Clinical trial NCT03890289
Conditions: Follicular Lymphoma
Keywords: Idelalisib Obinutuzumab Relapsed/Refractory Follicular Lymphoma
Sponsor: Fondazione Italiana Linfomi - ETS
Start date: 2019-10-18; Completion date: 2023-05-10
Enrollment: 5 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Single arm, prospective, multi-centric, phase II study. Patients with histologically confirmed follicular lymphoma, in need of a systemic approach and failing (i.e. with refractory disease \[no response or response lasting less than 6 months at any previous line of treatment\] or with a proven disease relapse) at least 2 previous lines of treatment, including any antibody directed against the CD20 antigen-containing chemotherapy, will undergo a combined chemo-free treatment with obinutuzumab and idelalisib.

Detailed description:
Single arm, prospective, multi-centric, phase II study. Patients with histologically confirmed follicular lymphoma, in need of a systemic approach and failing (i.e. with refractory disease \[no response or response lasting less than 6 months at any previous line of treatment\] or with a proven disease relapse) at least 2 previous lines of treatment, including any antibody directed against the CD20 antigen-containing chemotherapy, will undergo a combined chemo-free treatment with obinutuzumab and idelalisib.

Obinutuzumab will be administered intravenously at a flat dose of 1000 mg on day 1, 8, 15 of the first cycle, then repeated on day 1 of each subsequent cycle, for 6 cycles (each cycle is completed in 28 days). Idelalisib will be given concomitantly with obinutuzumab and on a daily 150 mg bid schedule. For patients achieving at least a partial response at the end of induction, a maintenance phase with obinutuzumab is scheduled (on day 1 every two months for two years or until progression or unacceptable toxicity, whichever comes first) If one of the two drugs has to be permanently discontinued due to any cause, patient may continue treatment with the other agent if it is judged to be a clinical benefit. Patients with at least a stable disease will enter the follow-up phase and will be followed with repeated CT scans every six months for two years or until death/progression occurs (whichever comes firsts).

Patients with progressive disease, whenever progression is documented, will enter a survival follow up period of two years after PD was documented. These patients are however considered evaluable for OS.

Arms: arm 1: Single arm: Regimen: GAUDEALIS q28 days

* Obinutuzumab Dose: 1000 mg IV Day 1, 8, 15 (1st cycle)
* Obinutuzumab Dose: 1000 mg IV Day 1 (2nd cycle onward)
* Idelalisib Dose: 150 mg BID oral Daily (24 weeks)
Interventions: intervention 1: Idelalisib intervention 2: Obinutuzumab
Intervention descriptions: intervention 1: Idelalisib Plus Obinutuzumab In Patients With Relapsed/Refractory Follicular Lymphoma intervention 2: Idelalisib Plus Obinutuzumab In Patients With Relapsed/Refractory Follicular Lymphoma

Protocol documents:
Prot_SAP_000.pdf: 
MD01-01_I01_PRDS00 
FIL_GAUDEALIS, version n. 2.0 of May 29, 2019 
Page 1 of 64 
 
 
 
 
 
Clinical Protocol 
 
 
Idelalisib plus Obinutuzumab in patients with relapsed/refractory follicular 
lymphoma: a phase 2, single-arm, multicentric study 
 
ID Study: FIL_GAUDEALIS 
EudraCT number: 2018-001229-18 
 
INVESTIGATOR SPONSOR 
Fondazione Italiana Linfomi ONLUS (FIL) 
 
COORDINATING INVESTIGATOR 
Pier Luigi Zinzani, Bologna (PI) 
WRITING COMMITTEE AND 
SCIENTIFIC SUPPORT 
Alessandro Broccoli, Bologna 
Lisa Argnani, Bologna 
 
 
 
REGISTRATION (SEE CHAPTER 12) 
www.filinf.it 
SAE REPORTING (SEE CHAPTER 17) 
www.drugvigilance.filinf.it 
 
 
 
 
 
Version and date of Protocol: Version 2.0 of May 29, 2019 
 
 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
The information contained in this document is the property of Fondazione Italiana Linfomi Onlus 
(FIL) and therefore is provided to you in confidence for review by you, your staff, an applicable 
Ethics Committee and regulatory authorities. It is understood that the information will not be 
disclosed to others without prior written approval from the Fondazione Italiana Linfomi Onlus (FIL), 
except to the extent necessary to obtain informed consent from those persons to whom the 
medication may be administered.  


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1. RESPONSIBILITIES 
 
Sponsor 
 : Fondazione Italiana Linfomi (FIL) ONLUS 
 : +39 0131 033 151 
 
Fax: +39.0131.263455 
 
Email: segreteria@filinf.it 
 
Coordinating Investigator 
 : Pier Luigi Zinzani, Istituto di Ematologia “L. e A. Seràgnoli”, AOU Policlinico S.Orsola-Malpighi, 
Via Massarenti, 9 - 40138 Bologna, Italy 
 : +39 051 214 4042 
 
 
Fax: +39 051 214 4037 
 
Email: pierluigi.zinzani@unibo.it 
 
Writing Committee 
 : Alessandro Broccoli, Istituto di Ematologia “L. e A. Seràgnoli”, AOU Policlinico S.Orsola-
Malpighi, Via Massarenti, 9 - 40138 Bologna, Italy 
 : +39 051 636 3680 
 
Fax: +39 051 636 4037 
 
Email: alessandro.broccoli@studio.unibo.it 
 
 : Lisa Argnani, Istituto di Ematologia “L. e A. Seràgnoli”, AOU Policlinico S.Orsola-Malpighi, Via 
Massarenti, 9 - 40138 Bologna, Italy 
 : +39 051 636 3680 
 
Fax: +39 051 636 4037 
 
Email: lisa.argnani@unibo.it 
 
Coordinating Pathologist 
 : Stefano Pileri, Divisione di Diagnosi Emolinfopatologica, Istituto Europeo di Oncologia, Via 
Ripamonti 435, 20141 Milano 
 : +39.02.57489770 
Fax: +39.02.94379320 
 
Email: stefano.pileri@ieo.it 
 
Pharmacovigilance 
 : Ufficio Farmacovigilanza, Uffici Studi FIL, Fondazione Italiana Linfomi Onlus, c/o.Uffici 
PACTO, Spalto Marengo 44, 15121 Alessandria 
 : +39 0131 033 156 
 
Fax: +39 0131 263 455 
 
Email: drugvigilance@filinf.it  
 
Start up 
 : Area Start up, Uffici Studi FIL, Fondazione Italiana Linfomi Onlus, c/o Uffici PACTO, Spalto 
Marengo 44, 15121 Alessandria 
 : +39 0131 033 153     Fax: +39-0131-263455 
Email: startup@filinf.it 
 
Study Coordinator 
 : Area gestione Studi, Uffici Studi FIL, Fondazione Italiana Linfomi Onlus c/o Dipartimento di 
Scienze Mediche e Chirurgiche Materno-Infantili e dell'Adulto, Centro Oncologico Modenese, via 
del Pozzo 71, 41124 Modena 
 : +39-059-4222577    Fax: +39-059-4223602 
 
Email: epesce@filinf.it; gestionestudi@filinf.it 
 
Coordinating Statistician 
 : Giovannino Ciccone, SSD Epidemiologia dei Tumori-CPO Piemonte, Via Santena 7, 10126 
Torino 
 : +39.011.6336857     Fax: +39.011.6334664 
Email: gianni.ciccone@cpo.it ; statistica@filinf.it 
 


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Support in protocol drfating 
 : Monica Bellei, Uffici Studi FIL, Fondazione Italiana Linfomi Onlus c/o Dipartimento di Scienze 
Mediche e Chirurgiche Materno-Infantili e dell'Adulto, Centro Oncologico Modenese, via del Pozzo 
71, 41124 Modena 
 : +39-059-4224020     Fax: +39-059-4223602 
Email: mbellei@filinf.it ; redazioneprotocolli@filinf.it 
 
 
 


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2. TABLE OF CONTENTS 
 
1. 
RESPONSIBILITIES ............................................................................................................... 2 
2. 
TABLE OF CONTENTS .......................................................................................................... 4 
3. 
INVESTIGATOR AGREEMENT .............................................................................................. 7 
4. 
SYNOPSIS .............................................................................................................................. 8 
5. 
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ................................................. 13 
6. 
STUDY FLOW CHART ......................................................................................................... 14 
7. 
BACKGROUND .................................................................................................................... 15 
7.1. 
Disease background .................................................................................................................... 15 
7.2. 
Current therapies for R/R Follicular Lymphoma ....................................................................... 15 
7.3. 
Study drugs background ............................................................................................................. 16 
7.3.1. 
Idelalisib ............................................................................................................................... 16 
7.3.2. 
Obinutuzumab ...................................................................................................................... 17 
8. 
STUDY RATIONALE ............................................................................................................ 18 
9. 
STUDY OBJECTIVES .......................................................................................................... 19 
9.1. 
Primary Objective ......................................................................................................................... 19 
9.2. 
Secondary Objective .................................................................................................................... 19 
9.3. 
Primary Endpoint ......................................................................................................................... 19 
9.4. 
Secondary Endpoint .................................................................................................................... 19 
10. STUDY DESIGN ................................................................................................................... 20 
10.1. 
Overview of study design ............................................................................................................ 20 
10.2. 
Number of patients ....................................................................................................................... 21 
10.3. 
Duration of the study ................................................................................................................... 21 
11. STUDY POPULATION .......................................................................................................... 21 
11.1. 
Inclusion criteria ........................................................................................................................... 21 
11.2. 
Exclusion criteria ......................................................................................................................... 22 
12. PATIENTS ENROLLMENT ................................................................................................... 22 
12.1. 
Informed consent ......................................................................................................................... 22 
12.2. 
Patient registration and data collection ..................................................................................... 23 
13. TREATMENT ........................................................................................................................ 23 
13.1. 
IDELALISIB ................................................................................................................................... 23 
13.1.1. 
Supplier ................................................................................................................................ 23 
13.1.2. 
Receipt of study drug .......................................................................................................... 23 
13.1.3. 
Preparation, reconstitution and administration ............................................................... 23 
13.1.4. 
Storage and handling .......................................................................................................... 24 
13.1.5. 
Unused study drug supplies .............................................................................................. 24 
13.2. 
OBINUTUZUMAB .......................................................................................................................... 24 
13.2.1. 
Supplier ................................................................................................................................ 24 
13.2.2. 
Preparation, reconstitution and administration ............................................................... 24 
13.2.3. 
Receipt of study drug .......................................................................................................... 25 
13.2.4. 
Storage and handling .......................................................................................................... 25 
13.2.5. 
Unused study drug supplies .............................................................................................. 25 
13.3. 
Treatment schedule and design ................................................................................................. 25 
13.4. 
Premedication ............................................................................................................................... 26 
13.4.1. 
Idelalisib ............................................................................................................................... 26 
13.4.2. 
Obinutuzumab ...................................................................................................................... 26 
13.5. 
Prophylactic measures ................................................................................................................ 26 
13.6. 
Patients HBV positive .................................................................................................................. 28 
13.7. 
Patients HCV positive .................................................................................................................. 28 
13.8. 
Patients HIV positive .................................................................................................................... 28 


