Phase II Study With Ga101-DHAP as Induction Therapy in Relapsed/Refractory Diffuse Large B-cell Lymphoma (DLBCL) Patients Before High-Dose Chemotherapy BEAM With Autologous Stem Cell Transplantation (ASCT)
Phase: PHASE2
Conditions: Diffuse, Large B-Cell, Lymphoma
Sponsor: Fondazione Italiana Linfomi - ETS

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 1 of 60 
 
 
 
 
 
 
 
Phase II study with Ga101-DHAP as induction therapy in relapsed/refractory 
Diffuse Large B-cell Lymphoma (DLBCL) patients before High-Dose 
chemotherapy BEAM with autologous stem cell transplantation (ASCT). 
 
 
STUDY DRUG Obinutuzumab (GA101) 
Study ID Phase II GA101-DHAP 
Version 2  
Emend sost_1, 09 September 2016 
EudraCT: 2013-004014-17 
 
 
 
STUDY CONTACT INFORMATION 
 
INVESTIGATOR AND SPONSOR 
Fondazione Italiana Linfomi Onlus (FIL) 
Secretary: c/o SC Ematologia Azienda Ospedaliera SS. Antonio e Biagio e Cesare 
Arrigo 
Address: via Venezia 16, 15121 Alessandria, Italy 
Phone no.: +39-0131-206132 
Fax no.: +39-0131-263455 
Email: segreteria@filinf.it 
 
 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 2 of 60 
 
PRINCIPAL INVESTIGATOR 
Maurizio Martelli, MD 
Address: UO Ematologia, Università La Sapienza, Roma 
Phone no.: +39-06-85795 
Email: martelli@bce.uniroma1.it 
 
CO-Investigators 
Massimo Federico, MD 
Address: Oncologia Medica ed Ematologia, Centro Oncologico,  Modena  
Phone no.:+39- 059-4223203  
Email: massimorosario.federico@unimore.it 
 
Umberto Vitolo, MD 
Address: SC Ematologia 2, A.O. Città della Salute e della Scienza di Torino San    
Giovanni Battista, Torino 
Phone no.: +39-011-6335937-6335550 
Fax no.: +39-011-6335611 
Email: uvitolo@cittadellasalute.to.it 
 
Luigi Rigacci, MD 
Address: SOD Ematologia, Azienda Ospedaliero Universitaria Careggi, Firenze 
Phone no.: +39-055-7947958 
Fax no.: +39-055-7947343 
Email: luigi.rigacci@unifi.it 
 
WRITING COMMITTEE AND SCIENTIFIC SUPPORT 
1. Luigi Rigacci, MD, SOD Ematologia, Azienda Ospedaliero Universitaria Careggi,  
Firenze 
2. Maurizio Martelli, MD, UO Ematologia, Università La Sapienza, Roma 
3. Umberto Vitolo, MD, SC Ematologia 2, Azienda Ospedaliero Universitaria San 
Giovanni Battista Torino 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 3 of 60 
4. Massimo Federico, MD, Oncologia e Ematologia, Centro Oncologico Modenese, 
Modena 
5. Massimo Di Nicola, MD, SC Medicina Oncologica 2, Istituto Nazionale dei 
Tumori. Milano 
6. Benedetta Puccini, MD, SOD Ematologia, Azienda Ospedaliero Universitaria 
Careggi, Firenze 
 
BIOMETRY 
Responsible: Giovannino Ciccone, MD  
Address: SCDU Epidemiologia dei Tumori – Università degli Studi di Torino e Azienda  
Ospedaliero Universitaria San Giovanni Battista – Torino 
Phone no.: +39-011-6336857  
Fax no.: +39-011-6706692 
 
PHARMACOVIGILANCE 
Responsible: Alessandro Levis, MD 
Address: Segreteria Fondazione Italiana Linfomi ONLUS c/o Ematologia Azienda  
Ospedaliera SS. Antonio e Biagio e Cesare Arrigo via Venezia 16,  15121  
Alessandria  
Phone no.: +39-0131-206132 (6156) 
Fax no.: +39-0131-263455 
 
HISTOPATOLOGY 
Responsible: Stefano Pileri, MD 
Address: Unità di Emolinfopatologia, Istituto Europeo di Oncologia, Via Ripamonti 435,     
Milano  
e‐mail: stefano.pileri@ieo.it 
 
 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 4 of 60 
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 
 
 
 
 
 
*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) 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 5 of 60 
1 BACKGROUND AND INTRODUCTION ..................................................................................... 8 
1.1 Diffuse large B cell Lymphoma ....................................................................................................................................... 8 
1.2 Relapsed /refractory DLBCL ........................................................................................................................................... 8 
1.3 Obinutuzumab (GA101) ................................................................................................................................................. 9 
1.3.1 
Pre-clinical efficacy with GA101 ............................................................................................................................ 10 
1.3.2 
Clinical experience with GA101 ............................................................................................................................. 10 
1.3.3 
Pharmacokinetic and pharmacodynamic results for GA101 ................................................................................. 14 
2 RATIONALE OF THE STUDY .................................................................................................... 15 
3 OBJECTIVES OF THE STUDY .................................................................................................. 15 
3.1 General objectives ....................................................................................................................................................... 15 
3.2 End-points ................................................................................................................................................................... 16 
3.2.1 
Primary endpoints ................................................................................................................................................. 16 
3.2.2 
Secondary endpoints ............................................................................................................................................. 16 
4 PATIENT SELECTION CRITERIA ............................................................................................. 17 
4.1 Inclusion criteria .......................................................................................................................................................... 17 
4.2 Exclusion criteria ......................................................................................................................................................... 19 
5 STUDY DESIGN........................................................................................................................... 20 
5.1 Rationale for the Study Design .................................................................................................................................... 21 
6 STATISTICAL CONSIDERATIONS .......................................................................................... 22 
6.1 Statistical design .......................................................................................................................................................... 22 
6.1.1 
Sample size, study duration and stopping rules .................................................................................................... 22 
6.1.2 
Statistical analysis .................................................................................................................................................. 23 
7 PATHOLOGICAL REVIEW ........................................................................................................ 23 
8 STUDY TREATMENT .................................................................................................................. 24 
8.1 Rationale for GA101 Dose ............................................................................................................................................ 24 
8.2 Scheme GA101-DHAP .................................................................................................................................................. 25 
8.2.1 
GA101 .................................................................................................................................................................... 26 
8.3 Mobilization and apheresis.......................................................................................................................................... 29 
8.4 BEAM or FEAM + ASCT ................................................................................................................................................. 30 
8.5 Risks Associated with GA101 Therapy ......................................................................................................................... 30 
8.5.1 
Infusion-Related Reactions and Hypersensitivity Reactions (Including Anaphylaxis) ........................................... 30 
8.5.2 
Tumor Lysis Syndrome .......................................................................................................................................... 31 
8.5.3 
Thrombocytopenia and Neutropenia .................................................................................................................... 31 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 6 of 60 
8.5.4 
Infection ................................................................................................................................................................ 31 
8.5.5 
Dose- adjustment for GA101 ................................................................................................................................. 32 
8.5.6 
Dose delay for GA101 on Cycle 1 Day 8 and Cycle 1 Day 15 ................................................................................. 32 
8.5.7 
Dose- adjustment for DHAP .................................................................................................................................. 33 
9 WITHDRAWAL ............................................................................................................................ 33 
9.1 Withdrawal of Consent ................................................................................................................................................ 34 
9.2 Patients Lost to Follow up ........................................................................................................................................... 34 
10 CONCOMITANT TREATMENT .................................................................................................. 34 
10.1  Recommended concomitant treatments ................................................................................................................... 34 
10.2  Permitted concomitant therapy ................................................................................................................................. 35 
10.3  Prohibited concomitant therapy ................................................................................................................................ 35 
10.4  Females of childbearing potential .............................................................................................................................. 36 
10.5  Male subjects ............................................................................................................................................................. 36 
11 CLINICAL EVALUATION, LABORATORY TESTS AND FOLLOW-UP ............................... 36 
11.1  Staging evaluation, baseline ...................................................................................................................................... 36 
11.2  Valuation at each GA101-DHAP corse ........................................................................................................................ 37 
11.3  Intermediate response evaluation ............................................................................................................................. 37 
11.4  Pre-ASCT evaluation - end of treatment .................................................................................................................... 37 
11.5  Post –ASCT evaluation ............................................................................................................................................... 38 
11.6  Follow-up .................................................................................................................................................................. 38 
12 FORMS AND PROCEDURES FOR COLLECTING DATA AND DATA MANAGING ......... 38 
13 ADVERSE EVENTS, SERIOUS ADVERSE EVENTS ............................................................. 39 
13.1  Definitions ................................................................................................................................................................. 39 
13.1.1 
Adverse Event ........................................................................................................................................................ 39 
13.1.2 
Serious Adverse Event ........................................................................................................................................... 39 
13.1.3 
Unlisted (Unexpected) Adverse Event ................................................................................................................... 40 
13.1.4 
Associated with the Use of the Drug ..................................................................................................................... 41 
13.1.5 
Product Quality Complaint .................................................................................................................................... 41 
13.2  Attribution Definitions............................................................................................................................................... 41 
13.2.1 
Intensity (Severity) Reporting and Attribution ...................................................................................................... 41 
13.3  Reporting Procedures ................................................................................................................................................ 42 
14 ETHICAL CONSIDERATIONS ................................................................................................... 46 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 7 of 60 
14.1  Patient protection ..................................................................................................................................................... 46 
15 SUBJECT IDENTIFICATION – PERSONAL DATA PROTECTION ...................................... 46 
15.1  Informed consent ...................................................................................................................................................... 47 
16 CONFLICT OF INTEREST ......................................................................................................... 48 
17 DATA OWNERSHIP .................................................................................................................... 48 
18 PUBLICATION POLICY .............................................................................................................. 48 
19 STUDY INSURANCE .................................................................................................................. 49 
20 DURATION OF THE STUDY ...................................................................................................... 49 
21 REFERENCES ............................................................................................................................. 50 
22 APPENDIXES ............................................................................................................................... 53 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 8 of 60 
1 
BACKGROUND AND INTRODUCTION 
 
1.1 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 outcome and results of ongoing prospective trials are soon 
expected.6   
 
1.2 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 salvage 
therapy before ASCT.  
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 ASCT:  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. Both 
3-year event-free survival (EFS, 47 vs 21%) and overall survival (OS, 66% vs 40%) were 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 9 of 60 
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.  
 
