Conditions: CD20 Positive Diffuse Large B-cell Lymphoma Elderly Unfit Patients
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 34
Healthy volunteers: no

Brief summary:
GA101-miniCHOP regimen for the treatment of elderly unfit patients with diffuse large B-cell non-Hodgkin's lymphoma.

Detailed description:
Considering that the treatment of elderly unfit patients with DLBCL cannot be based on a full course of R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone), and that using a less intense R-miniCHOP (an attenuated version of the standard R-CHOP: Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone) combination an acceptable cure rate can be achieved this study is designed to try to improve the cure rate in unfit patients with DLBCL (Diffuse Large B Cell Lymphoma) by adopting the R-miniCHOP scheme substituting Rituximab with the more active GA101 monoclonal antibody. The study hypothesis is that a higher activity of the treatment can be achieved without modifying the cytotoxic part of the treatment but using a more active immunotherapy. Differently from the previous experience with R-miniCHOP eligible patient are not only identified using anagraphic criteria but adopting CGA (Comprehensive Geriatric Assessment) as part of initial assessment and considering as eligible unfit patients.

Arms:
arm 1: 6 courses of GA101-miniCHOP regimen and 2 additional infusions of GA101, every 21 days (for a total of 6 courses of miniCHOP and 10 infusions of GA101).

GA101-miniCHOP regimen:

* Cycle 1 GA101: 1000 mg day 1, day 8 and day 15, iv Cyclophosphamide: 400 mg/mq, day 1, iv Doxorubicin: 25 mg/mq, day 1, iv Vincristine: 1 mg, day 1, iv Prednisone: 40 mg/mq, days 1-5, os
* Cycles 2-6 GA101: 1000 mg day 1, iv Cyclophosphamide: 400 mg/mq, day 1, iv Doxorubicin: 25 mg/mq, day 1, iv Vincristine: 1 mg, day 1, iv Prednisone: 40 mg/mq, days 1-5, os
* Two additional infusions of GA101: 1000 mg day 1, iv, every 21 days.

Interventions: intervention 1: Ga101
Intervention descriptions: intervention 1: None

Protocol document:
Prot_000.pdf: 
 
Fondazione Italiana Linfomi ONLUS 
 
Sede legale: piazza Turati 5, 15121 – Alessandria 
P.IVA IT 02143940068 C.F. 96039680069 
Uffici Studi FIL: c/o Uffici PACTO, Spalto Marengo 44, 15121, Alessandria 
 Tel. 0131– 033153, Fax 0131 - 263455; e-mail: startup@filinf.it; sito web: www.filinf.it 
 
 
 
 
Study ID: FIL_GAEL 
Eudract Number: 2014-005697-10 
ClinicalTrials.gov Identifier: NCT02495454 
 
Title: GA101-miniCHOP regimen for the treatment of elderly unfit patients 
with diffuse large B-cell non-Hodgkin’s lymphoma. A phase II study of the 
Fondazione Italiana Linfomi (FIL). 
 
Protocol: version 1, September 29th, 2014 
 
 


 
Clinical Protocol 
 
GA101-miniCHOP regimen for the treatment of elderly unfit patients with 
diffuse large B-cell non-Hodgkin’s lymphoma. 
A phase II study of the Fondazione Italiana Linfomi (FIL). 
 
 
Study ID: FIL_GAEL (GA101-miniCHOP elderly unfit) 
Eudract Number:  2014-005697-10 
Protocol version: version 1, 29 Sept 2014 
 
Sponsor:  
 
 
 
Fondazione Italiana Linfomi Onlus 
 
Principal Investrigator  
 
Francesco Merli (Reggio Emilia) 
 
 
Writing Committee 
 
 
Francesco Merli (Reggio Emilia) 
Annalisa Arcari (Piacenza) 
Guido Gini (Ancona) 
Alberto Santagostino (Vercelli) 
Vittorio Ruggero Zilioli (Milano Niguarda) 
 
Statistical Analysis 
 
 
Luigi Marcheselli (Modena) 
 
Administrative Office  
 
Francesca Massobrio (Alessandria) 
 
 
 
 
 
Marta Galliani (Alessandria)  
 
Trial Office   
 
 
Caterina Mammi ( Reggio Emilia) 
 
 


FIL Protocol_GAEL__version 1_29-Sept-2014 
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Contact information for the trial 
 
Study Coordinator 
 
dr. Francesco Merli 
SC Ematologia  
 
 
 
 
 
 
phone: + 39-0522-296618 
Arcispedale Santa Maria Nuova IRCCS  
 
 
 
fax: +39-0522-295654 
V.le Risorgimento 80   
 
 
 
 
 
email: merli.francesco@asmn.re.it 
42123 Reggio Emilia  
 
Writing Committee 
 
dr. Annalisa Arcari 
SC Ematologia e Centro Trapianti 
 
 
 
 
email: a.arcari@ausl.pc.it 
Ospedale Civile 
Piacenza 
 
dr Guido Gini 
Clinica di Ematologia  
 
 
 
 
 
email: g.gini@ospedaliriuniti.marche.it 
A.O.Universitaria Ospedali Riuniti  
Ancona  
Ospedale  
Piacenza 
 
dr Alberto Santagostino 
Onco-Ematologia 
 
 
 
 
 
 
email: albemail@libero.it 
Ospedale S.Andrea 
Vercelli 
 
dr Vittorio Ruggero Zilioli 
SC Ematologia  
 
 
 
 
email: vittorioruggero.zilioli@ospedaleniguarda.it 
A.O.Ospedale Niguarda Ca’ Granda 
Milano  
 
Statistical Analysis 
 
dr. Luigi Marcheselli 
Dipartimento di Oncologia, Ematologia  
 
 
 
email: lmarcheselli@unimore.it 
e Patologie dell’Apparato Respiratorio 
Università di Modena e Reggio Emilia 
COM Centro Oncologico Modenese 
Via del Pozzo 71 
41124 Modena  
 
Administrative Office 
 
Dr.ssa Francesca Massobrio 
Dr.ssa Marta Galliani 
Segreteria FIL  
 
 
 
 
 
 
phone: +39-0131-206288 
S.C. Ematologia, A.O.SS. Antonio e Biagio  
 
 
 
fax: +39-0131-263455 
Via Venezia 16  
 
 
 
 
 
 
email: segreteria@filinf.it 
15121 Alessandria 
 
 
 


FIL Protocol_GAEL__version 1_29-Sept-2014 
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Trial Office 
 
dr. ssa Caterina Mammì 
 
SC Ematologia  
 
 
 
 
 
 
phone: + 39-0522-295654 
Arcispedale Santa Maria Nuova IRCCS  
 
 
 
fax: +39-0522-295655 
V.le Risorgimento 80   
 
 
 
 
 
email: mammi.caterina@asmn.re.it 
42123 Reggio Emilia  
 
Pharmacovigilance Unit 
 
Dr. Alessandro Levis 
Segreteria FIL  
 
 
 
 
 
 
phone: +39-0131-206071-206066 
S.C. Ematologia, A.O.SS. Antonio e Biagio  
 
 
 
fax: +39-0131-263455 
Via Venezia 16  
 
 
 
 
 
 
email: segreteria@filinf.it 
15121 Alessandria 
 
Independent Review Committee (Appendix K) 
 
 


FIL Protocol_GAEL__version 1_29-Sept-2014 
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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 Protocol_GAEL__version 1_29-Sept-2014 
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TABLE OF CONTENTS 
Contact information for the trial...............................................................................................................................................2  
INVESTIGATOR AGREEMENT ..........................................................................................................................................4 
Synopsis ..................................................................................................................................................................................... 8 
1. BACKGROUND AND INTRODUCTION.......................................................................................................................18 
1.1 Diffuse large B-cell lymphoma.........................................................................................................................................18 
1.2 Diffuse large B-cell lymphoma in the elderly .................................................................................................................18 
1.3 Comprehensive Geriatric Assessment (CGA) ................................................................................................................20 
1.4 Treatment of unfit patients ..............................................................................................................................................21 
1.5 Obinutuzumab (GA101)...................................................................................................................................................21 
1.5.1 Structure and Mechanism of Action ............................................................................................................................21 
1.5.2 Pre-clinical efficacy with GA101 ..................................................................................................................................22 
1.5.3 Clinical experience with GA101 ...................................................................................................................................22 
1.5.4 Pharmacokinetic and Pharmacodynamic results for GA101.....................................................................................26 
2. RATIONALE OF THE STUDY........................................................................................................................................26 
3. OBJECTIVES OF THE STUDY.......................................................................................................................................27 
3.1 General Objectives............................................................................................................................................................27 
3.2 Endpoints...........................................................................................................................................................................27 
3.2.1 Primary Endpoints: .......................................................................................................................................................27 
3.2.2 Secondary Endpoints: ...................................................................................................................................................27 
4. STUDY DESIGN ................................................................................................................................................................28 
4.1 Description of the study....................................................................................................................................................28 
4.2 Study duration ..................................................................................................................................................................28 
4.3 Study time table ................................................................................................................................................................28 
5. PATIENT SELECTION CRITERIA ...............................................................................................................................28 
5.1 Inclusion Criteria..............................................................................................................................................................29 
5.2 Exclusion Criteria.............................................................................................................................................................29 
6. STUDY TREATMENT......................................................................................................................................................30  
6.1 Treatment Plan .................................................................................................................................................................30 
6.2 Dosage Delays and Modifications: GA101 and CHOP chemotherapy.........................................................................32 


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6.3 Permitted concomitant therapies and medications........................................................................................................33 
6.4 GA101 ................................................................................................................................................................................34 
6.4.1 Rationale for GA101 Dose.............................................................................................................................................34 
6.4.2 Rationale for Administration of Additional Loading Doses on Days 1 and 8...........................................................35 
6.4.3 GA101 Formulation.......................................................................................................................................................35 
6.4.4 GA101 Handling and Storage.......................................................................................................................................35 
6.4.5 GA101 Dose and Schedule ............................................................................................................................................36 
6.4.6 GA101 Preparation........................................................................................................................................................36 
6.4.7 GA101 Administration ..................................................................................................................................................36 
6.4.8 GA101 Pre-Medication..................................................................................................................................................38 
6.4.9 GA101: Management of Toxicities...............................................................................................................................39 
6.4.10 Excluded Therapy........................................................................................................................................................40 
7. STUDY PROCEDURES: CLINICAL EVALUATION, LABORATORY TEST AND FOLLOW UP......................41  
7.1 Baseline assessment ..........................................................................................................................................................41 
7.2 Investigation before each course......................................................................................................................................42 
7.3 Investigations during each course (day 10 +/- 2)............................................................................................................42 
7.4 Check for response after 4 courses of GA101-miniCHOP ............................................................................................42 
7.5 Investigations at the end of treatment.............................................................................................................................43 
7.6 Investigation during follow-up ........................................................................................................................................43 
8. REMOVAL OF SUBJECTS FROM TREATMENT AND/OR STUDY.......................................................................44  
8.1 Discontinuation of Treatment..........................................................................................................................................44 
8.2 Withdrawal of subjects from the study...........................................................................................................................44 
8.3 Completion of treatment ..................................................................................................................................................44 
9. STATISTICAL METHODS ..............................................................................................................................................45 
9.1 Sample Size........................................................................................................................................................................45 
10. EFFICACY AND SAFETY ASSESSMENT ..................................................................................................................46 
10.1 Efficacy Measurement....................................................................................................................................................46 
10.1.1 Efficacy parameters.....................................................................................................................................................46 
10.2 Safety Measurements......................................................................................................................................................46 
10.2.1 Safety parameters ........................................................................................................................................................47 


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10.2.2 Adverse Event Definitions...........................................................................................................................................47 
Unexpected Adverse Event ....................................................................................................................................................49 
10.2.3 Adverse Event Classifications.....................................................................................................................................50 
10.2.4 Adverse Event Procedures ..........................................................................................................................................51 
Post-Study Adverse Events...................................................................................................................................................52 
10.2.5 Safety contact information..........................................................................................................................................53 
11. FORMS AND PROCEDURES FOR COLLECTING DATA AND DATA MANAGEMENT..................................53  
12. ETHICAL CONSIDERATIONS.....................................................................................................................................53 
12.1 Patient protection............................................................................................................................................................53 
12.2 Subject identification – Personal Data protection........................................................................................................54 
12.3 Informed consent ............................................................................................................................................................54 
12.4 Conflict of Interest..........................................................................................................................................................55 
12.5 Data ownership ...............................................................................................................................................................55 
12.6. Publication Policy ..........................................................................................................................................................55 
12.7 Study insurance...............................................................................................................................................................56 
REFERENCES ....................................................................................................................................................................... 57 
APPENDIX A:  Comprehensive Geriatric Assessment (GCA) in onco-hematology ........................................................60 
APPENDIX B: Activity of Daily Living (ADL)....................................................................................................................61 
APPENDIX C: Instrumental Activity of Daily Living (IADL)...........................................................................................63 
APPENDIX D: Cumulative Illness Rating Scale  (CIRS) ...................................................................................................65 
APPENDIX E: Ann Arbor staging* - Cotswolds recommendations**..............................................................................67 
APPENDIX F: National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE), Version 4.0
.................................................................................................................................................................................................. 69 
APPENDIX G WHO performance status scale ...................................................................................................................70 
APPENDIX H: Quality of Life evaluation according to EORTC QLC-C30 version 3.0 questionnaire .........................71 
APPENDIX I: Study Flow Chart ..........................................................................................................................................73 
APPENDIX J: SAE FORM ...................................................................................................................................................74 
APPENDIX K: INDEPENDENT REVIEW COMMITTEE  .............................................................................................76 
 
 
 


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Synopsis  
 
 
STUDY TITLE 
GA101-miniCHOP regimen for the treatment of elderly unfit patients 
with diffuse large B-cell non-Hodgkin’s lymphoma. A phase II study of 
the Fondazione Italiana Linfomi (FIL). 
STUDY PHASE 
II 
OBJECTIVES 
Primary Objectives: 
 To evaluate the activity of GA101-miniCHOP regimen in terms of 
complete response rate (CRR) 
Secondary Objectives:  
 To evaluate the safety and tolerability of GA101 miniCHOP regiment 
in terms of adverse events 
 Partial and Overall Response Rate: PR and ORR (CR+PR) 
 Overall Survival (OS) 
 Progression Free Survival (PFS) 
 Dynamics of Comprehensive Geriatric Assessment (CGA) 
 Dynamics of Quality of Life (QoL) questionnaires 
 ENDPOINTS 
Primary Endpoints: 
 Complete Response Rate after 10 infusions of GA101 and 6 cycles of 
miniCHOP. The response rate to therapy will be based a central 
Independent Review Committee of response that will not consider the 
results of FDG-PET but will only use the conventional CT scan 
images (International Criteria, B. Cheson, JCO 1999)  (Appendix K) 
Secondary Endpoints: 
 Rate of Adverse Events  
 Partial and Overall Response Rate (PRR, ORR) 
 Overall Survival (OS) 
 Progression Free Survival (PFS) 
 Change in ADL, IADL and CIRS  
 Change in QoL  (EORTC QLQ C30) 
STUDY DESIGN 
 
Two stage phase 2, non-randomized, prospective, multicenter study.  
STUDY DURATION 
5 years: 30 months for patients enrolment plus 6 months of treatment and 24 
months of follow up 
INCLUSION CRITERIA 
1) Histologically proven CD20 positive Diffuse Large B-cell Lymphoma  


FIL Protocol_GAEL__version 1_29-Sept-2014 
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and Follicular grade IIIB lymphoma, according to WHO classification (local 
pathologist) 
2) Age ≥ 65 years 
3) No previous treatment  
4) CGA assessment performed before starting treatment 
5) UNFIT patients defined as follows (see Appendices A-D): 
Age > 80 years with FIT profile, i.e. 
ADL =6 residual functions 
IADL=8 residual functions 
CIRS: no comorbidity of  grade 3-4 and <5 of grade 2 
or Age < 80 with UNFIT profile, i.e 
ADL > 5 residual functions 
IADL > 6 residual functions 
CIRS: no comorbidity of grade 3-4 and 5-8 co-morbidities of grade 2 
6) Ann Arbor Stage I with bulky, II-IV (Appendix E) 
7) At least one bi-dimensionally measurable lesion defined as > 1.5 cm in its 
largest dimension on CT scan  
8) ECOG performance status of 0, 1, or 2 (Appendix G) 
9) Adequate hematologic function (unless caused by bone marrow infiltrate), 
defined as follows: 
Hemoglobin ≥ 10 g/dL 
Absolute neutrophil count ≥ 1.5 x 109/L 
Platelet count ≥ 100 x 109/L  
10) LVEF >50% 
11) Ability and willingness to comply with the study protocol procedure 
12) Life expectancy > 6 months 
13) Accessibility of patient for treatment and follow up 
14) Written informed consent  
EXCLUSION CRITERIA 
1) History of severe allergic or anaphylactic reactions to humanized or 
murine monoclonal antibodies or known sensitivity or allergy to murine 
products 
2) Contraindication to any of the individual components of CHOP, including 
prior receipt of anthracyclines 
3) History of other malignancies within 5 years prior to study entry except 
for adequately treated carcinoma in situ of the cervix or basal or squamous 


FIL Protocol_GAEL__version 1_29-Sept-2014 
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cell skin cancer  
4) Stage I without bulky 
5) Patients with transformed lymphoma  
6) Prior therapy for DLBCL, with the exception of nodal biopsy or local 
irradiation 
7) Previous exposure to cytotoxic agents 
8) Suspect or clinical evidence of CNS involvement by lymphoma 
9) HBsAg, HCV or HIV positivity; isolated HBcAb positivity is accepted 
only with concomitant treatment with Lamivudine 
10) AST /ALT > twice upper the normal range; bilirubin > twice upper the 
normal range; serum creatinine > 2.5 mg /dl (unless these abnormalities 
were related to the lymphoma) 
11) Evidence of any severe active acute or chronic infection 
12) Concurrent co-morbid medical condition which might exclude 
administration of full dose chemotherapy 
TREATMENT SCHEME 
(Appendix I) 
Patients will receive:  
6  courses  of  GA101-miniCHOP  regimen  and  2  additional  infusions  of 
GA101,  every  21  days  (for  a  total  of  6  courses  of  miniCHOP  and  10 
infusions of GA101) 
GA101-miniCHOP regimen 
Cycle 1 
GA101: 1000 mg day 1, day 8 and day 15, iv 
Cyclophosphamide: 400 mg/mq, day 1, iv 
Doxorubicin: 25 mg/mq, day 1, iv 
Vincristine: 1 mg, day 1, iv 
Prednisone: 40 mg/mq, days 1-5, os 
Cycles 2-6  
GA101: 1000 mg day 1, iv 
Cyclophosphamide: 400 mg/mq, day 1, iv 
Doxorubicin: 25 mg/mq, day 1, iv 
Vincristine: 1 mg, day 1, iv 
Prednisone: 40 mg/mq, days 1-5, os 
Two additional infusions of GA101: 1000 mg day 1, iv, every 21 days. 
 
