trial. In 249 out of 396 patients of the original clinical study, histopathological material 
from  biopsies performed at diagnosis or at relapse was available. The cell of origin (COO) was  analysed 
through both microarray procedures and immunohistochemical algorithm.23 

 
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Patients with GCB DLBCL according to the Hans algorithm, who were treated with R-DHAP, had a better 3-
year PFS than patients with non-GCB DLBCL (52%  vs  32, respectively; p .01). Otherwise, patients treated 
with R-ICE had a poor 3-year  PFS without significant difference between the GCB and non-GCB Hans 
phenotypes (3-year-PFS 31% vs 27% respectively; p .81;). Similar results were observed for OS.  Multivariate 
analysis showed an independent prognostic impact of the following parameters on PFS: 
• 
GCB/non-GCB Hans phenotype interaction with treatment (p .04) 
• 
prior rituximab exposure (p .0052), 
• 
secondary aaIIPI (P _ .039), and  
• 
FoxP1 expression (p .047).  
This analysis showed that R-DHAP carried more benefit than R-ICE in patients with GCB DLBCL as classified 
by Hans, which was independent from clinical variables, such as aaIPI. 
 
 
4.3 Bortezomib  
Bortezomib is a proteasome inhibitor with proven activity in different lymphoma subtypes.24-25 Its 
mechanism of action impacts different cellular processes, including the inhibition of the nuclear factor kappa-
B, which is constitutively activated in the ABC subtypes of DLBCL. Its principal  toxic effects are represented  
by peripheral neuropathy and by mielotoxicity, mainly thromboctophenia.   
Although as single agent bortezomib has demonstrated minimal activity in pretreated DLBCL, it can be safely 
used in combination with R-CHOP with moderate increase  in neurological toxicity.26-27 When combined to 
DA-EPOCH (dose-adjusted infusional etoposide, doxorubicin, vincristine, cyclophosphamide and prednisone) 
ORR of bortezomib + chemotherapy was significantly higher in cases with ABC (83%) than with GCB subtype 
(13%).28 Ruan and coworkers added bortezomib to RCHOP in 40 DLBCL.  Unlike in DLBCL treated with R-CHOP 
alone, ABC and GCB subtypes had similar outcomes29.  
The addition of bortezomib to cytarabine has already been tested by the MD Anderson group within  the 
Hyper-CVAD regimen in a mantle cell lymphoma population setting with no evidence of increased toxicity.30 
Otherwise, few clinical data are published on the association of bortezomib and cisplatinum in the solid 
tumor setting: cumulative peripheral neuropathy, which could be of concern in this association, has not 
emerged as the dose limiting toxicity.31 In addition, recent studies demonstrated the feasibility of bortezomib 
administered in subcutaneous injection (SC) instead of intravenous bolus (IV). In a phase I study conducted 
in 24 relapsed/refractory multiple myeloma, 12 patients were treated with bortezomib SC. Results 
underlined that there was no significant difference in overall proteasome inhibition activity and that similar 
efficacy and toxicities were seen with both the IV and SC routes of administration.32 A phase III randomised, 
trial was then conducted on 222 myeloma patients with the primary end-point of non-inferiority of SC versus 
IV bortezomib in terms of overall response rate. The study demonstrated that SC bortezomib offers non-
inferior efficacy to standard IV administration, with an improved safety profile especially in terms of 
peripheral neurotoxicity.33 

 
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5 
RATIONALE OF THE STUDY 
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.  
6 
OBJECTIVES OF THE STUDY 
6.1  General objectives  
Aim of this randomised screening trial is to assess whether the addition of Bortezomib to the standard R-
DHAP, as induction therapy before transplantation procedure, is a promising strategy, worthy a subsequent 
confirmatory phase III trial, in patients with relapsed/refractory DLBCL.  
Primary objective is to assess whether the experimental treatment achieves an absolute increase of the CR 
proportion of at least 20% (from 30% to 50%) with respect to the standard treatment.  
Secondary objectives are to compare BR-DHAP vs R-DHAP for: 
• 
Overall Response Rate (ORR) prior to consolidation  
• 
Progression free survival (PFS) 
• 
Overall Survival (OS) 
• 
Feasibility and toxicity  
• 
The mobilizing potential  
• 
The rate of patients actually proceeding to transplantation. 
Exploratory objectives are the subgroup analyses on the efficacy and safety endpoints to assess the potential 
heterogeneity of effects by biological lymphoma’s characteristics (Germinal Center B-cell vs non-Germinal 
Center, Activated B-cell, GCC vs ABC), secondary aaIIPI and other important modifying factors. 
 
6.2 End-points  
6.2.1 
Primary endpoint 
The complete response rate (CR) evaluated by PET scan after four cycles of R-DHAP ± Bortezomib before 
transplantation according to Cheson criteria 12 
6.2.2 
Secondary endpoints 
• 
Overall response rate (ORR): a patient is defined as a responder if he has a complete or partial response, 
evaluated by PET/TC, after four cycles of R-DHAP ± Bortezomib  

 
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• 
Progression free survival (PFS): measured from the date of randomization to the date of disease 
progression, relapse or death from any cause. Responding patients and patients who are lost to follow 
up will be censored at their last assessment date. 
• 
OS: measured from the date of randomization to the date of death from any cause. Patients alive at the 
time of the final analysis will be censored at the date of the last contact. For both PFS and OS minimum 
follow up time required for all patients will be 2 years. 
• 
Toxicity: severe, life- threatening, fatal (grade 3, 4 and 5) and/or serious adverse events are defined 
according to “Common Terminology Criteria for Adverse Events” (CTCAE), version 4.0. 
• 
Mobilizing potential: amount of CD34 + stem cell collected /Kg  
• 
Feasibility: proportion of randomized patients successfully completing transplantation 
 
7 
PATIENT SELECTION CRITERIA 
Patients with DLBCL who have received one previous chemotherapy line and who have failed or have 
relapsed after their last therapy will be enrolled.  
The specific inclusion and exclusion criteria for enrolling subjects in this study are described in the following 
sections. 
The following items are generally used in the definition of selection (eligibility) criteria: 
7.1 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) 

 
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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.  
7.2 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 

 
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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.  
 
 

 
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8 
STUDY DESIGN  
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 transplantation 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 28-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 . 
The main efficacy variable will be the response to treatment, defined as the incidence of complete response 
assessed by PET-scan after 4 cycles of chemotherapy. The rate of complete response will be the principal 
measure of efficacy. Study discontinuation because of death or worsening conditions will be considered as 
failures and included in the estimation of response rates. 
All toxic reactions will be annotated and their grade will be assessed according to the Common Toxicity 
Criteria (CTC) Version (see appendix). The rate of non-hematologic toxicity of grade 3 or greater will be the 
principal measure of safety. All patients given at least one dose of the experimental treatment will be 
included in the estimation of toxicity rates. 
During the treatment period of four cycles, all patients will receive a total of four 28-day courses of 
chemotherapy +/- bortezomib. Those randomized to BR-DHAP will be given Bortezomib 1.5 mg/m2 on Days 
1 & 4 of each 4-week cycle of BR-DHAP   
Duration of treatment will be 4 months (one cycle per-month) plus 30 days for response evaluation  
The Bortezomib 1.5 mg/m2 dose will be administered as a s.c  bolus (see Section Bortezomib administration). 
Prior to each Bortezomib administration, vital signs measurements (blood pressure, pulse, respiratory rate, 
and temperature) and hematology tests (as listed in Study Procedures) will be obtained. In addition, prior to 
Bortezomib administration on Day 1 of each cycle, a physical examination (that will include 
neurological/peripheral neurological examination) and chemistry tests (see Section) will be performed. If 
examinations and tests reveal dose-limiting toxicities as described in Section Dose Adjustments for 
Bortezomib, then adjustments to Bortezomib dosing must be made, or dosing discontinued, as described in 
Section. 
During the study, disease status will be evaluated after the 4th cycle by imaging test (18FDG-PET and CT 
scan), and every other cycle (i.e., after 2nd course) by CT scan. 18FDG-PET scan is also recommended after 
the 2nd course in order to assess the role of early response. Adverse events will be monitored from the first 
study-related procedure, throughout treatment, and for 30-42 days (i.e., until the End of Treatment Visit 

 
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before high dose chemotherapy ) following Bortezomib  discontinuation. National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) will be used to record the intensity (severity) of 
adverse events. 
Serious adverse events will be reported as described. 
Procedures to be performed during the study are summarized on the Appendix, Time and Events Schedule. 
Trial treatment and  the dosage of the investigational product as well as the description of the dosage form, 
packaging and labeling of the Bortezomib are described in section Dosage and Administration, and in 
Investigational Study Drug Information. 
The trial include four 4-days (RDHAP) or (BR-DHAP) courses (including the Bortezomib  administration on day 
4) at a 28 -days interval, followed by high dose-chemotherapy and stem cell rescue . Non-responding patients 
will be given salvage chemotherapy according to local policy. Thereafter, the follow-up period will last a 
minimum of five years as concern monitoring of the disease (See Section, Study Procedures). 
 