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13.9. 
Contraception ............................................................................................................................... 28 
13.10. 
Excluded/admitted concomitant medication ............................................................................. 29 
13.11. 
Warnings ....................................................................................................................................... 30 
13.12. 
Dose modification and Toxicity Management ........................................................................... 30 
14. REMOVAL OF SUBJECTS FROM TREATMENT AND/OR STUDY .................................... 36 
14.1. 
Discontinuation from study treatment ....................................................................................... 36 
14.2. 
Withdrawal of subjects from the study ...................................................................................... 37 
14.3. 
Withdrawal of Consent ................................................................................................................ 37 
14.4. 
Patients Lost to Follow up........................................................................................................... 37 
14.5. 
Premature termination of the study ........................................................................................... 37 
15. STUDY PROCEDURES TIMEPOINTS ................................................................................. 38 
15.1. 
Screening period .......................................................................................................................... 38 
15.2. 
Treatment period (Induction) ...................................................................................................... 38 
15.3. 
Assessment for restaging ............................................................................................................ 38 
15.4. 
EOT phase ..................................................................................................................................... 39 
15.5. 
Maintenance period ...................................................................................................................... 39 
15.6. 
Follow up period ........................................................................................................................... 40 
15.7. 
Survival Follow up ........................................................................................................................ 40 
15.8. 
Early withdrawn (EW) ................................................................................................................... 40 
15.9. 
Schedule of assessments ........................................................................................................... 41 
16. SAFETY MEASUREMENTS AND PARAMETERS............................................................... 43 
16.1. 
Safety measurements .................................................................................................................. 43 
16.2. 
Safety parameters ........................................................................................................................ 43 
16.3. 
Serious Adverse Events reporting rules.................................................................................... 45 
16.4. 
Pregnancy ..................................................................................................................................... 46 
16.5. 
Follow up of AEs and SAEs ........................................................................................................ 47 
16.6. 
Product Quality Complaint Handling ......................................................................................... 47 
17. STATISTICAL CONSIDERATIONS ...................................................................................... 47 
17.1. 
Sample size ................................................................................................................................... 47 
17.2. 
Safety monitoring and stopping rules ....................................................................................... 48 
17.3. 
Statistical analysis plan ............................................................................................................... 48 
18. INDEPENDENT DATA SAFETY MONITORING BOARD (DMSB) ....................................... 49 
19. INDEPENDENT EXTERNAL PATHOLOGY REVIEW .......................................................... 49 
20. GOOD CLINICAL PRACTICE, QUALITY CONTROL AND QUALITY ASSURANCE .......... 50 
20.1. 
Monitoring, Audits and Inspections ........................................................................................... 50 
20.2. 
Investigator(s) responsibilities ................................................................................................... 50 
21. ETHICAL AND REGULATORY STANDARDS ..................................................................... 50 
21.1. 
Independent Ethics Committee Review Approval .................................................................... 50 
21.2. 
Protocol Amendments Approval ................................................................................................ 51 
22. ADMINISTRATIVE PROCEDURES ...................................................................................... 51 
22.1. 
Curriculum vitae ........................................................................................................................... 51 
22.2. 
Confidentiality agreement ........................................................................................................... 51 
22.3. 
Record retention in investigating centers ................................................................................. 52 
22.4. 
Ownership of data and use of the study results ....................................................................... 52 
22.5. 
Authorship .................................................................................................................................... 52 
22.6. 
Insurance coverage ...................................................................................................................... 52 
22.7. 
Protocol amendments procedures ............................................................................................. 52 
23. DATA HANDLING AND RECORD KEEPING ....................................................................... 53 
23.1. 
Data/documents ........................................................................................................................... 53 
23.2. 
Data Management ......................................................................................................................... 53 
23.3. 
Retention of Records ................................................................................................................... 53 
24. PRIVACY OF PERSONAL DATA ......................................................................................... 53 


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25. REFERENCES ...................................................................................................................... 55 
26. APPENDICES ....................................................................................................................... 57 
APPENDIX A: ECOG Performance Status ................................................................................................... 57 
APPENDIX B: Common Terminology Criteria for Adverse Events (CTCAE) ........................................... 58 
APPENDIX D:  Pathology review guidelines ............................................................................................... 61 
APPENDIX E:  Reference Safety Information for Idelalisib ....................................................................... 62 
APPENDIX F:  Reference Safety Information for Obinutuzumab ............................................................. 63 
 


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3. 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). 


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4. SYNOPSIS 
Study ID 
FIL_GAUDEALIS 
Eudract N° 
2018-001229-18 
Title of the study 
Idelalisib Plus Obinutuzumab In Patients With Relapsed/Refractory 
Follicular Lymphoma: A Phase 2, Single-Arm, Multicentric Study. 
Phase of the study 
Phase II single arm study 
Investigational 
product 
Obinutuzumab  
Idelalisib  
Protocol version 
Version 2.0 of May 29, 2019 
Centers 
12 sites within FIL (Fondazione Italiana Linfomi) centres. Coordinating 
Center: Institute of Hematology, AOU Policlinico S.Orsola-Malpighi, 
University of Bologna 
Study Objectives and 
Endpoints 
Primary Objective 
To evaluate the efficacy in terms of clinical response in patients 
treated with combination therapy of idelalisib and obinutuzumab 
 
Secondary Objectives 
• 
To assess efficacy in terms of progression-free survival (PFS) 
and overall survival (OS). 
• 
To assess the safety of the combination therapy and patients’ 
compliance to treatment; 
 
Primary Endpoint 
Investigator’s assessed Overall response rate (ORR) at the end of 
induction phase of patients treated with a chemo-free combination 
with obinutuzumab and idelalisib. Overall response rate (ORR) is 
defined as the proportion of patients with at least a partial response 
(PR), as defined by 2014 Lugano criteria.  
 
Secondary Endpoints 
- 
Overall survival (OS) rate; 
- 
Progression-free survival (PFS) rate; 
- 
patients’ withdrawal rate, incidence and nature of any severe 
adverse events, hospitalization rate throughout the study, and 
patients’ compliance to oral treatment, incidence of any adverse 
events occurring during and right after treatment 
 
Study design 
Single arm, prospective, multi-centric, phase II study. 
Patients with histologically confirmed follicular lymphoma, in need of a 
systemic approach and failing (i.e. with refractory disease [no 
response or response lasting less than 6 months at any previous line 
of treatment] or with a proven disease relapse) at least 2 previous 
lines of treatment, including any antibody directed against the CD20 
antigen-containing chemotherapy, will undergo a combined chemo-
free treatment with obinutuzumab and idelalisib. 
Obinutuzumab will be administered intravenously at a flat dose of 
1000 mg on day 1, 8, 15 of the first cycle, then repeated on day 1 of 
each subsequent cycle, for 6 cycles (each cycle is completed in 28 
days). Idelalisib will be given concomitantly with obinutuzumab and on 
a daily 150 mg bid schedule. For patients achieving at least a partial 
response at the end of induction, a maintenance phase with 
obinutuzumab is scheduled (on day 1 every two months for two years 
or until progression or unacceptable toxicity, whichever comes first)  


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If one of the two drugs has to be permanently discontinued due to any 
cause, patient may continue treatment with the other agent if it is 
judged to be a clinical benefit. Patients with at least a stable disease 
will enter the follow-up phase and will be followed with repeated CT 
scans every six months for two years or until death/progression occurs 
(whichever comes firsts).  
Patients 
with 
progressive 
disease, 
whenever 
progression 
is 
documented, will enter a survival follow up period of two years after 
PD was documented. These patients are however considered 
evaluable for OS. 
Duration of the study 
1.5 year of enrolment + 6 months of induction + 2 years of 
maintenance+ 2 years of (survival) follow up (ca. 6,5 years in total) 
Number of patients 
43 patients (stage I: 15 patients; stage II: 28 patients) 
Inclusion criteria 
• Relapsed or refractory, histologically confirmed CD20-positive 
follicular non-Hodgkin’s lymphoma, grade 1, 2 or 3a according to 
WHO 2017 classification. 
• Age 18 ≥ years 
• At least 2 prior systemic therapies for follicular lymphoma including 
both any antibody directed against the CD20 antigen and a 
chemotherapy combination. 
• Treatment indications, with the presence of at least one of the 
following: 
- 
 bulky disease (nodal or extranodal mass – except spleen –
more than 7 cm in its greater diameter or involvement of at 
least 3 nodal or extranodal sites, each with a diameter equal to 
or greater than 3 cm); 
- 
at least one B-symptom (fever > 38°C of unclear etiology, night 
sweats, weight loss greater than 10% of body weight in the 
prior 6 months); 
- 
symptomatic splenomegaly; 
- 
compression syndrome (i.e. of orbits, ureters, gastrointestinal 
tract, biliary tract); 
- 
lymphoma-related cytopenias (hemoglobin < 10 g/dL and/or 
platelets < 100·109/L and/or neutrophils < 1.5·109/L); 
- 
pleural or peritoneal serous effusions. 
- 
 