Prophylactic granulocyte colony-stimulating factor (G-CSF) support is 


FIL Protocol_GAEL__version 1_29-Sept-2014 
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mandatory starting within 24-72 hours from day 1 of each cycle for no less 
than 4 doses or until neutrophils count exceeds 1.00×10⁹/L or more (ASCO 
guidelines_JCO -  2006). Alternatively a single dose of pegylated G-CSF or 
pegfilgrastim can be used.   
Use of erythropoietin is allowed according to clinical practice.   
 
A preliminary debulking or symptomatic phase of vincristine 1 mg or 
intermediate -- high dose steroid is allowed.  
In case of debulking with vincristine, this drug must be omitted from cycle1. 
 
Involved Site Radiotherapy (ISRT) is allowed on previous bulky sites or 
on PET positive lesion at the end of treatment. 
 
An interim check for response will be assessed after the completion of 4 
courses of GA101-miniCHOP in order to identify non responding patients: 
patients achieving a CR, PR, or SD will continue to complete combined 
immunochemotherapy as planned, patients with progressive disease will stop 
treatment and will be considered as failure. 
 
All patients stopping study treatment due to early disease progression will be 
followed for survival until the end of the study. 
 
Dosage Delays and Modifications: GA101 and CHOP chemotherapy 
Dose reductions and delays are based on all laboratory values obtained 
within 72 hours prior to a study treatment infusion. 
 
A dose delay of 21 days is permitted for miniCHOP and GA101 to allow 
recovery of hematologic toxicities to Grade ≤ 2 (platelets must return to 
Grade ≤ 1) or non-hematologic toxicities to Grade ≤ 1 or baseline status for 
the first episode. 
 
Dose Modifications of GA101-miniCHOP chemotherapy 
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 


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chemotherapy drugs should be delayed for the same time frame, e.g., if 
miniCHOP therapy is delayed, administration of GA101 should also be 
delayed so that they are given on day 1 of the same cycles. 
 
Hematologic and Non-Hematologic Toxicities 
Dosing of miniCHOP and GA101 may be resumed upon the resolution of 
hematologic toxicity to Grade ≤2 (platelets must resolve to Grade ≤ 1) or 
baseline status for the first episode. 
 
For non-hematologic toxicities, dosing of GA101-miniCHOP-may only be 
resumed upon resolution to Grade ≤1 or baseline status. 
For Grade ≥ 2 non-hematologic toxicities (excluding alopecia, nausea, and 
vomiting), treatment with GA101-miniCHOP will be delayed until 
resolution to Grade ≤1 (or baseline status for all except hemorrhagic 
cystitis), for a maximum of 21 days. 
 
In addition, resumption of dosing without complete resolution of toxicity 
may only be considered after careful weighing of the risks and benefits with 
the patient and agreement between the investigator and the Sponsor. 
 
If treatment is delayed for more than 21 days (except for hepatitis B 
reactivation), the patient will be withdrawn from study treatment. (note that 
lymphopenia is not considered a cytopenic toxicity, as it is an expected 
outcome of therapy.)  
Patients who discontinue all study treatment for adverse events should 
remain on the study and continue to have disease assessments until 
progression and standard follow-up. 
 
In the event of grade 2 neurological vincristine-related toxicity (sensory or 
motor polyneuritis, constipation, or visual or auditory changes) vincristine 
can be discontinued.  
 
Permitted concomitant therapies 
Prevention of tumour lysis syndrome by alkalinisation or hypouricaemic 
drugs is allowed if necessary.  


FIL Protocol_GAEL__version 1_29-Sept-2014 
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Antiemetic therapy with SHT3 antagonists can be given at each cycle. 
 
Patients will receive prophylactic treatment with Bactrim 2 cp/day twice a 
week during all the chemotherapy. 
 
CNS prophylaxis with intrathecal infusion of methotrexate and steriod is 
allowed according to local clinical practice (i.e. patients with testicular 
involvement or patients considered at high risk of CNS relapse). 
 
In patients HBcAb+, prophylaxis for hepatitis B reactivation with 
Lamivudine 100mg/die from the start of the treatment to one year after the 
end of the treatment is mandatory. 
 
Pre-medication for GA101 infusion with oral acetaminophen (e.g., 
650−1000 mg) and an antihistamine such as diphenhydramine hydrochloride 
(50−100 mg) 30−60 minutes prior to starting each infusion (unless 
contraindicated). An additional glucocorticoid (e.g., 100 mg IV prednisone 
or prednisolone or equivalent) is allowed at the investigator’s discretion. For 
patients who do not experience infusion-related symptoms with their 
previous infusion, pre-medication at subsequent infusions may be omitted at 
the investigator’s discretion. 
 
Prophylaxis with levofloxacine or ciprofloxacine and 
fluconazole/itraconazole/posaconazole are allowed.  
 
Platelets and red blood cell transfusion are allowed, if needed. 
STUDY PROCEDURES 
Baseline assessment 
All the baseline tests and procedures must be completed within 28 days 
before chemotherapy starts. 
 
Medical history, physical examination and concomitant medications 
 
Histological diagnosis on lymph node biopsy or other pathologic 
tissue with immunoistochemistry 
 
ECG, cardiac assessment 
 
Cardiac ultrasound to assess LVEF 


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 
Haematology (haemoglobin, haematocrit, platelet count, RBC, WBC 
with differential leucocyte count) 
 
Blood chemistry (glucose, serum creatinine, total serum bilirubin, 
AST, ALT, γ-GT, urea/BUN, electrolytes/ alkaline phosphatase, 
LDH, beta2-microglobulin, electrolytes/ Na, K, Cl, Ca, P, 
erythrocyte sedimentation rate, uric acid, total protein, serum 
albumin, protein electrophoresis) 
 
Viral markers (HIV Ab, HBsAg,antiHBsAb, HBcAb, HCV Ab) 
 
Neck, chest, abdomen and pelvis CT scan. Cerebral CT scan is 
recommended but not mandatory 
 
Bone marrow biopsy mandatory for patient in CT scan stage I-II, 
optional for patient in CT scan stage III-IV.  
 
Lung function (spirometry with DLCO) 
 
ADL, IADL, and CIRS assessments (Appendix B,C,D) 
 
Quality of Life evaluation according to EORTC QLC-C30 version 
3.0 questionnaire (Appendix H) 
 
Written informed consent 
 
All the following are optional: 
 
PET/CT  (strongly recommended) 
 
MRI (CNS, spinal cord), endoscopy and any other diagnostic 
imaging only if clinically relevant under medical judgment 
 
Chest X-ray 
 
Investigation before each course  
 
Physical examination, concomitant medications 
 
Collection of adverse events according to CTCAE v 4.0 
 
Haematology (haemoglobin, haematocrit, platelet count, RBC, WBC 
with differential leucocyte count) 
 
Blood chemistry  (glucose, serum creatinine, alkaline phosphathase, 
total serum bilirubin, AST, ALT, LDH, urea/BUN, uric acid) 
 
Any test or instrumental assessment considered relevant under 
medical judgement in case of clinical suspect of progression or 
toxicity 
Investigations during each course (day 10 +/- 2)  


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 
Physical examination, concomitant medications 
 
Collection of adverse events according to CTCAE v 4.0 
 
Haematology (haemoglobin, haematocrit, platelet count, RBC, WBC 
with differential leucocyte count) 
 
Blood chemistry (glucose, serum creatinine, alkaline phosphathase, 
total serum bilirubin, AST, ALT, LDH, urea/BUN, uric acid) 
 
Check for response after 4 courses of GA101-miniCHOP  
Check for response will be assessed after the completion of 4 courses of 
GA101-miniCHOP in order to identify non responding patients:  
 
ECOG performance status, physical examination 
 
Haematology (haemoglobin, haematocrit, platelet count, RBC, WBC 
with differential leucocyte count) 
 
Blood chemistry  (glucose, serum creatinine, alkaline phosphathase, 
total serum bilirubin, AST, ALT, LDH, urea/BUN, uric acid) 
 
Clinical/radiological assessment of target lesion to check for tumor 
response (CT-SCAN and/or echography and/or chest radiogram)  
 
Investigations at the end of treatment  
(28 days after the last study medication administration) 
 
Physical examination, concomitant medications 
 
Collection of adverse events during the month after the last dose of 
study drug administration according to CTCAE v 4.0 
 
ECG, cardiac assessment 
 
Cardiac ultrasound with LVEF 
 
Haematology (haemoglobin, haematocrit, platelet count, RBC, WBC 
with differential leucocyte count) 
 
Blood chemistry (glucose, serum creatinine, total serum bilirubin, 
AST, ALT, γ-GT, urea/BUN, electrolytes/ Na, K, Cl, Ca, P, alkaline 
phosphatase, LDH, beta2-microglobulin, erythrocyte sedimentation 
rate, uric acid, total protein, serum albumin, protein electrophoresis) 
 
Chest, abdomen and pelvis CT scan (mandatory) 
 
PET Total body (mandatory) 
 
ADL, IADL, and CIRS assessments 
 
Quality of Life evaluation according to EORTC QLC-C30 version 


FIL Protocol_GAEL__version 1_29-Sept-2014 
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3.0 questionnaire (Appendix H) 
 
Bone marrow biopsy is recommended if positive at diagnosis  
 
Lung function (spirometry with DLCO) 
 
All the following are optional: 
 
MRI (CNS, spinal cord), endoscopy and any other diagnostic 
imaging only if positive at the diagnosis or if useful according to 
clinical judgement 
 
Investigation during follow-up 
At month + 3, then every 6 months for two years 
 
Physical examination, concomitant medications 
 
Late adverse event assessment: late organ toxicity; second tumours 
 
Haematology (haemoglobin, haematocrit, platelet count, RBC, WBC 
with differential leucocyte count) 
 
Blood chemistry (glucose, serum creatinine, total serum bilirubin, 
AST, ALT, LDH) 
 
Chest, abdomen and pelvis CT scan (only at month + 3, then every 6 
months) 
 
ECG, cardiac assessment if clinically indicated 
 
ADL, IADL, and CIRS 
 
Quality of Life evaluation according to EORTC QLC-C30 version 
3.0 questionnaire  
 
At any time 
 
Any test or instrumental assessment considered relevant under 
medical judgement in case of clinical suspected disease progression 
or toxicity. 
PLANNED SAMPLE SIZE 
The primary objective of the study is to demonstrate a clinical benefit in 
Complete Remission Rate (CRR) with GA101-miniCHOP association in 
elderly unfit patients diagnosed with diffuse large B-cell lymphoma.  
 
For the purposes of this study, as the reference CR rate (Peyrade et al, 
Lancet Oncol – 2011) was defined with 1999 International Criteria for 
response (Cheson, JCO 1999), the response rate to therapy will be based on 


FIL Protocol_GAEL__version 1_29-Sept-2014 
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a Central Independent Review of response that will not consider the results 
of FDG-PET but will only use the conventional CT scan images.  
Response defined according to Cheson 2007 criteria will also be provided as 
study result.  
 
The sample size has been estimated according to a optimal Simon two-stages 
design. The null hypothesis (p0) has been set equal 0.60 on the basis of what 
reported by F. Peyrade et al. (Lancet Oncol - 2011). 
 
With a type I (alfa) error of  0.10 (10%) and a type II (beta) error of 0.10 
(power=90%) the alternative hypotesis (p1) is 0.75, i.e. a CR rate of 75% 
with the combination GA101-miniCHOP expected.  
A schema of the design is below reported. 
 
R1 = 21  N1 = 34   
R2 = 47   
Ntot = 71 
 
EN(p0) = 47 
PET(p0) = 64.6% 
 
According to the two-stage design patients enrolment will proceed as 
follows:  
- the enrolment of 34 patients (stage 1) is planned: if at least 22 patients will 
achieve CR the study will continue; 
- additional 37 patients are entered (stage II): if at least 48 patients out of 71 
will achieve a CR the study will be considered of possible evaluation for the 
efficacy of the treatment.  
Considering a withdrawal rate of 10%, the enrollment may continue until 78 
patients are accrued in order to have at least 71 eligible patients. 
 
If GA101-miniCHOP will be active, the probability to declare inactivity is 
0.0964 and the probability to stop the study at first stage is 0.0610. 
 
 
 


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1. BACKGROUND AND INTRODUCTION 
 
1.1 Diffuse large B-cell lymphoma 
Diffuse  large  B-cell  Lymphoma  (DLBCL)  is  the  most  frequent  Lymphoma  subtype  and  represents 
around 35-40% of all lymphomas. The incidence of DLBCL increases with age more than one third of 
cases involves patients older than 70 years [1]. With the synergistic effect of the increase in lymphoma 
incidence and the ageing population, a large increase in the number or DLBCL cases can be anticipated 
in elderly patients in the near future. 
The vast majority of patients with localized disease are curable with combined chemoimmunotherapy 
or combination chemotherapy alone [2]. Among patients with advanced-stage disease, 50% of patients 
are cured with doxorubicin-based combination chemotherapy and rituximab [3] [4] [5]. The addition of 
rituximab to CHOP-based chemotherapy improves patient outcomes, as demonstrated in three 
randomized,  prospective  studies,  consisting  of  approximately  2000  older  (<  60  or  ≥  60  years  old, 
depending on the study), previously untreated patients with advanced DLBCL [6].  
 
1.2 Diffuse large B-cell lymphoma in the elderly 
More than half of patients with DLBCL are older than 60 years and age is an adverse prognostic factor 
for them. When a cut of at 60 years is used, elderly patients have a reduced chance of responding to 
their therapy and show a shorter disease and overall survival compared with the younger subjects [7].  
The reason why age is a prognostic indicator is not fully understood but it can be assumed this is the 
combined result of the different biology of the elderly compared to young subjects, of the progressive 
accumulation of co-morbidities and of a reduced tolerability to cytotoxic therapies of the old subject; in 
addition, elderly patients have a natural reduction of their life expectation that might become relevant 
when the disease is diagnosed at a later age.  
Notwithstanding the complexity of the elderly subject, when DLBCL is diagnosed the only treatment 
that is currently considered as standard is the R-CHOP combination. The scientific evidence to support 
this choice is based on the results of large phase III trials that showed that the addition of anti-CD20 
monoclonal antibody rituximab to CHOP chemotherapy is safe and increases treatment efficacy [3-6]. 
Before rituximab was available activity and efficacy of chemotherapy in elderly patients with DLBCL 
was  very  low;  complete  response  rates  ranged  from  36%  to  59%  but  median  survival  was  usually 
shorter than 18 months [8] [9-11]. With the addition of rituximab it was shown that complete response 
rate could be increased to more than 70% and median survival prolonged to more than 8 years [12], 
without an increase in the rate of toxic events. Due to the adoption of strict inclusion criteria however, 


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transferability of study results to daily clinical practice is very difficult. In the randomized studies very 
few patients older than 80 years were included and patients with poor performance status or not able to 
tolerate full dose chemotherapy were not included. In the real life most elderly patients with DLBCL 
show one or more comorbid conditions that might limit the adoption of full dose therapy with curative 
intent  and  make  treatment  choice  a  real  challenge.  Though  immunotherapy  is  generally  safe  the 
chemotherapeutic regimens used in the adult population can cause unpredictable, severe and possibly 
lethal toxicities in the elderly. Cardiac toxicity caused by anthracyclines, pulmonary toxicity caused by 
bleomycin, neurological toxicity caused by vinca alkaloids can be more severe in elderly than in young 
patients.  Moreover  the  chances  of  recover  can  be  jeopardized  by  the  frequent  coexistence  of  co-
morbidities and multiple drug regimens which raise the risk of toxicity [13, 14]. 
As a consequence the standard R-CHOP therapy is not used in all patients and personalized approaches 
are  usually  prescribed  to  elderly  subjects  using  empirical  dose  reductions  of  the  toxic  drugs  or 
substituting standard drugs with less toxic formulations of the same substance (i.e. epidoxorubicin or 
liposomal  doxorubicin  instead  of  conventional  doxorubicin).  Currently  results  from  clinical  research 
specifically  dedicated  to  the  elderly  unfit  patient  or  to  the  very  old  subjects  is  lacking.  Among 
published  studies  specifically  designed  for  the  treatment  of  elderly  or  very  old  patient  with  DLBCL 
interesting data come form the use of modified, light versions of the three-weekly CHOP chemotherapy 
[15-18],  or  from  the  adoption  of  weekly  dosing  of  cytotoxic  drugs  [19].  Among  available  studies 
Peyrade et al. recently published the results of a large phase II trial on elderly patients with DLBCL 
investigating activity and toxicity of a R-mini-CHOP regimen. R-miniCHOP was an attenuated version 
of the standard R-CHOP in which rituximab was used at full doses while cytotoxic drugs (doxorubicin, 
vincristine and cyclophosphamide) and steroids were administered at half dose. In this study patients 
older than 80 years were included with ECOG PS of 2 or less and with a life expectancy of at least 3 
months. One hundred and fifty patients were treated and treatment could be completed in 72% of cases. 
Grade  3-4  neutropenia  was  the  most  frequent  adverse  event  and  occurred  in  40%  of  cases;  febrile 
neutropenia  was  reported  in  8%.  The  29  month  median  overall  survival  and  the  62%  complete  and 
unconfirmed response rates observed prompted the authors to suggest that immunochemotherapy with 
R-mini-CHOP  offers  a  good  compromise  between  efficacy  and  safety  for  the  initial  treatment  of 
selected patients older than 80 years with DLBCL and good performance status. This regimen can be 
considered as a platform for the introduction of new targeted drugs in the first line of this population.   
In addition to achieving higher efficacy with modification of study regimens additional improvement in 
the treatment of elderly patients with DLBCL should come from a better selection of patient. In the 
Peyrade study as well as in most studies on elderly patients the initial selection of patient was based on 
subjective assessment of patient performance status and ability to receive full dose chemotherapy done 


FIL Protocol_GAEL__version 1_29-Sept-2014 
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by  the  local  investigator.  This  approach  is  questionable  as  it  has  very  low  reproducibility  and  lacks 
standardization.  
 