8.1 Rationale for the Study Design 
The study is designed to compare the efficacy of RDHAP  in association to BORTEZOMIB  with RDHAP alone 
in patients with DLBCL  who have relapsed or are refractory to previous chemotherapy. The study is designed 
primarily for a preliminary efficacy assessment. The assessment of safety will be also made by measuring 
neuro and myelotoxicity during the drug administration period as described above.  
 
9 
STATISTICAL CONSIDERATIONS  
9.1 Statistical design 
This is a prospective, multicenter, two-arm randomized phase II screening trial (34) designed 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 stem cell transplant in terms of efficacy on an intermediate endpoint 
(CR) and safety.  
A result of this screening trial in favor of the experimental combination should be interpreted as a promising 
result to support the rationale of a next confirmatory phase III randomized trial, with adequate statistical 
power to detect a clinically meaningful advantage of the experimental regimen over the standard one, using 
a definitive clinical endpoint. 
Patients will be randomized at first relapse/progression  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).  
 
9.1.1 
 Sample size 
The principal aim is to test if the experimental therapy performs better than the standard one, assuming an 
absolute increase of at least 20% in CR after 4 courses of the experimental arm with Bortezomib in association 
to R-DHAP with respect to the standard salvage treatment R-DHAP. According to a one-sided test with an α 

 
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error of 0.10 and a β error of 0.20, and assuming a 30% CR for the standard arm R-DHAP based on the 
literature, a sample size of 54 patients for each arm is required.  for a total of 108 patients to be enrolled   
This design allows only to assess whether the experimental arm achieves an enough higher proportion of CR 
than the standard arm, with an acceptable toxicity profile, to justify a further randomized phase III 
confirmative trial on a definitive primary clinical endpoint. 
 
9.1.2 
Stratification and randomization 
All enrolled patients will be stratified in four groups with different prognosis, according to clinical 
(relapsed/refractory) characteristics.  
After stratification, all patients will be randomized, with a 1:1 ratio, into two arms:  
• 
Scheme 1: R-DHAP x 2, restaging, mobilization and harvest of peripheral stem cell + R-DHAP x 2, 
restaging with PET evaluation   
• 
Scheme 2: Bortezomib + R-DHAP x 2, restaging, mobilization and harvest of peripheral stem cell + 
Bortezomib + R-DHAP x 2, restaging with PET evaluation 
The web-based randomization procedure, developed centrally by the Trial Center of the Clinical Epidemiology 
Unit at the S. Giovanni Battista University Hospital (Turin), will be completely concealed to researchers. After 
registering the patient at the study dedicated area, each patient will be assigned a unique ID code. The 
randomization procedure will be accessible only after the baseline forms have been completely filled out. 
The procedure, based on computer generated random sequence in blocks of variable size and in random 
order, will be continuously accessible (24/24h a day).  
 
9.1.3 
Statistical analysis 
The main statistical analyses will be based on all the randomized patients (the intention-to-treat – ITT- 
population).  
The proportion of CR will be compared between the two arms with a chi-square test, without continuity 
correction, using a test critical value of 1.282 (corresponding to a one-sided p-value of 0.10) to reject the null 
hypothesis. For estimating purposes only, 95% confidence intervals will be calculated for all the study 
endpoints. 
The frequency of other dichotomous efficacy and safety endpoints will be compared between the two arms 
using a chi square test or the Fisher exact test, when appropriate. 
The time-to-event functions will be estimated by the Kaplan-Meier product-limit method and the difference 
between arms will be analyzed with the log-rank test. The Hazard Ratio (HR) will be estimated using the Cox 
proportional-hazards model. 
Exploratory analyses to detect important effect modifications across subgroups will be performed including 
treatment/covariate interaction terms in the appropriate (logistic or Cox) statistical models. 
 

 
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9.1.4 
Study duration 
This study is expected to start in October 2012. The last patient is expected to be enrolled at the end ofApril 
2018. After a minimum duration of follow-up of 24 months from the enrolment of the last patient the study 
will be concluded in April 2020. 
 
10 PATHOLOGICAL REVIEW AND BIOLOGIC STUDIES 
A centrally pathological review is planned at accrual for all patients enrolled into the trial; investigator centers 
will make available the archival tumor samples taken at the time of first diagnosis. The central revision will 
be perfomed by a panel of pathologist expert in DLBCL diagnosis and responsible of trial revision. Central 
revision will primarily concern the confirmation of the original diagnosis and the subdivision of DLBCL into 
Germinal Center Cell or non-Germinal/Activated-B-cell according to the most commonly used algorithms: 
Hans, Choi or Tally20,21,22  
Re-biopsy at relapse before study accrual is mandatory, although if a new biopsy is unfeasible, a core-biopsy 
will be performed.  If this is harmful for the patient, the patient can be enrolled if archivial tumor sample and 
block from first diagnosis are available. This new sample will be used for both immunohistochemical and 
molecular studies, including: BCL6 translocation/BLIMP1deletion, BCL2 translocation, c-MYC trans location; 
TP53 status (deletion and mutation); genetic profile of pathway of histone modifiers (CREBBP and EZH2); 
genetic profile of pathway of NF-kB (TNFAIP3, CARD11, CD79A, CD79B, MYD88); evaluation of NK-kB pathway 
activation in IHC (nuclear expression of p105/p50 and p100/p52).  
Additional histopathological studies of immunochemistry, gene profiling, molecular biology and 
pharmacogenetic will be conducted with the aim of identify prognostic biological factors.   
 
11 STUDY TREATMENT  
Patients will be  randomized at study entry  to receive: 
- 
Scheme 1: R-DHAP x 2, restaging, mobilization and harvest of peripheral stem cell + R-DHAP x 2, restaging 
with PET evaluation  
- 
Scheme 2: Bortezomib + R-DHAP x 2, restaging, mobilization and harvest of peripheral stem cell + 
Bortezomib + R-DHAP x 2, restaging with PET evaluation  
 
11.1 Initial dose and schedule  
Scheme 1: R-DHAP 
Out-patient version 
Rituximab 375 mg/sqm iv day 0 or 1 
Cisplatin 100 mg/sqm iv day 1 in 6-hours infusion (a 3-hours infusion is allowed) 
Cytarabine 2000 mg/sqm in 3-hours infusion iv day 2 and day 3 

 
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Dexametasone 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 
Scheme 2: B-R-DHAP  
Out-patient version 
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 (a 3-hours infusion is allowed) 
Cytarabine 2000 mg/sqm in 3-hours infusion iv day 2 and day 3 
Dexametasone 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. 
 