• Eastern Cooperative Oncology Group (ECOG) performance status 
(PS) ≤ 2. 
• Adequate hematological function, unless abnormalities due to 
underlying disease, within 28 days prior to signing informed consent, 
defined as follows: neutrophils > 1.5·109/L, platelets > 75·109/L, 
hemoglobin > 8,0 g/dL with transfusion independence. 
• Capacity and willingness to adhere to study visit schedule and 
specific protocol procedures. 
• Willingness to sign a written informed consent.   
• Compliance with effective contraception without interruption, from 28 
days before treatment start up (i.e., during the screening phase) to 
18 months after treatment discontinuation, agreeing not to donate 
the semen during treatment and for 18 months after discontinuation 
(if the patient is male), or to undergo ongoing pregnancy test during 
the course of the study (if the patient is female). Birth control 
methods considered acceptable for the study are those highly 
effective (IUS, hormonal methods, tubal sterilization, sexual 
intercourse with a vasectomized male partner) or effective (male 
condom, diaphragm, cervical cap). According to the usual lifestyle of 


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the subjects, if they are not willing to adopt the prescribed 
contraceptive methods, they have to practice true abstinence for all 
the period above reported. 
• Patients must agree to undergo JPJ prophylaxis throughout the 
treatment period and 2-6 months thereafter (before consulting with 
Medical Monitor). 
Exclusion criteria 
• Grade 3b follicular non-Hodgkin’s lymphoma or evidence of 
transformation to high-grade non-Hodgkin’s lymphoma. 
• Central nervous system or leptomeningeal involvement by 
lymphoma. 
• Major surgery (excluding any lymph node biopsy) within 28 
days prior to signing informed consent. 
• Seropositivity for HBV or evidence of active infection (HBsAg 
positivity, or HBsAg negativity with positive anti-HBs/anti-HBc 
and detectable viral DNA load); if viral load is negative or 
undetectable, the patient is eligible, provided their HBsAg 
negativity. 
• Positive viral HCV RNA  
• Seropositivity for HIV, regardless of viral load. 
• Known history of drug induced liver injury, chronic active 
hepatitis C (HCV), chronic active hepatitis B (HBV), alcoholic 
liver disease, non-alcoholic steatohepatitis, primary biliary 
cirrhosis, on-going extra-hepatic obstruction caused by 
cholelithiasis, cirrhosis of the liver or portal hypertension 
• Known history of drug induced pneumonitis 
• On-going inflammatory bowel disease 
• On-going alcohol or drug addiction 
• Life expectancy lower than 6 months. 
• Prior history of malignancies, other than follicular lymphoma, 
unless the patient has been free for at least 10 years 
(exceptions: 
localized 
non-melanoma 
skin 
cancer 
ad 
carcinoma in situ of the cervix). 
• Any of the following laboratory abnormalities: liver enzymes 
(AST/SGOT and/or ALT/SGPT) > 2.5-fold the upper limit of 
normal (except of liver involvement by lymphoma); total 
bilirubin > 1.5 mg/dL (except for patients with known Gilbert’s 
disease or biliary tree compression by lymphoma masses); 
creatinine clearance < 30 mL/min. 
• Uncontrolled intercurrent illness. 
• Known hypersensitivity or allergy to murine products or to any 
of the medicaments under investigation. 
• Pregnancy or breastfeeding, or unwillingness to comply with 
adequate contraception. 
• Any serious medical condition, laboratory abnormality or 
psychiatric illness that would prevent the patient from signing 
the informed consent or which may place the patient at 
unacceptable risk if participating in the study.  
• Any evidence of ongoing bacterial, viral and fungal infection. 
• 
Known hypersensitivity to the active substances or to any of 
the excipients. 
• 
Concomitant participation into another trial planning 
experimental therapy. 
Study treatment and 
response criteria 
Single arm: 
 Regimen: GAUDEALIS q28 days 
  
 - Obinutuzumab 
Dose: 1000 mg IV 
Day 1, 8, 15 (1st cycle) 


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 - Obinutuzumab 
Dose: 1000 mg IV 
Day 1 (2nd cycle onward) 
 - Idelalisib 
Dose: 150 mg BID 
oral 
Daily (24 weeks) 
 
Obinutuzumab will be administered intravenously at a flat dose of 
1000 mg on day 1, 8, 15, of the first cycle, then repeated on day 1 of 
each subsequent cycle, for 6 cycles in total (each cycle is completed 
in 28 days). Idelalisib will be given concomitantly with obinutuzumab 
on a daily 150 mg bid schedule orally and continuously (24 weeks). 
For patients achieving at least a partial response at the end of 
induction, a maintenance phase with obinutuzumab is scheduled (on 
day 1 every two months for two years or until progression or 
unacceptable toxicity, whichever comes first)  
If one of the two drugs has to be permanently discontinued due to any 
cause, patient may continue treatment with the other agent if it is 
judged to be a clinical benefit  
Overall response rate (ORR) is defined as the proportion of patients 
with at least a partial response (PR), as defined by 2014 Lugano 
criteria. 
Assessments 
schedule  
Patients will be evaluated before treatment by a staging total body 
computed tomography (CT) scan (a positron emission tomography 
(PET) scan is recommended for patients with grade 3A follicular 
lymphoma), as well with a bone marrow trephine biopsy and molecular 
evaluation of BCL-2 rearrangement on marrow blood. FL has to be 
confirmed by histology at relapse. Full blood counts, liver and renal 
function examinations, lactate dehydrogenase, serum proteins with 
electrophoresis and immunoglobulin levels will be collected at 
baseline and before each cycle. Full serological testing for hepatitis B 
and C virus, human immunodeficiency virus and cytomegalovirus 
(CMV) will be performed upon patients’ enrolment. CT scans will be 
repeated after induction cycle 3, at EOI, every 3 and 4 months for the 
first and second year of maintenance, respectively, at treatment 
completion after 2 years of maintenance or in case of early withdrawal 
(EOT), at relapse/progression and during follow-up; PET scans are 
mandatory at baseline, after induction cycle 3 and 6 (EOI), at the end 
of treatment after 2 years of maintenance or in case of early 
withdrawal (EOT) and at relapse/progression. At all additional 
timepoints (including follow-up) PET scans are optional and will be 
done at clinician discretion only if in accordance with center clinical 
practice; marrow biopsy and molecular biology examination will be 
performed only if positive at baseline. 
All the responder patients (CR, PR, SD) will enter a follow-up phase 
and will be followed with repeated CT scans every 6 months for two 
years (starting from the CT/PET scan performed at the end of 
treatment) or until death/progression whichever comes first.  
Patients 
with 
progressive 
disease, 
whenever 
progression 
is 
documented, are considered off treatment. Off-treatment patients are 
however considered evaluable for OS. 
Centralized analyses 
TEST 
APPENDIX 
REF 
REQUIRED QUANTITY 
Diagnosis 
Review 
Appendix D 
YES 
1 BLOCK or 20 
UNSTAINED 
SLIDES 
Upfront centralized diagnosis review is compulsory for treatment 
start, but the local pathology report is enough to enroll patient. 
 
Statistical 
considerations 
Optimal Simon's two-stage design has been used to calculate the 
sample size. 


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Based on previous clinical experiences, the null hypothesis was set as 
a true response rate is 55% (response rate of idelalisib single agent), 
that will be tested against a one-sided alternative response rate of 
75% (response of obinutuzumab in combination). Last available 
clinical response will be considered for patients who will permanently 
discontinue for any cause both drugs of the experimental combination 
before the completion of the 6th cycle (planned duration of induction 
phase). Patients who will have no tumor assessment after the start of 
therapy will be considered non-responsive.    
For the first stage, the accrual will be suspended when 15 patients will 
have started experimental therapy. If there are 9 or fewer responses in 
these 15 patients, the study will be stopped. 
Otherwise, enrollment will be reopened until 28 additional patients will 
start experimental therapy, for a total accrual of 43 patients. The null 
hypothesis will be rejected if 29 or more responses are observed in 43 
patients. 
This design yields a type I error rate of 5% and power of 80% when 
the true response rate is 75% 
 
Safety monitoring and stopping rules: 
In order to monitor the safety of the treatment in small cohorts of 
patients, the Bayesian approach of Thall, et al (1995) as extended by 
Thall and Sung (1998), for monitoring toxicity will be used. We have 
planned the monitoring of toxicity to ensure that the proportion of 
patients with non-hematological toxicity (defined as any non-
hematological toxicity of grade 3 or higher or treatment interruption for 
safety reasons or any toxic death) after 3 and 6 cycles of induction is 
not higher than an acceptable level of 25%. The prior probability of 
toxicity (25%) is modeled by a beta distribution [Beta (0.5,1.5)]. We will 
stop the enrolment in the experimental cohort if the posterior 
probability of the treatment being more toxic than expected is greater 
than 90%. Patients will be monitored, without suspending the 
enrollment, according to the following stopping boundaries for toxicity 
in cohorts of five patients as per assessment every 3 cycles: 
 
Patients assessed 
for toxicity 
Stop the enrollment in the cohort if the 
relevant toxicities are greater or equal to: 
5 
3 
10 
5 
15 
7 
20 
9 
25 
10 
30 
12 
35 
13 
40 
15 
 
Demographics and patients’ characteristics will be summarized by 
descriptive statistics. Point estimates of efficacy and toxicity will be 
provided with 95% confidence intervals. Overall response rate will be 
calculated as the sum of complete and partial response rates. Time-
to-event endpoints (progression free survival, overall survival) will be 
estimated by the Kaplan-Meier method. For the safety analyses, both 
at patient level and at therapy cycle level, summaries of incidence 
rates (frequency and percentages) of individual adverse events will be 
reported by type and grade according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (version 5.0). 