1.3 Comprehensive Geriatric Assessment (CGA) 
There  are  currently  several  tools  that  can  be  used  to  provide  an  accurate  description  of  the  elderly 
subject; they range from a very simple assessment of performance status (ECOG or Karnofsky scales) 
[20] to more complex scales that use a multidimensional approach. Among available multidimensional 
test Comprehensive Geriatric Assessment (CGA) has been proposed as useful and reproducible tool. 
CGA includes the evaluation of physical disability, nutrition conditions, psychological status and co-
morbidities, relying on scales profiling different aspects of the patient status. [21, 22] (Appendix A). 
Particularly: 
-  ADL (Activities of Daily Living) scale, includes the assessment of six basic self-care skills needed to 
maintain  independence  in  the  home;  particularly,  the  ability  of  bathing,  dressing,  toileting,  feeding 
oneself,  maintain  continence,  and  transferring  from  a  bed  or  chair  without  assistance  [23,  24];  
(Appendix B) 
-  IADL  (Instrumental  Activities  of  Daily  Living)  scale  includes  the  assessment  of  eight  skills  to 
maintain  independence  in  the  community:  using  the  phone,  shopping,  cooking  meals,  housekeeping, 
doing laundry, using public transport, taking medications and managing money [25] (Appendix C); 
-  CIRS  (Cumulative  Illness  Rating  Scale)  plans  a  global  assessment  of  severity  of  possible  co-
morbidities [26, 27] (Appendix D) 
 
Some studies have showed that ADL and IADL are more appropriate to define functional deficits in 
elderly than Performance Status. By the use of the above mentioned scales and the age of the patient 
CGA  allows  the  qualification  of  subject  status.  Patients  are  considered  as  FIT  if  young  and  without 
impairment of ADL or IADL and with only mild co-morbidities, or frail if old (80 years as cutoff), 
and/or with severe impairment or functional status and/or with severe co-morbidities. The qualification 
of patient fitness status has relevant clinical implication as it might be used to define therapeutic goals 
in patients with potentially curable disease such as DLBCL. 
 
Since 1996 the FIL has adopted the use of CGA to initially identify patients that are able to undergo 
treatment with curative intent and to distinguish them from those who are frail and should be addressed 
to palliative therapy [17] [28]. 
 


FIL Protocol_GAEL__version 1_29-Sept-2014 
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This  approach  has  been  used  by  the  FIL  for  the  design  of  trials  investigating  treatment  options  of 
elderly patients with malignant lymphoma either of Hodgkin or of Non Hodgkin subtype. In all recent 
FIL prospective trials for elderly patients with lymphoma CGA was considered among the screening 
procedures  and  patients  were  required  to  qualify  as  FIT  to  be  included  in  the  study  and  receive  the 
study treatment. Frail patients were excluded as they were not considered able to tolerate treatment with 
curative intent. 
 
- FIT patients, without any co-morbidity and potentially able to receive standard treatment; 
-  UNFIT  patients,  with  mild  co-morbidities  and  possibly  able  to  receive  reduce-dose  of  a  standard 
treatment; 
- FRAIL patients, with severe co-morbidities and able to receive only palliative treatment  
 
1.4 Treatment of unfit patients 
Currently  there  is  no  doubt  that  R-CHOP  is  the  standard  therapy  for  elderly  FIT  patients  with 
DLBLCL. Also, it is reasonable to adopt a palliative approach in FRAIL patients for whom the costs of 
treatment in terms of toxicity is not acceptable. Regarding the intermediate UNFIT category the choice 
of treatment is more problematic as for these patients the risk to benefit ratio of therapy is crucial. So 
far no or very few studies have tried to identify a specific therapy tailored for unfit patient as currently 
available standard option apply to fit patients. Based on available data R-miniCHOP regimen represents 
a good platform for further improvement [18]. What is questionable from the Peyrade study however is 
the adoption of age and of performance status as selection criteria for study enrolment. As observed by 
the same authors among treated patients impaired IADL score was associated with poor survival and 
was  independent  of  ECOG.  This  observation  clearly  demonstrates  that  the  use  of  more  complete 
assessment of patients status is useful to better identify those subjects that may benefit from therapy. As 
previously  described  CGA  represents  a  good  tool  to  improve  the  definition  of  patients  status  and  to 
define treatment objectives for elderly patients with DLBCL. In particular as used by the FIL CGA can 
be  added  to  anagraphic  criteria  and  improves  the  ability  to  define  which  patient  can  tolerate  a  full 
treatment course, an intermediate therapy or palliation. 
 
1.5 Obinutuzumab (GA101)  
1.5.1 Structure and Mechanism of Action 
RO5072759 (GA101) is a humanized and glyco-engineered monoclonal antibody, derived by 
humanization of the parental B-Ly1 mouse antibody and subsequent glyco-engineering leading to the 
following characteristics [29] [30]. 


FIL Protocol_GAEL__version 1_29-Sept-2014 
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- 
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 FcγRIIIa 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 
 
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 
FcγRIIIa low-affinity receptor polymorphism. 
 
1.5.2 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 [29] 
 
1.5.3 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. 


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 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. 
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.  


FIL Protocol_GAEL__version 1_29-Sept-2014 
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The  end-of-treatment  response  rate  was  24% (DLBCL:  2  patients  with  PR,  1  with  CR  unconfirmed; 
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 cyclesdelivered.  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  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 


FIL Protocol_GAEL__version 1_29-Sept-2014 
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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. 
Study GAO4753g (Phase III):  GA101 in Combination with Chemotherapy 
This is an ongoing, 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. Approximately 360 patients will be enrolled.  The first patient was enrolled in April 2010. The 
study is ongoing, and the results remain blinded. All these data demonstrate that the new anti-CD20 
antibody is safe either in untreated patients or in pre-treated patients. Therefore at now no more data on 
safety are needed in particular as a primary objective in a study evaluation.  
 
 
 


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1.5.4 Pharmacokinetic and Pharmacodynamic results for GA101  
A population pharmacokinetic (PK) model has been developed for StudiesBO20999 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  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 
Considering that the treatment of elderly unfit patients with DLBCL cannot be based on a full course of 
R-CHOP,  and  that  using  a  less  intense  R-miniCHOP  combination  an  acceptable  cure  rate  can  be 
achieved  this  study  is  designed  to  try  to  improve  the  cure  rate  in  unfit  patients  with  DLBCL  by 
adopting  the  R-miniCHOP  scheme  substituting  Rituximab  with  the  more  active  GA101  monoclonal 
antibody.  The  study  hypothesis  is  that  a  higher  activity  of  the  treatment  can  be  achieved  without 
modifying the cytotoxic part of the treatment but using a more active immunotherapy. Differently from 
the  previous  experience  with  R-miniCHOP  eligible  patient  are  not  only  identified  using  anagraphic 
criteria but adopting CGA as part of initial assessment and considering as eligible unfit patients (i.e. 
those older than 80 year without significant inabilities or co-morbidities and patients younger than 80 
years with mild inabilities or non severe co-morbidities). 
 
 
 
 


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3. OBJECTIVES OF THE STUDY 
3.1 General Objectives 
The purpose of the study is to evaluate feasibility and activity of GA101-miniCHOP combination in 
elderly unfit patients with diffuse large B-cell lymphoma (DLBCL). Addition of a new and more active 
monoclonal antibody to the same chemotherapy should consist in an increase of response for elderly 
unfit patients with DLBCL newly diagnosed. 
Primary Objectives 
 Primary  objectives  is  to  asses  whether  the  regimen  GA101-miniCHOP  achieves  an  absolute 
increase  of  the  CR  proportion  of  al  least  15%  (from  60%  to  75%  respect  to  R-miniCHOP 
regimen  [18]).    To  evaluate  the  activity  of  GA101-miniCHOP  regimen  in  terms  of  complete 
response rate (CRR) 
Secondary Objectives:  
 To evaluate the safety and tolerability of GA101-miniCHOP regimen in terms of rate of adverse 
events  
 Partial and Overall Response Rate: PR and ORR (CR+PR) 
 Overall Survival (OS) 
 Progression Free Survival (PFS) 
 Dynamics of Comprehensive Geriatric Assessment (CGA) 
 Dynamics of Quality of Life (QoL) questionnaire 
 
3.2 Endpoints 
3.2.1 Primary Endpoints: 
 Complete Response Rate (CRR) after 10 infusions of GA101 and 6 cycles of miniCHOP. The 
response rate to therapy will be based a central Independent Review Committee of response that 
will not consider the results of FDG-PET (according to the revised Cheson criteria [31]) but 
will  only  use  the  conventional  CT  scan  images  (according  to  Cheson  criteria,  1999)  [32].  
(Appendix K) 
3.2.2 Secondary Endpoints: 
 Rate of Adverse Events  
 Partial and Overall Response Rate (PRR, ORR) 
o ORR: defined as the sum of complete or partial response evaluated by CT scan, after 6 
GA101-miniCHOP courses plus 2 GA101 infusions 
 Overall Survival (OS) 
o OS is defined as the time from entry onto the study until death as a results of any cause 


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 Progression Free Survival (PFS) 
o PFS  is  defined  as  the  time  from  entry  onto  the  study  until  lymphoma  progression  or 
death as a results of any cause 
 Change in ADL, IADL and CIRS  
o Change in ADL, IADL and CIRS from study entry to end of treatment/follow up 
 Change in QoL  (EORTC QLQ C30) 
o Change in QoL from study entry to end of treatment/follow up  
 
4. STUDY DESIGN  
4.1 Description of the study  
This is a prospective, multicenter, single arm, phase II trial in elderly patients (≥ 65 years) affected by 
DLBCL defined as unfit according to CGA and previously untreated.  
After  providing  written  informed  consent,  patients  will  be  evaluated  for  eligibility  during  a  28-day 
screening period. If they continue to meet eligibility criteria they will receive the fist dose of GA101-
miniCHOP.  
Duration of treatment will be approximately 6 months (6 courses of GA101-miniCHOP + 2 GA101, 
every 21 days); during the study disease status will be evaluated for tumor response after the 4
th cycle 
by clinical/radiological assessment of target lesion (CT/SCAN and/or echography). Final response will 
be  evaluated  within  28  days  after  the  last  study  medication  administration.  All  patients  will  be 
monitored during follow up, every 3-6 months for 2 years.  
 
4.2 Study duration  
Five  years: 30 months for patients enrolment plus 6 months of treatment and 24 months of follow up 
 
4.3 Study time table 
This study is expected to start in May 2015. The last patient is expected to be enrolled at November 
2017. This trial is due to be completed by the end of April 2020. 
 
5. PATIENT SELECTION CRITERIA 
Elderly  patients,  aged  ≥  65  years,  classified  as  “unfit”  according  to  CGA  (Appendix  A),  with 
histologically proven diagnosis of CD20+ Diffuse Large B-Cell non-Hodgkin’s Lymphoma (DLBCL) 
at diagnosis (not previously treated) will be candidate for the study. 
Eligible  patients  who  are  in  conformance  with  the  following  inclusion  and  exclusion  criteria  may 
enrolled in this study. 


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5.1 Inclusion Criteria 
1)  Histologically  proven  CD20  positive  Diffuse  Large  B-cell  Lymphoma  and  Follicular  grade  IIIB 
lymphoma, according to WHO classification (local pathologist) 
2) Age ≥ 65 years 
3) No previous treatment  
4) CGA assessment performed before starting treatment 
5) UNFIT patients defined as follows (see Appendices A-D): 
Age > 80 years with FIT profile, i.e. 
ADL =6 residual functions 
IADL=8 residual functions 
CIRS: no comorbidity of  grade 3-4 and <5 of grade 2 
or Age < 80 with UNFIT profile, i.e 
ADL > 5 residual functions 
IADL > 6 residual functions 
CIRS: no comorbidity of grade 3-4 and 5-8 co-morbidities of grade 2 
6) Ann Arbor Stage I with bulky, II-IV (Appendix E) 
7) At least one bi-dimensionally measurable lesion defined as > 1.5 cm in its largest dimension on CT 
scan  
8) ECOG performance status of 0, 1, or 2 (Appendix G) 
9) Adequate hematologic function (unless caused by bone marrow infiltrate), defined as follows: 
Hemoglobin ≥ 10 g/dL 
Absolute neutrophil count ≥ 1.5 x 109/L 
Platelet count ≥ 100 x 109/L  
10) LVEF >50% 
11) Ability and willingness to comply with the study protocol procedure 
12) Life expectancy > 6 months 
13) Accessibility of patient for treatment and follow up 
14) Written informed consent 
 
5.2 Exclusion Criteria 
1) History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies 
or known sensitivity or allergy to murine products 
2) Contraindication to any of the individual components of CHOP, including prior receipt of 
anthracyclines 


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3)  History  of  other  malignancies  within  5  years  prior  to  study  entry  except  for  adequately  treated 
carcinoma in situ of the cervix or basal or squamous cell skin cancer  
4) Stage I without bulky 
5) Patients with transformed lymphoma  
6) Prior therapy for DLBCL, with the exception of nodal biopsy or local irradiation 
7) Previous exposure to cytotoxic agents 
8) Suspect or clinical evidence of CNS involvement by lymphoma 
9)  HBsAg,  HCV  or  HIV  positivity;  isolated  HBcAb  positivity  is  accepted  only  with  concomitant 
treatment with Lamivudine 
10)  AST  /ALT  >  twice  upper  the  normal  range;  bilirubin  >  twice  upper  the  normal  range;  serum 
creatinine > 2.5 mg /dl (unless these abnormalities were related to the lymphoma) 
11) Evidence of any severe active acute or chronic infection 
12) Concurrent co-morbid medical condition which might exclude administration of full dose 
chemotherapy 
 
6. STUDY TREATMENT 
6.1 Treatment Plan 
Patients will receive: 
6 courses of GA101-miniCHOP regimen and 2 additional infusions of GA101, every 21 days (for a 
total of 6 courses of miniCHOP and 10 infusions of GA101) 
 
 
 


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GA101-miniCHOP regimen 
Cycle 1 
GA101: 1000 mg day 1, day 8 and day 15, iv 
Cyclophosphamide: 400 mg/mq, day 1, iv 
Doxorubicin: 25 mg/mq, day 1, iv 
Vincristine: 1 mg, day 1, iv 
Prednisone: 40 mg/mq, days 1-5, os 
 
Cycles 2-6  
GA101: 1000 mg day 1, iv 
Cyclophosphamide: 400 mg/mq, day 1, iv 
Doxorubicin: 25 mg/mq, day 1, iv 
Vincristine: 1 mg, day 1, iv 
Prednisone: 40 mg/mq, days 1-5, os 
Two additional infusions of GA101: 1000 mg day 1, iv, every 21 days. 
 
An interim check for response will be assessed after the completion of 4 courses of GA101-miniCHOP 
in  order  to  identify  non  responding  patients:  patients  achieving  a  CR,  PR,  or  SD  will  continue  to 
complete  combined  immunochemotherapy  as  planned,  patients  with  progressive  disease  will  stop 
treatment and will be considered as failure. 
 
All patients stopping study treatment due to early disease progression will be followed for survival until 
the end of the study. 
 
Prophylactic granulocyte colony-stimulating factor (G-CSF) support is mandatory starting within 24-72 
hours from day 1 of each cycle for no less than 4 doses or until neutrophils count exceeds 1.00×10
⁹/L 
or more [33]. Alternatively a single dose of pegylated G-CSF or pegfilgrastim can be used. 
 