11.2 Mobilization and apheresis 
Mobilization of peripheral stem cell  is planned  after II or III courses of R-DHAP or BR-DHAP, with Rituximab 
pre-apheresis; harvest of at least 3x106 cells CD34+/kg is recommended . Apheresis after 3rd curse should be 
reserved to patients with bone marrow involvement by lymphoma at accrual, provided  bone marrow 
clearance is  checked after 2nd course .  
Suggested regimen for transplantation according to local policies: 
BEAM or FEAM (BCNU or Fotemustine 300 mg/sqm iv day -7, Cytarabine 200 mg/sqm every 12 hours iv days 
-6, -5, -4, -3 (8 total doses), VP-16 100 mg/sqm every 12 hours iv days -6, -5, -4, -3 (8 total doses), Melphalan 
140 mg/sqm iv day -2, Reinfusion of PBSC (CD34+ > 3 x106/Kg) day 0, Pegfilgrastim 6 mg sc monodose day  0) 
or Thiotepa/Endoxan/Melphalan cointaining regimens. 
In selected cases, in progressive DLBCL patients during first line treatment or in refractory disease, an 
allograft should be considered 
 
11.3 Dose Modification and Delay 
11.3.1 Dose-adjustment for Bortezomib  
If a Bortezomib dose due to toxicity or another reason is missed, then that dose is skipped and 
treatment continues with next planned dose. 
Observed toxicities, considered by the investigator to be related specifically to Bortezomib are to be 

 
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managed as follows: 
- If leucocytes are < 1.0 x 109/l (and/or platelet counts < 25,000 cells/μl), scheduled Bortezomib 
application will be skipped until recovery to NCI toxicity < 2. 
- For any ³grade 3 non-hematologic toxicity other than neuropathic pain and/or peripheral sensory 
neuropathy, considered by the investigator to be related to Bortezomib, scheduled Bortezomib 
application will be skipped until the toxicity returns to Grade 2 or better. 
- If a dose of Bortezomib was skipped due to toxicity then reduce the drug doses as follows: 
- If the patient was receiving 1.5 mg/m2, reduce the dose to 1.3 mg/m2. 
- If the patient was receiving 1.3 mg/m2, reduce the dose to 1.0 mg/m2. 
- If the patient was receiving 1.0 mg/m2, reduce the dose to 0.7 mg/m2 
- If the patient was receiving 0.7 mg/m2, discontinue study drug, unless patient is 
responding, in which case this should be discussed with the study coordinators. Dose 
reductions below 0.7 mg/m2 should be avoided, but will be considered if patient is having a 
good response. 
- Patients who experience Bortezomib- related neuropathic pain and/or peripheral sensory neuropathy are 
to be managed as follows: 
 

 
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11.3.2 Dose- adjustment for Rituximab 
No adjustment of dose.  
11.3.3 Dose- adjustment for DHAP  
Before each course FBC will be taken and, if at day 28 ANC <1500/mm3 and/or platelets <100.000/mm3, the 
whole regimen will be delayed by one week.  If at day 35  the ANC is >1000-1500/mm3 and/or PLT 75-
100.000/mm3 the dosage of each chemotherapeutic drug will be reduced at 75%. If FBC  has not recovered 
one further delay-week is admitted.  
If at day 42 ANC are still <1000//mm3, and/or platelets < 75.000/mm3, the patient will go off-study.Drugs 
regimens, expected toxicity, dose modification 
11.4 General information  
The study drug is the bortezomib (VELCADE®).  
11.5 Drug supply  
Drug ordering procedures, as well as name(s) and full address(es) with phone and fax numbers of the persons 
from whom the drug should be ordered will be provide with specific operative procedure.  
11.6 Packaging, dispensing and storage 
Description of the packaging and labeling of the drugs, instructions for use, recommendations for storage 
will be provide with specific operative procedure.  

 
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11.7 Known Anticipated Risks of VELCADE 
Adverse Events Attributed to the Natural History of the Disease Under Study and Disease ProgressionIn 
patients with malignancy, signs and symptoms that are consistent with the natural history of the disease 
under study and disease progression are common; therefore, such findings are anticipated in this patient 
population. 
11.7.1 Consolidated Known Anticipated Risks of VELCADE 
The known anticipated risks of VELCADE are presented in Table 1. Adverse events are grouped according to 
the combined frequency observed in a pooled analysis of studies as of 29 October 2008. 
There may be risks with the use of bortezomib that are not yet known, and these may cause unforeseeable 
risks to the embryo or fetus (for both maternal and paternal exposure). Because of this the subjects included 
should not become pregnant or father of a baby while participating in this study. 

 
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11.7.2 Table 1 - Known Anticipated Risks of VELCADE by MedDRA System Organ Class, Observed Incidence, 
and Preferred Term 
 
System Organ Class 
Observed Incidence 
Preferred Term 
Blood and Lymphatic System 
Disorders  
 
Most common  
Thrombocytopenia*, anaemia* 
Very common 
Neutropenia* 
Common 
Lymphopenia, 
pancytopenia*, 
leukopenia*, 
febrile 
neutropenia 
 
 
Cardiac Disorders 
 
Common 
Tachycardia, atrial fibrillation, palpitations, cardiac failure 
congestive* 
Uncommon 
Cardiogenic shock*, atrial flutter, cardiac tamponade*±, 
bradycardia, atrioventricular block complete, arrhythmia, 
cardiac arrest*, cardiac failure, arrhythmia, pericardial 
effusion, 
pericarditis, 
pericardial 
disease±, 
cardiopulmonary failure± 
 
 
Ear and Labyrinth Disorders 
 
Uncommon 
Deafness, hearing impaired 
 
 
Eye Disorders 
 
Common 
Blurred vision, conjunctivitis, conjunctival haemorrhage 
 
 
Gastrointestinal Disorders  
 
Most common  
Constipation, diarrhoea*, nausea, vomiting* 
Very common 
Abdominal pain (excluding oral and throat) 
Common 
Dyspepsia, pharyngolaryngeal pain, gastroesophageal reflux, 
abdominal 
distension, 
gastritis, 
stomatitis, 
mouth 
ulceration, dysphagia, gastrointestinal haemorrhage*, 

 
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System Organ Class 
Observed Incidence 
Preferred Term 
lower 
gastrointestinal 
haemorrhage*± 
rectal 
haemorrhage 
Uncommon 
Eructation, gastrointestinal pain, tongue ulceration, retching, 
upper gastrointestinal haemorrhage*, haematemesis*, 
oral 
mucosal 
petechiae, 
ileus 
paralytic*, 
ileus, 
odynophagia, enteritis, colitis, oesophagitis, enterocolitis, 
diarrhoea haemorrhagic, acute pancreatitis*, intestinal 
obstruction 
General 
Disorders 
and 
Administration 
Site 
Conditions 
 
Most common  
Fatigue, pyrexia 
Very common 
Chills, oedema peripheral, asthenia 
Common 
Neuralgia, 
lethargy, 
malaise, 
chest 
pain, 
mucosal 
inflammation* 
Uncommon 
Injection site pain, injection site irritation, injection site 
phlebitis, general physical health deterioration*, catheter-
related complication 
 
 
Hepatobiliary Disorders 
 
Uncommon 
Hyperbilirubinaemia, hepatitis*± 
 
 
Immune System Disorders 
 
Uncommon 
Drug hypersensitivity, angioedema 
 
 
Infections and Infestations 
 
Very common 
Upper 
respiratory 
tract 
infection, 
nasopharyngitis, 
pneumonia*, Herpes zoster* 
Common 
Lower respiratory tract infection*, sinusitis, pharyngitis, oral 
candidiasis, 
urinary 
tract 
infection*, 
sepsis*, 
bactaeremia*, cellulitis*, Herpes simplex, bronchitis, 
gastroenteritis*, infection 

 
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System Organ Class 
Observed Incidence 
Preferred Term 
Uncommon 
Septic shock*, catheter-related infection*, skin infection*, 
Herpes zoster disseminated*, lung infection*, infusion site 
cellulitis, catheter site cellulitis, infusion site infection, 
urosepsis*, Aspergillosis*, tinea infection, Herpes zoster 
ophthalmic, 
Herpes 
simplex 
ophthalmic, 
meningoencephalitis herpetic±, varicella, empyema±, 
fungal oesophagitis± 
 
 
Injury, Poisoning, and Procedural 
Complications 
 
Common 
Fall 
Uncommon 
Subdural haematoma 
 
 
Investigations 
 
Common 
Weight decreased, alanine aminotransferase (ALT) increased, 
aspartate aminotransferase (AST) increased, blood 
alkaline phosphatase increased, liver function test 
abnormal, blood creatinine increased* 
Uncommon 
Gamma-glutamyltransferase 
(GGT) 
increased, 
oxygen 
saturation decreased*, blood albumin decreased, ejection 
fraction decreased* 
 
 
Metabolism 
and 
Nutritional 
Disorders 
 
Very common 
Decreased appetite, anorexia, dehydration* 
Common 
Hyperglycaemia, 
hypoglycaemia, 
hyponatraemia, 
hypokalaemia, hypercalcaemia* 
 