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5. LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS  
 
ABBREVIATION 
TERM 
AE 
Adverse Event 
ALT (SGPT) 
ALanine Transaminase (Serum Glutamic Pyruvic Transaminase) 
AST (SGOT) 
ASpartate Transaminase (Serum Glutamic Oxaloacetic Transaminase) 
β-HCG 
beta-Human Chorionic Gonadotropin 
CBC 
Complete Blood Cell 
CMV 
Cytomegalovirus 
CNS 
Central Nervous System 
CR 
Complete Response 
CRF 
Case Report Form 
CRu 
Complete Response unconfirmed 
CT 
Computed Tomography  
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOI 
End of induction (after 6 cycles of GAUDEALIS regimen) 
EOT 
End of treatment (at the end of maintenance) 
FCBP 
Female of ChildBearing Potential 
FIL 
Fondazione Italiana Linfomi 
GCP 
Good Clinical Practice 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Review Committee 
IMP 
Investigational Medicine Product 
IP 
Investigational Product 
ITT 
Intent To Treat  
IV 
Intra Venous 
LDH 
Lactic DeHydrogenase 
LVEF 
Left Ventricular Ejection Fraction 
MoH 
Ministry of Health  
MRI 
Magnetic Resonance Imaging 
NHL 
Non-Hodgkin’s Lymphoma 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PET 
18F-FDG Positon Emission Tomography 
PFS 
Progression Free Survival 
PK 
PharmacoKinetics 
PR 
Partial Response 
PS 
Performance Status 
SAE 
Serious Adverse Event 
SCT 
Stem Cell Transplant 
SD 
Stable Disease 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SUV 
Standardized Uptake Value 
ULN 
Upper Limit of Normal 
WHO 
World Health Organization 


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6. STUDY FLOW CHART 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Patients in PD at any restaging during maintenance will be addressed to Survival follow-up 


 
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7. BACKGROUND 
 
7.1. Disease background 
Follicular Lymphoma (FL) is a chronic, indolent but potentially life-threatening malignancy whose 
natural history is characterized by several periods of remissions ultimately followed by a relapse, 
which requires sequential treatments with agents that provide alternative mechanisms of tumor 
control. 
There is not a general consensus yet regarding the salvage treatment for patients affected by FL 
who relapse or show refractoriness to a first line rituximab-containing chemotherapy.  
Single agent rituximab, radioimmunotherapy and chemotherapy with bendamustine have received 
approval for treatment of refractory or relapsed disease.  
Single-agent rituximab can offer disease palliation with good tolerability in some patients, but tumor 
control is not lasting. 
Radioimmunotherapy with yttrium90-ibritumomab tiuxetan and iodine131-tositumomab has been 
limited because of several medical and practical restrictions to the use of these agents.  
Bendamustine in combination with rituximab has been evaluated in Europe in 63 patients with 
relapsed or refractory lymphomas [1]. The overall response rate (ORR) was 90%, with a 
remarkable complete response (CR) rate of 60%. The median progression-free survival (PFS) was 
24 months. A separate study conducted in the United States, Canada and Australia [2] confirmed 
these results (ORR of 93%, CR rate of nearly 50% and median PFS of 23 months). 
 
7.2. Current therapies for R/R Follicular Lymphoma  
Multiple options exist for the treatment of patients with FL who have failed first-line therapy, and the 
decision of which therapy to use depends on a number of factors, including the prior treatment 
used, duration of prior response, patient age, comorbid illnesses, and goals of therapy. 
Bendamustine 
Bendamustine is approved in the United States for use in patients with rituximab-refractory indolent 
B-cell lymphoma. A pivotal trial in 100 patients reported an ORR of 75% with a median PFS of 9.3 
months [3]. The US Food and Drug Administration (FDA)–approved dose of single-agent 
bendamustine is 120 mg/m2 given IV on days 1 and 2 of 21-day cycles. Approximately two-thirds of 
patients required dose modifications or delays, mainly due to cumulative myelosuppression. In 
addition, most practitioners prefer to administer bendamustine with rituximab. An expert panel has 
published guidelines on bendamustine dosing when combined with rituximab, and recommends 90 
mg/m2 on days 1 and 2 repeated every 28 days [4]. Lower doses (such as 70 mg/m2) may be more 
appropriate in the elderly. 
Fludarabine-based regimens 
Fludarabine-based regimens are another option for patients who relapse after an alkylator-based 
therapy. They should be used with caution in heavily pretreated or elderly patients, however, due 
to immunosuppression. 
Radioimmunotherapy 
Radioimmunotherapy is also an option for patients with non-bulky, indolent B-cell NHL if the bone 
marrow is minimally involved. With 90Y ibritumomab tiuxetan, response rates are 70% and 
response duration is, on average, 11-15 months. 
Single-agent rituximab 
Single-agent rituximab can be used in relapsed FL, but more patients are becoming rituximab 
refractory after receiving the drug with primary therapy and as maintenance. For patients who are 
still rituximab sensitive, it is an attractive option, particularly in the elderly, since after first line they 
would not tolerate cytotoxic agents. 
Obinutuzumab 
For patients who are rituximab refractory, the combination of bendamustine and obinutuzumab 
(type II anti-CD20 monoclonal antibody) was shown to be superior to bendamustine alone, 
approximately doubling the PFS in a randomized clinical trial [5]. Obinutuzumab is also under 
investigation in the frontline setting (see paragraph 7.3.2 for more details). 


 
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Idelalisib 
A new option for relapsed FL is the phosphatidylinositol 3- kinase d (PI3Kd) inhibitor idelalisib. 
Idelalisib targets the d isoform of PI3K, an enzyme downstream from the BCR, which eventually 
signals through AKT and mammalian target of rapamycin. In a phase 2 study of 125 patients with 
indolent NHL who were refractory to both rituximab and an alkylating agent, idelalisib was 
administered at a dose of 150 mg twice daily until PD or patient withdrawal [6]. The response rate 
was 57% with a median duration of 12.5 months. Response rates and duration in the FL subset 
were similar to the overall population. Grade 3 or higher toxicities included neutropenia (27%), 
transaminase elevations (13%), diarrhea (13%), and pneumonia (7%). Based upon this data, 
idelalisib received accelerated approval by the FDA in 2014. 
Novel agents under development 
A variety of novel agents are under development in FL, including other PI3K inhibitors, 
immunomodulatory agents, inhibitors of BTK, antibody-drug conjugates, novel anti-CD20 
monoclonal antibodies, chimeric antigen receptor T-cell therapy, immune checkpoint inhibitors, 
inhibitors of nuclear export proteins, and others. An exhaustive review of agents in development is 
beyond the scope of this review, but examples of novel agents with outcome data in FL are 
summarized in [7–11] 
Stem cell transplantation 
High-dose chemotherapy with autoSCT and alloSCT are both useful strategies in the management 
of FL, particularly for younger patients with high-risk features, such as a brief remission to previous 
therapy. A review of 904 patients in the International Bone Marrow Transplant Registry who 
underwent autologous or allogeneic transplantation for FL revealed that durable remissions could 
be induced with either technique [12]. A lower 5-year recurrence rate with allogeneic 
transplantations was offset by a higher treatment-related mortality compared with autologous 
transplantation, leading to similar 5-year survival rates of 51% to 62%. To reduce the treatment-
related mortality of alloSCT, most centers now favor a nonmyeloablative strategy in FL. 
Results utilizing a nonmyeloablative alloSCT strategy vary widely in the literature. For example, a 
series of 62 patients treated at the Fred Hutchinson Cancer Center demonstrated a 3-year OS and 
PFS of 67% and 54%, respectively [13]. Alternatively, a highly selected group (n 547) treated at the 
MD Anderson Cancer Center achieved an 11-year OS and PFS of 78% and 72%, respectively [14]. 
There is one small, randomized clinical trial (the Chemotherapy vs Unpurged stem cell transplant 
vs Purged stem cell transplant [CUP] trial) examining autoSCT vs standard therapy in patients with 
relapsed FL [15]. The study, conducted in the pre-rituximab era, found improved PFS and a trend 
toward improved OS with autoSCT. An interesting long-term analysis of patients receiving 
myeloablative chemotherapy followed by autoSCT comes from investigators at St. Bartholomew’s 
Hospital (London, United Kingdom) and the Dana-Farber Cancer Institute (Boston, MA) [16]. A 
cohort of 121 patients, with a median follow-up of 13.5 years, was noted to have a plateau in the 
remission duration curve beginning around year 8. Nearly half of the patients were still in remission 
at 10 to 15 years, suggesting some patients may be cured. Results were substantially better for 
patients treated in second remission as opposed to later in the disease course, suggesting the 
optimal window to consider autoSCT in FL is second or third remission. Later application appears 
to be associated with diminishing returns, and patients with multiply-relapsed FL are more 
appropriately considered for alloSCT or novel agents. Trials evaluating autoSCT in first remission 
do not support its use in that setting [17]. 
 