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Use of erythropoietin is allowed according to clinical practice; other supportive measures care will be 
administered according to medical judgement. 
A preliminary debulking or symptomatic phase of vincristine 1 mg or intermediate - high dose steroid 
is allowed. In case of debulking with vincristine, this drug must be omitted from cycle 1. 
 
Involved Site Radiotherapy (ISRT) is allowed on previous bulky sites or on PET positive lesion at 
the end of treatment. 
 
6.2 Dosage Delays and Modifications: GA101 and CHOP chemotherapy 
Dose reductions and delays are based on all laboratory values obtained within 72 hours prior to a study 
treatment infusion. 
 
A  dose  delay  of  21  days  is  permitted  for  miniCHOP  and  GA101  to  allow  recovery  of  hematologic 
toxicities to Grade ≤ 2 (platelets must return to Grade ≤ 1) or non-hematologic toxicities to Grade ≤ 1 
or baseline status for the first episode. 
 
Dose Modifications of GA101-miniCHOP chemotherapy 
 
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 miniCHOP therapy is delayed, administration of GA101 should also be delayed so that they are given 
on day 1 of the same cycles. 
 
Hematologic and Non-Hematologic Toxicities 
 
Dosing  of  miniCHOP  and  GA101  may  be  resumed  upon  the  resolution  of  hematologic  toxicity  to 
Grade ≤2 (platelets must resolve to Grade ≤ 1) or baseline status for the first episode. 
 
For non-hematologic toxicities, dosing of GA101-miniCHOP-may only be resumed upon resolution to 
Grade ≤1 or baseline status. 
For Grade ≥ 2 non-hematologic toxicities (excluding alopecia, nausea, and vomiting), treatment with 
GA101-miniCHOP  will  be  delayed  until  resolution  to  Grade  ≤1  (or  baseline  status  for  all  except 
hemorrhagic cystitis), for a maximum of 21 days. 


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In addition, resumption of dosing without complete resolution of toxicity may only be considered after 
careful weighing of the risks and benefits with the patient and agreement between the investigator and 
the Sponsor. 
 
If treatment is delayed for more than 21 days (except for hepatitis B reactivation), the patient will be 
withdrawn from study treatment. (note that lymphopenia is not considered a cytopenic toxicity, as it is 
an expected outcome of therapy.)  
 
Patients  who  discontinue  all  study  treatment  for  adverse  events  should  remain  on  the  study  and 
continue to have disease assessments until progression and standard follow-up. 
 
In  the  event  of  grade  2  neurological  vincristine-related  toxicity  (sensory  or 
motor  polyneuritis, 
constipation, or visual or auditory changes) vincristine can be discontinued.  
 
6.3 Permitted concomitant therapies and medications  
Concomitant therapy includes any prescription medications or over-the-counter preparations used by a 
patient between the 7 days preceding the baseline evaluations and the end of last study visit.  
All  concomitant  medications  should  be  reported  to  the  investigator  and  recorded  on  the  appropriate 
CRF.  
 
Prevention  of  tumour  lysis  syndrome  by  alkalinisation  or  hypouricaemic  drugs  is  allowed  if 
necessary.  
 
Antiemetic therapy with SHT3 antagonists can be given at each cycle. 
 
Patients will receive prophylactic treatment with Bactrim 2 cp/day twice a week during all the 
chemotherapy. 
 
CNS prophylaxis with intrathecal infusion of methotrexate and steriod is allowed according to 
local  clinical  practice  (i.e.  patients  with  testicular  involvement  or  patients  considered  at  high 
risk of CNS relapse). 
 
In patients HBcAb+, prophylaxis for hepatitis B reactivation with Lamivudine 100mg/die from 
the start of the treatment to one year after the end of the treatment is mandatory. 
 
Pre-medication  for  GA101  infusion  with  oral  acetaminophen  (e.g.,  650−1000  mg)  and  an 
antihistamine  such  as  diphenhydramine  hydrochloride  (50−100  mg)  30−60  minutes  prior  to 
starting each infusion (unless contraindicated). An additional glucocorticoid (e.g., 100 mg IV 
prednisone  or  prednisolone  or  equivalent)  is  allowed  at  the  investigator’s  discretion.  For 


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patients  who  do  not  experience  infusion-related  symptoms  with  their  previous  infusion,  pre-
medication at subsequent infusions may be omitted at the investigator’s discretion. 
 
Prophylaxis with levofloxacine or ciprofloxacine and fluconazole/itraconazole/posaconazole are 
allowed.  
 
Platelets and red blood cell transfusion are allowed, if needed. 
 
CNS  Prophylaxis:  CNS  prophylaxis  with  intrathecal  chemotherapy  only  should  be  given 
according to institutional practice and its use documented on the CRF. 
 
Prophylaxis for Hemorrhagic Cystitis: Patients should be adequately hydrated prior to and after 
cyclophosphamide administration and should be instructed to void frequently. Mesna may be 
used as prophylaxis according to institutional practice. 
 
6.4 GA101  
6.4.1 Rationale for GA101 Dose 
PK analyses of the GA101 Phase I studies, together with published data on rituximab [34], 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
375mg/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 


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DLBCL and relapsed MCL and small numbers (25 patients with DLBCL and 15 patients with MCL) 
might have prevented a more compelling result. 
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. 
 
6.4.2 Rationale for Administration of Additional Loading Doses on Days 1 and 8 
In the Phase II part of Study BO20999, the first two doses of GA101 in the HD cohort were set at 1600 
mg. Although well tolerated by patients, the dosing scheme resulted in administration times of up to 
and exceeded 5 hours. With the goal in mind to maintain the loading dose concept, and to provide a 
significant  amount  of  antibody  early  on  during  the  treatment  course,  it  was  decided  to  split  GA101 
administration and to change the schedule and dose during the first 2 weeks of any future studies from 
1600  mg  on  Days  1  and  8  to  1000  mg  on  Days  1,  8,  and  15,  providing  comparably  fast  rising  PK 
exposure and early target saturation, while avoiding the practical challenges of delivering 1600 mg of 
drug in a single day together with chemotherapy. The dose for subsequent cycles is also set at 1000 mg. 
This  dose  and  schedule  result  in  a  GA101  exposure  of  3000  mg  during  the  first  2  weeks  for  a 
cumulative exposure of 10,000 mg and is therefore very close to the regimen that has delivered the best 
results thus far for GA101 in both indolent and aggressive lymphoma. There is no indication that the 
additional  GA101  doses  on  Days  8  and  15  in  the  first  cycle  would  negatively  affect  the  safety  of 
patients. In this study, GA101 will be given for a total  of  10  infusions,  regardless  of  the  number  of 
miniCHOP cycles, with additional doses of GA101 to be administered to patients on Days 8 and 15 of 
Cycle 1 
 
6.4.3 GA101 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. 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. 
 
6.4.4 GA101 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) 


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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. 
 
6.4.5 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 8 cycles.  
GA101 will be administered prior to miniCHOP, and patients should be observed 30 minutes prior to 
starting  miniCHOP.  If  miniCHOP  is  not  started  because  of  the  long  duration  of  GA101  therapy, 
miniCHOP chemotherapy may be administered on Day 2.  
During Cycle 1, GA101 will also be infused on Days 8 and 15. 
 
6.4.6 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.  
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. 
 
6.4.7 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 


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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 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 miniCHOP are given, GA101 will be administered prior to miniCHOP 
and patients should be observed 30 minutes prior to starting miniCHOP.  
MiniCHOP chemotherapy may be administered the next day if it cannot be given on the same day as 
GA101 administration.  


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Prior  to  each  GA101  infusion  that  is  given  in  combination  with  miniCHOP  (Day  1  of  Cycles  1–6) 
patients  should  take  the  Day  1  dose  of  oral  prednisone  (40  mg/mq)  specified  for  each  cycle  of  the 
miniCHOP regimen. 
The prophylactic use of corticosteroids (e.g., 100 mg of IV prednisolone or equivalent) may also be 
considered for patients thought to be at high risk for IRRs, if deemed appropriate by the investigator, 
and should be also administered prior to the GA101 infusion.)  
 
Table 2 Premedication to be administered before Obinutuzumab infusion to reduce the risk of Infusion 
Related Reactions (recommended for ALL patients). 
 
1100 mg di prednisone/prednisolone or 20 mg di dexamethasone or 80 mg di methylprednisolone. 
Hydrocortisone should not be used as it has not been effective in reducing rates of IRR. 
 2 e.g. 1.000 mg acetaminophen/paracetamol 
3 e.g. 50 mg di diphenhydramine 
 
 
6.4.8 GA101 Pre-Medication 
All GA101 infusions should be administered to patients after pre-medication with oral acetaminophen 
(e.g., 650-1000 mg) and an antihistamine such as diphenhydramine hydrochloride (50-100 mg) 30-60 
minutes prior to starting each infusion (unless contraindicated).  
An additional glucocorticoid (e.g., 100 mg IV prednisone or prednisolone or equivalent) is allowed at 
the investigator’s discretion.  
Day of 
Treatment 
Cycle 
Patients requirement 
premedication  
Premedication 
Administration 
Intravenous corticosteroid1 
Completed at least 1 
hour prior to 
obinutuzumab infusion 
Oral analgesic/anti-pyretic2 
Cycle 1: 
Day 1 
All patients 
Anti-histaminic drug3  
At least 30 minutes 
before obinutuzumab 
infusion 
Patients with a Grade 3 
IRR with the previous 
infusion OR  
Patients with the 
lymphocyte counts 
> 25 x 109/L prior the 
next treatment  
Intravenous corticosteroid1 
Completed at least 1 
hour prior to 
obinutuzumab infusion 
All patients 
Oral analgesic/anti-pyretic2 
Cycle 1: 
Day 8,  
Day15 
 
Cycle  2-6: 
Day 1 
Patients with an IRR 
(Grade 1 or more) with 
the previuos infusion 
Anti-histaminic drug3 
At least 30 minutes 
before obinutuzumab 
infusion 


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For  patients  who  do  not  experience  infusion-related  symptoms  with  their  previous  infusion,  pre-
medication at subsequent infusions may be omitted at the investigator’s discretion. 
 
Patients with high tumor burden and who are considered by the investigator to be at risk for tumor lysis 
should also receive tumor lysis prophylaxis prior to the initiation of treatment. Patients should be well 
hydrated. Starting 1 or 2 days before the first dose of GA101, it is desirable to maintain a fluid intake of 
approximately 3 L/day. In addition, all patients with high tumor burden and who are considered to be at 
risk  for  tumor  lysis  should  be  treated  with  300  mg/day  of  allopurinol  PO  or  a  suitable  alternative 
treatment  starting  48–72  hours  prior  to  Cycle  1,  Day  1  of  treatment  and  hydration.  Patients  should 
continue  to  receive  repeated  prophylaxis  with  allopurinol  and  adequate  hydration  prior  to  each 
subsequent infusion, if deemed appropriate by the investigator. 
Patients who have preexisting cardiac or pulmonary conditions should be monitored carefully 
throughout the GA101 infusion and the post-infusion period. 
 
6.4.9 GA101: Management of Toxicities 
a. Life-Threatening Infusion-Related Reactions and Anaphylaxis 
Medications (including epinephrine  for  subcutaneous  injections,  corticosteroids,  diphenhydramine 
hydrochloride  for  IV  injection)  and  resuscitation  equipment  should  be  available  for  immediate  use. 
Management  of  infusion-related  symptoms  for  GA101  are  summarized  in  Table  3  according  to  the 
administration rates.. In the event of a life-threatening IRR (which may include pulmonary or cardiac 
events) or IgE-mediated anaphylactic reaction, GA101 should be discontinued and no additional drug 
should  be  administered.  Patients  who  experience  any  of  these  reactions  should  receive  aggressive 
symptomatic  treatment  and  will  be  discontinued  from  study  treatment.  Patients  who  experience 
GA101-associated infusion-related temperature elevations of > 38.5 C or other minor infusion-related 
symptoms  may  be  treated  symptomatically  with  acetaminophen  (≥  500  mg)  and/or  H1-  and  H2-
histamine–receptor  antagonists  (e.g.,  diphenhydramine  hydrochloride,  ranitidine).  Serious  infusion-
related  events,  manifested  by  dyspnea,  hypotension,  wheezing,  bronchospasm,  tachycardia,  reduced 
oxygen saturation, or respiratory distress, should be managed with additional supportive therapies (e.g., 
supplemental oxygen, β2-agonists, epinephrine, and/or corticosteroids) as clinically indicated according 
to standard clinical practice. For the management of IRRs and anaphylaxis, see Table 3. 
 


FIL Protocol_GAEL__version 1_29-Sept-2014 
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b. Tumor Lysis Syndrome 
Patients should be closely monitored for the development of tumor lysis syndrome. For patients with 
evidence of tumor lysis syndrome, all study treatment (GA101-miniCHOP) should be discontinued and 
the patient should be treated as clinically indicated. Following the complete resolution of tumor lysis 
syndrome complications, treatment with GA101-miniCHOP may be resumed at the full dose at the next 
scheduled infusion in conjunction with prophylactic therapy. 
 
6.4.10 Excluded Therapy 
Treatment  with  other  concomitant  anti-tumor  agents  not  defined  in  this  protocol  as  study  treatment, 
radiotherapy, or other concurrent investigational agents of any type will result in withdrawal of patients 
from study treatment.  
Use of the following therapies is prohibited during the study: 
- Cytotoxic chemotherapy (other than miniCHOP) 
- Experimental agent  
- Immunotherapy 
- Hormone therapy (other than hormone-replacement therapy, or megestrol acetate) 


FIL Protocol_GAEL__version 1_29-Sept-2014 
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-  Any  therapies  (other  than  intrathecal  CNS  prophylaxis)  intended  for  the  treatment  of  lymphoma 
whether  European  Medicines  Agencies  (EMA)  or  FDA  approved  or  experimental  (outside  of  this 
study) 
Patients who require the use of any of these agents will be discontinued from study treatment.  
Patients who are discontinued from study treatment for reasons other than PD will complete an early 
study treatment termination visit, including a tumor response assessment. 
 
7. STUDY PROCEDURES: CLINICAL EVALUATION, LABORATORY TEST AND 
FOLLOW UP 
7.1 Baseline assessment 
All the baseline tests and procedures must be completed within 28 days before chemotherapy start. 
 
Medical history, physical examination and concomitant medications 
 
Histological 
diagnosis 
on 
lymph 
node 
biopsy 
or 
other 
pathologic 
tissue 
with 
immunoistochemistry 
 
ECG, cardiac assessment 
 
Cardiac ultrasound to assess LVEF 
 
Haematology (haemoglobin, haematocrit, platelet count, RBC, WBC with differential leucocyte 
count) 
 
Blood chemistry (glucose, serum creatinine, total serum bilirubin, AST, ALT, γ-GT, urea/BUN, 
electrolytes/  alkaline  phosphatase,  LDH,  beta2-microglobulin,  electrolytes/  Na,  K,  Cl,  Ca,  P, 
erythrocyte sedimentation rate, uric acid, total protein, serum albumin, protein electrophoresis) 
 
Viral markers (HIV Ab, HBsAg, antiHBsAb, HBcAb, HCV Ab) 
 
Neck, chest, abdomen and pelvis CT scan. Cerebral CT scan is recommended but not 
mandatory 
 
Bone marrow biopsy mandatory for patient in CT scan stage I-II, optional for patient in CT scan 
stage III-IV.  
 
Lung function (spirometry with DLCO) 
 
ADL, IADL, and CIRS assessments (Appendix B,C,D) 
 
Quality of Life evaluation according to EORTC QLC-C30 version 3.0 questionnaire (Appendix 
H) 
 
Written informed consent 
All the following are optional: 
 
PET/CT  (strongly recommended) 


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 
MRI (CNS, spinal cord), endoscopy and any other diagnostic imaging only if clinically relevant 
under medical judgment 
 
Chest X-ray 
 
7.2 Investigation before each course  
 
Physical examination, concomitant medications 
 
Collection of adverse events according to CTCAE v 4.0 
 
Haematology (haemoglobin, haematocrit, platelet count, RBC, WBC with differential leucocyte 
count) 
 
Blood chemistry  (glucose, serum creatinine, alkaline phosphathase, total serum bilirubin, AST, 
ALT, LDH, urea/BUN, uric acid) 
 
Any  test  or  instrumental  assessment  considered  relevant  under  medical  judgement  in  case  of 
clinical suspect of progression or toxicity 
 
7.3 Investigations during each course (day 10 +/- 2)  
 
Physical examination, concomitant medications 
 
Collection of adverse events according to CTCAE v 4.0 
 
Haematology (haemoglobin, haematocrit, platelet count, RBC, WBC with differential leucocyte 
count) 
 
Blood chemistry (glucose, serum creatinine, alkaline phosphathase, total serum bilirubin, AST, 
ALT, LDH, urea/BUN, uric acid) 
 
7.4 Check for response after 4 courses of GA101-miniCHOP  
Check for response will be assessed after the completion of 4 courses of GA101-miniCHOP in order to 
identify non responding patients:  
 
ECOG performance status, physical examination 
 
Haematology (haemoglobin, haematocrit, platelet count, RBC, WBC with differential leucocyte 
count) 
 
Blood chemistry  (glucose, serum creatinine, alkaline phosphathase, total serum bilirubin, AST, 
ALT, LDH, urea/BUN, uric acid) 
 
Clinical/radiological assessment of target lesion to check for tumor response (CT/SCAN and/or 
echography and/or chest radiogram)  
 
 


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7.5 Investigations at the end of treatment  
(28 days after the last study medication administration) 
 
Physical examination, concomitant medications 
 
Collection of adverse events during the month after the last dose of study drug administration 
according to CTCAE v 4.0 
 
ECG, cardiac assessment 
 
Cardiac ultrasound with LVEF 
 
Haematology (haemoglobin, haematocrit, platelet count, RBC, WBC with differential leucocyte 
count) 
 
Blood chemistry (glucose, serum creatinine, total serum bilirubin, AST, ALT, γ-GT, urea/BUN, 
electrolytes/  Na,  K,  Cl,  Ca,  P,  alkaline  phosphatase,  LDH,  beta2-microglobulin,  erythrocyte 
sedimentation rate, uric acid, total protein, serum albumin, protein electrophoresis) 
 
Chest, abdomen and pelvis CT scan (mandatory) 
 
PET/CT (mandatory) 
 
ADL, IADL, and CIRS assessments 
 
Quality of Life evaluation according to EORTC QLC-C30 version 3.0 questionnaire  
 
Bone marrow biopsy is recommended if positive at diagnosis  
 
Lung function (spirometry with DLCO) 
All the following are optional: 
 
MRI  (CNS,  spinal  cord),  endoscopy  and  any  other  diagnostic  imaging  only  if  positive  at  the 
diagnosis or if useful according to clinical judgement 
 
7.6 Investigation during follow-up 
At month + 3, then every 6 months for two years 
 
Physical examination, concomitant medications 
 
Late adverse event assessment: late organ toxicity; second tumours 
 
Haematology (haemoglobin, haematocrit, platelet count, RBC, WBC with differential leucocyte 
count) 
 
Blood chemistry (glucose, serum creatinine, total serum bilirubin, AST, ALT, LDH) 
 
Chest, abdomen and pelvis CT scan (only at month + 3, then every 6 months) 
 
ECG, cardiac assessment (if clinically indicated) 
 
ADL, IADL, and CIRS 
 
Quality of Life evaluation according to EORTC QLC-C30 version 3.0 questionnaire  
 


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At any time 
 
Any  test  or  instrumental  assessment  considered  relevant  under  medical  judgement  in  case  of 
clinical suspected disease progression or toxicity. 
 