 
Musculoskeletal and Connective 
Tissue Disorders 
 
Very common 
Bone pain, myalgia, arthralgia, back pain 
Common 
Muscular weakness 

 
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System Organ Class 
Observed Incidence 
Preferred Term 
Uncommon 
Limb discomfort 
 
 
Neoplasms, Benign, Malignant, 
and Unspecified (including 
cysts and polyps) 
 
Uncommon 
Tumour lysis syndrome* 
 
 
Nervous System Disorders 
 
Most common 
Peripheral neuropathy (including all preferred terms under the 
MedDRA High-level term Peripheral neuropathy NEC) 
Very common 
Paresthesia, dizziness excluding vertigo, headache 
Common 
Polyneuropathy, syncope, dysesthesia, dysgeusia, postherpetic 
neuralgia 
Uncommon 
Convulsion, loss of consciousness, ageusia, encephalopathy, 
paralysis*,autonomic neuropathy, reversible posterior 
encephalopathy syndrome# 
Psychiatric Disorders 
 
Very common 
Anxiety, insomnia  
Common 
Confusional state 
Uncommon 
Delirium 
 
 
Renal and Urinary Disorders  
 
Common 
Renal impairment*, renal failure*, haematuria 
Uncommon 
Micturition disorder 
 
 
Respiratory, 
Thoracic, 
and 
Mediastinal Disorders 
 
Very common 
Cough, dyspnoea 
Common 
Epistaxis, dyspnoea exertional, pleural effusion*, rhinorrhea, 
hypoxia*, pulmonary oedema * 

 
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System Organ Class 
Observed Incidence 
Preferred Term 
Uncommon 
Hemoptysis*, 
acute 
respiratory 
distress 
syndrome*, 
respiratory failure*, pneumonitis*, lung infiltration, 
pulmonary alveolar haemorrhage*, interstitial lung 
disease*, pulmonary hypertension*, pleurisy, pleuritic pain 
 
 
Skin and Subcutaneous Tissue 
Disorders 
 
Very common 
Rash 
Common 
Rash pruritic, rash erythematous, urticaria, petechiae 
Uncommon 
Cutaneous vasculitis, leukocytoclastic vasculitis± 
 
 
Vascular Disorders 
 
Common 
Hypotension*, orthostatic hypotension 
Uncommon 
Cerebral haemorrhage* 
Most common = ≥ 30%, Very common = 10% to 29%, Common = 1% to 9%, Uncommon = < 1%. 
* 
Fatal outcomes have been reported. 
± 
Indicates a Preferred term not listed, however the event is deemed medically important and so is 
included. 
# 
Prior to MedDRA version 14.0, posterior reversible encephalopathy syndrome (PRES) was termed 
“reversible posterior leukoencephalopathy syndrome (RPLS)”. 
 
8.4.3 Medical Events From Postmarketing Experience 
 
Adverse drug reactions, as listed in the postmarketing section of the VELCADE USPI (Package Insert) or 
SmPC (Summary of Product Characteristics) are listed in Table 2. 
 
Table 2 Reports of Adverse Reactions from Postmarketing Experience 
 

 
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System Organ Class  
Preferred Term 
Observed 
Incidencea 
 
 
Blood and lymphatic system disorders 
 
Disseminated intravascular coagulation 
Rare 
 
 
Cardiac Disorders 
 
Atrioventricular block complete  
Rare 
Cardiac tamponade 
Rare 
 
 
Ear and labyrinth disorders 
 
Deafness bilateral 
Rare 
 
 
Eye Disorders 
 
Ophthalmic herpes 
Optic neuropathy 
Blindness 
 
Rare 
Rare 
Rare 
 
 
Gastrointestinal Disorders 
 
Acute pancreatitis  
Rare 
Ischemic colitis 
Rare 
 
 
Hepatobiliary disorders 
 
Hepatitis 
Uncommon 
Liver failure 
Unknown 
 
 
Immune System Disorders 
 
Angioedema 
Rare 

 
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System Organ Class  
Preferred Term 
Observed 
Incidencea 
 
Infections and infestations 
 
Herpes meningoencephalitis 
Rare 
Septic shock 
Progressive multifocal leukoencephalopathy  
Rare 
Very Rare 
 
 
Nervous System Disorders 
 
Autonomic neuropathy 
Rare 
Dysautonomia 
Unknown 
Encephalopathy 
Rare 
 
 
Respiratory, 
thoracic 
and 
mediastinal 
disorders 
 
Acute diffuse infiltrative pulmonary diseaseb 
Rare 
Acute respiratory distress syndrome (ARDS) 
Rare 
Interstitial pneumonia 
Rare 
Lung infiltration 
Rare 
Pneumonitis 
Rare 
Pulmonary hypertension 
Rare 
 
 
Skin and subcutaneous system disorders 
 
Acute febrile neutrophilic dermatosis 
Unknown 
Toxic epidermal necrolysis 
Unknown 
 
 
 
a 
Incidence is assigned using the following convention: very common (≥ 1/10); common (≥ 1/100 and < 
1/10); uncommon (≥ 1/1,000 and < 1/100); rare (≥ 1/10,000 and < 1/1,000 ); very rare (< 1/10,000, 
including isolated reports). 

 
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b 
Acute diffuse infiltrative pulmonary disease is a MedDRA Lower Level Term which corresponds to a 
Preferred Term of Interstitial lung disease. 
 
12 WITHDRAWAL AND UNBLINDING CRITERIA  
Patients may voluntarily withdraw from the study or be dropped from it at the discretion of the Investigator 
at any time. If such withdrawal occurs, or if the patient fails to return for visits, the Investigator must 
determine the primary reason for a patient’s premature withdrawal from the study and record this 
information on the End of Treatment CRF. Therapy may be interrupted for one of the following reasons:  
Adverse event(s); Abnormal laboratory value(s); Abnormal test procedure result(s);  Protocol deviation; 
Subject withdrew consent; Lost to follow-up; Administrative problems; Death; Initiation of new cancer 
therapy; Disease progression. 
13 CONCOMITANT TREATMENT 
13.1 Recommended concomitant treatments 
During treatment are recommended as concomitant therapy: 
- 
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 BR or R-DHAP) 
- 
Cotrimoxazole BACTRIM 3 tablets/week (or 1 x 2/day per two days/week) or Pentamidine aerosol every 
15 days in patients with Bactrim allergy or in patients with G6PD deficiency throughout the treatment 
and consolidation phase  
- 
Antiviral prophylaxis with acyclovir 800-1200 mg at day since the beginning of therapy 
- 
In patients with Ab antiHBcAg +, Ab antiHBsAg +/- prophylaxis against hepatitis B reactivation with 
Lamivudine 100 mg/die from one week prior the start of the treatment to at least one year after the end 
of the treatment 
- 
All concomitant medications for medical conditions other than B-NHL are permitted, as clinically 
indicated 
- 
All supportive therapies other than anti-cancer treatment needed for the management of patients 
enrolled in this study are permitted 
13.2 Permitted concomitant therapy 
The following medications and support therapies that may be used if needed during this study: 
- 
Additional prophylaxis with levofloxacine or ciprofloxacine and fluconazole/itraconazole will be 
administrated in case of neutropenia <1.0 x 109/l. 
- 
Mozobil- Plerixafor in addition to GSCF during mobilization was permitted 
- 
Immunoglobulin assay is advisable once a month during the therapy with immunoglobulin replacement 
in case of IgG level < 0.3-0.5 gr/dl and frequent infectious events.  
- 
Platelets and red blood cell transfusion are allowed, if needed. Packed red cells and platelets transfusions 

 
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will be given with filtered and irradiated products in case of Hb < 8 g/dL or Plts < 10 x 109/L.  
- 
Erytropoietin therapy is allowed according to ASH/ASCO guidelines. 
- 
Bowel care is recommended to prevent constipation and should be administered per standard practice. 
- 
Antiemetic agents. 
- 
Premedication for rituximab infusion with paracetamol and diphenhydramine should be considered 
before each infusion of rituximab, because it may reduce infusion reactions. 
 