1.3 Obinutuzumab (GA101) 
RO5072759 (GA 101) is the first Fc-engineered type II CD20 humanized IgG1 antibody 19 20. 
The type II antibodies exhibit lower C1q binding and CDC compared with type I. In this type 
II antibodies is increased the direct and immune effector cell-mediated induction of B-cell 
death. An additional factor that contributes to the increased ADCC induction by GA 101 is 
the higher binding affinity of the antibody to FcyRIIIa receptor achieved via Fc 
glycoengineering. In vitro studies showed that if compared with Rituximab, GA 101 exhibited 
10- to 25-fold greater potency and was 1.5- to 2.5-fold more effective in terms of absolute B-
cell depletion. In addition, GA 101 demonstrated in vivo efficacy superior to rituximab in 
various human lymphoma xenograft models. Of particular interest are the results in second 
line therapy setting using human SUDHL-4 DLBCL model subcutaneously injected in mice. 
All animals were pre-treated with rituximab at the dose of 30 mg/Kg, when the tumors 
regrowth animals were randomized to three treatment: rituximab (30 mg/Kg), GA 101 (30 
mg/Kg) or vehicle. Tumors continued to grow rapidly in rituximab and vehicle treated group 
whereas the treatment with GA 101 was able to control tumor growth 21. 
Characteristics of this humanized glycol-engineered antibody: 
• High-affinity binding to CD20 
• Type II binding to the CD20 epitope, leading to low complement-dependent 
cytotoxicity (CDC) activity related to the recognition of the CD20 epitope and the lack 
of CD20 localization into lipid rafts after binding of the monoclonal antibody to CD20 
• Compared 
with 
the 
chimeric 
Type 
I 
anti-CD20 
antibody 
rituximab, 
increased antibody-dependent cellular cytotoxicity (ADCC) related to an improved 
binding of GA101 to the different allotypes of FcRIIIa expressed by natural killer 
cells and monocytes 
• Compared with rituximab, increased direct cell-death induction related to an elbow 
hinge amino acid exchange of the Fab region and Type II binding of the CD20 
epitope 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 10 of 60 
Given the significantly greater ADCC and direct cell-death induction, it is possible that 
GA101 may have greater efficacy than rituximab, particularly in the 80%−85% of patients 
who are carriers of  the FcRIIIa low-affinity receptor polymorphism. 
 
1.3.1 Pre-clinical efficacy with GA101 
GA101 has demonstrated in vivo efficacy superior to that of rituximab in various human 
lymphoma xenograft models.  Both antibodies have been compared in human SUDHL-4 
cells (a DLBCL model) that were subcutaneously injected into severely immunodeficient 
beige mice.  Therapy began when tumors were established and were rapidly growing. It was 
shown that, at 10 mg/kg, rituximab inhibited tumor growth more than rituximab at 1 mg/kg; 
however, increasing the dose to 30 mg/kg did not result in increased efficacy of rituximab.In 
contrast, GA101 showed a dose-dependent increase in efficacy in the range of 1−30 mg/kg 
and resulted in complete tumor regression in all animals and in lasting tumor eradication in 
9 of 10 animals at the highest dose of 30 mg/kg and in 1 of 10 animals  at a dose of 10 
mg/kg. 
Additional studies have also shown similar results, in which GA101 treatment was able to 
control tumor growth when vehicle- and rituximab-treated tumors were not controlled 22.   
 
1.3.2 Clinical experience with GA101 
For more detailed clinical information on GA101, please refer to the current version of the 
Investigator’s Brochure.   
As of June 2013, clinical data on GA101 regarding efficacy and safety are available from 
four Phase I/II studies (BO20999, BO21003, BO21000, and JO21900) and two Phase III 
studies (GAO4753g and BO21004/CLL-11). As of 2 July 2013, an estimated 503 CLL 
patients and 1476 NHL patients from the 12 studies have been exposed to obinutuzumab, 
either as monotherapy or in combination therapy. 
 Phase II results from the aggressive and indolent NHL cohorts of patients in ongoing 
studies are described below.  For information about chronic lymphocytic leukemia (CLL) and 
all Phase I studies, please refer to the GA101 Investigator’s Brochure.   
 
Study BO20999 (Phase I/II):  GA101 Monotherapy 
The results from the Phase II part of the study are presented as follows. 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 11 of 60 
Patients with Indolent NHL.  Forty patients with relapsed or refractory indolent NHL were 
randomized to receive GA101 in a low-dose (LD) cohort (n = 18) or a high-dose (HD) cohort 
(n = 22).  Patients were pre-treated with a median of four prior regimens (range:  1–13), and 
the majority (39 of 40 patients) had received prior rituximab treatment.  More than half of 
these patients (24 of 40) were considered to be rituximab refractory, and 25% (10 of 40) of 
all patients had previously received an autologous stem-cell transplant.  The treatment 
regimen in the LD cohort was 400 mg for Cycles 1–8 (21-day cycles), with an additional 
400-mg dose on Day 8 of Cycle 1.  The treatment regimen in the HD cohort was 1600 mg 
on Days 1 and 8 of Cycle 1 and 800 mg for Cycles 2–8 (21-day cycles).  The end-of-
treatment response rate (response evaluation 4 weeks after the end of treatment) was 17% 
in the LD cohort (3 patients with partial response [PR], 6 with stable disease [SD], 7 with 
progressive disease [PD], and 2 unevaluable) and 55% in the HD cohort (2 patients with 
CR, 10 with PR, 6 with SD, and 4 with PD). 
GA101 
was 
well 
tolerated 
in 
both 
cohorts. 
 
During 
the 
treatment 
period, 
9 patients experienced a total of 12 serious adverse events, with four events (herpes zoster, 
neutropenia, febrile neutropenia, and pancreatitis; all in the HD cohort) assessed by the 
investigator as related to GA101.  During the additional follow-up period, 2 patients 
experienced serious adverse events of pyrexia (LD cohort) and bacteremia (HD cohort).  
The most common adverse events (all grades), occurring with an incidence of  10%, were 
infusion-related reaction (IRR; 73%), asthenia (33%), nasopharyngitis (13%), peripheral 
edema (10%), pyrexia (10%), abdominal pain (10%), bronchitis (10%), and nausea (10%).  
Thirty-three percent of patients had Grade 3 or 4 adverse events, the three most common 
being lymphopenia (8%), neutropenia (8%), and infections (10%).   
 
Patients with Aggressive NHL.  Forty patients with aggressive NHL were enrolled in the 
Phase II part of the study.  Of these patients with aggressive NHL (25 with DLBCL and 15 
with mantle-cell lymphoma [MCL]), 19 were treated in the HD cohort (15 with DLBCL and 4 
with MCL) and 21 in the LD cohort (10 with DLBCL and 11 with MCL).  Preliminary safety 
and efficacy data are available (data on file).  The primary endpoint was end-of-treatment 
response, assessed 4 weeks after the last infusion (25 weeks after treatment start).  
Patients were heavily pre-treated (median of three prior therapies), with 63% of patients 
having not responded to or relapsed within 6 months after a previous rituximab-containing 
regimen (rituximab refractory), and 45% of patients completed all nine infusions.  The end-
of-treatment response rate was 24% (DLBCL:  2 patients with PR, 1 with CR unconfirmed; 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 12 of 60 
MCL:  2 with CR) in the LD cohort and 32% (DLBCL:  4 with PR; MCL:  2 with PR) in the HD 
cohort.  
The five most common adverse events were IRR (75%), infection (25%), asthenia (18%), 
anemia (15%), and lymphopenia (15%).  Fifty percent of patients had Grade 3 or 4 adverse 
events, with the five most common being lymphopenia (15%), anemia (10%), 
thrombocytopenia (8%), IRR (8%), and tumor lysis syndrome (5%).  Serious adverse events 
occurring in 2 or more patients included cardiac failure (n = 2), IRR (n = 3), tumor lysis 
syndrome (n = 2), and anemia (n = 2).  There was one Grade 5 adverse event, 
cardiorespiratory arrest, which was thought to be secondary to ventricular arrhythmia.   
 
Study BO21003 (Phase II):  GA101 Monotherapy plus Maintenance 
This is an ongoing, open-label, multicenter, randomized, Phase I/II study to investigate the 
efficacy and safety of GA101 monotherapy compared with rituximab monotherapy in 
patients with relapsed indolent NHL.  The Phase II portion of the study began in July 2009, 
and approximately 176 patients have been enrolled.  An interim analysis for safety and a 
futility analysis for efficacy was performed in July 2010 using data from 78 patients.  
According to the protocol, futility stopping rules recommended a halt to the trial if the 
rituximab arm had 2 or more patients with a response at the end of treatment than the 
GA101 arm (Δ  −3.14%).  The internal monitoring committee’s recommendation was to 
continue the study as planned.  No new safety issues were identified. 
 