 
8. REMOVAL OF SUBJECTS FROM TREATMENT AND/OR STUDY  
8.1 Discontinuation of Treatment 
A subject must be discontinued from study treatment in case of: 
 personal reason 
 the  investigator  believes  that  for  safety  reasons  it  is  in  the  best  interest  of  the  subject  to 
discontinue the treatment 
 disease progression at any time 
 occurrence of an unacceptable adverse event (> grade 3 toxicity for > 2 weeks) 
 If the treatment is discontinued for more than 3 weeks patient is withdrawn from study.  
 
8.2 Withdrawal of subjects from the study  
A subject has the right to withdraw from the study at any time and for any reason without prejudice to 
his or her future medical care by the physician or at the institution. 
A subject must be withdrawn from study treatment if: 
 The  investigator  believes  that  for  safety  reasons  it  is  in  the  best  interest  of  the  subject  to 
discontinue the treatment 
 the subject starts taking any concomitant lymphoma therapy 
 disease progression at any time 
If the patient withdraws the consent or doesn’t fulfil the inclusion criteria he must be considered off 
protocol and cannot be calculated for study endpoints. 
At the time of withdrawal all study procedures outlined for the end of treatment should be completed. 
The primary reason for a patient’s withdrawal from the study is to be recorded in the source document 
and documented on the case report forms (CRF). 
 
8.3 Completion of treatment 
A subject will be considered as having completed the study if all assessments of the treatment phase and 
follow-up have been completed. 


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Subjects who discontinue study treatment due to lack of efficacy are also considered to have completed 
the study. 
9. STATISTICAL METHODS 
9.1 Sample Size 
The  primary  objective  of  the  study  is  to  demonstrate  a  clinical  benefit  in  Complete  Remission  Rate 
(CRR) and safety with GA101-miniCHOP association in elderly unfit patients newly diagnosed with 
diffuse large B-cell lymphoma.  
 
For the purposes of this study, as the reference CR rate (Peyrade et al, Lancet Oncol – 2011)  [18] was 
defined with 1999 International Criteria for response (Cheson, JCO 1999) [32], the response rate to 
therapy will be based on a Central Independent Review of response that will not consider the results of 
FDG-PET but will only use the conventional CT scan images.  
Response defined according to Cheson 2007 International Criteria [31] will also be provided as study 
result.  
 
The  sample  size  has  been  estimated  according  to  a  optimal  Simon  two-stages  design.  The  null 
hypothesis (p0) has been set equal 0.60 on the basis of what reported by F. Peyrade et al. [18].. 
 
With a type I (alfa) error of  0.10 (10%) and a type II (beta) error of 0.10 (power=90%) the alternative 
hypothesis (p1) is 0.75, i.e. a CR rate of 75% with the combination GA101-miniCHOP expected.  
A schema of the design is below reported. 
 
R1 = 21  N1 = 34   
R2 = 47   
Ntot = 71 
 
EN(p0) = 47 
PET(p0) = 64.6% 
 
According to the two-stage design patients enrolment will proceed as follows:  
- the enrolment of 34 patients (stage 1) is planned: if at least 22 patients will achieve CR the study will 
continue; 
- additional 37 patients are entered (stage II): if at least 48 patients out of 71 will achieve a CR the 
study will be considered of possible evaluation for the efficacy of the treatment.  
Considering a withdrawal rate of 10%, the enrollment may continue until 78 patients are accrued in 
order to have at least 71 eligible patients. 


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If GA101-miniCHOP will be active, the probability to declare inactivity is 0.0964 and the probability 
to stop the study at first stage is 0.0610. 
 
10. EFFICACY AND SAFETY ASSESSMENT 
10.1 Efficacy Measurement 
Patients receiving at least 1 course of GA101-miniCHOP will be considered for the Efficacy Population 
(EP). 
 
10.1.1 Efficacy parameters 
Primary variable 
Efficacy of GA101-miniCHOP will be measured by Complete Response Rate (CRR) calculated for the 
EP. 
Complete Response Rate will be evaluated according to 1999 Cheson criteria [32]. 
A patient is defined as a responder if she/he has a complete (confirmed or not) response. Patients in the 
EP without response assessment (due to whatever reason) will be considered as non-responders. 
The analysis of efficacy parameter will be performed according to the Intent to Treat principle for the 
EP. 
Secondary variables 
 
Progression  free  survival  (PFS):  defined  as  the  time  from  entry  into  the  study  until  lymphoma 
relapse/ progression or death as a result of any cause. Responding patients, patients who are lost to 
follow up, who withdrawal the consent or drop-out due to adverse event will be censored at their 
last assessment date. Patients died due to tumor will be considered in progression. Patients died for 
any other cause will be censored to the death date. 
 
Overall survival (OS), defined as the time from the date of treatment start into the study until the 
date of death irrespective of cause. Patients who have not died at the time of end of the whole study, 
and patients who are lost to follow up, will be censored at the date of the last contact 
The complete response rate will be estimated with the 95% confidence interval. 
Time to event data (PFS, OS) will be estimated using the Kaplan-Meier method. 
The curves will be plotted and the 95% confidence interval for median time will be calculated. 
 
10.2 Safety Measurements 
All patients who have received at least one dose of study medication will be considered for the Safety 
Population  (SP)  and  will  be  evaluated  for  toxicity  from  the  time  of  their  first  drug  administration. 


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When toxicity occurs, it should be graded according to the NCI Common Toxicity Criteria, version 4.0 
(Appendix F). 
Any  clinically  significant  abnormalities  persisting  at  the  end  of  the  study  will  be  followed  by  the 
investigator until resolution or until reaching a clinically stable endpoint. 
The study will include the evaluations of safety and tolerability using adverse events, clinical laboratory 
results, vital signs, physical examinations, and electrocardiograms (ECGs) as described in the following 
sections.  
Adverse events, including toxicities, will be analyzed calculating the number and percentage of patients 
and cycles with event. 
 
10.2.1 Safety parameters 
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. 
 
10.2.2 Adverse Event Definitions 
Adverse Event 
An  Adverse  Event  (AE)  is  any  untoward  medical  occurrence  in  a  clinical  investigation  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 laboratory finding), symptom, or disease temporally associated with the use of 
an investigational medicinal product, whether or not considered related to the investigational medicinal 
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. 
 Recurrence of an intermittent medical condition (e.g., headache) not present at baseline 
 Adverse events that are related to a protocol-mandated intervention, including those that occur 
prior to assignment of study treatment (e.g., screening invasive procedures such as biopsies) 
 
Adverse Events will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the 
subject’s legally acceptable representative) for the duration of the study. 
The  Investigator  must  collect  adverse  events  starting  from  the  time  of  signing  the  informed  consent 
through the end of the designated FU period. 
Abnormal laboratory values defined as adverse events 


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An abnormal laboratory value is considered to be an AE if the laboratory abnormality is characterized 
by any of the following: 
-results in discontinuation from the study 
-requires treatment, modification/interruption of study drug dose, or any other therapeutic intervention 
-is judged by the Investigator to be significant clinical importance 
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis or 
syndrome should be recorded on the AE page of the CRF. If the abnormality was not part of a diagnosis 
or syndrome, then the laboratory abnormality should be recorded as the AE. 
Serious Adverse Event 
A  Serious  Adverse  Event  (SAE)  as  defined  by  ICH  is  any  untoward  medical  occurrence  that  at  any 
dose:  
- 
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.) 
- 
Requires or prolongs inpatient hospitalization 
- 
results in persistent or significant disability/ incapacity, or 
- 
is a congenital anomaly/birth defect 
Note: Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in situations other than those listed above. For example, important medical events may 
not be immediately life-threatening or result in death or hospitalization, but may jeopardize the subject 
or may require intervention to prevent one of the outcomes listed in the definition 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. 
Events not considered to be SAEs are hospitalizations which: were planned before entry into the clinical 
study; are for elective treatment of a condition unrelated to the studied indication or its treatment; occur 
on an emergency outpatient basis and do not result in admission (unless fulfilling other criteria above); 
are part of the normal treatment or monitoring of the studied indication and are not associated with any 
deterioration in condition. 
If  an  AE  is  considered  serious,  both  the  AE  pages  of  the  CRF  and  the  SAE  Report  form  must  be 
completed. 
For each SAE, the investigator will provide information on severity, start and stop dates, relationship to 
(investigational  product)  study  drug,  action  taken  regarding  (investigational  product)  study  drug  and 
outcome. 
 


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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: 
-  Cases of potential drug-induced liver injury that include an elevated ALT or AST in combination with 
either an elevated bilirubin or clinical jaundice,as defined below : 
The finding of an elevated ALT or AST ( 3  ULN) in combination with either an elevated total 
bilirubin ( 2  ULN) or clinical jaundice in the absence of cholestasis or other causes of 
hyperbilirubinemia is considered to be an indicator of severe liver injury.  Therefore, investigators must 
report as an adverse event the occurrence of either of the following: 
Treatment-emergent ALT or AST  3  ULN in combination with total bilirubin  2  ULN 
Treatment-emergent ALT or AST  3  ULN in combination with clinical jaundice 
-  Suspected transmission of an infectious agent by the study drug, as defined below 
Any organism, virus, or infectious particle (e.g., prion protein transmitting  transmissible 
spongiform encephalopathy), pathogenic or non-pathogenic, is considered an infectious agent.  
A transmission of an infectious agent may be suspected from clinical symptoms or laboratory 
findings that indicate an infection in a patient exposed to a medicinal product.  This term 
applies only when a contamination of the study drug is suspected. 
-  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 
 
Unexpected Adverse Event 
An  adverse  event,  the  nature  or  severity  of  which  is  not  consistent  with  the  applicable  product 
information (for an investigational medicinal product, the Investigator’s Brochure). 
 
 


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10.2.3 Adverse Event Classifications 
Classification of severity 
For  both  AEs  and  SAEs,  the  investigator(s)  must  assess  the  severity  of  the  event.  The  severity  of 
adverse  events  (AEs)  will  be  graded  on  a  scale  of  1  to  5  according  to  the  National  Cancer  Institute 
(NCI) Common Terminology Criteria for Adverse Events Version 4.0 (NCI CTCAE). The NCI CTCAE 
V 4.0 can be viewed on-line at the following NCI web site: http://ctep.cancer.gov/reporting/ctc.html. If 
a specific event is not included in the NCI CTCAE toxicity scale, the following scale should be used to 
grade the event. 
 
Grade  Definition  
     1  
Mild Awareness of sign, symptom, or event, usually transient, requiring no
special treatment and generally not interfering with usual daily activities  
     2  
Moderate Discomfort that causes interference with usual activities; usually 
ameliorated by basic therapeutic manoeuvres  
     3  
Severe  Incapacitating  with  inability  to  do  usual  activities  or  significantly
affects clinical status and warrants intervention. Hospitalization may or may 
not be required  
    4  
 
Life-threatening Immediate risk of death; requires hospitalization and
clinical intervention.  
    5  
Death  
  
Association With the Use of the Investigational Medicinal Product (IMP) 
An adverse event is considered associated with the use of the investigational product if the attribution is 
possible, probable, or very likely by the definitions listed above. 
 
Attribution Definitions 
 Not related. 
An adverse event that is not related to the use of the investigational product. 
 Doubtful. 
An AE 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. 


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An AE that might be due to the use of the investigational product. 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  AE  that  might  be  due  to  the  use  of  the  investigational  product.  The  relationship  in  time  is 
suggestive (e.g., confirmed by dechallenge). An alternative explanation is less likely, e.g., 
concomitant drug(s), concomitant disease(s). 
 Very likely. 
An  AE  that  is  listed  as  a  possible  adverse  event  reaction,  and  cannot  be  reasonably  explained  by  an 
alternative explanation, e.g., concomitant investigational drug(s), concomitant disease(s). The 
relationship in time is very suggestive (e.g., it is confirmed by dechallenge and rechallenge). 
Classification of Relationship/Causality of adverse events (AE/SAE) to study drug 
The Investigator(s) must determine the relationship between the administration of study drug and the 
occurrence of an AE/SAE as Not Suspected or Suspected as defined below: 
 
Not suspected: 
The temporal relationship of the adverse event to study drug 
administration  makes  a  causal  relationship  unlikely  or  remote,  or  other
medications, therapeutic interventions, or underlying conditions provide a
sufficient explanation for the observed event 
Suspected: 
The temporal relationship of the adverse event to study drug 
administration makes a causal relationship possible, and other
medications,  therapeutic  interventions,  or  underlying  conditions  do  not
provide a sufficient explanation for the observed event. 
 
Treatment-related mortality 
If an adverse event considered associated with the study medication results in a patient’s death, then the 
event will be listed as a “treatment-related mortality”. 
 
10.2.4 Adverse Event Procedures 
All Adverse Events 
All AEs that occur between the fist study-related procedures and for 30 days following the last dose of 
investigational product will be reported. Resolution information after 30 days should also be provided 
for grade 3 to 4 drug related events. This subset should be followed up until resolution to a grade 1 or 
better. 


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Adverse events occurring after 30 days should also be reported if considered related to investigational 
product. 
Clinically relevant changes in laboratory values must be recorded in the adverse event section of the 
CRF. 
All  AEs,  regardless  of  seriousness,  severity,  or  presumed  relationship  to  study  therapy,  must  be 
recorded  in  the  source  document  and  the  CRF.  Investigators  must  record  in  the  CRF  their  opinion 
concerning the relationship of the adverse event to the study therapy. All measures required for adverse 
event management must be recorded in the source document. 
Immediate reporting by Investigator to the Trial Office (SAE) 
The investigator will inform the Trial Office of any serious adverse event and/or non serious AESIs. 
This applies to all SAEs, regardless of relationship to the study medication, that occur during the study, 
those made known to the Investigator(s) within 30 days after a subject’s last dose of study drug, and 
those  made  known  to  the  investigator(s)  at  any  time  that  are  suspected  of  being  related  to  the  study 
medication. This must be documented on an SAE form (Appendix J). This form must be completed and 
supplied to Trial Office within 24 hours/1 business day or at the latest on the following working day. 
The initial report must be as complete as possible, including details of the current illness and serious 
adverse event, and an assessment of the causal relationship between the event and the investigational 
product(s). Information not available at the time of the initial report (e.g., an end date for the adverse 
event or laboratory values received after the report) must be documented on a follow-up SAE form. 
SAE reporting to Regulatory Authorities and Ethic Committees  
The pharmacovigilance team will inform relevant Regulatory Authorities and the Ethics Committee: 
(a)- of all relevant information about serious unexpected adverse events suspected to be related to the 
study medication that are fatal or life threatening as soon as possible, and in any case no later than seven 
days after knowledge of such a case. Relevant follow-up information for these cases will subsequently 
be submitted within an additional eight days. 
(b)- of all other serious unexpected events suspected to be related to the study medication as soon as 
possible, but within a maximum of fifteen days of first knowledge by the investigator(s). 
Post-Study Adverse Events 
The Sponsor should be notified if the investigator becomes aware of any serious adverse event/AESI 
that occurs after the end of the adverse event reporting period, if the event is believed to be related to 
prior study drug treatment. During this period, the investigator is required to report such events to the 
Sponsor although he/she is not required to actively monitor patients for adverse events.  
 