13.3 Prohibited concomitant therapy 
The following medications and supportive therapies are prohibited at all times: 
• 
Any antineoplastic agent other than those planned by the study program.  
• 
Any experimental agent. 
14 CLINICAL EVALUATION, LABORATORY TESTS AND FOLLOW-UP  
14.1 Staging evaluation, baseline 
Baseline assessment must be performed during 28 days before starting therapy. 
- 
Complete medical history, ECOG performance status, physical examination 
- 
ECG and echocardiogram or MUGA scan for LVEF evaluation 
- 
Complete blood count, hematology workup and biochemistry including LDH and Beta2-microglobulin 
- 
Lymph-node or tissue biopsy for histological diagnosis and shipment of paraffin block for centrally 
pathology review and for biological studies 
- 
Aspirate and bone marrow biopsy 
- 
Diagnostic Lumbar Puncture for determination of cell count, differential, cytologic and cytoflussimetry 
examination (if possible) of tumor cells; in patients with clinical suspect of CNS involvement, according 
to SIE criteria  
- 
CT scan neck, chest, abdomen and pelvis 
- 
Total body PET scan (recommended)  
- 
Neurological visit if clinically indicated 
- 
Other assessment: RMN brain/column, endoscopy, ORL visit, etc. according to physician judge and if 
clinically relevant 
- 
Pregnancy test (if applicable) 
- 
Written informed consent 
14.2 Evaluation at each R-DHAP and BR-DHAP courses 
- 
Blood count and complete workup with biochemistry, physical examination and hematological and 
extrahaematological toxicity evaluation the day before or day 1 of therapy and between two cycles and 

 
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during aplasia phase (recommended at day +8-10-12-14-16 and/or till granulocytes and platelets 
recovery) 
 
14.3 Intermediate response evaluation 
The evaluation of intermediate response will be assessed after 2 courses of R-DHAP or BR-DHAP. 
ECOG performance status, physical examination 
Blood count and complete workup with biochemistry  
Aspirate and bone marrow biopsy (if positive at baseline)  
CT scan neck, chest, abdomen and pelvis 
Total body PET scan (recommended) 
 
Responsive patients (in partial or complete response) after two cycles of therapy, will continue the trial and 
will be treated with two further  courses of R-DHAP or BR-DHAP as planned. 
Patients with  progressive disease or stable disease after the first two cycles of therapy will stop treatment 
and will be considered as  failure.  
 
14.3.1 Pre-transplantation  evaluation - end of study 
The evaluation of pre-transplantation  response will be assessed after 4 courses of R-DHAP or BR-DHAP. 
ECOG performance status, physical examination 
Blood count and complete workup with biochemistry 
Aspirate and bone marrow biopsy (if positive at baseline)  
CT scan neck, chest, abdomen and pelvis 
PET total body (mandatory) 
Responsive patients (in partial or complete response) after four cycles of therapy, will be treated with 
transplantation according to local policy. 
Patients in progression disease or stable disease after the first two cycles of therapy stopped treatment and 
will be considered failure.  
  
14.3.2 Follow-up 
Every three months during the first two years after chemotherapy and then every 4-6 months in the third 
year after chemotherapy, will be evaluated : 
ECOG performance status, physical examination 
Blood count and complete workup with biochemistry  

 
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Every 6 months during the first two years after chemotherapy (at month 6-12-18-24) will be evaluated: 
ECOG performance status, physical examination 
Blood count and complete workup with biochemistry  
CT scan neck, chest, abdomen and pelvis 
Aspirate and bone marrow biopsy (if positive at baseline)  
15 FORMS AND PROCEDURES FOR COLLECTING DATA AND DATA MANAGING 
The web study area, with a dedicated database, the electronic Case Report Form (CRF) and all the required 
functions, will be developed in a dedicated area (https://www.filinf.it). All participating centers will receive a 
password to access the internet-based database.  
Several systematic quality controls will be active during data entry; periodic statistical checks and 
personalized queries will be performed during the study. 
Frequency of on-site monitoring will be planned according to the results of the statistical quality controls. 
16 ADVERSE EVENTS, SERIOUS ADVERSE EVENTS 
Timely, accurate, and complete reporting and analysis of safety information from clinical studies are crucial 
for the protection of subjects and are mandated by regulatory agencies worldwide.  
16.1 Definitions 
Adverse Event Definitions and Classifications 
16.1.1 Adverse Event 
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
pharmaceutical product. An adverse event does not necessarily have a causal relationship with the 
treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal 
finding), symptom, or disease temporally associated with the use of a medicinal (investigational or non-
investigational) product, whether or not related to the medicinal (investigational or non-investigational) 
product. (Definition per International Conference on Harmonization [ICH]) 
This includes any occurrence that is new in onset or aggravated in severity or frequency from the baseline 
condition, or abnormal results of diagnostic procedures, including laboratory test abnormalities. 
The Adverse Events collection for each subject will start with the signing of informed consent form. 
 
16.1.2  Serious Adverse Event 
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal Products for 
Human Use ICH is any untoward medical occurrence that at any dose meets any of the following conditions: 
• 
results in death 
• 
is life-threatening 
 
(the subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.) 

 
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• 
requires inpatient hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability/incapacity, 
• 
is a congenital anomaly/birth defect 
• 
ismedically important* 
16.1.3 * Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical or  events that may not be immediately 
life-threatening or result in a deathor hospitalization but that may jeopardize the patient or require 
intervention to prevent one of the other outcomes listed in the definition above. These should usually 
be considered serious. Unlisted (Unexpected) Adverse Event 
An unlisted adverse event, the nature or severity of which is not consistent with the applicable product 
reference safety information. For an investigational product, the expectedness of an adverse event will be 
determined by whether or not it is listed in the Investigator's Brochure. For a comparator product with a 
marketing authorization, the expectedness of an adverse event will be determined by whether or not it is 
listed in the summary of product characteristics (SmPC). 
16.1.4 Associated with the Use of the Drug 
An adverse event is considered associated with the use of the drug if the attribution is possible, probable, or 
very likely by the definitions listed in Section 1.2. 
16.1.5 Product Quality Complaint 
A product quality complaint (PQC) is defined as any suspicion of a product defect related to manufacturing, 
labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, durability, or reliability of a 
product, including its labeling or package integrity. A PQC may have an impact on the safety and efficacy of 
the product. Timely, accurate, and complete reporting and analysis of PQC information from studies are 
crucial for the protection of subjects, investigators, and the sponsor, and are mandated by regulatory 
agencies worldwide. The sponsor has established procedures in conformity with regulatory requirements 
worldwide to ensure appropriate reporting of PQC information; all studies conducted by the sponsor or its 
affiliates will be conducted in accordance with those procedures. 
16.2 Attribution Definitions 
16.2.1 Intensity (Severity) Reporting and Attribution  
For both serious and non-serious adverse events, the investigator must determine both the intensity of the 
event and the relationship of the event to study drug administration. 
Intensity for each adverse event will be determined by using Version 4.0 of the National Cancer Institute 
Common Toxicity Criteria (NCI CTC) as a guideline (homepage http://ctep.info.nih.gov), wherever possible. 
The criteria will be provided to the investigator as a separate document. In those cases where the NCI CTC 
do not apply, intensity should be defined according to the following criteria: 
Mild: 
Awareness of sign or symptom, but easily tolerated, causing minimal discomfort and not interfering 
with everyday activities; 
Moderate: Sufficient discomfort is present to cause interference with normal activities.  

 
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Severe: Extreme distress causing significant impairment of functioning or incapacitation. Prevents normal 
everyday activities The investigator should use clinical judgment in assessing the intensity of events not 
directly experienced by the subject (eg, laboratory abnormalities). 
 