Study BO21000 (Phase Ib):  GA101 in Combination with Chemotherapy 
Study BO21000 is an ongoing trial, investigating two doses of GA101 (400 mg and 1600/800 
mg) in combination with chemotherapy given every 4 weeks for a maximum of six cycles 
(GA101 plus fludarabine and cyclophosphamide [G-FC]), or a maximum of eight cycles 
(GA101 plus CHOP [G-CHOP]) in patients with relapsed follicular lymphoma.  In the 
1600/800-mg G-CHOP arm, patients receive a cumulative dose of 7200–8000 mg, depending 
on the standard number of cycles delivered.  In addition, the protocol has recently been 
amended to include GA101 at a flat dose of 1000 mg plus bendamustine (G-bendamustine) or 
CHOP (G-CHOP) in previously untreated patients with follicular lymphoma.  Patients with a 
PR or CR who complete a minimum of four cycles of G-FC, six cycles of G-CHOP, or four 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 13 of 60 
cycles of G-bendamustine have the option of receiving maintenance therapy with GA101 
alone every 3 months for up to 2 years. 
Fifty-six patients with relapsed or refractory follicular lymphoma have been enrolled in the 
study to receive either 6 or 8 cycles of G-CHOP every 21 days (n = 28) or 4 or 6 cycles of 
G-FC every 28 days (n = 28), with an additional GA101 dose administered to patients on 
Day 8 of Cycle 1.  All 28 patients treated with G-CHOP have completed induction treatment, 
whereas 6 of the 28 patients who started G-FC withdrew early from induction treatment.  
Reasons for discontinuation of study treatment for the 6 patients who withdrew from the G-
FC arm were PD for 1 patient and adverse events in 5 patients:  neutropenia (3 patients), 
and rash and infection (1 patient each). 
Overall, between the LD and HD arms, the rate of adverse events by system organ class 
did not differ greatly, and given the small numbers of patients, definitive conclusions cannot 
be drawn about differences between GA101 adverse events rates in these arms.  All 56 
patients experienced at least one adverse event.  The most commonly reported events were 
classified under the system organ class “general disorders and administration-site 
conditions,” with the highest rate for IRR events regardless of the chemotherapy backbone 
and dose level group considered. 
The percentage of patients with IRRs was 68% in the G-CHOP arm and 82% in the G-FC 
arm, with 7% of events being Grade 3 or 4 events in both chemotherapy arms.  Events in 
the gastrointestinal disorders system organ class were the second most common reported 
adverse events and were reported in 86% and 71% of patients in the G-CHOP and G-FC 
arms, respectively.  Infections and infestations events were experienced by 79% (93% HD; 
64% LD) of patients in the G-CHOP arm and 57% (57% HD; 57% LD) of patients in the G-
FC arm.  Grade 3 and 4 infections and infestations events were reported in 21% of patients 
in the G-CHOP arm and 29% of patients in the G-FC arm. 
Blood and lymphatic system events, with neutropenia being the most common event, were 
observed for 57% and 64% of the patients in the G-CHOP and G-FC arms, respectively.  Of 
these events, 46% and 61% were considered Grade 3 or 4 events. 
Neutropenic 
events 
(i.e., 
neutropenia, 
febrile 
neutropenia, 
neutropenic 
sepsis, 
and neutropenic infections) were reported in 14 patients (50%) and 17 patients (61%) in the 
G-CHOP and G-FC arms, respectively. 
Serious adverse events were reported in 8 (29%) and 7 (25%) patients receiving G-CHOP 
and G-FC induction, respectively.  Infections were the most commonly reported events. 
No deaths have been reported during the induction treatment period. 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 14 of 60 
Study GAO4753g (Phase III):  GA101 in Combination with Chemotherapy 
This is an open-label, multicenter, randomized, Phase III study to investigate the efficacy 
and safety of bendamustine compared with G-bendamustine in patients with rituximab-
refractory indolent NHL.   
Between April 15, 2010, and Sept 1, 2014, when the study was stopped after a pre-planned 
interim analysis, 396 patients were randomly assigned (194 to obinutuzumab plus 
bendamustine and 202 to bendamustine monotherapy).  
After a median follow-up time of 21·9 months (IQR 12·1–31·0) in the obinutuzumab plus 
bendamustine group and 20·3 months (9·5–29·7) in the bendamustine monotherapy group, 
progression-free survival was significantly longer with obinutuzumab plus bendamustine 
(median not reached [95% CI 22·5 months–not estimable]) than with bendamustine 
monotherapy (14·9 months [12·8–16·6]; hazard ratio 0·55 [95% CI 0·40–0·74]; p=0·0001). 
Grade 3–5 adverse events occurred in 132 (68%) of 194 patients in the obinutuzumab plus 
bendamustine group and in 123 (62%) of 198 patients in the bendamustine monotherapy 
group. The most frequent grade 3 or worse adverse events were neutropenia (64 [33%] in 
the obinutuzumab plus bendamustine group vs 52 [26%] in the bendamustine monotherapy 
group), thrombocytopenia (21 [11%] vs 32 [16%]), anaemia (15 [8%] vs 20 [10%]) and 
infusion-related reactions (21 [11%] vs 11 [6%]). Serious adverse events occurred in 74 
patients (38%) in the obinutuzumab plus bendamustine group and in 65 patients (33%) in 
the bendamustine monotherapy group, and deaths due to adverse events occurred in 12 
patients (6%) and 12 patients (6%), respectively. Three (25%) of 12 adverse event-related 
deaths in the obinutuzumab plus bendamustine group and five (42%) of 12 in the 
bendamustine monotherapy group were treatment related.  
The results of this study showed that patients receiving obinutuzumab plus bendamustine 
had a significant improvement in independent review committee-assessed  progression-free 
survival compared with bendamustine monotherapy, and the median progression-free 
survival for obinutuzumab plus bendamustine has not yet been reached. Other efficacy 
parameters, such as time to new anti-lymphoma treatment and duration of response, also 
showed a benefi t for combination therapy compared with bendamustine monotherapy 23.  
 
1.3.3 Pharmacokinetic and pharmacodynamic results for GA101 
A population pharmacokinetic (PK) model has been developed for Studies BO20999 and 
BO21003 to characterize the pharmacokinetics of GA101 and its variability.  A 
two-compartment model, comprising both a linear clearance pathway and a non-linear time-
varying clearance pathway, was fitted to the data.  Data are available for 134 patients 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 15 of 60 
following intravenous (IV) administration of GA101 in Studies BO20999 (114 patients) and 
BO21003 (20 patients). Following infusion of GA101, the elimination appears to be 
characterized by clearance that is dependent on time, i.e., starting at a typical value of 
594 mL/day and then gradually declining to an asymptote of 112 mL/day at steady state.  
Tumor burden potentially contributes significantly to the clearance of GA101, especially at 
the beginning of treatment when there is an excess of CD20-expressing cells.  As tumor 
burden decreases, clearance reaches an asymptote, which was thought to be primarily a 
function of the proteolytic metabolic clearance.  Consequently, some patients with a high 
tumor burden appear to clear the drug from the plasma faster than patients with a low tumor 
burden as GA101 binds to the CD20-positive tumor cells and is effectively removed from the 
plasma.  Therefore, the clearance of the drug will vary with time since repeated treatment 
with GA101 is expected to reduce the number of CD20-positive tumor cells. Treatment with 
GA101 resulted in extensive B-cell depletion, with all patients showing a reduction in cell 
count to absolute zero and most reductions occurring after the first infusion.  Overall, no 
notable increase has been observed in complement levels pre- and post-infusion, but 
changes have been observed in the levels of interleukin-6 and interleukin-8 before and after 
infusion. 
 
2 
RATIONALE OF THE STUDY 
The probability to achieve CR with R-chemotherapy in patients failing a rituximab containing 
first line regimen is quite low.  Addition of a new monoclonal antibody to the same 
chemotherapy should consist in an increase of response and should circumvent acquired 
resistence to rituximab. 
 
3 
OBJECTIVES OF THE STUDY 
3.1 General objectives  
Aim of this trial is to assess the efficacy and safety of new anti-CD20 antibody (GA101) in 
association with DHAP as induction therapy before high dose chemotherapy BEAM with 
ASCT in patients with relapsed/refractory DLBCL.  
Primary objective is to assess whether the treatment achieves an absolute increase of the 
CR proportion of at least 20% (from 30% to 50%) with respect to the standard treatment 
with an acceptable extra-hematological toxicity grade 3-4 of 0.25 (unacceptable extra-
hematological toxicity=0.40).   

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 16 of 60 
Secondary objectives were: 
• Overall Response Rate (ORR) prior to consolidation with BEAM and ASCT  
• Progression free survival (PFS) at 6 month after the end of treatment (EOT); 
• Overall Survival (OS) at 2 years after the EOT; 
• Feasibility and overall toxicity  
• The hematopoietic cell mobilization  
• The rate of patients actually proceeding to ASCT. 
 
3.2  End-points  
3.2.1 Primary endpoints  
The complete response rate (CR) evaluated by PET scan after four cycles of GA101-DHAP 
before ASCT according to Cheson criteria 12. Historical data with which we will compare the 
results of our study were obtained in the same study population but with different response 
evaluation criteria (Cheson criteria 1999)13.  
Severe, life-threatening, fatal (grade 3, 4 and 5) extra-hematological  toxicity till one month 
after the last obinutuzumab administration (cycle 4) according to “Common Terminology 
Criteria for Adverse Events” (CTCAE), version 4.0 are defined for primary toxicity 
evaluation. 
 
3.2.2 Secondary endpoints  
• Overall response rate (ORR): a patient is defined as a responder if she/he has a 
complete or partial response, evaluated by PET/TC, after four cycles of GA101-
DHAP  
• Progression free survival (PFS): measured from the date of starting salvage therapy 
to the date of disease progression, relapse or death from any cause. Responding 
patients and patients who are lost to follow up will be surveyed at their last 
assessment date. 
• OS: measured from the date of starting salvage therapy to the date of death from any 
cause. Patients alive at the time of the final analysis will be surveyed at the date of 
the last contact. For both PFS and OS minimum follow up time required for all 
patients will be 2 years. 
• Overall Toxicity: severe, life-threatening, fatal (grade 3, 4 and 5) and/or serious 
adverse events are defined according to “Common Terminology Criteria for Adverse 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 17 of 60 
Events” (CTCAE), version 4.0. and adverse events of special interests (AESI), 
evaluated up to 6 months from the end of autologous transplantation. 
• Mobilizing potential: amount of CD34 + stem cell collected /Kg  
• Proportion of patients successfully completing ASCT 
 
4 
PATIENT SELECTION CRITERIA 
Patients with DLBCL who failed or relapsed after one previous chemotherapy regimen 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: 
 
4.1  Inclusion criteria  
1. 
18≥ Age < 65  
2. 
Relapsed/refractory disease after receiving one line of standard R-CHOP like 
chemotherapy 
3. 
Diffuse Large B-cell Lymphoma at relapse. The re-biopsie is particularly 
recommended if relapse is over 1 year from previous complete remission. If this is 
harmful for the patient, the patient can be enrolled if archivial tumor sample and block 
from first diagnosis are available. 
4. 
Measurable and/or evaluable disease 
5. 
Any Ann Arbor stage and IPI group at relapse  
6. 
Performance status < 2 according to ECOG scale unless due to lymphoma 
7. 
No Central Nervous System (CNS) disease (meningeal and/or brain involvement by 
lymphoma) 
8. 
Adequate haematological counts: ANC > 1.5 x 109/L, Hgb > 10.5 g/dl (transfusion 
independent), Platelet count > 75 x 109/L (transfusion independent), with the 
exception of cytopenia due to lymphoma bone marrow involvement 
9. 
Normal liver function (ALP, AST, ALT, GGT, conjugated bilirubin total < 2 x ULN) if 
not related to lymphoma 
10. 
Normal kidney function (creatinine clearance > 80 ml/min) 
11. 
Cardiac ejection fraction > 50% (MUGA scan or echocardiography) 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 18 of 60 
12. 
Normal lung function  
13. 
Absence of active infections 
14. 
Non peripheral neuropathy or active neurological non neoplastic disease of CNS 
15. 
Non major surgical intervention prior 3 months to randomization if not due to 
lymphoma and/or not other disease life-threatening that can compromise 
chemotherapy treatment 
16. 
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 
17. 
Life expectancy > 6 months 
18. 
No psychiatric illness that precludes understanding concepts of the trial or signing 
informed consent 
19. 
Written informed consent 
20. 
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 18 months after terminating treatment.  
21. 
Women of childbearing potential must have a negative serum or urine beta-human 
chorionic gonadotropin (beta-hCG) pregnancy test at screening  
22. 
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 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 19 of 60 
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.  
 