 


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10.2.5 Safety contact information 
 
PHARMACOVIGILANCE 
 
 
SC Ematologia, AO SS Antonio e Biagio  
Via Venezia, 16-15121 Alessandria, Italy 
 
 
 
Safety 
phone number 
 
Safety 
Fax/e-mail 
Dr Alessandro Levis (responsible) 
+39 0131 206066-6071 
+39 0131 263455 
alevis.sandro@gmail.com 
 
 
11. FORMS AND PROCEDURES FOR COLLECTING DATA AND DATA MANAGEMENT 
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. Electronic CRFs will be realized 
with OpenClinica [Open Source Software versione 3.1.2 (Isovera INC, USA) and maintained by Data 
River srl, Modena, Italy]. A confirmation email will be sent to the investigator, to the trial office and to 
the  study  coordinator(s).  If  electronic  CRFs  are  not  available  at  study  opening,  paper  CRFs  will  be 
distributed to be used by Investigators only until the electronic version is finalized. 
Several  systematic  quality  controls  will  be  active  during  data  entry;  periodic  statistical  checks  and 
personalized queries will be performed during the study. 
Frequency  of  on-site  monitoring  will  be  planned  according  to  the  results  of  the  statistical  quality 
controls. 
 
12. ETHICAL CONSIDERATIONS  
12.1 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”).  
 


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12.2 Subject identification – Personal Data protection 
All  records  identifying  the  subject  must  be  kept  confidential  and,  to  the  extent  permitted  by  the 
applicable laws and/or regulations, not be made publicly available. The name of the patient will not be 
asked  for  nor  recorded  at  the  Data  Center.  A  sequential  identification  number  will  be  automatically 
attributed  to  each  patient  registered  in  the  study.  This  number  will  identify  the  patient  and  must  be 
included on all case report forms. In order to avoid identification errors, patient initials and date of birth 
will also be reported on the case report forms. 
Any and all patient information or documentation pertaining to a clinical trial, to the extent permitting, 
through a “key” kept anywhere, regardless of whether such key is supplied along with the information 
or documentation or not, must be considered as containing sensitive personal data of the patient, and is 
therefore subjected to the provisions of applicable data protection (“privacy”) regulations. Breach of 
such regulations may result in administrative or even criminal sanctions. 
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 12.3 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.  
 
12.3 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 Protocol_GAEL__version 1_29-Sept-2014 
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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”. 
 
 
12.4 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. 
 
12.5 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. 
 
12.6. 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 FIL’s Procedure.  
The results of this study will be submitted for publication in peer reviewed journals and for presentation 
at appropriate scientific meetings according to the rules of FIL publication policy.  
No publication of any results will occur without the agreement of the study chairs 
 
 
 


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12.7 Study insurance 
The 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. 
A specific insurance with company HDI - GERLING Versicherung AG INDUSTRIES was concluded 
for patients enrolled in this study.  
No  extra  expenses,  neither  for  therapies  nor  for  clinical  or  laboratory  procedures  can  be  asked  or 
expected to be paid by SSN or patients. 


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Tirelli U, Zagonel V, Errante D, Fratino L, Monfardini S. Treatment of non-Hodgkin's 
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Vose  JM,  Armitage  JO,  Weisenburger  DD,  Bierman  PJ,  Sorensen  S,  Hutchins  M,  et  al.  The 
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Luminari  S,  Montanini  A,  Caballero  D,  Bologna  S,  Notter  M,  Dyer  MJ,  et  al.  Nonpegylated 
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Merli F, Bertini M, Luminari S, Mozzana R, Botto B, Liberati AM, et al. Long term results of a 
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VEBEC in elderly patients with diffuse large B-cell lymphoma. Leuk Lymphoma 2007,48:367-
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diffuse large B-cell lymphoma: results from the ANZINTER3 trial of the Intergruppo Italiano 
Linfomi. Leuk Lymphoma 2012,53:581-588. 
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Peyrade  F,  Jardin  F,  Thieblemont  C,  Thyss  A,  Emile  JF,  Castaigne  S,  et  al.  Attenuated 
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diffuse large B-cell lymphoma: a multicentre, single-arm, phase 2 trial. Lancet Oncol 
2011,12:460-468. 
19. 
Bertini M, Freilone R, Vitolo U, Botto B, Pizzuti M, Gavarotti P, et al. P-VEBEC: a new 8-
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lymphoma (NHL). Ann Oncol 1994,5:895-900. 
20. 
Verger  E,  Salamero  M,  Conill  C.  Can  Karnofsky  performance  status  be  transformed  to  the 
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21. 
Extermann M, Hurria A. Comprehensive geriatric assessment for older patients with cancer. J 
Clin Oncol 2007,25:1824-1831. 
22. 
Wedding U, Honecker F, Bokemeyer C, Pientka L, Hoffken K. Tolerance to chemotherapy in 
elderly patients with cancer. Cancer Control 2007,14:44-56. 
23. 
Katz S, Ford AB, Moskowitz RW, Jackson BA, Jaffe MW. Studies of Illness in the Aged. The 
Index of Adl: A Standardized Measure of Biological and Psychosocial Function. JAMA 
1963,185:914-919. 
24. 
Katz  S,  Downs  TD,  Cash  HR,  Grotz  RC.  Progress  in  development  of  the  index  of  ADL. 
Gerontologist 1970,10:20-30. 
25. 
Lawton MP, Brody EM. Assessment of older people: self-maintaining and instrumental 
activities of daily living. Gerontologist 1969,9:179-186. 
26. 
Linn BS, Linn MW, Gurel L. Cumulative illness rating scale. J Am Geriatr Soc 1968,16:622-
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27. 
Parmelee  PA,  Thuras  PD,  Katz  IR,  Lawton  MP.  Validation  of  the  Cumulative  Illness  Rating 
Scale in a geriatric residential population. J Am Geriatr Soc 1995,43:130-137. 
28. 
Merli  F,  Luminari  S,  Rossi  G,  Mammi  C,  Marcheselli  L,  Ferrari  A,  et  al.  Outcome  of  frail 
elderly patients with diffuse large B-cell lymphoma prospectively identified by Comprehensive 
Geriatric Assessment: results from a study of the Fondazione Italiana Linfomi. Leuk Lymphoma 
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29. 
Mossner E, Brunker P, Moser S, Puntener U, Schmidt C, Herter S, et al. Increasing the efficacy 
of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with 
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Beers SA, French RR, Chan HT, Lim SH, Jarrett TC, Vidal RM, et al. Antigenic modulation 
limits the efficacy of anti-CD20 antibodies: implications for antibody selection. Blood 
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Cheson  BD,  Pfistner  B,  Juweid  ME,  Gascoyne  RD,  Specht  L,  Horning  SJ,  et  al.  Revised 
response criteria for malignant lymphoma. J Clin Oncol 2007,25:579-586. 
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Cheson  BD,  Horning  SJ,  Coiffier  B,  Shipp  MA,  Fisher  RI,  Connors  JM,  et  al.  Report  of  an 
international  workshop  to  standardize  response  criteria  for  non-Hodgkin's  lymphomas.  NCI 
Sponsored International Working Group. J Clin Oncol 1999,17:1244. 
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APPENDIX A:  Comprehensive Geriatric Assessment (GCA) in onco-hematology 
 
Definition of FIT, UNFIT and FRAIL elderly patients [21, 22] 
 
 
FIT: 
non UNFIT, non FRAIL 
UNFIT: 
CHRONOLOGIC CRITERIA: age> 80 years and FIT 
CLINICAL FUNCTIONAL CRITERIA: according to ADL, IADL and CIRS scores 
FRAIL: 
CHRONOLOGIC CRITERIA: age> 80 years and UNFIT 
CLINICAL FUNCTIONAL CRITERIA: according to ADL, IADL and CIRS scores 
 
 
 
 


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APPENDIX B: Activity of Daily Living (ADL)  
Valutazione delle attività di base della vita quotidiana (ADL) [23, 24] 
 
A Fare il bagno (vasca, doccia, spugnature) 
[1] Fa il bagno da solo (entra ed esce dalla vasca da solo)    
 
 
 
 
1 
[2] Ha bisogno di assistenza soltanto nella pulizia di una parte del corpo (es. schiena)  
 
1 
[3] Ha bisogno di assistenza per più di una parte del corpo  
 
 
 
 
0 
 
B Vestirsi (prendere i vestiti dall’armadio e/o cassetti), inclusa biancheria intima, vestiti, uso delle 
allacciature o delle bretelle, se utilizzate) 
 
[1] Prende i vestiti e si veste completamente da solo senza bisogno di assistenza   
 
1 
[2] Prende i vestiti e si veste senza bisogno di assistenza eccetto che per allacciare le scarpe  
1 
[3]  Ha  bisogno  di  assistenza  per  prendere  i  vestiti  o  nel  vestirsi  oppure  rimane  parzialmente  o 
completamente svestito 
 
 
 
 
 
 
 
 
 
0 
 
C Toilette (andare nella stanza da bagno per la minzione e l’evacuazione, pulirsi, rivestirsi) 
[1] Va in bagno, si pulisce e si riveste senza bisogno di assistenza (può utilizzare  mezzi  di supporto, 
come  bastone,  deambulatore  o  seggiola  a  rotelle,  può  usare    vaso  da  notte  o  comoda  svuotandoli  al 
mattino)  
 
 
 
 
 
 
 
 
 
 
 
1 
[2] Ha bisogno di assistenza nell’andare in bagno o nel pulirsi o nel rivestirsi o nell’uso del  
vaso da notte o della comoda. 
 
 
 
 
 
 
 
 
0 
[3] Non si reca in bagno per l’evacuazione    
 
 
 
 
 
 
0 
 
D Spostarsi 
[1] Si sposta dentro e fuori dal letto ed in poltrona senza assistenza eventualmente 
con canadesi o deambulatore)  
 
 
 
 
 
 
 
 
1 
[2] Compie questi trasferimenti se aiutato   
 
 
 
 
 
 
0 
[3] Allettato, non esce dal letto  
 
 
 
 
 
 
 
 
0 
 
E Continenza di feci e urine 
[1] Controlla completamente feci e urine  
 
 
 
 
 
 
 
1 
[2] “Incidenti” occasionali   
 
 
 
 
 
 
 
 
0 
[3] Necessita di supervisione per il controllo di feci e urine, usa il catetere, è Incontinente 
0 


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F Alimentazione 
[1] Senza assistenza    
 
 
 
 
 
 
 
 
 
1 
[2] Assistenza solo per tagliare la carne o imburrare il pane  
 
 
 
 
1 
[3] Richiede assistenza per portare il cibo alla bocca o viene nutrito parzialmente o  
completamente per via parenterale  
 
 
 
 
 
 
 
0 
 
PUNTEGGIO TOTALE (numero totale funzioni residue):______________  
 


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APPENDIX C: Instrumental Activity of Daily Living (IADL) 
 
Valutazione delle attività strumentali della vita quotidiana (IADL) [25] 
A Capacità di usare il telefono 
[1] Usa il telefono di propria iniziativa  
 
 
 
 
 
 
 
1 
[2] Compone solo alcuni numeri ben conosciuti  
 
 
 
 
 
 
1 
[3] Risponde ma non è capace di comporre il numero  
 
 
 
 
 
1 
[4] Non risponde al telefono   
 
 
 
 
 
 
 
 
0 
Non applicabile  
 
 
 
 
 
 
 
 
 
 
NA 
B Fare acquisti 
[1] Fa tutte le proprie spese senza aiuto  
 
 
 
 
 
 
 
1 
[2] Fa piccoli acquisti senza aiuto  
 
 
 
 
 
 
 
 
0 
[3] Ha bisogno di essere accompagnato  
 
 
 
 
 
 
 
0 
[4] Completamente incapace di fare acquisti  
 
 
 
 
 
 
0 
Non applicabile  
 
 
 
 
 
 
 
 
 
 
NA 
C Preparazione del cibo 
[1] Organizza, prepara e serve pasti adeguatamente preparati  
 
 
 
 
1 
[2] Prepara pasti adeguati solo se sono procurati gli ingredienti  
 
 
 
 
0 
[3] Scalda o serve pasti preparati oppure prepara cibi ma non mantiene una dieta adeguata  
0 
[4] Ha bisogno di avere cibi preparati e serviti  
 
 
 
 
 
 
0 
Non applicabile  
 
 
 
 
 
 
 
 
 
 
NA 
D Governo della casa 
[1] Mantiene la casa da solo o con occasionale assistenza (per es. aiuto per i lavori pesanti)   
1 
[2] Esegue compiti quotidiani leggeri ma non mantiene un accettabile livello di pulizia  della casa 1 
[3] Ha bisogno di aiuto in ogni operazione di governo della casa  
 
 
 
1 
[4] Non partecipa a nessuna operazione di governo della casa 
 
 
 
 
0 
Non applicabile 
 
 
 
 
 
 
 
 
 
 
NA 
E Biancheria 
[1] Fa il bucato personalmente e completamente  
 
 
 
 
 
 
1 
[2] Lava le piccole cose (calze, fazzoletti)   
 
 
 
 
 
 
1 
[3] Tutta la biancheria deve essere lavata da altri  
 
 
 
 
 
 
0 
Non applicabile  
 
 
 
 
 
 
 
 
 
 
NA 
F Mezzi di trasporto 
[1] Si sposta da solo sui mezzi pubblici o guida la propria auto  
 
 
 
 
1 


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[2] Si sposta in taxi ma non usa mezzi di trasporto pubblici  
 
 
 
 
1 
[3] Usa i mezzi di trasporto se assistito o accompagnato  
 
 
 
 
 
1 
[4] Può spostarsi solo con taxi o auto e con assistenza  
 
 
 
 
 
0 
[5] Non si sposta per niente    
 
 
 
 
 
 
 
 
0 
Non applicabile  
 
 
 
 
 
 
 
 
 
 
NA 
G Responsabilità nell'uso dei farmaci 
[1] Prende le medicine che gli sono state prescritte   
 
 
 
 
 
1 
[2] Prende le medicine se sono preparate in anticipo e in dosi separate  
 
 
 
0 
[3] Non è in grado di prendere le medicine da solo   
 
 
 
 
 
0 
Non applicabile  
 
 
 
 
 
 
 
 
 
 
NA 
H Capacità di maneggiare il denaro 
[1] Maneggia le proprie finanze in modo indipendente  
 
 
 
 
 
1 
[2] E' in grado di fare piccoli acquisti  
 
 
 
 
 
 
 
1 
[3] E' incapace di maneggiare i soldi  
 
 
 
 
 
 
 
0 
Non applicabile  
 
 
 
 
 
 
 
 
 
 
NA  
 
PUNTEGGIO TOTALE (numero totale funzioni residue):_____________ 


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APPENDIX D: Cumulative Illness Rating Scale  (CIRS) 
 
Valutazione dell’indice di comorbidità (CIRS) [26, 27] 
 
1) Patologie cardiache (solo cuore)    
 
 
0 
 1  
2  
3  
4 
 
2) Ipertensione  
 
 
 
 
 
0  
1  
2  
3  
4 
si valuta la severità, gli organi coinvolti sono considerati separatamente 
 
3) Patologie vascolari  
 
 
 
 
0  
1  
2  
3  
4 
sangue, vasi, midollo, milza, sistema linfatico 
 
4) Patologie respiratorie  
 
 
 
 
0  
1  
2  
3  
4 
polmoni, bronchi, trachea sotto la laringe 
 
5) O.O.N.G.L.  
 
 
 
 
 
0  
1  
2  
3  
4 
occhio, orecchio, naso, gola, laringe 
 
6) Apparato GI superiore  
 
 
 
 
0  
1  
2  
3  
4 
esofago, stomaco, duodeno, albero biliare, pancreas 
 
7) Apparato GI inferiore  
 
 
 
 
0  
1  
2  
3  
4 
intestino, ernie 
 
8) Patologie epatiche   
 
 
 
 
0  
1  
2  
3  
4 
solo fegato 
 
9) Patologie renali  
 
 
 
 
 
0  
1  
2  
3 
 4 
solo rene 
 
10) Altre patologie genito-urinarie   
 
 
0  
1  
2  
3  
4 
ureteri, vescica, uretra, prostata, genitali 
 
11) Sistema muscolo-scheletro-cute   
 
 
0  
1  
2  
3  
4 


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muscoli, scheletro, tegumenti 
 
12) Patologie sistema nervoso  
 
 
 
 
0  
1  
2  
3  
4 
sistema nervoso centrale e periferico; non include la demenza 
 
13) Patologie endocrine-metaboliche  
 
 
 
0  
1  
2  
3  
4 
include diabete, infezioni, sepsi, stati tossici 
 
14) Patologie psichiatriche-comportamentali  
 
 
0  
1  
2  
3  
4 
include demenza, depressione, ansia, agitazione, psicosi 
 
 
0: assente; 1: lieve; 2: moderato; 3: grave; 4: molto grave 
 
 
Indice di severità:___________ indice di comorbidità: ___________ 
 


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APPENDIX E: Ann Arbor staging* - Cotswolds recommendations** 
 
(Sources: * Carbone PP, Kaplan HS, Musshoff K, et al. Report of the committee on Hodgkin's disease 
staging classification. Cancer. Res. 31:1860-1861, 1971. ** Lister TA, Crowther D, Sutcliffe SB, et al. 
Staging for Hodgkin's disease. Report of a committee convened todiscuss the evaluation and staging of 
patients  with  Hodgkin's  disease:  Cotswolds  meeting.  J.  Clin.  Oncol.  7:1630-1636,1989  [Erratum  J. 
Clin. Oncol. 8:1602,1990]) 
 
Stage I: involvement of a single lymphatic region (I), or localized involvement of a single 
extralymphatic organ or site (IE). 
Stage  II:  involvement  of  two  or  more  lymphatic  regions  on  the  same  side  of  diaphragm  (II)  or 
localized  involvement  of  an  extralymphatic  organ  or  site  and  one  ore  more  lymph  node  regions  the 
same side of diaphragm (IIE). 
Stage III: involvement of two or more lymphatic regions on both sides of diaphragm (III) which may 
also be accompanied either by localized involvement of an extralymphatic organ or site (IIIE), or by 
involvement of the spleen (IIIS). 
Stage IV: Diffuse or disseminated involvement of one or more extralymphatic organs or tissue, with or 
without associated lymph node involvement. 
Bone marrow or liver involvement will always be considered as stage IV. 
Lymphatic  structures  include  lymph  nodes,  spleen,  thymus,  Waldeyer’s  ring  including  tonsils.  The 
lymphatic  regions  are  defined  according  to  Ann  Arbor  as  (a)  clinical  enlargement  of  a  node  when 
alternative  pathology  may  reasonably  be  ruled  out  (suspicious  nodes  should  always  be  biopsied  if 
treatment  decisions  are  based  on  their  involvement)  ;  and  (b)  enlargement  on  plain  radiograph,  CT 
scan, or lymphography. 
 