Relationship to study drug administration will be determined as follows: 
Not related  
An adverse event which is not related to the use of the drug. 
Doubtful 
An adverse event for which an alternative explanation is more likely, e.g., concomitant drug(s), concomitant 
disease(s), or the relationship in time suggests that a causal relationship is unlikely. 
Possible 
An adverse event which might be due to the use of the drug. An alternative explanation, e.g., concomitant 
drug(s), concomitant disease(s), is inconclusive. The relationship in time is reasonable; therefore, the causal 
relationship cannot be excluded. 
Probable 
An adverse event which might be due to the use of the drug. The relationship in time is suggestive (e.g., 
confirmed by dechallenge). An alternative explanation is less likely, e.g., concomitant drug(s), concomitant 
disease(s). 
Very Likely 
An adverse event which is listed as a possible adverse reaction and cannot be reasonably explained by an 
alternative explanation, e.g., concomitant drug(s), concomitant disease(s). The relationship in time is very 
suggestive (e.g., it is confirmed by dechallenge and rechallenge). 
16.2.2 Special Reporting Situations 
The following special situations must be reported to the appropriated Sponsor-Investigator’s contact person 
by investigational  staff within 24 hours of acknowledge using the SAE form:  
• 
Drug exposure during pregnancy (maternal, paternal) 
• 
Suspected transmission of any infectious agent via administration of a medicinal product  
The following special situations should be reported to the Sponsor – Investigator if associated with an SAE: 
• 
Exposure to a medicinal product from breastfeeding 
• 
Overdose of a medicinal product 
• 
Medication error involving a medicinal product (with or without subject/patient exposure to the 
medicinal product, eg, name confusion) 
• 
Suspected abuse/misuse of a medicinal product 
• 
Unexpected therapeutic benefit  
• 
inadvertent or accidental exposure to a medicinal product 

 
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Special reporting situations should be recorded in the CRF. Any special reporting situation that meets the 
criteria of a serious adverse event should be recorded on the serious adverse event page of the CRF. 
 
16.2.3 Reporting Procedures 
All Adverse Events 
All adverse events will be registered in CRF from the time a signed and dated informed consent form is 
obtained until 30 days after the administration of the last dose of study drug. Those meeting the definition 
of serious adverse events must be reported using the Serious Adverse Event Form. 
Serious Adverse events occurring after 30 days should be reported if considered at least possibly related to 
the investigational medicinal product by the investigator. 
Clinically relevant changes in laboratory values must be recorded in the adverse event section of the CRF. For 
example, laboratory abnormalities leading to an action regarding the study drug (dose change, temporary 
stop, delay of the start of a cycle or permanent stop) or the start of concomitant therapy should be reported. 
For each laboratory abnormality reported as an adverse event, the following laboratory values should be 
reported in the laboratory section of the CRF: the value indicative of the onset of each toxicity grade, the 
most abnormal value observed during the adverse event, and the value supporting recovery to Grade 0 or 1 
or to baseline condition. 
All adverse events, regardless of seriousness, severity, or presumed relationship to study therapy, must be 
recorded using medical terminology in the source document and the CRF. Whenever possible, diagnoses 
should be given when signs and symptoms are due to a common etiology (e.g., cough, runny nose, sneezing, 
sore throat, and head congestion should be reported as “upper respiratory infection”). Investigators must 
record in the CRF their opinion concerning the relationship of the adverse event to study therapy. All 
measures required for adverse event management must be recorded in the source document and reported 
according to Sponsor-Investigator instructions. 
The Sponsor-Investigator assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The Sponsor-Investigators will also report to the Investigator, Independent Ethics 
Committee/Institutional Review Board (IEC/IRB) and to the Italian Drug Agency (AIFA) all serious adverse 
events of this study that are unlisted and associated with the use of the drug.  
Subjects must be provided with a “study card” indicating the name of the investigational product, the study 
number, the investigator’s name, a 24-hour  emergency contact number, and, if applicable, excluded 
concomitant medications. 
Pregnancies 
While pregnancy, in itself, is not an adverse event, any subject pregnancy or pregnancies in partners of male 
subjects included in the study must be submitted by investigational staff to the Sponsor-Investigator within 
24 hours of their knowledge of the event using the pregnancy notification form. 
Abnormal pregnancy outcomes (eg spontaneous abortion, fetal death, stillbirth, congenital anomalies, 
ectopic pregnancy) are considered serious adverse events and must be reported using the Serious Adverse 
Event Form. Any subject who becomes pregnant during the study must be promptly withdrawn from the 
study.  

 
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Pregnancies in partners of male subjects included in the study will be reported by the investigational staff 
within 24 hours of their knowledge of the event using the pregnancy notification form. 
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the infant will 
be required. 
 
Serious Adverse Events and/or Pregnancies and/or Product Quality Complaint 
All SAEs (and/or Pregnancies and/or PQC) occurring during clinical studies must be reported to the 
appropriated Sponsor-Investigator’s contact person by investigational staff within 24 hours of their 
knowledge of the event. 
Information regarding SAEs (and/or Pregnancies) will be transmitted to the Sponsor-Investigator using the 
Serious Adverse Event Form (and/or a pregnancy notification form), which must be signed by a member of 
the investigational staff. It is preferable that serious adverse events be reported via fax. Subsequent to a 
telephone report of a serious adverse event (and/or a Pregnancy), a Serious Adverse Event Form (a pregnancy 
notification form) must be completed by the investigational staff and transmitted to the Sponsor-Investigator 
within 24 hours.  
The Product Quality Complaint may be reported to the appropriate Sponsor-Investigator contact person in 
different forms including but not limited to telephone, fax, electronic communication or in person 
 
The SAE(s) and/or Pregnancy report(s)  must be sent to the Sponsor-Investigator Pharmacovigilance 
Contact Person to the following fax number: 
Sponsor contact: 
Dr. Alessandro Levis 
Address: S.C. Ematologia Azienda Ospedaliera Santi Antonio e Biagio e Cesare Arrigo - Alessandria 
Phone no.: +39-0131-206066- 
Fax no.: +39-0131-263455 
 
All serious adverse events that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the subject’s participation in the study, must be followed until any of the following occurs: 
The event resolves 
The event stabilizes 
The event returns to baseline, if a baseline value is available 
The event can be attributed to agents other than the study drug or to factors unrelated to study conduct 

 
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It becomes unlikely that any additional information can be obtained (subject or health care practitioner 
refusal to provide additional information, lost to follow up after demonstration of due diligence with follow-
up efforts). 
The cause of death of a subject in a clinical study, whether or not the event is expected or associated with 
the investigational agent, is considered a serious adverse event. Suspected transmission of an infectious 
agent by a medicinal product should be reported as a serious adverse event. Any event requiring 
hospitalization (or prolongation of hospitalization) that occurs during the course of a subject’s participation 
in a clinical study must be reported as a serious adverse event, except hospitalizations for: 
social reasons in absence of an adverse event 
surgery or procedure planned before entry into the study (must be documented in the CRF) 
study drug administration 
study related procedures defined in the protocol. 
 
17 ETHICAL CONSIDERATIONS 
17.1 Patient protection 
The responsible investigator will ensure that this study is conducted in agreement with either the Declaration 
of Helsinki (Tokyo, Venice, Hong Kong and Somerset West amendments) or the laws and regulations of the 
country, whichever provides the greatest protection of the patient. 
The protocol has been written, and the study will be conducted according to the ICH Guideline for Good 
Clinical Practice  
The protocol and its annexes are subject to review and approval by the competent Independent Ethics 
Committee(s) (“IEC”). 
 
18 SUBJECT IDENTIFICATION PERSONAL DATA PROTECTION 
All records identifying the subject must be kept confidential and, to the extent permitted by the applicable 
laws and/or regulations, not be made publicly available. The name of the patient will not be asked for nor 
recorded at the Data Center. A sequential identification number will be automatically attributed to each 
patient registered in the study. This number will identify the patient and must be included on all case report 
forms. In order to avoid identification errors, patient initials and date of birth will also be reported on the 
case report forms. 
Any and all patient information or documentation pertaining to a clinical trial, to the extent permitting, 
through a “key” kept anywhere, regardless of whether such key is supplied along with the information or 
documentation or not, must be considered as containing sensitive personal data of the patient, and is 
therefore subjected to the provisions of applicable data protection (“privacy”) regulations. Breach of such 
regulations may result in administrative or even criminal sanctions. 