4.2  Exclusion criteria  
1. 
Diagnosis of Lymphoblastic Lymphoma, Burkitt Lymphoma, Non Hodgkin Lymphoma 
CD20 negative, Mantle Cell Lymphoma, Follicular Lymphoma, Primary Mediastinal 
Lymphoma 
2. 
Age ≥ 65 years 
3. 
Patients ineligible to high-dose chemotherapy 
4. 
Performance status > 2 according to ECOG scale if not due to lymphoma 
5. 
Patients who previously received GA101 (obinutuzumab) are excluded. 
6. 
Patient has known or suspected hypersensitivity or intolerance to Rituximab 
7. 
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. 
8. 
CNS disease (meningeal and/or brain involvement by lymphoma)  
9. 
History of clinically relevant liver or renal insufficiency; significant cardiac, vascular, 
pulmonary, gastrointestinal, endocrine, neurologic, rheumatologic, hematologic, 
psychiatric, or metabolic disturbances 
10. 
Positive test results for chronic hepatitis B infection (defined as positive HBsAg 
serology). Patients with occult or prior hepatitis B infection (defined as positive total 
hepatitis B core antibody and negative HBsAg) may be included if HBV DNA is 
undetectable.  These patients must be willing to undergo monthly DNA testing. 
11. 
Positive test results for hepatitis C (HCV antibody serology testing). Patients positive 
for HCV antibody are eligible only if PCR is negative for HCV RNA. 
12. 
Known history of HIV seropositive status. For patients with unknown HIV status, HIV 
testing will be performed at screening if required by local regulations. 
13. 
Uncontrolled diabetes (if receiving antidiabetic agents, subjects must be on a stable 
dose for at least 3 months before first dose of study drug 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 20 of 60 
14. 
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 
15. 
Cardiac ejection fraction < 45% (MUGA scan or echocardiography) 
16. 
Creatinine clearance < 45 ml/min 
17. 
Presence of major neurological disorders 
18. 
Active  infection  
19. 
Major surgical intervention prior 3 months to randomization if not due to lymphoma 
and/or other disease life-threatening that can compromise chemotherapy treatment 
20. 
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 
21. 
Life expectancy < 6 months 
22. 
Any other coexisting medical or psychological condition that would preclude 
participation in the study or compromise ability to give informed consent. 
23. 
If female, the patient is pregnant or breast-feeding.  
 
5 
STUDY DESIGN    
This is a prospective, multicenter, single arm, phase II trial 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 assess whether the addition of GA101 to DHAP is more promising 
than standard R-DHAP, as induction therapy before high dose chemotherapy BEAM with 
ASCT with respect to response and safety.   
After providing written informed consent, patients will be evaluated for eligibility during a 21-
day screening period. If they continue to meet eligibility criteria they will receive the first 
dose of GA101-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 proportion 
of complete response will be the principal measure of efficacy. Study discontinuation 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 21 of 60 
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 proportion of non-hematologic 
toxicity (of grade 3 or greater) and of the patients not mobilizing enough peripheral stem 
cells for ASCT  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.    
Duration of treatment will be 4 months (one cycle per-month) plus 30 days for response 
evaluation.  
During the study, disease status will be evaluated after the 4th cycle by imaging test 
(18FDG-PET and CT scan), and a CT after 2nd cycle.  
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 before high dose 
chemotherapy). 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. 
 
5.1  Rationale for the Study Design 
The study is designed primarily to evaluate the efficacy and safety of GA101-DHAP in 
patients with DLBCL who have relapsed or are refractory to one chemotherapy regimen and 
secondarily to assess safety and capability to mobilize peripheral stem cells. The study is 
designed with two stages and with stopping rules after the first stage. In particular, at the 
end of the first stage, the study will be stopped if the efficacy is too low or if the toxicity, 
measured during the drug administration period, is too high with respect to pre-defined 
thresholds. 
 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 22 of 60 
6 
 STATISTICAL CONSIDERATIONS  
6.1  Statistical design 
This is a prospective, multicenter, single arm, two stage phase II trial designed to assess 
whether the addition of GA101to DHAP will show a favorable efficacy and safety profile in 
comparison with standard R-DHAP as induction therapy before high dose chemotherapy 
BEAM with ASCT in terms number of CR. Historical data with which we will compare the 
results of our study were obtained in the same study population but with different response 
evaluation criteria 13. 
 
6.1.1 Sample size, study duration and stopping rules 
The principal aim of the study is to test whether the efficacy of the experimental induction 
therapy is better than standard ones in determining a CR and warrants further investigation. 
According to the Briant and Day24 two-stage design for a phase II clinical trial, with an alpha 
error=0.05, a beta error=0.15, an unacceptable response proportion of 0.30 and an 
acceptable response of 0.50 and with an alpha error=0.10 an acceptable toxicity of 0.25 and 
an unacceptable extra-hematological toxicity grade 3-4 of 0.40, the sample size of the first 
stage is 29. At the end of the first stage the study will be stopped if the number of patients 
with a CR is <10/29 or the number of patients who do not experience toxicity is less than 
19/29. With 10 or more CR out of the first 29 patients and with 19 or more patients that do 
not experience extra-hematological toxicity grade 3-4 the study will proceed to the second 
stage until a total sample size of 78 patients is reached. For toxicity evaluation all types of 
extra-hematological toxicity grade 3-4 emerging till one month after the last obinutuzumab 
administration (cycle 4) will be considered. At the end of the study, the experimental 
induction therapy will not be considered worthy for further investigation if the total number of 
CR is less than 31 or the total number of patients who do not experience extra-
hematological toxicity grade 3-4 is less than 52.  
Safety analyses for extra-hematological toxicity grade 3-4 will be also performed at the end 
of each patient’s treatment in order to better evaluate the safety profile. 
The overall hematological and extra-hematological toxicities will be also described and 
evaluated up to 6 months from the end of autologous transplantation, but they are not part 
of the definition of stopping rules.  
The expected study duration is 88 months (52 for enrollment and 36 for the follow-up). The 
accrual of 78 patients is expected to be reached in 52 months allowing for a period of 
temporary study closure at the end of the enrollment of the 29 patients of the first stage). 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 23 of 60 
 
6.1.2 Statistical analysis 
The main efficacy and safety statistical analyses will be based on all enrolled patients (the 
intention-to-treat – ITT- population). A detailed safety analyses will be based on all patients 
receiving at least one dose of the experimental treatment. 
All dichotomous endpoints (response, toxicity, ASCT feasibility) will be estimated using 
proportions and corresponding 95% confidence intervals. 
ASCT feasibility will be evaluated as the proportion of patients successfully completing 
ASCT. 
Survival probabilities for time to event endpoints (PFS, OS), will be estimated with the 
Kaplan Meier method. 
Exploratory analyses on the prognostic role of biological markers on response and on 
PFS/OS will be performed using the logistic and the Cox proportional Hazard models, 
respectively. According to response and toxicity all biological markers will be measured at 
the end of induction treatment (GA101-DHAP) from +30 to +45 days, according to PFS/OS 
they will be measured after ASCT completion from +60 to + 90 days.  
 
7 
 PATHOLOGICAL REVIEW  
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 first diagnosis, if re-biopsy at relapse is not available; 
- at relapse if available. 
A re-biopsy at relapse is not mandatory at study entry, but recommended for patients 
relapsed at a certain distance from the initial therapy (> 1 year). 
Re-biopsy at relapse is mandatory at study entry for all patients with superficial adenopathy.  
The central revision will be perfomed by a panel of pathologists 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 algorithms25,26. 
Immunohistochemistry panel: CD5, CD20, CD10, BCL6, IRF4, CD30, BCL2, MYC, Ki-67   
 
 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 24 of 60 
8 
 STUDY TREATMENT  
Patients receive: 
• GA101-DHAP x 2, restaging, mobilization and harvest of peripheral stem cell + 
GA101-DHAP x 2, restaging with PET evaluation and consolidation with 
BEAM/FEAM and ASCT in responsive patients (CR + PR)  
 
8.1 Rationale for GA101 Dose 
PK analyses of the GA101 Phase I studies, together with published data on rituximab 
(Daydé et al. 2009), demonstrate that patients with higher disease burden have a faster 
antibody clearance.  Although dosing according to target volume is difficult, these data 
suggest that patients with high tumor burden may require higher doses to saturate the 
target.  This finding was further substantiated by modeling and simulation experiments, 
which showed a higher degree of clearance variability observed at lower GA101 doses.  
To further understand a potential dose effect, in the Phase II part of Study BO20999, 
patients were randomized to two different GA101 dose cohorts.  In the LD cohort, patients 
received 8 cycles of 400 mg of GA101, with an additional 400-mg dose given on Day 8 of 
the first cycle.  In the HD cohort, GA101 was given at 1600 mg on Days 1 and 8 of the first 
cycle, followed by 800 mg at Cycles 2–8.  Cumulative doses were 3600 mg and 8800 mg in 
the LD and HD cohorts, respectively.  In comparison, a typical dose for the reference 
antibody rituximab is approximately 5000–6000 mg (8  375 mg/m2), which would be in 
between the low and high doses tested for GA101.  PK simulations show that the 95% 
confidence limits for exposure are between the low and high doses and are not overlapping.  
No dose-limiting toxicities were observed across the two doses and, although there was a 
slight increase of IRRs and neutropenia rates in the HD cohort, GA101 was generally very 
well tolerated.  As expected, PK variability was lower at the higher dose.  Importantly, 
increased overall response rate have been observed in the HD cohort compared with those 
in the LD cohort (55% vs. 13%, respectively) in the subset of patients with indolent 
lymphoma.  Findings in the aggressive lymphoma cohort did not show a marked difference 
in response rates between patients receiving the high and low doses (32% and 24%, 
respectively), yet this cohort was further subdivided by the inclusion of patients with 
relapsed DLBCL and relapsed MCL and small numbers (25 patients with DLBCL and 
15 patients with MCL) might have prevented a more compelling result. 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 25 of 60 
In summary, it was concluded that a higher dose—1000 mg—of GA101 can be delivered 
intravenously and that the available evidence from nonclinical studies, PK studies, modeling 
and simulation, and clinical trials (Phase I and Phase II) in patients with NHL are suggestive 
of a higher dose being more appropriate to saturate the target in the majority of patients with 
NHL irrespective of their tumor load and, thus, more efficacious than a lower dose. 
 