7.3. Study drugs background  
7.3.1. Idelalisib 
Idelalisib is indicated in combination with rituximab, ofatumumab or bendamustine with rituximab 
for the treatment of patients with chronic lymphocytic leukemia who have received at least one 
prior therapy and for the treatment of patients with refractory indolent non-Hodgkin lymphoma 
(iNHL). Idelalisib should be used only in patients with limited treatment options. Idelalisib is a 
potent competitive inhibitor of the ATP binding site of the PI3K p110δ catalytic domain, which has 
been shown to be prominently expressed in cells of hematopoietic origin [18, 19]. Inhibition of 


 
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PI3Kδ has been shown to modulate cellular functions including motility, proliferation, survival, and 
recruitment of additional intracellular signaling enzymes through the B-cell receptor (BCR). B-cell 
receptor signaling is a central pathologic mechanism in B-cell malignancies in that it promotes 
leukemia and lymphoma cell survival and proliferation; disruption of BCR signaling can be lethal to 
malignant B cells. The effects of p110δ on lymphocyte activation/function, cellular proliferation, and 
protection from apoptosis provide the rationale for targeting this isoform as a therapy for 
hematologic malignancies. 
Idelalisib is an orally bioavailable, new chemical entity with a molecular weight of approximately 
415 daltons. Its chemical name is 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl] 
quinazolin-4(3H)-one). Idelalisib is a chiral compound with a single chiral center at C3. The 
compound is a single enantiomer with the (S) configuration. 
Idelalisib is a new valid option for relapsed FL.  In a phase 2 study of 125 patients with indolent 
NHL who were refractory to both rituximab and an alkylating agent, idelalisib was administered at a 
dose of 150 mg twice daily until PD or patient withdrawal [6]. The response rate was 57% with a 
median duration of 12.5 months. Response rates and duration in the FL subset were similar to the 
overall population. Grade 3 or higher toxicities included neutropenia (27%), transaminase 
elevations (13%), diarrhea (13%), and pneumonia (7%). Based upon this data, idelalisib received 
accelerated approval by the FDA in 2014. Efficacy results were confirmed even in a real life 
context [20].  
Idelalisib in combination. with rituximab, bendamustine and or rituximab+bendamustine is also 
being evaluated in subjects with relapsed/refractory iNHL with an ORR >75% in all the four cohorts 
(phase I study) [21]. Due to safety signal observed in idealisib combination front-line CLL and 
early-line relapsed iNHL studies have been terminated as the risk/benefit profile was deemed 
unlikely to be favorable. Following completion of the CHMP (Committee of Human Medicinal 
Products) review, the benefit-risk balance of idelalisib in combination with rituximab for the 
treatment of relapsed CLL, including patients with 17p deletion or TP53 mutation, and idelalisib 
monotherapy for the treatment of refractory FL remains positive. CHMP concluded that the risk of 
serious infection is relevant to all indications. Risk minimization measures for serious infections 
have been implemented, in particular for Pneumocystis jirovecii pneumonia (PJP) and 
cytomegalovirus (CMV) infection. For further details please consult the last drug Investigator 
Brochure (IB). 
 
7.3.2. Obinutuzumab  
Obinutuzumab (also known as RO5072759, GA101, GAZYVA®, GAZYVAROTM) is a humanized 
glycoengineered type II anti-CD20 monoclonal antibody (moAb). Obinutuzumab was derived by 
humanization of the parental B-Ly1 mouse antibody and subsequent glycoengineering leading to 
the following characteristics: high-affinity binding to the CD20 antigen, high antibody-dependent 
cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP); low 
complement-dependent cytotoxicity (CDC) activity; and high direct cell death induction. As of July 
2016, obinutuzumab in combination with bendamustine received regulatory approval for the 
treatment of patients with relapsed/ refractory FL in multiple countries including the US, 
Switzerland, and the EU. 
Obinutuzumab drug substance is manufactured by fermentation of a recombinant mammalian cell 
line and subsequent purification of the antibody. An antibody-producing cell line was established 
from a Chinese hamster ovary (CHO) K1 cell line. 
In the monotherapy setting (studies BO20999, BO21003, YP25623, and JO21900), the proportion 
of patients who had a response (CR or PR) at the end of treatment ranged from 28% (11/40 
patients) to 58% (7/12 patients). Although these patients had treatment-refractory or relapsed 
disease and been treated with several prior therapies, some patients in studies BO20999, 
BO21003 Phase II, and JO21900 achieved a CR by the end-of-treatment assessment. In addition, 
in study YP25623 one DLBCL patient achieved a CRu and 2 patients achieved a PR. Six of the 13 
patients with FL (46%) had a PR; no patient with NHL (DLBCL and FL) achieved a CR. 


 
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In the chemotherapy combination studies BO21000 and GAO4915g the proportion of patients 
achieving a response (CR or PR) was 82% among previously untreated DLBCL patients using 
Cheson 2007 criteria [22] and exceeded 90% among patients with previously untreated or 
relapsed/refractory FL. The CR rate was also higher than in the monotherapy studies (35-39% in 
previously untreated FL, 39-50% in relapsed/refractory FL and 55% in previously untreated 
DLBCL). 
At a pre-planned interim analysis, the pivotal study GAO4753g met its primary objective of showing 
a difference in IRC-assessed PFS between treatment arms. Treatment with G-bendamustine 
resulted in a clinically meaningful and statistically significant reduction by 45% in the risk of IRC-
assessed PFS (progression or death) compared with bendamustine alone (stratified analysis: HR 
0.55, 95% CI [0.40, 0.74]; log-rank p-value ≤ 0.0001). 
Furthermore, on 20 May 2016 a pre-planned interim analysis of the pivotal study BO21223 was 
performed, and the IDMC recommended to unblind and fully analyze the study. The results 
showed that obinutuzumab-based treatment significantly reduced the risk of disease progression 
or death (PFS, as assessed by investigator) compared to rituximab-based treatment in patients 
with previously untreated advanced FL. No new safety signals were detected. EMA has approved 
obinutuzumab in combination with bendamustine chemotherapy followed by obinutuzumab 
maintenance in people with FL who did not respond or who progressed during or up to six months 
after treatment with rituximab or a rituximab-containing regimen. 
The approval is based on results from the pivotal phase III GADOLIN study [5, 23] which showed 
that obinutuzumab plus bendamustine, followed by obinutuzumab alone resulted in a 52 percent 
reduction (HR=0.48, 95 percent CI 0.34-0.68, p<0.0001) in the risk of disease worsening or death 
(PFS), compared to bendamustine alone, as evaluated by an independent review committee. As 
assessed by investigator review, median PFS with the obinutuzumab regimen was more than 
double that with bendamustine alone (29.2 months vs. 13.7 months; HR=0.48, 95 percent CI 0.35-
0.67, p<0.0001). People who received the obinutuzumab regimen also showed a 38 percent 
reduction (HR=0.62, 95 percent CI 0.39-0.98) in the risk of death (OS) compared to those who 
received bendamustine alone. For further details please consult the last drug IB. 
Obinutuzumab has also been investigated in the frontline setting. The GALLIUM study 
(clinicaltrials.gov identifier NCT01332968) is an international randomized phase 3 study comparing 
obinutuzumab plus chemotherapy (with obinutuzumab maintenance) to rituximab plus 
chemotherapy (with rituximab maintenance) in previously untreated advanced-stage FL. A total of 
1202 patients with follicular lymphoma were randomized in the GALLIUM trial (601 patients in each 
group) [24]. After a median follow-up of 34.5 months, a planned interim analysis showed that 
obinutuzumab-based chemotherapy resulted in a significantly lower risk of progression, relapse, or 
death than rituximab-based chemotherapy (estimated 3-year PFS rate of 80.0% and 73.3%, 
respectively; P = 0.001). No difference emerged between the two groups with respect to other 
time-to-event endpoints. No significant difference was observed in the rate of response according 
to CT-based assessment as well. Grade 3-5 adverse events and SAEs were more frequent with 
obinutuzumab than with rituximab (74.6% vs. 67.8% and 46.1% vs. 39.9%, respectively), but the 
rates of toxic deaths were similar in the two groups (4.0% and 3.4%, respectively). The most 
common adverse events were infusion-related events that were considered by the investigators to 
be largely due to obinutuzumab in 353 of 595 patients and to rituximab in 292 of 597 patients 
(59.3% and 48.9%, respectively; P<0.001). In conclusion, the GALLIUM trial showed that the 
replacement of rituximab with obinutuzumab in the context of immunochemotherapy and 
maintenance therapy in first line resulted in significantly longer PFS, but at the expenses of an 
higher frequency of high-grade adverse events [24]. 
 
 
8. STUDY RATIONALE 
 
The new frontier in the treatment of FL is the development of non-cytotoxic combination therapies, 
able to offer to patients a “chemo-free” approach, with the same efficacy of conventional 


 
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chemotherapy but less toxicity. The paradigm of this approach is currently represented by the R-
square regimen (rituximab + lenalidomide) which has shown an ORR of 77% with a CR rate of 
41% [25] in relapsed/refractory FL and is currently under investigation in the frontline setting. 
The combination of idelalisib with obinutuzumab would address a persistent unmet medical need 
with the same non-chemo approach: the design and conduct of this study is supported by 
knowledge of the natural history and current therapies for the disease, and the information 
regarding idelalisib and obinutuzumab mechanism of action and safety profile.  
Idelalisib is a potent and highly selective, small-molecule, oral inhibitor of the delta isoform of the 
phosphatidilinositol-3 kinase (PI3Kδ), being able to block the PI3Kδ-AKT signaling and promoting 
apoptosis, as shown in vitro in lymphoid cell lines and in vivo. Idelalisib has shown an ORR of 56% 
in heavily pretreated FL patients refractory to both rituximab and alkylating agents, with a CR rate 
of 14% and a median PFS of 11 months [6]. The potential for clinical efficacy of idelalisib in 
combination with an anti-CD20 monoclonal antibody in patients with relapsed or refractory indolent 
non-Hodgkin lymphomas (in particular in FL) is supported by the observed antitumor activity of 
idelalisib given in combination with rituximab in a phase I study with an ORR of 75% and a CR rate 
of 22% [21]. 
Obinutuzumab is a type II glycoengineered humanized anti-CD20 monoclonal antibody. Compared 
to rituximab, it shows an increased direct cell death induction and antibody-dependent cytotoxicity 
due to the glycoengineering, with also a superior B-cell depletion effect. It has shown its efficacy as 
single agent in heavily pretreated relapsed/refractory FL patients with a ORR of 55% and a CR of 
9%, being well tolerated and with no dose limiting toxicities [26]. Moreover, it has been also safely 
and effectively combined with CHOP and FC chemotherapy regimens in the GAUDI study [27], 
showing remarkable ORR (96% and 93% respectively). 
 
Benefit/Risk balance of the combination idelalisib + obinutuzumab 
The association of idelalisib and obinutuzumab is a "chemo-free" therapy with potential good 
therapeutic efficacy counterbalanced by an acceptable toxicity profile. In particular, the reduced 
duration of idelalisib administration planned by the study significantly decreases the risk for toxicity 
previously reported with longer therapy, even if it still maintains the same therapeutic efficacy. 
Furthermore, idelalisib has a completely different mechanism of action with respect the classic 
chemotherapy, as well as the addition advantage of the oral administration. 
 