 
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Particularly, an information sheet prepared according to such regulations and a form to evidence the consent 
of patients to the processing of such data must therefore accompany the informed consent administered to 
the patient (see paragraph 14.3 below). Such information must (i) identify the roles of the holder (“titolare”) 
and processor (“responsabile”, appointed by the holder) of the patient personal data (also if not directly 
identifying the patient), as well as the purposes of the personal data collection and processing (medical 
treatment and related/unrelated scientific research), (ii) adequately describe the flows of communication 
involving them, particularly if third parties should become involved, and (iii) seek the patient’s prior and 
specific consent to such processing. 
Patient information or documentation may be considered “anonymous”, and as such not subject to privacy 
regulations, only when no key whatsoever, permitting the identification of the patient, is any longer available. 
Particular attention should therefore be paid (and information/consent materials adapted accordingly) 
whenever patient data are supplied to third parties and may be autonomously processed, or biological 
samples/materials are taken and kept for future research purposes, associated or not with the pathology 
considered in the study.  
A copy of  Informed consent should be attached to this Protocol Template. 
18.1 Informed consent 
All patients will be informed of the aims of the study, the possible adverse events, the procedures and 
possible hazards to which he/she will be exposed, and the mechanism of treatment allocation. They will be 
informed as to the strict confidentiality of their patient data, but that their medical records may be reviewed 
for study purposes by authorized individuals other than their treating physician. An example of a patient 
informed consent statement is given as an appendix to this protocol. 
It will be emphasized that the participation is voluntary and that the patient is allowed to refuse further 
participation in the protocol whenever he/she wants. This will not prejudice the patient’s subsequent care. 
Documented informed consent must be obtained for all patients included in the study before they are 
registered or randomized at the Data Center. This must be done in accordance with the national and local 
regulatory requirements. 
For European Union member states, the informed consent procedure must conform to the ICH guidelines on 
Good Clinical Practice. This implies that “the written informed consent form should be signed and personally 
dated by the patient or by the patient’s legally acceptable representative”. 
A copy of  Informed consent should be attached to this Protocol Template. 
19 CONFLICT OF INTEREST 
Any investigator and/or research staff member who has a conflict of interest with this study (such as patent 
ownership, royalties, or financial gain greater than the minimum allowable by their institution) must fully 
disclose the nature of the conflict of interest.   
20 DATA OWNERSHIP 
According to the ICH Guidelines on Good Clinical Practice the sponsor of a study (the Institution, should the 
investigator or study coordinator act as sponsor in the performance of her/his institutional duties under the 
employment or collaboration agreement with Humanitas) is the owner of the data resulting therefrom. All 

 
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centers and investigators participating in the study should be made aware of such circumstance and invited 
not to disseminate information or data without the Institution’s prior express consent. 
21 PUBLICATION POLICY 
This section should be adapted to the statutes of the cooperative group. 
After completion of the study, the project coordinator will prepare a draft manuscript containing final results 
of the study on the basis of the statistical analysis. The manuscript will be derived to the co-authors for 
comments and after revision will be sent to a major scientific journal. 
All publications, abstracts, presentations, manuscripts and slides including data from the present study will 
be submitted to and reviewed by the Study Coordinator for coordination and homogeneity purposes: specific 
advance periods  for submission and review may be specified in the protocol. The timing of publications (in 
the event several Centers should be participating in the Study) may be coordinated, and publication delayed 
if patentable inventions should be involved (for the time required in order to file the relevant patent 
applications); otherwise, according to the MoH’s Decree of May 12, 2006, investigators cannot be precluded 
from or limited in publishing the results of their studies (IECs must verify that no excessive restriction is 
contained in the protocols submitted to their review and approval).  
22 STUDY INSURANCE 
The Investigator-sponsor of the Study  must ensure that adequate insurance coverage is available to the 
patients, in accordance with Section 5.8 of the ICH Guidelines of Good Clinical Practice. Such coverage must 
extend to all damages deriving from the study, to the exclusion of those attributable to willful misconduct or 
negligence of the institution or investigator. A copy, or excerpt, or insurer’s certificate, attesting the existence 
and amount of such coverage at least for the duration of the study must be supplied as part of the study 
documentation to the review and approval of the IEC. 
Based on section 2.4 of the MoH’s decree of December 17, 2004, the insurance coverage must be supplied 
by the hospital or medical research department  in case of no profit drug evaluation trial.  
 
 

 
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30. Romaguera JE, Fayad LE, McLaughlin P. Phase I trial of bortezomib in combination with rituximab-
HyperCVAD alternating with rituximab, methotrexate and cytarabine for untreated aggressive 
mantle cell lymphoma. Br J Haematol 2010; 151 (1): 47-53. 
31. Voortman J, Smit EF, Honeywell R, et al. A parallel dose-escalation study of weekly and twice-weekly 
bortezomib in combination with gemcitabine and cisplatin in the first-line treatment of patients with 
advanced solid tumors. Clin Cancer Res 2007 Jun 15; 13 (12): 3642-51. 
32. Moreau P, Coiteux V, Hulin C, et al. Prospective comparison of subcutaneous to intravenous 
administration of bortezomib in patients with multiple myeloma: Pharmacokinetics, efficacy and 
toxicity. J Clin Oncol 2007; 25 (18S): abs 8046, 452s. 
33. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of 
bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority 
study. Lancet Oncol 2011; 12 (5): 431-40. 
34. Rubinstein LV, Korn EL, Freidlin B, Hunsberger S, Ivy SP, Smith MA. Design issues of randomized phase 
II trials and a proposal for phase II screening trials. J Clin Oncol. 2005;23:7199-206 

 
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24 APPENDIXES  
24.1 Appendix 1: Timing of treatment and investigations 
 
aNegative pregnancy test is required 1 week before treatment for both pre-menopausal women and women 
who are <1 years after onset of menopause 
b HBsAg, HBcAb, HCV and HIV serology 
Staging 
Pre-Treatment 
R-DHAP/BR-DHAP 
Treatment 
End 
of
Treatment 
Follow-Up 
Screening phase C1 C2 Intermediat
e EvaluationC3 C4 Final 
Evaluation 
Up to 2-years 
Informed consent X 
Inclusion/Exclusion 
criteria 
X 
Pregnancy testa 
X 
Serum virologyb 
X 
Ecg/Echo/MUGA 
X 
Anti-tumor activity 
X 
X 
X 
Bone 
marrow 
biopsy 
X 
X e 
X e 
X e 
Stem cell collection 
Xc 
Xc 
GC/ABC value on 
diagnostic tissue 
X 
PET scan 
X 
X 
X 
CT 
of 
chest 
& 
abdomen 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
Biochemistry 
Xd 
X 
X 
X 
X 
X 
X 
X 
Physical 
examination 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 

 
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c Stem cell mobilization will be monitored after 2nd cycle in patients with negative bone marrow biopsy at 
screening, and after third cycle in patients with positive bone marrow biopsy at screening.  
d Biochemistry should include LDH and Beta2-microglobulin at screening 
e only if positive at baseline 
 
 
 
 
 
 
 

 
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24.2 Appendix 2: Response Criteria 
 
 
 

 
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24.3 Appendix 3: NCI Common toxicity criteria 
 
In the present study, adverse events and/or adverse drug reactions will be recorded according to the: 
Common Terminology Criteria for Adverse Events (CTCA), version 4.0. 
At the time this protocol was issued, the full CTC document was available on the NCI web site, at the following 
address: http://ctep.cancer.gov/reporting/ctc.html.  
 
 
 
 

 
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24.4 Appendix 4: Dispensing information for rituximab 
DESCRIPTION 
Rituximab is a mouse/human chimeric antibody. The rituximab antibody is produced by a Chinese hamster 
ovary transfectoma. Rituximab will be provided in l00 mg (l0 mL) and 500 mg (50 mL) pharmaceutical grade 
vials at a concentration of l0.0 mg of protein per mL (actual concentration should be noted on the product 
label). 
RECOMMENDED PREPARATION AND ADMINISTRATION 
1. 
Refer to the clinical trial protocol for details about the dose and dose schedule. 
2. 
Rituximab  should be stored at 2-8°C. Do not freeze or store at room temperature. The product is a 
protein - HANDLE GENTLY AND AVOID FOAMING. The avoidance of foaming during product handling, 
preparation and administration is important, as foaming may lead to the de-naturing of the product proteins. 
3. 
All transfer procedures require strict adherence to aseptic techniques, preferably in a laminar flow 
hood. 
4. 
Prepare the rituximab infusion solution as follows: 
(a) 
Refrigerate (2-8°C) all materials and solutions prior to use. 
(b) 
Use sterile, non-pyrogenic, disposable containers, syringes, needles, stopcocks and transfer tubing, 
etc. 
(c) 
Transfer of the rituximab  from the glass vial should be made by using a suitable sterile graduated 
syringe and large gauge needle. 
(d) 
Transfer the appropriate amount of rituximab from the graduated syringe, into a partially filled IV 
pack containing sterile pyrogen-free 0.9% sodium chloride solution, USP (saline solution). The final 
concentration of rituximab in saline solution should be a maximum of 1 mg/ml. Mix by inverting the bag 
gently. DO NOT USE A VACUUM APPARATUS to transfer the product from the syringe to the plastic bag. 
(e) 
Place an IV administration into the outflow port of the bag containing the infusion solution. 
(f) 
NOTE: DO NOT USE evacuated glass containers which require vented administration sets because 
this causes foaming as air bubbles pass through the solution. 
5. 
The administration of rituximab will be accomplished by slow IV infusion. CAUTION: DO NOT 
ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS. 
6. 
IV pumps such as the IMED 960 may be used with the rituximab infusion. DO NOT INFUSE 
CONCOMITANTLY with another IV solution or IV medications. Prime the line with the rituximab solution such 
that approximately 30 mL are delivered 
7. 
Administration of rituximab 
Pre-administration of allopurinol (or suitable alternative): 
Patients thought to be at risk of tumor lysis syndrome should be well-hydrated and treated with allopurinol 
(300 mg p.o.) or suitable alternative treatment for 12-24 hours before prior to the first dose of therapy with 
rituximab. 