8.2 Scheme GA101-DHAP  
GA101-DHAP scheme could be performed as in-patient or out-patient due to different 
organizational needs. No differences are reported in literature in term of efficacy of 
the two schemes 27,28  
In-patient version 
• GA101 1000 mg iv day 1, 8, 15 on first cycle (starting from cycle 2, GA101 1000 mg 
day 1) 
• Cisplatin 100 mg/sqm iv day 1 of every cycles in 24-hours infusion 
• Cytarabine 2000 mg/sqm in 3-hours infusion every 12 hours iv day 2 of every cycles 
• Dexametasone 40 mg day 1-4 of every cycles 
• Pegfilgrastim 6 mg sc single dose 24 hours after the end of chemotherapy or G-CSF 
from day 4 till stem cell harvest during mobilization’s course (II o III cycle GA101-
DHAP) 
• GA101 1000 mg iv 24 hours before apheresis as purging in vivo during second 
courses of therapy 
 
Out-patient version 
• GA101 1000 mg iv day 1, 8, 15 on first cycle (starting form cycle 2, GA101 1000 
mg day 1) 
• Cisplatin 100 mg/sqm iv day 1 of every cycles in 3-hours infusion 
• Cytarabine 2000 mg/sqm in 3-hours infusion iv day 2 and day 3 of every cycles 
• Dexametasone 40 mg day 1-4 of every cycles 
• 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 or III cycle 
GA101-DHAP) 
• GA101 1000 mg iv 24 hours before apheresis as purging in vivo during second 
courses of therapy 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 26 of 60 
 
8.2.1 GA101 
a) Formulation  
GA101 is provided as a single-dose, sterile liquid formulation in a 50-mL  pharmaceutical 
grade glass vial containing a nominal 1000 mg of GA101 (G3 material).  The formulated drug 
product consists of 25 mg/mL drug substance (G3) formulated in histidine, trehalose, and 
poloxamer 188.  The vial contains 41 mL (with 2.5% overfill). For further details, see the 
GA101 Investigator’s Brochure. 
b) Handling and Storage 
The recommended storage conditions for the GA101 drug product are between 2C and 8C 
protected from light.  Chemical and physical in-use stability for GA101 dilutions in 0.9% sodium 
chloride (NaCl) have been demonstrated for 24 hours at 2C–8C and at ambient temperature 
and ambient room lighting.  The prepared diluted product should be used immediately.  If not 
used immediately, in-use storage times and conditions prior to use are the responsibility of the 
user and would normally not be longer than 24 hours at 2C–8C.  GA101 should not be frozen 
or shaken.  Mix gently.  All transfer procedures require strict adherence to aseptic techniques.  
Do not use an additional in-line filter because of potential adsorption. For further details, see 
the GA101 Investigator’s Brochure. 
c) GA101 Dose and Schedule 
GA101 will be administered by IV infusion as an absolute (flat) dose of 1000 mg on Day 1 of 
each 28-day cycle for 4 cycles.  GA101 will be administered prior to DHAP, and patients 
should be observed 30 minutes prior to starting DHAP.  If DHAP is not started or completed 
on Day 1 because of the long duration of GA101 therapy, DHAP chemotherapy may be 
administered on Day 2.  During Cycle 1, GA101 will also be infused on Days 8 and 15. 
d) GA101 Preparation 
GA101 drug product intended for IV infusion is prepared by dilution of the drug product into 
an infusion bag containing 0.9% NaCl to the final drug concentration of 4 mg/mL.  Using a 
250-mL infusion bag containing 0.9% NaCl, withdraw and discard 40 mL of the sodium 
chloride.  Withdraw 40 mL of GA101 from a single glass vial and inject into the infusion bag 
(discard any unused portion of GA101 left in the vial).  Gently invert the infusion bag to mix 
the solution; do not shake.  

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 27 of 60 
Administration sets with polyvinyl chloride (PVC), polyurethane (PUR), or polyethylene as 
product contact surface and IV bags with polyolefine, polypropylene (PP), PVC, 
or polyethylene, as product contact surface are compatible and may be used. 
Do not use GA101 beyond the expiration date stamped on the carton. 
e) GA101 Administration 
GA101 should be administered to patients in a clinical setting (inpatient or outpatient), 
where full emergency resuscitation facilities are immediately available and patients should 
be under close supervision of the investigator at all times.  Do not administer as an IV push 
or bolus.  After the end of the first infusion, the IV line or central venous catheter should 
remain in place for  2 hours in order to be able to administer IV drugs if necessary.  If no 
adverse events occur after 2 hours, the IV line may be removed or the central venous 
catheter may be de-accessed.  For subsequent infusions, access (either through an IV line 
or central venous catheter) should remain in place for at least 1 hour from the end of 
infusion, and if no adverse events occur after 1 hour, the IV access may be removed. 
Instructions for the first and subsequent infusions of GA101 are presented in Table 1. 
 
Table 1 
Administration of First and Subsequent Infusions of GA101 
First Infusion (Day 1) 
Subsequent Infusions 
Begin infusion at and initial rate of 50 mg/hr. 
If no infusion reaction occurs, increase the infusion 
rate in 50-mg/hr increments every 30 minutes, to a 
maximum of 400 mg/hr. 
If an infusion reaction develops, stop or slow the 
infusion.  Administer infusion-reaction medications and 
supportive care in accordance with institutional 
protocol.  Resume the infusion at a 50% reduction in 
rate (the rate being used at the time that the 
hypersensitivity or infusion-related reaction occurred) if 
the reaction has resolved. 
If a patient experienced an infusion reaction during 
the prior infusion, start at the same rate as the first 
infusion (50 mg/hr) and follow directions as noted. 
If the patient tolerated the prior infusion well (defined 
as an absence of Grade 2 reactions during a final infusion 
rate of  100 mg/hr), begin the infusion at a rate of 
100 mg/hr. 
If no infusion reaction occurs, increase the infusion 
rate in 100-mg/hr increments every 30 minutes, to a 
maximum of 400 mg/hr. 
If an infusion reaction develops, stop or slow the 
infusion.  Administer infusion-reaction medications 
and supportive care in accordance with institutional 
protocol.  Resume the infusion at a 50% reduction in 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 28 of 60 
rate (the rate being used at the time that the 
hypersensitivity 
or 
infusion-related 
reaction 
occurred) if the reaction has resolved. 
 
GA101 should be given as a slow IV infusion through a dedicated line.  IV infusion pumps 
should be used to control the infusion rate of GA101.  Do not administer as an IV push or 
bolus.   
On days when both GA101 and DHAP are given, GA101 will be administered prior to DHAP 
and patients should be observed 30 minutes prior to starting DHAP.  DHAP chemotherapy 
may be administered the next day if it cannot be given on the same day as GA101 
administration.  Prior to each GA101 infusion that is given in combination with DHAP, 
patients should take the Day 1 the premedication for each cycle of the DHAP regimen (Tab 
1).  
Table 2  
Premedication to be administered before Obinutuzumab infusion to reduce the risk of 
Infusion Related Reactions (recommended for ALL patients). 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 29 of 60 
 
For patients with a high lymphocyte count or bulky lymphadenopathy, the infusion may be 
given extremely slowly over a longer period of time, or the dose may be split and given over 
more than one day.  
If a patient does not experience a IRR (grade 1 or more) during the first infusion, the 
premedication for a subsequent infusions can be omitted. 
For more detailed nonclinical information about GA101, please refer to the current version 
the Investigator’s Brochure. 
 
8.3 Mobilization and apheresis 
Mobilization after II or III cycle (only in case of bone marrow positivity at relapse) of 
GA101-DHAP, with GA101 pre-apheresis; recommended harvest of at least 3x106 cells  
CD34+/kg.  
If at relapse or progression the bone marrow biopsy was positive, after the second 
cycle a new biopsy was necessary to define negativization and to schedule apheresis 
after the third cycle.  

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 30 of 60 
 
8.4 BEAM or FEAM + ASCT  
• BCNU 300 mg/sqm iv day -7 (BCNU can be replaced with Fotemustine 300 mg/sqm)  
• 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 day  + 1   
                  
8.5 Risks Associated with GA101 Therapy 
No evidence available at the time of the release of this protocol indicates that special 
warnings or precautions are appropriate, other than those noted in the GA101 Investigator’s 
Brochure and as described in the following sections. 
 
8.5.1 Infusion-Related 
Reactions 
and 
Hypersensitivity 
Reactions 
(Including Anaphylaxis) 
To date, the commonly experienced IRRs have been characterized by fever, chills, flushing, 
nausea, vomiting, hypotension, hypertension, and fatigue, as well as other symptoms. 
Respiratory infusion-related symptoms, such as hypoxia, dyspnea, bronchospasm, larynx 
and throat irritation, and laryngeal edema, have also been reported.  These IRRs were 
mostly mild or moderate (NCI CTCAE, v3.0, Grade 1 and 2 events), and  10% of the 
events were severe (Grade 3 events), occurring predominantly during the first hour of the 
infusion or shortly after the first infusion had finished; the events resolved with slowing or 
interruption of the infusion and supportive care.  The incidence and severity of IRRs 
decreased with subsequent infusions.  Extensive tumor burden predominantly localized in 
the blood circulation (e.g., high peripheral lymphocyte count in patients with CLL) may be a 
predisposing factor for the development of IRRs. 
IRRs may be clinically indistinguishable from IgE-mediated allergic or anaphylactic 
reactions. 
 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 31 of 60 
8.5.2 Tumor Lysis Syndrome 
Cases of tumor lysis syndrome have been reported with GA101 administration.  To date, no 
patient has required hemodialysis for renal failure.  Patients with a high tumor burden, 
including patients with a lymphocyte count  25  109/L (particularly patients with B-cell CLL 
and MCL), are at increased risk for tumor lysis syndrome and severe IRRs.  
 