Localized  involvement  of  an  extralymphatic  site  (extranodal  site  or  E-lesion)  is  diagnosed  when  the 
involvement is small enough to be in principle accessible for curative radiotherapy (thereby excluding 
diffuse organ involvement corresponding to stage IV). 
 
Criteria for “B” symptoms 
The presence of (a) unexplained weight loss of more than 10% of the body weight during the 6 months 
before initial staging investigation and/or (b) unexplained, persistent, or recurrent fever with 
temperatures above 38 C during the previous month and/or (c) recurrent drenching night sweats during 
the previous months is denoted by the suffix letter ‘B’. ‘A’ indicates the absence of these symptoms. 


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Criteria for Bulky disease 
 
Bulky disease is present if:  
− there is massive lymphoma development in a lymph node with a greatest diameter of ≥7.5 cm or a 
conglomerate tumour with a greatest diameter ≥7.5 cm  
− there is a mediastinal tumour with a diameter ≥7.5 cm, whereby the hili and the pericardium should 
not be included in the measurement. 
 


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APPENDIX  F:  National  Cancer  Institute  Common  Toxicity  Criteria  for  Adverse  Events  (NCI 
CTCAE), Version 4.0 
 
 
 
In the present study, adverse events and/or adverse drug reactions will be recorded according to the: 
Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. 
 
At the time this protocol was issued, the full CTC document was available on the NCI web site, at the 
following address: http://ctep.cancer.gov/reporting/ctc.html. 


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APPENDIX G WHO performance status scale 
 
Grade Performance scale 
0 Able to carry out all normal activity without restriction  
1 Restricted in physically strenuous activity but ambulatory and able to carry out light work 
2 Ambulatory and capable of all self-care but unable to carry out any work; up and about more than 
50% of waking hours 
3 Capable of only limited self-care; confined to bed or chair more than 50% of waking hours 
4 Completely disabled; cannot carry on any self-care; totally confined to bed or chair 


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APPENDIX  H:  Quality  of  Life  evaluation  according  to 
EORTC  QLC-C30  version  3.0 
questionnaire  
 


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APPENDIX I: Study Flow Chart 
 
 
 
GA101-miniCHOP regimen 
Patients  will  receive  6  courses  of  GA101-miniCHOP  regimen  and  2  additional  infusions  of 
GA101, every 21 days (for a total of 6 courses of miniCHOP and 10 infusions of GA101) 
Cycle 1 
 
GA101: 1000 mg day 1, day 8 and day 15, iv 
 
Cyclophosphamide: 400 mg/mq, day 1, iv 
 
Doxorubicin: 25 mg/mq, day 1, iv 
 
Vincristine: 1 mg, day 1, iv 
 
Prednisone: 40 mg/mq, days 1-5, os 
Cycles 2-6  
 
GA101: 1000 mg day 1, iv 
 
Cyclophosphamide: 400 mg/mq, day 1, iv 
 
Doxorubicin: 25 mg/mq, day 1, iv 
 
Vincristine: 1 mg, day 1, iv 
 
Prednisone: 40 mg/mq, days 1-5, os 


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APPENDIX J: SAE FORM 
 


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APPENDIX K: INDEPENDENT REVIEW COMMITTEE  
For the purposes of this study, as the reference CR rate (Peyrade et al, Lancet Oncol – 2011) after 
10 infusions of GA101 and 6 cycles of miniCHOP,  was defined with 1999 International Criteria 
for  response  (Cheson,  JCO  1999),  the  response  rate  to  therapy  will  be  based  on  a  Central 
Independent Review of response that will not consider the results of FDG-PET but will only use the 
conventional CT scan images.  
Response defined according to Cheson 2007 criteria will also be provided as study result.  
CT scan images will be sent by Centers to the Independent Review Committee, coordinated by Dr. 
Francesco Merli.  
All details (timing, shipment information, etc.) concerning CT review are available in the specific 
operating procedure. 
 
 

SAP_001.pdf: 
 
Fondazione Italiana Linfomi ONLUS 
 
Sede legale: piazza Turati 5, 15121 – Alessandria 
P.IVA IT 02143940068 C.F. 96039680069 
Uffici Studi FIL: c/o Uffici PACTO, Spalto Marengo 44, 15121, Alessandria 
 Tel. 0131– 033153, Fax 0131 - 263455; e-mail: startup@filinf.it; sito web: www.filinf.it 
 
 
 
 
 
Study ID: FIL_GAEL 
Eudract Number: 2014-005697-10 
ClinicalTrials.gov Identifier: NCT02495454 
 
Title: GA101-miniCHOP regimen for the treatment of elderly unfit patients 
with diffuse large B-cell non-Hodgkin’s lymphoma. A phase II study of the 
Fondazione Italiana Linfomi (FIL). 
 
Final Study Report: version 1, April 30th, 2020 
 
 


 
 
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FINAL STUDY REPORT 
Name of 
Sponsor/Company: 
Fondazione Italiana Linfomi ONLUS (FIL) 
 
 
Study type: 
Interventional/clinical study 
Study phase:  
II 
Study title:  
GA101-miniCHOP  regimen  for  the  treatment  of  elderly  unfit  patients  with 
diffuse large B-cell non-Hodgkin’s lymphoma. A phase II study of the 
Fondazione Italiana Linfomi (FIL). 
EudraCT:  
2014-005697-10 
ID study: 
FIL_GAEL 
Version: 
1 
Date: 
September 29th, 2014 
 
 
Name 
of 
Active 
Ingredient: 
GA101 (Obinutuzumab) 
Cyclophosphamide 
Doxorubicin  
Vincristine 
Prednisone 
Conditions (diagnosis): Elderly unfit patients with CD20 positive Diffuse Large B-cell Lymphoma and 
Follicular grade IIIB, according to WHO classification 
 
 
Studied period (years):  
CA authorization: 
24/04/2015 
lead EC opinion date: 
25/03/2015 
date of first enrolment: 
25/08/2015 
date of last completed: 
19/02/2020 
date of Interim Analysis 
(If applicable): 
22/03/2017 
 
 
Study coordinator:   
 
 
Francesco Merli, MD: 
 
Azienda  Unitа  Sanitaria  Locale-IRCCS  -  Arcispedale  Santa  Maria  Nuova  – 
Ematologia – Reggio Emilia 
Study centres: 
 
 
Manuela Zanni, MD: 
 
A.O. SS. Antonio e Biagio e Cesare Arrigo - S.C. Ematologia - Alessandria 
 
 
 
Guido Gini, MD: 
 
AOU Ospedali Riuniti - Clinica di Ematologia - Ancona 
 
 
 
Annarita Conconi, MD 
 
Ospedale Degli Infermi - S.C.  Oncologia - Biella 
 
 
 
Alessandra Tucci, MD 
 
ASST Spedali Civili di Brescia – Ematologia - Brescia 
 
 
 
Gerardo Musuraca, MD 
 
Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.) – 
Ematologia - Meldola 


 
 
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Paola Matteucci, MD 
 
Fondazione  IRCCS  Istituto  Nazionale  dei  Tumori  di  Milano  –  Ematologia  - 
Milano 
 
 
 
Samantha Pozzi, MD 
 
Azienda  Ospedaliero-Universitaria  Policlinico  di  Modena  -  Dipartimento  di 
Scienze Mediche e Chirurgiche Materno-Infantili e dell'Adulto - Modena 
 
 
 
Gianluca Gaidano, Prof. 
 
AOU Maggiore della Caritа di Novara - SCDU Ematologia - Novara 
 
 
 
Dario Marino, MD 
 
I.R.C.C.S. Istituto Oncologico Veneto - Oncologia 1 – Padova 
 
 
 
Maurizio Musso, MD 
 
Casa  di  Cura  La  Maddalena  -  Oncoematologia  e  TMO  Dip.  Oncologia  - 
Palermo 
 
 
 
Claudia Cellini, MD 
 
Ospedale delle Croci – Ematologia - Ravenna 
 
 
 
Annalia Molinari, MD 
 
Ospedale degli Infermi di Rimini - U.O. di Ematologia - Rimini 
 
 
 
Anna Marina Liberati, Prof.ssa 
 
A.O. S. Maria di Terni - S.C. Oncoematologia - Terni 
 
 
 
Federica Cavallo, MD 
 
A.O.U. Città della Salute e della Scienza di Torino - Ematologia Universitaria - 
Torino 
 
 
 
Merli Michele, MD 
 
Ospedale di Circolo - U.O.C Ematologia - Varese 
 
 
Date of last database 
download: 
27/04/2020 
Report date: 
30/04/2020 
 
 
 
List of abbreviations 
 
ADL 
Activity of Daily Living 
 
AE 
Adverse Events 
 
ALC 
Absolute Lymphocyte Count 
 
ALT 
Alanine Aminotransferase 
 
AST  
Aspartate Aminotransferase 
 
ASCO 
American Society of Clinical Oncology 
 
B2M 
Beta2-microglobuline 
 
BM 
Bone Marrow  
 
CGA 
Comprehensive Geriatric Assessment 
 
CHOP 
Cyclophosphamide, Doxorubicin, Vincristine, Prednisone 
 
CI 
Confidence interval 
 
CIRS 
Cumulative Illness Rating Scale 


 
 
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CNS 
Central Nervous System 
 
CR 
Complete Remission 
 
CRR 
Complete Remission Rate 
 
CT scan 
Computed Tomography Scan 
 
CTCAE 
Common Terminology Criteria for Adverse Events 
 
DLBCL 
Diffuse Large B Cell Lymphoma 
 
ECOG 
Eastern Cooperative Oncology Group 
 
EORTC 
European Platform of Cancer Research 
 
FDG-PET 
Fluorodeoxyglucose Positron Emission Tomography 
 
FIL 
Fondazione Italiana Linfomi 
 
FU 
Follow Up 
 
GA101  
Obinutuzumab 
 
G-CSF 
Granulocyte Colony-Stimulating Factor 
 
Hb 
Hemoglobin 
 
HBcAb 
Hepatitis B Core Antibody 
 
HBsAg 
Hepatitis B surface antigen 
 
HCV 
Hepatitis C Virus 
 
HIV 
Human Immunodeficiency Virus 
 
I 
Initial 
 
IADL 
Instrumental Activity of Daily Living 
 
ISRT 
Involved Site Radiation Therapy 
 
IPI 
International Prognostic Index 
 
LVEF 
Left Ventricular Ejection Fraction 
 
MEDdra 
Medical Dictionary for Regulatory Activities 
 
ORR 
Overall Response Rate 
 
OS 
Overall Survival 
 
PET 
Positron Emission Tomography 
 
PFS 
Progression Free Survival 
 
PR 
Partial Remission 
 
PRR 
Partial Response Rate 
 
QoL 
Quality of Life 
 
SAE 
Serious Adverse Event 
 
SD 
Stable Disease 
 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
 
TLBCL 
T-cell/histiocyte LBCL 
 
ULN 
Upper Limit of Normality 
 
WBC 
White Blood Cell 
 
WHO 
World Health Organization 
 
 
Study description (Aim 
of the study) 
 
Primary objectives 
The  primary  objective  is  to  assess  whether  the  regimen  GA101-miniCHOP 
achieves an absolute increase of the CR proportion of at least 15% (from 60% 
to 75% respect to R-miniCHOP regimen. To evaluate the activity of GA101-
miniCHOP regimen in terms of complete response rate (CRR) 
Secondary objectives: 
- To evaluate the safety and tolerability of GA101 miniCHOP regiment 
in terms of adverse events 
- Partial and Overall Response Rate: PR and ORR (CR+PR) 
- Overall Survival (OS) 
- Progression Free Survival (PFS) 


 
 
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- Dynamics of Comprehensive Geriatric Assessment (CGA) 
- Dynamics of Quality of Life (QoL) questionnaires 
Primary end-points: 
Complete Response Rate after 10 infusions of GA101 and 6 cycles of 
miniCHOP. The response rate to therapy will be based a central Independent 
Review Committee of response that will not consider the results of FDG-PET 
but will only use the conventional CT scan images (International Criteria, B. 
Cheson, JCO 1999) 
Secondary end-points: 
- Rate of Adverse Events 
- Partial and Overall Response Rate (PRR, ORR) 
- Overall Survival (OS) 
- Progression Free Survival (PFS) 
- Change in ADL, IADL and CIRS 
- Change in QoL (EORTC QLQ C30) 
Eligibility criteria 
 
Inclusion 
1)  Histologically  proven  CD20  positive  Diffuse  Large  B-cell  Lymphomaand 
Follicular grade IIIB lymphoma, according to WHO classification (local 
pathologist) 
2) Age ≥ 65 years 
3) No previous treatment 
4) CGA assessment performed before starting treatment 
5) UNFIT patients defined as follows 
- Age > 80 years with FIT profile, i.e. 
- ADL =6 residual functions 
- IADL=8 residual functions 
- CIRS: no comorbidity of grade 3-4 and <5 of grade 2 or Age < 80 with UNFIT 
profile, i.e 
- ADL > 5 residual functions 
- IADL > 6 residual functions 
- CIRS: no comorbidity of grade 3-4 and 5-8 co-morbidities of grade 2 
6) Ann Arbor Stage I with bulky, II-IV 
7) At least one bi-dimensionally measurable lesion defined as > 1.5 cm in its 
largest dimension on CT scan 
8) ECOG performance status of 0, 1, or 2  
9)  Adequate  hematologic  function  (unless  caused  by  bone  marrow  infiltrate) 
defined as follows: 
- Hemoglobin ≥ 10 g/dL 
- Absolute neutrophil count ≥ 1.5 x 109/L 
- Platelet count ≥ 100 x 109/L 
10) LVEF >50% 
11) Ability and willingness to comply with the study protocol procedure 
12) Life expectancy > 6 months 
13) Accessibility of patient for treatment and follow up 
14) Written informed consent 
Exclusion 
1) History of severe allergic or anaphylactic reactions to humanized or murine 
monoclonal antibodies or known sensitivity or allergy to murine products 
2) Contraindication to any of the individual components of CHOP, including 
prior receipt of anthracyclines 
3) History of other malignancies within 5 years prior to study entry except for 
adequately treated carcinoma in situ of the cervix or basal or squamous cell skin 
cancer 
4) Stage I without bulky 
5) Patients with transformed lymphoma 


 
 
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6)  Prior  therapy  for  DLBCL,  with  the  exception  of  nodal  biopsy  or  local 
irradiation 
7) Previous exposure to cytotoxic agents 
8) Suspect or clinical evidence of CNS involvement by lymphoma 
9) HBsAg, HCV or HIV positivity; isolated HBcAb positivity is accepted only 
with concomitant treatment with Lamivudine 
10)  AST  /ALT  >  twice  upper  the  normal  range;  bilirubin  >  twice  upper  the 
normal range; serum creatinine > 2.5 mg /dl (unless these abnormalities were 
related to the lymphoma) 
11) Evidence of any severe active acute or chronic infection 
12) Concurrent co-morbid medical condition which might exclude 
administration of full dose chemotherapy 
 
 
Treatments description  
 
6  courses  of  GA101-miniCHOP  regimen  and  2  additional  infusions  of 
GA101, every 21 days (for a total of 6 courses of miniCHOP and 10 infusions 
of GA101) 
 
GA101-miniCHOP regimen 
Cycle 1 
GA101: 1000 mg day 1, day 8 and day 15, iv 
Cyclophosphamide: 400 mg/mq, day 1, iv 
Doxorubicin: 25 mg/mq, day 1, iv 
Vincristine: 1 mg, day 1, iv 
Prednisone: 40 mg/mq, days 1-5, os 
 
Cycles 2-6 
GA101: 1000 mg day 1, iv 
Cyclophosphamide: 400 mg/mq, day 1, iv 
Doxorubicin: 25 mg/mq, day 1, iv 
Vincristine: 1 mg, day 1, iv 
Prednisone: 40 mg/mq, days 1-5, os 
Two additional infusions of GA101: 1000 mg day 1, iv, every 21 days. 
 
Prophylactic granulocyte colony-stimulating factor (G-CSF) support is 
mandatory starting within 24-72 hours from day 1 of each cycle for no less than 
4 doses or until neutrophils count exceeds 1.00×10⁹/L or more (ASCO 
guidelines_JCO  -  2006).  Alternatively,  a  single  dose  of  pegylated  G-CSF  or 
pegfilgrastim can be used. 
Use of erythropoietin is allowed according to clinical practice. 
 