9. STUDY OBJECTIVES 
9.1. Primary Objective 
• To evaluate the efficacy in terms of clinical response in patients treated with the combination of 
obinutuzumab and idelalisib. 
 
9.2. Secondary Objective 
• To assess efficacy in terms of progression-free survival and overall survival  
• To assess the safety and the feasibility of the combination of obinutuzumab and idelalisib. 
 
9.3. Primary Endpoint 
Overall response rate (ORR): ORR will be assessed by investigator after the 6th cycle (end of 
induction phase) of therapy with the combination of obinutuzumab and idelalisib as defined by 
2014 Lugano criteria [28]. Last available clinical response will be considered for patients who will 
permanently discontinue both drugs of the experimental combination before the completion of the 
6th cycle (planned duration of induction phase) for any cause. Patients who will have no tumor 
assessment after the start of therapy will be considered non-responsive. 
 
9.4. 
Secondary Endpoint 
• Overall survival (OS) rate, measured from the date of starting therapy to the date of death 
from any cause. Patients alive and patients who are lost to follow up at the time of the final 


 
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analysis will be censored at the date of the last contact. The minimum follow-up time required 
for OS assessment for all patients will be 2 years. 
• Progression-free survival (PFS) rate, measured from the date of starting therapy to the date 
of disease progression, relapse or death from any cause. Responding patients and patients who 
are lost to follow up will be censored at their last assessment date. Patients who will have no 
tumor assessment after the start of therapy due to interruption of both drugs will be considered 
failures at the date of treatment interruption in the PFS analysis. The minimum follow-up time 
required for PFS assessment for all patients will be 2 years. 
• Treatment safety through the measurement of: patients’ withdrawal rate, incidence, type and 
grade of any adverse event (AE) and serious adverse event (SAE), hospitalization rate 
throughout the study, and patients’ compliance to oral treatment. 
 
10. STUDY DESIGN 
10.1. Overview of study design 
This is a prospective, multicenter, single arm, phase II study. 
Patients with histologically confirmed FL, in need of a systemic approach and failing (i.e. with 
refractory disease [no response or response lasting less than 6 months] or with a proven disease 
relapse) at least 2 previous lines of treatment, including any antibody directed against the CD20 
antigen-containing chemotherapy, will undergo a combined treatment of obinutuzumab and 
idelalisib. 
After providing written informed consent, patient will be evaluated for eligibility during a 28-day 
screening period. In the meanwhile, their bioptic samples will be submitted to the central laboratory 
designed by FIL to undergo central diagnosis review. If they continue to meet eligibility criteria, 
they will start the obinutuzumab plus idelalisib regimen and PJP prophylaxis. Histological 
centralized review is compulsory for treatment start, but the local pathology report is sufficient for 
patient enrollment. 
Obinutuzumab will be administered intravenously at a flat dose of 1000 mg on day 1, 8, 15 of the 
first cycle, then repeated on day 1 of each subsequent cycle, for a total of 6 cycles (each cycle is 
completed in 28 days). Idelalisib will be given continuously on a daily 150 mg bid schedule (24 
weeks).  
If one of the two drugs has to be permanently discontinued due to any cause, patient may continue 
treatment with the other agent if it is judged to be a clinical benefit. 
For patients achieving at least a partial response at the end of induction, a maintenance phase with 
obinutuzumab is scheduled (on day 1 every two months for two years or until progression or 
unacceptable toxicity, whichever comes first).  
Patients with a stable disease at EOI will enter a follow-up phase and will be followed with 
repeated CT scans every six months for two years or until progression or death. The same applies 
to patients in SD at EOT.  
Patients with progressive disease, if progression is documented during induction or maintenance 
phase, are considered off-treatment, but will enter a survival follow up period of two years after 
treatment discontinuation and will be considered evaluable for OS till study end. 
If progression is documented during follow up period, patients will enter a survival follow up period 
until globally 2 years of follow up are achieved. 
 
Patients who will interrupt therapy (for any reason), if at least in stable disease at time of treatment 
discontinuation, will enter the follow-up period and will be re-evaluated for response every 6 
months for 2 years or until progression/start of new anti-lymphoma therapy/death. If these patients 
experience progression/start of new lymphoma treatment will be followed up for survival for a total 
of 2 years from treatment discontinuation. These patients are however considered evaluable for 
PFS and OS. 
Non-responder, relapsing or progressive patients will be treated according to best clinical practice. 


 
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These patients are however considered evaluable for OS. 
 
CT scans have to be performed at baseline, after induction cycle 3 and 6 (EOI), every 3 months 
during the first year of maintenance, every 4 months during the second year of maintenance, at the 
end of treatment after 2 years of maintenance or in case of early withdrawal (EOT), at 
relapse/progression and during follow-up. 
PET scans are mandatory at baseline, after induction cycle 3 and 6 (EOI), at the end of treatment 
after 2 years of maintenance or in case of early withdrawal (EOT) and at relapse/progression. At all 
additional timepoints (including follow-up) they are optional and will be done at clinician discretion 
only if in accordance with center clinical practice. 
 
10.2. Number of patients  
A total of 43 patient will be enrolled in the study: 15 patients at the Stage 1 of the study.  
If there are 9 or fewer responses in these 15 patients, the study will be stopped. Otherwise, 28 
additional patients will be accrued for a total of 43 patients.  
 
10.3. Duration of the study 
Patients will be recruited over 1.5 year + 6 months of induction + 2 years of maintenance and 
followed for 2 years after the end of the treatment phase (6,5 years).  
End of study is defined by the last visit planned by the protocol of the last patient in follow-up that 
means 2 years after the EOT visit (LPLV). The Final Study Report will be provided after the end of 
the Study. 
 
11. STUDY POPULATION 
11.1. Inclusion criteria 
• 
Relapsed or refractory, histologically confirmed CD20-positive follicular non-Hodgkin’s 
lymphoma, grade 1, 2 or 3A according to the WHO 2017 classification. 
• 
Age ≥ 18 years. 
• 
At least 2 prior systemic therapies for follicular lymphoma including both any antibody 
directed against the CD20 antigen and a chemotherapy combination. 
• 
Treatment indications, with the presence of at least one of the following: 
− bulky disease (nodal or extranodal – except spleen – mass more than 7 cm in its 
greater diameter or involvement of at least 3 nodal or extranodal sites, each with a 
diameter equal to or greater than 3 cm); 
− at least one B-symptom (fever > 38°C of unclear etiology, night sweats, weight loss 
greater than 10% of body weight in the prior 6 months); 
− symptomatic splenomegaly; 
− compression syndrome (i.e. of orbits, ureters, gastrointestinal tract, biliary tract); 
− lymphoma-related cytopenias (hemoglobin < 10 g/dL and/or platelets < 100·109/L 
and/or neutrophils < 1.5·109/L); 
− pleural or peritoneal serous effusions. 
−  
• 
Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2. 
• 
Adequate hematological function, unless abnormalities due to underlying disease, within 28 
days prior to signing informed consent, defined as follows: neutrophils > 1.5·109/L, platelets 
> 75·109/L, hemoglobin > 8,0 g/dL with transfusion independence. 
• 
Capacity and willingness to adhere to study visit schedule and specific protocol procedures. 
• 
Willingness to sign a written informed consent.  
• 
Compliance with effective contraception without interruption, from 28 days before treatment 
start up to 18 months after treatment discontinuation (see paragraph 13.9), agreeing not to 
donate the semen during treatment and for 18 months after discontinuation (if the patient is 
male), or to undergo ongoing pregnancy test during the course of the study (if the patient is 


 
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female). Birth control methods considered acceptable for the study are those highly 
effective (IUS, hormonal methods, tubal sterilization, sexual intercourse with a 
vasectomized male partner) or effective (male condom, diaphragm, cervical cap). 
According to the usual lifestyle of the subjects, if they are not willing to adopt the prescribed 
contraceptive methods, they have to practice true abstinence for all the period above 
reported. 
• 
Patients must agree to undergo JPJ prophylaxis throughout the treatment period and 2-6 
months thereafter (before consulting with Medical monitor). 
 
11.2. Exclusion criteria 
• 
Grade 3b follicular non-Hodgkin’s lymphoma or evidence of transformation to high-grade 
non-Hodgkin’s lymphoma. 
• 
Central nervous system or leptomeningeal involvement by lymphoma. 
• 
Major surgery (excluding any lymph node biopsy) within 28 days prior to signing informed 
consent. 
• 
Seropositivity for HBV or evidence of active infection (HBsAg positivity, or HBsAg negativity 
with positive anti-HBs/anti-HBc and detectable viral DNA load); if viral load is negative or 
undetectable, the patient is eligible, provided their HBsAg negativity. 
• 
Positive viral HCV RNA.  
• 
Seropositivity for HIV, regardless of viral load. 
• 
Known history of drug induced liver injury, chronic active hepatitis C (HCV), chronic active 
hepatitis B (HBV), alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary 
cirrhosis, on-going extra-hepatic obstruction caused by cholelithiasis, cirrhosis of the liver or 
portal hypertension. 
• 
Known history of drug induced pneumonitis. 
• 
On-going inflammatory bowel disease. 
• 
On-going alcohol or drug addiction. 
• 
Life expectancy lower than 6 months. 
• 
Prior history of malignancies, other than follicular lymphoma, unless the patient has been 
free for at least 10 years (exceptions: localized non-melanoma skin cancer ad carcinoma in 
situ of the cervix). 
• 
Any of the following laboratory abnormalities: liver enzymes (AST/SGOT and/or ALT/SGPT) 
> 2.5-fold the upper limit of normal (except of liver involvement by lymphoma); total bilirubin 
> 1.5 mg/dL (except for patients with known Gilbert’s disease or biliary tree compression by 
lymphoma masses); creatinine clearance < 30 mL/min. 
• 
Uncontrolled intercurrent illness. 
• 
Known hypersensitivity or allergy to murine products or to any of the medicaments under 
investigation. 
• 
Pregnancy or breastfeeding, or unwillingness to comply with adequate contraception. 
• 
Any serious medical condition, laboratory abnormality or psychiatric illness that would 
prevent the patient from signing the informed consent or which may place the patient at 
unacceptable risk if participating in the study.  
• 
Any evidence of ongoing bacterial, viral and fungal infection. 
• 
Known hypersensitivity to the active substances or to any of the excipients. 
• 
Concomitant participation into another trial planning experimental therapy. 
 