8.5.3 Thrombocytopenia and Neutropenia 
Cases of Grade 3 or 4 thrombocytopenia and neutropenia, including febrile neutropenia, 
have been reported with GA101 administration.  Grade 3 or 4 neutropenia has 
predominantly been observed in patients with CLL.  Patients who experience Grade 3 or 4 
neutropenia or thrombocytopenia should be monitored until neutrophil and platelet values 
return to at least Grade 2.  Use of granulocyte colony-stimulating factors (G-CSF) has been 
found to result in a rapid normalization of neutrophils, similar to what has been observed in 
patients treated with rituximab.  The use of G-CSF is allowed for treatment of neutropenia in 
this study.  Primary prophylaxis with G-CSF is recommended according to the American 
Society of Clinical Oncology (ASCO), EORTC, and European Society for Medical Oncology 
(ESMO) guidelines, namely for patients who are  60 years old and/or with co-morbidities 
(Lyman et al. 2004).  The use of G-CSF is strongly recommended in all patients treated with 
G-CHOP. 
 
8.5.4 Infection 
Based on its anticipated mode of action, resulting in profound B-cell depletion, GA101 may 
be associated with an increased risk of infections.  Infections have been reported in patients 
receiving GA101.  Therefore, GA101 should not be administered to patients with active 
severe infections.  
Reactivation of hepatitis B as well as other serious viral infections (e.g., infections caused 
by cytomegalovirus, Varicella zoster virus, herpes simplex virus, John Cunningham virus 
(JCV), and hepatitis C virus) that were new, reactivation, or exacerbation, have been 
reported with the B cell–depleting antibody rituximab mainly in patients who had received 
the drug in combination with chemotherapy or as part of a hematopoietic stem-cell 
transplant.  The risk of such infections with GA101 is unknown.  Particular attention should 
be given to patients who have previously received significant immunosuppressive treatment 
such as high-dose chemotherapy and stem-cell transplant.   

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 32 of 60 
Cases (including fatal) of JCV infection that resulted in progressive multifocal 
leukoencephalopathy (PML, destructive infection of oligodendrocytes of the CNS white 
matter) have been reported in patients treated with anti-CD20 therapies, including  GA101. 
The diagnosis of PML should be considered in any patient presenting with new-onset 
neurologic manifestations.  The symptoms of PML are very unspecific and can vary 
depending on the affected region of the brain.  Motor involvement with corticospinal tract 
findings, sensory involvement, cerebellar deficits, and visual field defects are common.  
Some syndromes regarded as “cortical” (e.g., aphasia or visual-spatial disorientation) can 
occur.  
Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain 
magnetic resonance imaging (MRI), and lumbar puncture to quantify DNA of JCV in the 
cerebrospinal fluid. 
Therapy with GA101 should be withheld during the investigation of potential PML and 
permanently discontinued in case of PML.  Discontinuation or reduction of any concomitant 
chemotherapy or immunosuppressive therapy should also be considered.  The patient 
should be referred to a neurologist for the treatment of PML. 
There may also be potential health risks, including unknown risks derived from exposure to 
GA101.   
 
8.5.5 Dose- adjustment for GA101 
No dose modifications of GA101 (1000 mg) are allowed. 
If administration of chemotherapy is delayed, there will be no dose modification of GA101, 
and the administration of GA101 and all chemotherapy drugs should be delayed for the 
same time frame, e.g., if DHAP therapy is delayed, administration of GA101 should also be 
delayed so that they are given on Day 1 of the same cycles.   
 
8.5.6 Dose delay for GA101 on Cycle 1 Day 8 and Cycle 1 Day 15 
Guidelines for dose delay on Cycle 1 Day 8 and Day 15.  
Event(s) 
Dose Delay or Modification 
Febrile neutropenia or 
neutropenia with infection 
 
Hold GA101 dose until it resolves 
If Cycle 1 Day 8 is delayed long enough that you are approaching Day 15, 
then skip Day 8 and administer Day 15 as previously scheduled (if infection 
or neutropenic fever has resolved) 
If Cycle 1 Day 15 is delayed long enough that you are approaching 
Cycle 2, then skip Day 15 dosing and administer Cycle 2 Day 1 of 
GA101+ DHAP as scheduled (if infection or fever has resolved) 
Note: GA101 should not to be held for asymptomatic neutropenia 
Severe thrombocytopenia 
(platelets < 10,000/µL) 
and/or 
Hold GA101 only in case of severe thrombocytopenia (platelets 
< 10,000/µL) or symptomatic bleeding (irrespective of platelet count) until it 
resolves  

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 33 of 60 
symptomatic bleeding in 
patients who are not 
receiving concomitant 
anticoagulants or platelet 
ihibitors 
 
If Cycle 1 Day 8 is delayed then skip Day 8 and administer Day 15 
as previously scheduled (if symptomatic bleeding has resolved) 
If Cycle 1 Day 15 is delayed then skip Day 15 dosing and administer 
Cycle 2 Day 1 of GA101 + DHAP as scheduled (if symptomatic 
bleeding has resolved) 
Thrombocytopenia with 
platelets < 20,000/µL 
and/or symptomatic 
bleeding in patients who 
are receiving concomitant 
anticoagulants or platelet 
ihibitors a, b 
 
Hold GA101 only in case of platelets < 20,000/µL or (irrespective of platelet 
count) until it resolves.  
If Cycle 1 Day 8 is delayed then skip Day 8 and administer Day 15 
as previously scheduled (if symptomatic bleeding has resolved) 
If Cycle 1 Day 15 is delayed then skip Day 15 dosing and administer 
Cycle 2 Day 1 of GA101 + DHAP as scheduled (if symptomatic 
bleeding has resolved).  
 
For patients who are receiving LMWH, when thrombocytopenia with 
platelets < 20,000/µL develops, reduce the dose of LMWH used b 
 
For patients who are on platelet inhibitors, when thrombocytopenia with 
platelets < 20,000/µL develops, consider temporarily holding their use b 
 
a If the clinical condition of the patient requires the use of concomitant anticoagulants, the patients are at 
increased risk of bleeding when thrombocytopenia with platelets < 20,000/µL develops. When possible, 
replace prior therapy with vitamin K antagonists with LMWH before Cycle 1, Day 1.  
b Clinical decision making may be adjusted depending on the patient-specific assessment of benefit and risk 
 
8.5.7  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. 
 
9 
 WITHDRAWAL  
From GA101 perspective, patients must discontinue study drug if they experience any of the 
following: 
• Pregnancy 
• PML 
• Grade 4 IRR 
Patient should be withdrawn immediately and treatment must be discontinued 
permanently. 
• Grade 3 IRR at re-challenge despite adequate premedication: patient must be 
withdrawn immediately and treatment must be discontinued permanently 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 34 of 60 
• Grade 3 or 4 hematological toxicity that has not resolved to Grade ≤ 2 and requires to 
delay treatment by more that 14 days (Thrombocytopenia needs to resolve to Grade 
≤ 1) 
• Grade ≥ 2 non-hematological toxicity that does not resolve to Grade ≤ 1/baseline and 
requires to delay treatment by more that 14 days  
• Hepatitis B reactivation 
 
9.1 Withdrawal of Consent 
Patients are free to withdraw from the study at any time without prejudice to their treatment. 
When a patient decides to withdraw from the study, she/he should always be contacted in 
order to obtain information about the reason for withdrawal and to record any adverse 
events. When possible, the patient should return for a study visit at the time of, or soon after 
withdrawal, and the relevant assessments should be performed. 
If the patient explicitly states his/her wish not to contribute further data to the study, the 
assigned FIL Study Coordinator should be informed and the withdrawal of consent should 
be documented by the investigator in the patient’s case report form. Data of the patient will 
or won’t be kept in the data base, according to patient’s wish and regulatory requirements. 
 
9.2 Patients Lost to Follow up 
Every effort will be made to contact patients who fail to return for scheduled visits. A patient 
is considered lost to follow-up if no information has been obtained when the last patient has 
completed the clinical phase of the study. During this time site investigator must document 
attempts to contact the patient either by phone or letter. 
 
10 
 CONCOMITANT TREATMENT  
10.1 Recommended concomitant treatments 
During treatment are recommended as concomitant therapy: 
• Pegfilgrastim 6 mg sc, 24 hours after the end of chemotherapy or G-CSF from day 5 
till neutrophil recovery or  till stem cell harvest during mobilization’s course (II or III 
cycle GA101-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  
• In patients with Ab antiHBcAg +, Ab antiHBsAg +/- prophylaxis against hepatitis B 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 35 of 60 
reactivation with Lamivudine 100 mg from one week prior the start of the treatment to 
one year after the end of the treatment 
• Antimicrobial prophylaxis is strongly recommended, if necessary  
• 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 
 
10.2 Permitted concomitant therapy 
The following medications and support therapies that may be used if needed during this 
study: 
• Antiviral prophylaxis with acyclovir 800-1200 mg at day since the beginning of 
therapy is strongly recommended in patients with herpes virus infection reactivation 
• 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 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 GA101 infusion should be considered before each infusion of 
rituximab, because it may reduce infusion reactions, according to Tab 1. 
 
10.3 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. 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 36 of 60 
 
10.4 Females of childbearing potential 
The patient has to use a contraceptive during the course of the treatment and for 30 days 
after completion of therapy. The accepted methods of contraception include: coil (IUD), 
hormonal contraceptives (pill, injection or implant), condoms, diaphragm, tubal ligament, 
vasectomies (in men) or complete abstinence. 
 
10.5 Male subjects 
If the partner of the patient is a woman of childbearing age has to use a contraceptive 
during the course of the treatment and for 30 days after completion of therapy. The 
accepted methods of contraception include: coil (IUD), hormonal contraceptives (pill, 
injection or implant), condoms, diaphragm, tubal ligament, vasectomies (in men) or 
complete abstinence. 
              