A preliminary debulking or symptomatic phase of vincristine 1 mg or 
intermediate -- high dose steroid is allowed. 
In case of debulking with vincristine, this drug must be omitted from cycle1. 
Involved Site Radiotherapy (ISRT) is allowed on previous bulky sites or on 
PET positive lesion at the end of treatment. 
An interim check for response will be assessed after the completion of 4 courses 
of GA101-miniCHOP in order to identify nonresponding patients: 
patients  achieving  a  CR,  PR,  or  SD  will  continue  to  complete  combined 
immunochemotherapy as planned, patients with progressive disease will stop 
treatment and will be considered as failure. 
 


 
 
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All patients stopping study treatment due to early disease progression will be 
followed for survival until the end of the study. 
 
Dosage Delays and Modifications: GA101 and CHOP chemotherapy 
Dose reductions and delays are based on all laboratory values obtained within 
72 hours prior to a study treatment infusion. 
 
A  dose  delay  of  21  days  is  permitted  for  miniCHOP  and  GA101  to  allow 
recovery of hematologic toxicities to Grade ≤ 2 (platelets must return to Grade 
≤ 1) or non-hematologic toxicities to Grade ≤ 1 or baseline status for the first 
episode. 
 
Dose Modifications of GA101-miniCHOP chemotherapy 
No dose modifications of GA101 (1000 mg) are allowed. 
If administration of chemotherapy is delayed, there will be no dosemodification 
of GA101, and the administration of GA101 and all 
chemotherapy  drugs  should  be  delayed  for  the  same  time  frame,  e.g.,  if 
miniCHOP therapy is delayed, administration of GA101 should also be delayed 
so that they are given on day 1 of the same cycles. 
 
Hematologic and Non-Hematologic Toxicities 
Dosing  of  miniCHOP  and  GA101  may  be  resumed  upon  the  resolution  of 
hematologic  toxicity  to  Grade  ≤2  (platelets  must  resolve  to  Grade  ≤  1)  or 
baseline status for the first episode. 
 
For  non-hematologic  toxicities,  dosing  of  GA101-miniCHOP-may  only  be 
resumed upon resolution to Grade ≤1 or baseline status. 
For  Grade  ≥  2  non-hematologic  toxicities  (excluding  alopecia,  nausea,  and 
vomiting), treatment with GA101-miniCHOP will be delayed until resolution to 
Grade ≤1 (or baseline status for all except hemorrhagic cystitis), for a maximum 
of 21 days. 
 
In addition, resumption of dosing without complete resolution of toxicity may 
only  be  considered  after  careful  weighing  of  the  risks  and  benefits  with  the 
patient and agreement between the investigator and the Sponsor. 
 
If treatment is delayed for more than 21 days (except for hepatitis B 
reactivation),  the  patient  will  be  withdrawn  from  study  treatment  (note  that 
lymphopenia is not considered a cytopenic toxicity, as it is an expected outcome 
of therapy). 
Patients who discontinue all study treatment for adverse events should remain 
on  the  study  and  continue  to  have  disease  assessments  until  progression  and 
standard follow-up. 
In the event of grade 2 neurological vincristine-related toxicity (sensory or motor 
polyneuritis,  constipation,  or  visual  or  auditory  changes)  vincristine  can  be 
discontinued. 
Permitted concomitant therapies 
Prevention of tumour lysis syndrome by alkalinisation or hypouricaemic drugs 
is allowed if necessary. 
 
Antiemetic therapy with SHT3 antagonists can be given at each cycle. 
 


 
 
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Patients will receive prophylactic treatment with Bactrim 2 cp/day twice a week 
during all the chemotherapy. 
CNS  prophylaxis  with  intrathecal  infusion  of  methotrexate  and  steroid  is 
allowed according to local clinical practice (i.e. patients with testicular 
involvement or patients considered at high risk of CNS relapse). 
 
In patients HBcAb+, prophylaxis for hepatitis B reactivation with 
Lamivudine 100mg/die from the start of the treatment to one year after the end 
of the treatment is mandatory. 
 
Pre-medication for GA101 infusion with oral acetaminophen (e.g., 
650−1000  mg)  and  an  antihistamine  such  as  diphenhydramine  hydrochloride 
(50−100 mg) 30−60 minutes prior to starting each infusion (unless 
contraindicated). An additional glucocorticoid (e.g., 100 mg IV prednisone or 
prednisolone  or  equivalent)  is  allowed  at  the  investigator’s  discretion.  For 
patients who do not experience infusion-related symptoms with their previous 
infusion, pre-medication at subsequent infusions may be omitted at the 
investigator’s discretion. 
 
Prophylaxis 
with 
levofloxacine 
or 
ciprofloxacine 
and 
fluconazole/itraconazole/posaconazole are allowed. 
Platelets and red blood cell transfusion are allowed, if needed. 
 
 
Treatment duration 
6 months 
 
 
Statistical methods: 
The  primary  objective  of  the  study  is  to  demonstrate  a  clinical  benefit  in 
Complete Remission Rate (CRR) and safety with GA101-miniCHOP 
association in elderly unfit patients newly diagnosed with diffuse large B-cell 
lymphoma. 
For the purposes of this study, as the reference CR rate (Peyrade et al, Lancet 
Oncol  –  2011)    was  defined  with  1999  International  Criteria  for  response 
(Cheson, JCO 1999), the response rate to therapy will be based on a Central 
Independent Review of response that will not consider the results of FDG-PET 
but will only use the conventional CT scan images. Response defined according 
to Cheson 2007 International Criteria will also be provided as study result. 
 
Sample size: 
The sample size has been estimated according to a optimal Simon two-stages 
design. The null hypothesis (p0) has been set equal 0.60 on the basis of what 
reported by F. Peyrade et al.  
With  a  type  I  (alfa)  error  of  0.10  (10%)  and  a  type  II  (beta)  error  of  0.10 
(power=90%) the alternative hypothesis (p1) is 0.75, i.e. a CR rate of 75% with 
the combination GA101-miniCHOP expected. 
A schema of the design is below reported. 
 
R1 = 21 N1 = 34 R2 = 47 Ntot = 71 EN(p0) = 47 PET(p0) = 64.6% 
 
According to the two-stage design patients enrolment will proceed as follows: 
- the enrolment of 34 patients (stage 1) is planned: if at least 22 patients will 
achieve CR the study will continue; 
- additional 37 patients are entered (stage II): if at least 48 patients out of 71 will 
achieve a CR the study will be considered of possible evaluation for the efficacy 
of the treatment. 


 
 
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Considering a withdrawal rate of 10%, the enrollment may continue until  78 
patients  are  accrued in  order  to  have  at least  71  eligible  patients.  If  GA101-
miniCHOP will be active, the probability to declare inactivity is 0.0964 and the 
probability to stop the study at first stage is 0.0610. 
 
Study Flow Chart 
 
Number 
of 
patients 
planned 
34 patients 
Number 
of 
patients 
analysed 
33 
Number 
of 
excluded 
patients 
4 
 
 
 
 
 
 
 
 


 
 
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Overall Study 
 
Table 1: Overall Study and Treatment Administration 
 
 
Therapy: GA101-miniCHOP 
Started 
N. Patients enrolled 33 
Completed 
N. Patients that have completed therapy 26 
Not Completed 
7 
Lack of Efficacy 
19 
 
Table 2: Demographic characteristic of enrolled patients (n=33) 
Variable 
Median (2.5-97.5 percentile) 
Age, years 
82 (68-89) 
Hb, g/dL 
12.9 (8.9-15.7) 
WBC 109/l 
7.7 (3.6-20.5) 
ALC 109/l 
1.2 (0.2-3.5) 
 
Variable 
Status 
N (%) 
Gender 
M 
18 (55) 
 
F 
15 (45) 
Stage 
II 
6 (18) 
 
III 
11 (33) 
 
IV 
16 (48) 
BM 
- 
27 (82) 
 
+ 
6 (18) 
ECOG PS 
0 
12 (35) 
 
1 
19 (58) 
 
2 
1 (3) 
 
3 
1 (3) 
B-symptoms 
A 
27 (82) 
 
B 
6 (18) 
Histology 
DLBCL 
32 (97) 
 
T LBCL 
1 (3) 
LDH 
≤ULN 
10 (30) 
 
>ULN 
23 (70) 
B2M 
≤ULN 
2 (7) 
 
>ULN 
25 (93) 
IPI 
0-1 
4 (12) 
 
2 
8 (24) 
 
3-5 
21 (64) 
CGA 
UNFIT 
28 (85) 
 
FRAIL 
5 (15) 
 
 
 
 
Missing: ALC n=1, B2M n=6 
DLBCL: diffuse large B-cell lymphoma, TLBCL: T-cell/histiocyte LBCL 
WBC:  white  blood  cell;  ALC:  absolute  lymphocyte  count;  ULN:  upper  limit  of  normality;  B2M:  beta2-
microglobuline; LDH lactate dehydrogenase; BM bone marrow involvement 
 


 
 
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Efficacy evaluation: 
Table 3. Complete remission (CR) rate according to Cheson 1999. 
 
 
Final response 
Response 
N 
% (95CI) 
CR 
14 
42.4 (25.5-60.8) 
PR 
8 
24.2 (11.1-42.3) 
SD 
2 
6.1 (0.7-20.2) 
PD 
8 
24.2 (11.1-42.3) 
NA 
1 
3.0 (0.1-15.8) 
Total 
33 
 
CR: complete remission, PR: partial remission, SD: stable disease, PD: progression disease, NA: not assessed. 
95CI: 95% confidence interval (Clopper-Pearson) 
NA: one patents withdrawal after 1 cycle due fever hospitalization. 
 
# CR 14: it does not exceed the threshold of 21 CR as expected from the optimal Simon two stage. Interim 
analysis failed for efficacy. 
 
Table 4. Dose Intensity (mean, 95%CI) according to Hryniuk. 
Cycles 
GA101 
Doxorubicin 
Cyclophosphamide 
Vincristine 
1-4 
0.94 (0.92-0.96) 
0.93 (0.90-0.95) 
0.93 (0.90-0.95) 
0.94 (0.91-0.96) 
5-8 (6) 
0.99 (0.95-1.04) 
0.98 (0.95-1.01) 
0.97 (0.94-1.00) 
0.98 (0.93-1.03) 
 
Safety Evaluation:  
Table  5.  Hematological  and  extra-hematological  adverse  events  (AE).  Maximum  adverse  event  collected 
during induction treatment (n=33). 


 
 
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One patient was dead after with heart failure grade 4  
 
 
 
 
 
Adverse Event - Haematological
n
%
n
%
Anemia
6
18,2
0
0,0
Leukopenia
2
6,1
2
6,1
Neutropenia
2
6,1
13
39,4
Piastrinopenia
10
30,3
1
3,0
Febrile neutropenia  
0
0,0
0
0,0
Adverse Event - Non-heamatological
n
%
n
%
Cardiac disorders
3
9,1
2
6,1
Congenital/familial/genetic disorders
0
0,0
0
0,0
Ear and labyrinth disorders
0
0,0
0
0,0
Endocrine disorders
0
0,0
0
0,0
Eye disorders
0
0,0
0
0,0
Gastrointestinal disorders
11
33,3
1
3,0
General disorders and administration site conditions
4
12,1
2
6,1
Hepatobiliary disorders
0
0,0
2
6,1
Immune system disorders
0
0,0
0
0,0
Infections
6
18,2
1
3,0
Injury/poisoning/procedural complications 
0
0,0
2
6,1
Investigations 
2
6,1
1
3,0
Metabolism and nutrition disorders 
5
15,2
3
9,1
Musculoskeletal and connective tissue disorders 
5
15,2
3
9,1
Neoplasms benign/malignant/unspecified
0
0,0
2
6,1
Nervous system disorders/Psychiatric disorders
6
18,2
1
3,0
Pregnancy/puerperium and perinatal conditions 
0
0,0
0
0,0
Renal and urinary disorders 
2
6,1
0
0,0
Reproductive system and breast disorders 
0
0,0
0
0,0
Respiratory/thoracic and mediastinal disorders 
5
15,2
0
0,0
Skin and subcutaneous tissue disorders 
0
0,0
0
0,0
Social circumstances 
0
0,0
0
0,0
Surgical and medical procedures 
0
0,0
0
0,0
Vascular disorders 
1
3,0
0
0,0
Other (specify) 
8
24,2
0
0,0
Grade 1-2
Grade 3-4
Grade 1-2
Grade 3-4


 
 
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Collected ad Other toxicities (n=8) - 
description 
grade 
Epigastric pain 
2 
Dysgeusia 
1 
Fever 
2 
Infusion reaction 
2 
Asthenia; bone pain 
2 
Infiammatory edema 
1 
Fever 
2 
Pain 
2 
 
Table 6. List of serious advent events (SAE)  
 
I: Initial; FU: adverse event follow-up 
ID 0036: SAE recorded before starting 1st cycle of treatment. Not included in the 33 evaluable patients. 
ID 0026: SUSAR during follow-up post induction. 
SAE/SUSAR reported in 7 patients (Six evaluated and one exit before treatment).  
Secondary End-Point 
Overall Response Rate (ORR: CR+PR): 67% (95%CI 48-82%) 
Overall survival (OS): After a median of 32 months (95%CI 15-38 months), from the date of registration in 
the study, were observed 11 death: 7 for progression of disease, 1 for probable progression of lymphoma, 1 for 
heart failure, 1 for sepsis and one due unknown cause. 
The 24-months OS% was 69% (95%CI 50-82%). 
Progression Free Survival (PFS): Were observed 17 events, with a 24-months PFS of 53% (34-68%). 
 
 
 
 
 
ID
Date of Onset SAE/SUSAR Report (I or FU)
Event Short Description
Gravity of the event
Outcome of the event at report time
Relationship 
Suspected Drug
0002GAEL
20/12/2015 SAE
I
nausea
Caused/Prolonged Hospitalisation
Not Recovered/Not Resolved
Unrelated
none
0002GAEL
19/02/2016 SAE
I
femure fracture
Caused/Prolonged Hospitalisation
Not Recovered/Not Resolved
Unrelated
none
0002GAEL
19/02/2016 SAE
FU
femure fracture
Caused/Prolonged Hospitalisation
Recovered/Resolved
Unrelated
none
0002GAEL
31/03/2016 SUSAR
I
congestive heart failure
Caused/Prolonged Hospitalisation
Not Recovered/Not Resolved
Unrelated
none
0002GAEL
22/06/2016 SAE
I/FU
congestive heart failure
Death
Fatal
Possible
GA101
0004GAEL
08/12/2015 SAE
I
lumbar pain, vertebral collapse
Caused/Prolonged Hospitalisation
Not Recovered/Not Resolved
Unrelated
obinutuzumab miniCHOP
0005GAEL
08/02/2016 SAE
I
fever
Caused/Prolonged Hospitalisation
Not Recovered/Not Resolved
Unrelated
obinutuzumab miniCHOP
0005GAEL
08/02/2016 SAE
FU
sepsis
Caused/Prolonged Hospitalisation
Recovered/Resolved
Unrelated
none
0005GAEL
07/08/2016 SAE
I/FU
sepsis
Death
Fatal
Unrelated
0015GAEL
15/04/2016 SAE
I
BPCO - Heart Failure
Caused/Prolonged Hospitalisation
Not Recovered/Not Resolved
Probable
obinutuzumab miniCHOP
0026GAEL
09/05/2017 SUSAR
I
breast cancer
Other medically important condition
Not Recovered/Not Resolved
Unrelated
GA101
0026GAEL
09/05/2017 SUSAR
FU
breast cancer
Other medically important condition
Not Recovered/Not Resolved
Unrelated
doxorubicina, vincristina, ciclofosfamide 
0026GAEL
09/05/2017 SUSAR
FU
breast cancer
Other medically important condition
Not Recovered/Not Resolved
Unrelated
prednisone
0026GAEL
19/07/2017 SUSAR
I
non small cell lung cancer
Other medically important condition
Unknown
Unrelated
obinutuzumab
0026GAEL
19/07/2017 SUSAR
FU
non small cell lung cancer
Other medically important condition
Unknown
Unrelated
obinutuzumab/vincristina/doxorubicina/ciclofosfamide
0026GAEL
19/07/2017 SUSAR
FU
non small cell lung cancer
Other medically important condition
Unknown
Unrelated
prednisone
0032GAEL
16/06/2016 SAE
I
Fever
Caused/Prolonged Hospitalisation
Not Recovered/Not Resolved
Possible
GA101
0036GAEL
16/06/2016 SAE
I
Atrial fibrillation
Caused/Prolonged Hospitalisation
Unknown
Unrelated
not started
0036GAEL
18/06/2016 SAE
FU
Atrial fibrillation - sepsi due to Klebsiella Pneumoniae
Caused/Prolonged Hospitalisation
Fatal
Possible
not started


 
 
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Summary – Conclusions: 
In conclusion, our phase II study confirmed the activity and safety of Ga101-miniCHOP for the treatment of 
older, unfit patients with DLBCL, but was not able to show it as a promising regimen to challenge the current 
standard  R-miniCHOP.  To  improve  treatment  efficacy  in  this  hard  to-treat  patient  population,  different 
strategies should be adopted that include better patient and/or lymphoma profiling and the use of new drugs 
with a novel non-cross-resistant mechanism of action. 
 
We attest the accuracy and truthfulness of the information contained in this Report. 
 
Date of report: April 30th, 2020 
 
Dr. Francesco Merli 
Principal Investigator and 
 President of Fondazione Italiana Linfomi