12. PATIENTS ENROLLMENT 
12.1. Informed consent  
The Investigator(s) must obtain informed consent of a patient or his/her designee prior to any study 
related procedures as per Good Clinical Practices (GCP). Documentation that informed consent 
occurred prior to the patient’s entry into the study and of the informed consent process should be 
recorded in the patient’s source documents. Subjects will be informed that their participation is 


 
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voluntary and that they may withdraw consent to participate at any time. They will be informed that 
choosing not to participate will not affect the care the subject will receive for the treatment of 
his/her disease. Subjects will be told that alternative treatments are available if they refuse to take 
part and that such refusal will not prejudice future treatment. The subject will be given sufficient 
time to read the informed consent form and the opportunity to ask questions. After this explanation 
and before entry to the study, consent should be appropriately recorded by means of the subject's 
dated signature. After having obtained the consent, a copy of the informed consent form must be 
given to the subject.  
The original consent form signed and dated by the patient and by the person consenting the 
patient prior to the patient’s entry into the study must be maintained in the Investigator’s study files 
and a copy given to the patient. In addition, if a protocol is amended and the changes impact on 
the content of the informed consent, the informed consent must be revised. Patients participating in 
the study when the amended protocol is implemented must be re-consented with the revised 
version of the informed consent. The revised consent form signed and dated by the patient and by 
the person consenting the patient must be maintained in the Investigator’s study files and a copy 
given to the patient. 
 
12.2. Patient registration and data collection 
Following confirmation of eligibility and written informed consent, patients should be registered 
online at www.filinf.it, in the dedicated section. An email of confirmation will be sent to the local 
investigator to coordinating investigator of the study and to the FIL Trial office staff. The electronic 
Case Report Forms (CRFs) for data collection could be reached in the restricted area of the FIL 
website by authorized users. 
 
13. TREATMENT 
13.1. IDELALISIB  
Idelalisib will be provided in tablets intended for oral administration. Each tablet contains 150 mg or 
100 mg of active idelalisib. The 150-mg tablets will be used for initial therapy; the 100-mg tablets 
are provided for use by those subjects who require a dose reduction. The 150-mg tablets are pink, 
film-coated, and include the following inactive excipients: microcrystalline cellulose, hydroxypropyl 
cellulose, croscarmellose sodium, sodium starch glycolate, magnesium stearate, red iron oxide, 
polyethylene glycol, talc, polyvinyl alcohol (PVA), and titanium dioxide. The 100-mg tablets are 
orange, film-coated, and include the following inactive excipients: microcrystalline cellulose, 
hydroxypropyl cellulose, croscarmellose sodium, sodium starch glycolate, magnesium stearate, 
yellow iron oxide, polyethylene glycol, talc, PVA, and titanium dioxide.  
 
13.1.1. Supplier 
Idelalisib tablets will be supplied free of charge by Gilead Sciences (Zydelig®). 
 
13.1.2. Receipt of study drug  
The investigator and/or the responsible site personnel must maintain accurate records of the 
receipt of all study drug shipped by FIL or its designee, including, but not limited to, the date 
received, lot number, amount received, and the disposition of all study drug. Study drug 
accountability records must also be maintained that include the subject number to whom the study 
drug was dispensed, the date, quantity and lot number of the study drug dispensed. 
 
13.1.3. Preparation, reconstitution and administration 
Idelalisib will be provided in bottles. Each bottle contains 60 tablets (4-week supply plus a modest 
overage) of one of the relevant dose strengths (150 mg, 100 mg) and a polyester coil. Bottles are 
white and are made of high-density polyethylene. Each bottle is closed with a white, continuous-
thread, child-resistant, polypropylene screw cap fitted with an induction-sealed, aluminum-faced 
liner. 


 
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Each bottle will have a unique number. The clinic staff will be responsible for dispensing idelalisib. 
It is planned that drug will be dispensed at 12-week intervals. Study drug may be dispensed at 
alternate intervals at the discretion of the investigator. Tablets should be dispensed in the original 
bottles provided. 
 
13.1.4. Storage and handling 
Bottles containing tablets of idelalisib should be stored at controlled room temperature (ie, ~25°C, 
with a range of 15 to 30°C). While stability of study drug tablets stored at controlled room 
temperature has been confirmed, brief excursions to temperatures as low as -20°C or as high as 
40°C (eg, during shipping) will not adversely affect the drug.  
The clinic staff will write the subject number on each bottle that is dispensed. Immediately before 
dispensing, the clinic staff will write the bottle number for each dispensed bottle in the study drug 
administration record corresponding to the subject number.  
The disposition of idelalisib should be documented from the time of receipt at the site through 
subject dispensing and return. 
Study personnel must ensure that all study drug is kept in a secure locked area with access limited 
to authorized personnel. The study drug must not be used outside the context of this protocol. 
Under no circumstances should the investigator or site personnel supply study drug to other 
investigators or clinics or allow the study drug to be used other than as directed by this protocol. 
 
13.1.5. Unused study drug supplies 
Idelalisib should be retrieved from each subject at the end of each dispensing interval. The quantity 
of study drug and the date returned by the subject should be recorded in the study drug 
accountability records. Patients will be instructed to return empty bottles or unused capsules.  
Unused or returned study drug will be destroyed locally in compliance with local pharmacy 
destruction procedures and drug disposition must be appropriately documented in the study file.  If 
any study drug is lost or damaged, its disposition should be documented in the source documents. 
Records documenting the date of study drug shipping or destruction, relevant lot numbers, and 
amount shipped or destroyed should be maintained. 
 
 
13.2. OBINUTUZUMAB   
13.2.1. Supplier 
Obinutuzumab will be supplied free of charge by F. Hoffmann-La Roche AG (GazyvaroTM). 
 
13.2.2. Preparation, reconstitution and administration 
Obinutuzumab is provided as a single dose 1000 mg liquid concentrate for infusion containing of 
25 mg/mL obinutuzumab. The 1000 mg dose is supplied in 50 mL glass vials containing 40 mL of 
the 25 mg/mL liquid concentrate. In addition to the drug substance, the liquid is also composed of 
histidine/histidine-HCl, trehalose and poloxamer 188. Obinutuzumab should be prepared by a 
healthcare professional using aseptic technique. The required amount of liquid concentrate should 
be drawn from the vial and diluted in PVC or non-PVC polyolefin infusion bags containing sterile, 
nonpyrogenic 0.9% aqueous sodium chloride (NaCl) solution. Other diluents such as dextrose 
(5%) solution should not be used. 
 
Obinutuzumab should be administered as a slow IV infusion through a dedicated line. IV infusion 
pumps should be used to control the infusion rate of obinutuzumab. Do not administer as an IV 
push or bolus. Do not use an additional in-line filter because of potential adsorption. 
The recommended storage conditions for obinutuzumab drug product are between 2°C and 8°C, 
protected from light. For clinical formulation-specific and batch-specific instructions and information 
on in-use stability, see the packaging label. 
 
Administration of First and Subsequent Infusions of Obinutuzumab are shown in table below: 


 
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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 or 
hypersensitivity during the prior infusion, use full 
premedication 
including 
100 
mg 
prednisone/prednisolone (until no further IRR 
occurs), begin infusion at an initial rate of 50 
mg/hr, and follow instructions for first infusion. 
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 guidelines. If reaction has 
resolved, resume the infusion at a 50% 
reduction in rate (i.e., 50% of rate used at the 
time the reaction occurred) 
 
 
13.2.3. Receipt of study drug  
The investigator and/or the responsible site personnel must maintain accurate records of the 
receipt of all study drug shipped by FIL or its designee, including, but not limited to, the date 
received, lot number, amount received, and the disposition of all study drug. Study drug 
accountability records must also be maintained that include the subject number to whom the study 
drug was dispensed, the date, quantity and lot number of the study drug dispensed. 
 
13.2.4. Storage and handling 
The recommended storage conditions for obinutuzumab drug product are between 2°C and 8°C, 
protected from light. 
 
13.2.5. Unused study drug supplies 
Patients will be instructed to return empty bottles or unused capsules.  Unused or returned study 
drug will be destroyed locally in compliance with local pharmacy destruction procedures and drug 
disposition must be appropriately documented in the study file.  If any study drug is lost or 
damaged, its disposition should be documented in the source documents. 
 
13.3. Treatment schedule and design 
All eligible patients will undergo a combined treatment with obinutuzumab and idelalisib for 6 
cycles (each cycle is completed in 28 days). 
 
1st CYCLE 
 
- Obinutuzumab 
Dose: 1 g 
IV 
Day 1, 8, 15  
- Idelalisib 
 
Dose: 150 mg oral 
BID Daily 
 
2nd – 6th CYCLE 
 
- Obinutuzumab 
Dose: 1 g 
IV 
Day 1  


 
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- Idelalisib 
 
Dose: 150 mg oral 
BID Daily  
 
If one of the two drugs has to be permanently discontinued due to any cause, patient may continue 
treatment with the other agent if it is judged to be a clinical benefit. 
  
Maintenance 
For patients achieving at least a partial response at the end of induction, a maintenance phase with 
obinutuzumab is scheduled (on day 1 every two months for two years or until progression or 
unacceptable toxicity, whichever comes first) 
 
13.4. Premedication 
13.4.1. Idelalisib 
Idelalisib does not require specific premedications or supporting medications. However, patients 
must undergo JPJ prophylaxis throughout the treatment period and 2-6 months thereafter (before 
consulting with Medical monitor) and must undergo two-weeks CMV monitoring starting from 
baseline. 
 