11 
CLINICAL EVALUATION, LABORATORY TESTS AND FOLLOW-UP  
11.1 Staging evaluation, baseline 
Baseline assessment must be performed during 30 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 (dosage serum Ig)  
• Serum virology (HBsAg, HBcAb, HCV and HIV serology) 
• Lymph-node or tissue biopsy for histological diagnosis and shipment of paraffin block 
for centrally pathology review and for pathological studies 
• GC/ABC value on diagnostic tissue 
• 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)  
• Other assessment: RMN brain/column, endoscopy, ORL visit, etc. according to 
physician judge and if clinically relevant 
• Pregnancy test (if applicable) 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 37 of 60 
• Written informed consent 
 
11.2 Valuation at each GA101-DHAP corse 
• Blood count and complete workup with biochemistry (dosage serum Ig at the end of 
the cycle 4), physical examination and hematological and extrahaematological 
toxicity evaluation the day before or day 1 of therapy and between two cycles and 
during aplasia phase (recommended at day +8-12-16-20 and/or till granulocytes and 
platelets recovery) 
 
11.3 Intermediate response evaluation 
The evaluation of intermediate response will be assessed after 2 courses of GA101-DHAP. 
• ECOG performance status, physical examination 
• Blood count and complete workup with biochemistry  
• Aspirate and bone marrow biopsy (if positive at baseline), necessary to schedule the 
apheresis 
• CT scan neck, chest, abdomen and pelvis 
• Total body PET scan (recommended, not mandatory) 
 
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 GA101-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.  
 
11.4 Pre-ASCT evaluation - end of treatment 
The evaluation of pre-ASCT response will be assessed after 4 courses of Ga101 
-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) 
Patients in complete remission after four cycles of therapy, will continue the trial and will be 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 38 of 60 
treated with BEAM + ASCT as planned. 
Patients in partial remission after four cycles of therapy, will continue the trial and will be 
treated with BEAM +ASCT at investigator discretion. 
Patients in progression disease or stable disease after the first two cycles of therapy 
stopped treatment and will be considered failure.  
 
11.5 Post –ASCT evaluation  
Final evaluation will be performed two months after the end of BEAM + ASCT. 
• 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) 
Complete response, Partial response or no response will defined according to Cheson 2007 
response criteria.  
 
11.6 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  
Every 6 months during the first two years after chemotherapy (at month 6-12-18-24) will be 
evaluated: 
• CT scan neck, chest, abdomen and pelvis 
 
12 
 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 through the FIL website (http://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. 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 39 of 60 
Frequency of on-site monitoring will be planned according to the results of the statistical 
quality controls. 
 
13 
 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.  
 
13.1 Definitions 
Adverse Event Definitions and Classifications 
 
13.1.1  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. 
 
 
13.1.2  Serious Adverse Event 
A serious adverse event as defined by 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.) 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 40 of 60 
• requires inpatient hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability/incapacity, or is a congenital anomaly/birth 
defect 
• other medically important condition: would be any important medical or clinical event that 
may not be immediately life-threatening or result in a fatality or hospitalization but that may 
jeopardize the patient or require intervention to prevent another outcome e.g 
significant/persistent disability, life-threatening reaction congenital anomaly. Examples of 
such potentially serious events (according to medical judgment) include a suspected 
transmission of infections agent by a medicinal product, allergic bronchospasm, blood 
dyscrasias or convulsion, development of drug dependency or drug abuse, cancer. Whether 
the event should meet one of these requirements, please report into the category “Other 
Medically Important Condition” on the SAE form. 
Note: Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is also appropriate in situations other than those listed above. Any adverse event 
is considered a serious adverse event if it is associated with clinical signs or symptoms 
judged by the investigator to have a significant clinical impact. 
 
Adverse events of special interest (AESI) 
The following types of events are considered to be AESIs due to their observed frequency 
and/or clinical relevance: 
• SAE associated with obinutuzumab infusion (defined as any treatment-related AEs 
occurring during or within 24 hours of an obinutuzumab infusion and related to 
obinutuzumab) 
• Serious infections 
• Serious neutropenia 
• Tumor lysis syndrome (TLS) 
• Progressive multifocal leukoencephalopathy (PML) 
• Hepatitis B reactivation 
 
13.1.3  Unlisted (Unexpected) Adverse Event 
An unlisted adverse event, the nature or severity of which is not consistent with the 
applicable product 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 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 41 of 60 
event will be determined by whether or not it is listed in the summary of product 
characteristics (SmPC). 
 
13.1.4  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. 
 
13.1.5  Product Quality Complaint 
A product quality complaint (PQC) is defined as a complaint specific to the product itself, its 
supporting devices or packaging, as opposed to its effect on the patient. Examples include 
damaged or missing tablets; wrong strength or color of tablets; damaged packaging; a label 
that cannot be read; a liquid that should be clear but is cloudy or contains unexpected 
particles; a bent needle; a broken syringe; a missing patient information leaflet, or the 
identification of a potentially counterfeit medicine. 
 
13.2  Attribution Definitions 
13.2.1  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 3.0 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; 
no 
medical 
intervention/therapy is required. 
• Moderate Discomfort:  
Enough to cause mild to moderate interference with 
normal daily activities, some assistance may be needed, no minimal medical 
intervention/therapy is required. 
• Severe: 
Extreme distress causing significant impairment of functioning or 
incapacitation and inability to perform normal daily activities. Some assistance is 
usually required; medically intervention/therapy is required and hospitalization may 
be required 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 42 of 60 
• Life Threatening: 
Extreme limitation in activity. Risk of death from the reaction as it 
occurred. 
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. 
• Unlikely/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). 
• Definite/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). 
 
13.3  Reporting Procedures 
All Adverse Events 
After informed consent has been obtained but prior to initiation of study drug, only SAEs 
caused by a protocol-mandated intervention should be reported (e.g., SAEs related to 
invasive procedures such as biopsies). 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 43 of 60 
After initiation of study drug, all AEs regardless of relationship to study drug, should be 
reported until the Final Response Assessment. Grade 3 and 4 infections should be reported 
until 24 months after EOT Visit. 
After the end of the study, all SAEs, non-serious AESIs (regardless of causality), late onset 
neutropenia, and secondary malignancies occurring to a patient after the treatment of that 
patient has ended, should be reported to the Sponsor if the investigator becomes aware of 
them. Grade3–5 infections should be reported for up to 2 years after the end of the study 
and all related SAEs indefinitely.  
The investigator is not required to actively monitor patients after the study has ended. 
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 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 44 of 60 
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 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.  
Because the study drug may have an effect on sperm, or if the effect is unknown, 
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 and/or non serious AESIs) 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 and/or PQC) will be transmitted to the 
Sponsor-Investigator using the Serious Adverse Event Form (and/or the Product Quality 
Complaints 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 and/or a PQC), a Serious Adverse 
Event Form (and/or a PQC form) must be completed by the investigational staff and 
transmitted to the Sponsor-Investigator within 1 working day.  
The SAE(s) and/or Pregnancy report(s) and/or PQC must be sent to the Sponsor-
Investigator Pharmacovigilance Contact Person to the following fax number: 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 45 of 60 
 
Sponsor contact: 
Dr. Alessandro Levis 
Address: Segreteria Fondazione Italiana Linfomi ONLUS c/o Ematologia Azienda 
Ospedaliera SS. Antonio e Biagio e Cesare Arrigo via Venezia 16, 15121 Alessandria  
Phone no.: +39-0131-206129 
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 
• 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. 
 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 46 of 60 
Inbound reporting process by the Sponsor-Investigator to Roche 
The Sponsor-Investigator is responsible for checking the completeness of SAE (and/or 
Pregnancy and/or PQC) information, both for the initial report and for follow-up and for 
sending a copy of all SAE (and/or Pregnancy and/or PQC) information to Roche Local 
Safety Officer (LSO) as agreed in the Safety Data Exchange Agreement (SDEA).  
If any clarification regarding SAE/Pregnancy/PQC reported is needed, the Sponsor-
Investigator will receive a query by e-mail from the Roche LSO and he will be then 
responsible for forwarding it to the appropriate site. 
The satellite site will reply to the query and will send it back to the Sponsor-Investigator who 
is then responsible for forwarding the answer to Roche LSO within 24 hours.  
  
Reconciliation 
Reconciliation between Sponsor and Roche LSO of serious adverse event and Pregnancy 
listing will be every three months. The Sponsor-Investigator is then responsible for initiating 
corrective actions if needed. 
 
14 
 ETHICAL CONSIDERATIONS 
14.1  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”). 
 
15 
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 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 47 of 60 
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. 
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.  
 
15.1  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. 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 48 of 60 
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”. 
 
16 
 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.   
 
 
17 
 DATA OWNERSHIP 
According to the ICH Guidelines on Good Clinical Practice the sponsor of a study is the 
owner of the data resulting therefrom. All centers and investigators participating in the study 
should be made aware of such circumstance and invited not to disseminate information or 
data without the Sponsor’s prior express consent. 
  
18 
 PUBLICATION POLICY 
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 are 
specified in the Sponsor’s Procedure. 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 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 49 of 60 
(IECs must verify that no excessive restriction is contained in the protocols submitted to 
their review and approval).  
 
19 
 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.  
 
20 
DURATION OF THE STUDY 
The study duration is estimated 88 months (52 for enrollment and 36 for the follow-up).  
End of study (Last Patient Last Visit [LPLV]) will be upon completion of the follow up period 
for the last patient treated in the study. Completion of follow-up for the last patient will occur 
when the last patient in the study has expired, has been followed for 6 months after their 
last dose of study treatment, has been lost to follow-up, or has withdrawn consent, 
whichever occurs first.  
 