 
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Caution: Do not administer rituximab as an intravenous push or bolus. 
Rituximab will be administered intravenously in an out- or in-patient setting. Oral premedication (1000 mg 
of paracethamole and 50-100 mg diphenhydramine hydrochloride) needs to be administered 30-60 minutes 
prior to starting each infusion of rituximab. Prednisone/prednisolone as part of the chemotherapy protocol 
will be administered in the prescribed dose before the infusion of rituximab, preferably as oral medication. 
A peripheral or central intravenous (iv) line will be established. Before starting the infusion, there should be 
a ready supply of epinephrine for subcutaneous injection and diphenhydramine hydrochloride for 
intravenous injection, and resuscitation equipment for the emergency handling of anaphylactic reactions. 
The infusion will be started at an initial rate of 50 mg/hour for the first hour. During the rituximab infusion, 
the patient's vital signs (blood pressure, pulse, respiration and temperature) will be monitored every 15 
minutes (4x) for one hour or until stable and then hourly until the infusion is discontinued. If no toxicity is 
seen during the first hour, the dose rate may be escalated gradually (by increments of 50 mg/hour at 30 
minute intervals) to a maximum of 300 mg/hour. If the first dose of rituximab is well-tolerated, the starting 
flow rate for administration of the second and subsequent infusions will be 100 mg/hour and then increased 
gradually (by 100 mg/hour increments at 30 minute intervals) not to exceed 400 mg/hour. Patients may 
experience transient fever and rigors with infusion. If any of the effects below are noted, the antibody 
infusion should be temporarily discontinued, the patient should be observed, and when the symptoms 
improve, the infusion should be continued but at half the previous rate. 
Dose Rate 
Fever 
Rigors/chills 
Mucosal congestion 
Edema 
Drop in Systolic 
Blood Pressure 
Decrease to 1/2 
If any of these 
Events seen: 
> 38.5°C 
Mild/Moderate 
Mild/Moderate 
> 30 mm Hg 
Following the infusion the intravenous line should be kept open for medications, as needed. If there are no 
complications, the intravenous line may be discontinued after one hour of observation.Dosage: 375 mg/m² 
body surface.  
1st application 
further Applications 
Hours 
mg/h *) 
mg-total 
mg/h *) 
mg-total 
0 – 1 
50 
50 
100 
100 
1 – 1.5 
100 
100 
150 
175 
1.5 – 2 
150 
175 
200 
275 
2 – 2.5 
200 
275 
250 
400 
2.5 – 3 
250 
400 
300 
550 
3 – 3.5 
300 
550 
350 
725 
3.5 – 4 
300 
700 
400 
925 

 
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4 – 4.5 
300 
850 
 
*) With a concentration of 1 mg/ml the values of mg/h are equal to ml/h. 
Suggested Rituximab Rapid infusion 
If no adverse events occurred during first Rituximab infusion,with adeguate premedication, II-III and IV 
Rituximab infusion will be performed as follow: 
 
RITUXIMAB 375 mg/m2 
First dose of 100 mg in saline solution 100 ml 
Second dose (to total dose) mg in saline solution 250 ml 
 
time 
ml/h 
0-60 
100 
61-180 
125 
 
24.5 Appendix 5: Dispensing information for bortezomib 
 
PACKAGING  
BORTEZOMIB  will be available as a sterile lyophilized powder in a single-use 10 mL glass vial. Each vial 
contains the equivalent of 3.5 mg of BORTEZOMIB  in the form of a mannitol boronic ester. Each vials 
secured into a blister package. 
 
LABELING  
Study drug labels will contain information to meet the applicable regulatory requirements. The 
investigational products will be labelled and handled as open-label materials. 
 
PREPARATION AND HANDLING  
Vials for SC administration: each vial of BORTEZOMIB  for Injection should be reconstituted under a 
laminar flow biological cabinet (hood), within 8 hours before dosing, with 1.4 mL of normal (0.9%) 
saline, sodium chloride injection, so that the reconstituted solution contains Velcade at a 
concentration of 2.5 mg/mL. 

 
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The reconstituted solution is clear and colorless, with a final pH of approximately 5 to 6. Dissolution 
is completed in approximately 10 seconds. Reconstituted BORTEZOMIB  should be administered 
promptly and in no case more than 8 hours after reconstitution. In case of skin contact, wash the 
affected area immediately and thoroughly with soap and water and dilutedhydrogen peroxide for 15 
minutes. If product contacts eye, immediately flush eye thoroughly with water for at least 15 
minutes. Always contact a physician after any form of body contact. All materials that have been 
used for preparation should be disposed of according to standard practices. A log must be kept of 
all disposed materials. 
 
  
 
 

 
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24.6 Appendix 6: Suggested Body Surface Area Calculation 
BSA should be determined using the appropriate following calculation: 
BSA = 
3131
)
(
)
(
lb
Wt
inches
Ht

 
OR 
BSA = 
3600
)
(
)
(
kg
Wt
cm
Ht 
 
 
 
 

 
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24.7 Appendix 7: Creatinine Clearance Calculation 
Creatinine clearance for men and women will be calculated according to the Cockcroft-Gault formula as 
follows: 
 
 
In men:  
(
)
()


(
)


dL
mg
creatini
kg
weig
age
/
72
140


−
 
 
        In women:            
(
)
()


( )

8
.0
/
72
140



−
dL
mg
creatinin
kg
weigh
age
 
 
 
Note:  Age 
(in 
years), 
weight 
(in 
kg), 
serum-creatinine 
(in 
mg/dL)  
72 (normalized to 72 kg body weight and a body surface of 1.72 m2) 
 
 
 

 
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24.8 Appendix 8: ECOG performance status scale 
 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light housework or office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
50% of waking hours 
3 
Capable of only limited self-care, confined to a bed or chair 
50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
 
 
 
 

 
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24.9 Appendix 9: New York Heart Association Classification of Cardiac Disease 
 
The following table presents the NYHA classification of cardiac disease: 
Class 
Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting limitations 
of physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation, dyspnea, or anginal pain. 
No objective evidence of cardiovascular 
disease. 
II 
Patients with cardiac disease resulting in slight limitation of 
physical activity. They are comfortable at rest. Ordinary 
physical activity results in fatigue, palpitation, dyspnea, or 
anginal pain. 
Objective 
evidence 
of 
minimal 
cardiovascular disease. 
III 
Patients with cardiac disease resulting in marked limitation of 
physical activity. They are comfortable at rest. Less than 
ordinary activity causes fatigue, palpitation, dyspnea, or 
anginal pain. 
Objective 
evidence 
of 
moderately 
severe cardiovascular disease. 
IV 
Patients with cardiac disease resulting in inability to carry on 
any physical activity without discomfort. Symptoms of heart 
failure or the anginal syndrome may be present even at rest. 
If any physical activity is undertaken, discomfort is increased. 
Objective 
evidence 
of 
severe 
cardiovascular disease. 
Source: The Criteria Committee of the New York Heart Association, Inc.: Diseases of the heart and blood 
vessels; Nomenclature and criteria for diagnosis, 6th Ed. Boston: Little, Brown; 1964.