 
 
 
 
 
 
 
 
 
 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 50 of 60 
21 REFERENCES  
1. Groves FD, Linet MS, Travis LB et al. Cancer Surveillance Series: Non-Hodgkin’s 
Lymphoma Incidence by Histologic Subtype in the United States From 1978 Through 
1995. J Natl Cancer Inst 2000; 92 (15): 1240-51. 
2. Effect of age on the characteristics and clinical behavior of non-Hodgkin's Lymphoma 
patients. The Non-Hodgkin's Lymphoma Classification Project. Ann Oncol 1997; 8 
(10): 973-78. 
3. Coiffier B, Thieblemont C, Van Den Neste E, et al. Long-term outcome of patients in 
the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard 
CHOP chemotherapy in DLBCL patients: a study by the Groupe d’Etudes des 
Lymphomes de l’Adulte. Blood 2010; 116 (12): 2040-45. 
4. Pfreundschuh M, Kuhnt E, Trumper L, et al. Randomized Intergroup trial of first line 
treatment for young low risk patients (< 61 years) with diffuse large B cell non 
Hodgkin’s lymphoma with a CHOP like regimen with or without the anti-CD20 
antibody rituximab: a 6-year follow-up of the Mint study of the Mabthera International 
Trial (MInT) Group. Proc Am Soc Hematol 2010; abstr 111.  
5. Pfreundschuh M, Shubert J, Ziepert M, et al. Six versus eight cycles of bi-weekly 
CHOP-14 with or without Rituximab in elderly patients with aggressive CD20+ B-Cell 
Lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol 2008; 9 (2): 
105-16.  
6. Vitolo U, Chiappella A, Angelucci E, et al. Dose-dense and high-dose chemotherapy 
plus rituximab with autologous stem cell transplantation for primary treatment of 
diffuse large B-cell lymphoma with a poor prognosis: a phase II multicenter study. 
Haematologica 2009; 94 (9): 1250-58. 
7. Philip T, Guglielmi C, Hagenbeek A, et al. Autologous bone marrow transplantation 
as compared with salvage chemotherapy in relapses of chemotherapy–sensitive 
nonHodgkin’s lymphoma. N Eng J Med 1005; 333: 1540-45.  
8.  Guglielmi C, Gomez F, Sebban C, et al. Time to relapse has prognostic value in 
patients with aggressive lymphoma enrolled onto the PARMA trial. J Clin Oncol 1998; 
16: 3264-3269.  
9. Costa LJ, Micallef IN, Inwards DJ, et al. Time to relapse after initial therapy 
significantly adds to the prognostic valure of the IPI-R in patients with relapsed 
DLBCL undergoing autologous stem cell transplantation. Bone Marrow Transplant 
2008; 41: 715-720.  
10. Hamlin PA, Zelenetz AD, Kewalramani T, et al. Age-adjusted International Prognostic 
Index predicts autologous stem cell transplantation outcome for patients with 
relapsed or primary refractory diffuse large B cell lymphoma. Blood 2003; 102 (6): 
1989-1996.  
11. Lerner RE, Thomas W, DeFor TE, et al. The International prognostic Index assessed 
at relapse predicts outcomes of autologous transplantation for diffuse large non 
Hodgkin lymphoma in second complete or partial remission. Biol Blood Marrow 
Transplant 2007; 13: 486-492.  
12. Cheson BD, Pfistner B, Juweid ME,  et al.  Revised response criteria for malignant 
lymphoma. J Clin Oncol 2007; 25 (5): 579-86. 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 51 of 60 
13. Cheson BD, Horning SJ, Coiffier B et al.  Report of an international workshop to 
standardize response criteria for non-Hodgkin’s lymphomas. NCI sponsored 
International Working Group.  J. Clin. Oncol. 1999; 17(4): 1244. 
14. Filmont JE, Gisselbrecht C, Cuenca X, et al. The impact of pre and post 
transplantation positron emission tomography using 18-fluorodeoxyglucose on ppor-
prognosis lymphoma patients undergoing autologous stem cell transplantation. 
Cancer 2007; 10 (6): 1361-1369.  
15. Derenzini E, Musuraca G, Fanti S, et al. Pretransplantation positron emission 
tomography scan is the main predictor of autologous stem cell transplantation out 
come in aggressive B-cell non Hodgkin lymphoma. Cancer 2008; 113: 2496-2503.  
16. Terasawa T, Dahaberh IJ, Nihashi T, et al. Fluorine-18-fluorodexyglucose Positron 
Emission Tomography in response assessment before high dose chemoptehrapy for 
lymphoma: a systematic review and metanalysis. Oncologist 2010; 15 (7): 750-759.  
17. Vellenga E, van Putten WLJ, van’t Verr MB, et al. Rituximab improves the treatment 
of DHAP-VIM-DHAP and ASCT in relapsed/progressive aggressive CD20+ NHL: a 
prospective randomized HOVON trial. Blood 2008: 11 (2): 537-543.  
18. Martin A, Conde E, Arnan A, et al. R-ESHAP as salvage therapy for patients with 
relapsed or refractory diffuse large B-cell lymphoma: the influence of prior exposure 
to rituximab on outcome. A GEL/TAMO study. Haematologica 2008; 93 (12): 1829.  
19. Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous 
transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol 
2010; 28 (27): 4184-90.  
20. Wang SY, Racila E, Taylor RP, Weiner GJ. NK-cell activation and antibody-dependet 
cellular cytotoxicity induced by rituximab-coated target cells is inhibited by the C3b 
component of complement. Blood 2008; 111(3): 1456-1463. 
21. Glennie MJ, French RR, Cragg MS, Taylor RP. Mechanisms of killing by anti-CD20 
monoclonal antibodies. Mol Immunol 2007; 44(16): 3823-3837.   
22. Mossner E, Brunker P, Moser S, et al.  Increasing the efficacy of CD20 antibody 
therapy through the engineering of a new type II anti-CD20 antibody with enhanced 
direct and immune effector cell-mediated B-cell cytotoxicity.  Blood 2010; 115(22): 
4393-4402. 
23. Sehn LH, Chua N, Mayer J, Dueck G, Trněný M, Bouabdallah K, Fowler N, Delwail V, 
Press O, Salles G, Gribben J, Lennard A, Lugtenburg PJ, Dimier N, Wassner-Fritsch 
E, Fingerle-Rowson G, Cheson BD. Obinutuzumab plus bendamustine versus 
bendamustine monotherapy in patients with rituximab-refractory indolent non-
Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, 
phase 3 trial. Lancet Oncol. 2016 Aug;17(8):1081-93. 
24. Bryant J, Day R. Incorporating toxicity considerations into the design of two-stage 
phase 2 clinical trials. Biometrics 1995;51:1372-1383. 
25. Hans CP, Weisenburger DD, Greiner TC Confirmation of the molecular classification 
of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray.  
Hans CP, Weisenburger DD, Greiner TC et al.  Blood 2004; 103: 275-282 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 52 of 60 
26. Choi WW, Weisenburger DD, Greiner TC et al.  A new immunostain algorithm 
classifies diffuse large B-cell lymphoma into molecular subtypes with high accuracy.  
Clin. Cancer Res. 2009; 15: 5494-5502. 
27. Olivieri A, Brunori M, Capelli D et al.  Salvage therapy with an outpatient DHAP 
schedule followed by PBSC transplantation in 79 lymphoma patients: an intention to 
mobilize and transplant analysis.  Eur. J. Hematology 2004; 72(1): 10-17 
28. Rigacci L, Fabbri A, Puccini B et al.    Oxaliplatin-based chemotherapy 
(desametazone, high dose cytarabine and oxaliplatin) +/- Rituximab is an effective 
salvage regimen in patients with relapsed r refractory lymphoma. Cancer 2010: 116 
(19); Cancer 2010  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 53 of 60 
22  APPENDIXES  
Appendix 1: Timing of treatment and investigations  
Stage 
Baseline 
GA101 –DHAP Treatment  
ASCT 
Follow-Up 
Period 
  
Cy 1 
Cy 2 
Intermediate 
response 
evaluation 
Cy 3 
Cy 4 
Pre- 
Post- 
Every 3 
months for 
1st, 2nd year 
Every 4-6 
months for   
3rd year 
  
Day 1 
Day 8 
Day  15 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
Review Inclusion/Exclusion 
criteria 
X 
  
  
  
  
  
  
  
  
  
Pregnancy test (if 
applicable) 
X 
  
  
  
  
  
  
  
  
  
Serum virology 
X 
  
  
  
  
  
  
  
  
  
Ecg/Echo/MUGA 
X 
  
  
X 
  
  
  
  
  
  
Anti-tumor activity 
X 
  
  
X 
  
  
  
  
XC  
  
Clinical examination 
X 
  
  
  
  
  
  
  
  
  
Aspirate and bone marrow 
biopsy 
X 
  
  
XA 
  
  
XA 
XA 
  
  
GC/ABC value on 
diagnostic tissue 
X 
  
  
  
  
  
  
  
  
  
PET scan 
X 
  
  
XB 
  
  
X 
X 
  
  
CT of neck,chest, abdomen 
and pelvis  
X 
  
  
X 
  
  
X 
X 
 XC 
  
Adverse events 
  
X 
X 
  
X 
X 
  
  
  
  
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biochemistry 
XD 
X 
X 
X 
X 
XD 
X 
X 
X 
X 
Physical examination, 
complete medical history, 
ECOG performance status, 
vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lymph-node or tissue 
biopsy (centrally pathology 
review) 
X 
  
  
  
  
  
  
  
  
  
Diagnostic Lumbar 
Puncture  
X 
  
  
  
  
  
  
  
  
  
RMN brain/column, 
endoscopy, ORL visit, etc. 
according to physician 
judge and if clinically 
relevant 
X 
  
  
  
  
  
  
  
  
  
 
A : if positive at baseline  
B : recommended not mandatory  
C : every 6 months during the first two years after chemotherapy (at month 6-12-18-24) 
D:  is required dosage of serum Ig  
 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 54 of 60 
 
Appendix 2: Response Criteria 
 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 55 of 60 
 
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.  
 
 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 56 of 60 
 
Appendix 4: Suggested Body Surface Area Calculation 
BSA should be determined using the appropriate following calculation: 
BSA = √𝐻𝑡(𝑖𝑛𝑐ℎ𝑒𝑠)×𝑊𝑡(𝑙𝑏𝑠)
3131
 
OR 
BSA = √𝐻𝑡(𝑐𝑚)×𝑊𝑡(𝑘𝑔)
3600
 
 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 57 of 60 
 
Appendix 5: Creatinine Clearance Calculation 
Creatinine clearance for men and women will be calculated according to the Cockcroft-
Gault formula as follows: 
 
 
In men: 
 
[(140−𝑎𝑔𝑒)×𝑤𝑒𝑖𝑔ℎ𝑡(𝑘𝑔)]
[72×𝑐𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒(𝑚𝑔/𝑑𝐿)] 
 
 In women: 
[(140−𝑎𝑔𝑒)×𝑤𝑒𝑖𝑔ℎ𝑡(𝑘𝑔)]
[72×𝑐𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒(𝑚𝑔/𝑑𝐿)] × 0.85 
 
 
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) 
 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 58 of 60 
 
Appendix 6: 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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 59 of 60 
 
Appendix 7: 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. 
 
 
 
 
 
 
 
 
 
 
 
 

FIL_GA101-DHAP v. 2_Emend sost_1 09 September 2016                                                           Page 60 of 60 
 
Appendix 8: Study Flow Chart