13.4.2. Obinutuzumab 
All obinutuzumab infusions should be administered after premedication with oral acetaminophen 
and an antihistamine. 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 infusion-related 
reactions (IRRs), if deemed appropriate by the investigator, and should be administered prior to the 
obinutuzumab infusion. On Cycle 1 Day 1, it is recommended that oral prednisone, prednisolone, 
or methylprednisolone be given within 12 hours as a premedication but at least 60 minutes prior to 
the obinutuzumab infusion. 
Premedication with prednisone or prednisolone is mandatory in patients who had an IRR and 
should continue until IRRs no longer occur during antibody infusion.  
If it is the strong preference of the investigator or of the site (e.g., for logistical reasons) or if the 
patient is at increased risk for an IRR (high tumor burden, high peripheral lymphocyte count), the 
administration of obinutuzumab infusion can be split over 2 days. In all parts of the study, 
obinutuzumab must be administered in a clinical (inpatient or outpatient) setting. Full emergency 
resuscitation facilities should be immediately available, and patients should be under the close 
supervision of the investigator at all times.  
The commonly experienced IRRs have been characterized by fever, chills, flushing, nausea, 
vomiting, hypotension, hypertension, fatigue, and other symptoms. 
Respiratory infusion-related symptoms, such as hypoxia, dyspnea, bronchospasm, larynx and 
throat irritation, and laryngeal edema, have also been reported. These IRRs were mostly mild or 
moderate (NCI CTCAE v. 5.0, Grade 1 and 2 events), and< 10% of the events were severe (Grade 
3 events), occurring predominantly during the first hour of the infusion or shortly after the first 
infusion had finished. The events resolved with the slowing or interruption of the infusion and 
supportive care. The incidence and severity of IRRs decreased with subsequent infusions. 
Extensive tumor burden predominantly localized in the blood circulation may be a predisposing 
factor for the development of IRRs. 
IRRs may be clinically indistinguishable from IgE-mediated allergic or anaphylactic reactions. 
 
13.5. Prophylactic measures  
 
Prevention of infections 
Fatal and/or serious infections occurred in patients treated with idelalisib monotherapy or in 
combination with rituximab or with unapproved combination therapies. The most common 
infections were pneumonia, sepsis, and febrile neutropenia. Treatment with idelalisib should not be 
initiated in patients with any evidence of ongoing systemic bacterial, fungal, or viral infection. Treat 
infections prior to initiation of idelalisib therapy. 


 
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On the basis of its anticipated mode of action, resulting in profound B-cell depletion, obinutuzumab 
may be associated with an increased risk of infections. Infections have been reported in patients 
receiving obinutuzumab. Therefore, obinutuzumab should not be administered to patients with 
active severe infections. 
Serious or fatal Pneumocystis jirovecii pneumonia (PJP) or cytomegalovirus (CMV) occurred in 
<1% of patients treated with idelalisib. Provide PJP prophylaxis during treatment with idelalisib. 
Regular clinical and laboratory monitoring for CMV infection is recommended in patients with 
history of CMV infection or positive CMV serology at the start of treatment with idelalisib.  
 
Treatment-emergent Grade 3 or 4 neutropenia occurred in patients treated with idelalisib 
monotherapy or in combination with rituximab or with unapproved combination therapies.  
Grade 3 or 4 neutropenia, including febrile neutropenia, have been reported with obinutuzumab 
administration.  
In case of Grade 3 or 4 neutropenia blood counts should be monitored at least every 2 weeks for 
the first 6 months of therapy, and at least weekly in patients while neutrophil counts are less than 
1.0, until neutrophil values return to at least Grade 2. 
Use of G-CSF has been found to result in a rapid normalization of neutrophils, similar to what has 
been observed in patients treated with rituximab. The use of G-CSF is allowed for treatment of 
neutropenia in this study. Primary prophylaxis with G-CSF is recommended according to the 
American Society of Clinical Oncology (ASCO) [29], European Organisation for Research and 
Treatment of Cancer (EORTC) [30], and European Society for Medical Oncology (ESMO) [31] 
guidelines, namely for patients who are ≥ 60 years old and/or with comorbidities.  
Patients with Grade 3 to 4 neutropenia lasting more than one week are strongly recommended to 
receive antimicrobial prophylaxis until resolution of neutropenia to Grade 1 or 2. Antiviral and 
antifungal prophylaxis should be considered. 
 
Thrombocytopenia 
Severe and life-threatening thrombocytopenia, including acute thrombocytopenia (occurring within 
24 hours after the infusion), has been observed during treatment with obinutuzumab. Fatal 
hemorrhagic events have also been reported in patients treated with obinutuzumab. It seems that 
the first cycle is the greatest risk of hemorrhage in patients treated with obinutuzumab. A clear 
relationship between thrombocytopenia and hemorrhagic events has not been established. 
Patients should be closely monitored for thrombocytopenia, especially during the first cycle; regular 
laboratory tests should be performed until the event resolves, and dose delays should be 
considered in case of severe or life-threatening thrombocytopenia. Transfusion of blood products 
(i.e., platelet transfusion) according to institutional practice is at the discretion of the treating 
physician. 
Patients treated with concomitant medication, which could possibly worsen thrombocytopenia-
related events (e.g., platelet inhibitors and anticoagulants), may be at greater risk of bleeding when 
the platelet count is < 20,000/μL. When possible, replace prior therapy with Vitamin K antagonists, 
such as warfarin, with low-molecular weight heparin (LMWH) or new oral anticoagulants (NOACs) 
before Cycle 1 Day 1. 
Clinical decision making may be adjusted depending on the patient-specific assessment of benefit 
and risk. 
 
Tumor lysis syndrome (TLS) Prophylaxis 
TLS has been reported with obinutuzumab administration. Patients with a high tumor burden, 
including patients with a lymphocyte count ≥ 25 × 109/L are at increased risk for TLS and severe 
IRRs. All patients with peripheral blood lymphocyte count of ≥ 25 × 109/L or bulky adenopathy must 
receive prophylaxis for TLS prior to the initiation of study treatment. This includes appropriate 
hydration, consisting of fluid intake of approximately 3 L/day, starting 1−2 days prior to the first 
dose of obinutuzumab, and administration of allopurinol (300 mg/day orally) or a suitable 
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obinutuzumab (Cycle 1, Day 1). All patients should then be carefully monitored during the initial 
weeks of treatment. Patients still considered at risk for TLS because of persistently high tumor 
burden (i.e., peripheral blood lymphocyte counts ≥ 25 × 109/L) before the second and subsequent 
infusions of obinutuzumab should receive continuous TLS prophylaxis with allopurinol or a suitable 
alternative (i.e., rasburicase) and adequate hydration until the risk is abated, as determined by the 
investigator. For treatment of TLS, correct electrolyte abnormalities, monitor renal function and fluid 
balance, and administer supportive care, including dialysis as indicated. 
 
Worsening of Preexisting Cardiac Condition 
In patients with underlying cardiac disease and treated with obinutuzumab, adverse events such as 
angina pectoris, acute coronary syndrome, myocardial infarction, heart failure, and arrhythmias, 
including atrial fibrillation and tachyarrhythmia, have been observed. These events may occur as 
part of an IRR and can be fatal. Therefore, patients with a history of cardiac disease should be 
monitored closely. In addition, these patients should be hydrated with caution to prevent a potential 
fluid overload. 
 
13.6. Patients HBV positive 
Not included in this study as per inclusion/exclusion criteria. 
 
13.7. Patients HCV positive 
Not included in this study as per inclusion/exclusion criteria. 
 
13.8. Patients HIV positive 
Not included in this study as per inclusion/exclusion criteria. 
 
13.9. Contraception 
Non-sterilized female patients of reproductive age group and male patients should use effective 
methods of contraception through defined periods during and after study treatment as specified 
below. 
Female patients must meet 1 of the following: 
• 
Postmenopausal for at least 1 year before the screening visit, or 
• 
Surgically sterile, or 
• 
If they are of childbearing potential, agree to practice 2 effective methods of contraception 
from the time of signing of the informed consent form through 18 months after the last dose 
of study drug, or 
• 
Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation 
methods] and withdrawal are not acceptable methods of contraception.) 
Male patients, even if surgically sterilized (i.e., status postvasectomy) must agree to 1 of the 
following: 
• 
Practice effective barrier contraception during the entire study treatment period and through 
18 months after the last dose of study drug, or 
• 
Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation 
methods for the female partner] and withdrawal are not acceptable methods of 
contraception.) 
Birth control methods considered acceptable for use in the trial  
Highly effective methods 
Additional effective methods 
Levonorgestrel-releasing intrauterine system (IUS) 
Male condom 
Hormonal methods (Ovulation inhibitory 
progesterone-only pills (i.e. desogestrel); 
Medroxyprogesterone acetate depot; Implant  
Diaphragm  


 
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Tubal sterilization 
Cervical Cap 
Sexual intercourse with a vasectomized male 
partner only; vasectomy must be confirmed by two 
negative semen analyses 
 
 
13.10. Excluded/admitted concomitant medication 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter drugs, 
herbal or homeopathic remedies, and nutritional supplements) used by a patient from 7 days prior 
to the screening evaluation to the end of study visits. All concomitant medications should be 
reported to the investigator and recorded on the appropriate electronic Case Report Form (eCRF). 
Patients who use oral contraceptives, hormone-replacement therapy, or other maintenance 
therapy should continue their use. Concomitant use of hematopoietic growth factors is allowed in 
accordance with instructions provided in the package inserts. 
 
Idelalisib 
CYP3A inducers 
Idelalisib exposure may be reduced when co-administered with CYP3A inducers such as 
rifampicin, phenytoin, St. John’s wort (Hypericum perforatum), or carbamazepine. Since a 
reduction in idelalisib plasma concentrations may result in decreased efficacy, co-administration of 
idelalisib with moderate or strong CYP3A inducers should be avoided. 
CYP3A substrates 
The primary metabolite of idelalisib, GS-563117, is a strong CYP3A4 inhibitor. Thus, idelalisib has 
the potential to interact with medicinal products that are metabolized by CYP3A, which may lead to 
increased serum concentrations of the other product that may increase their systemic exposures 
and increase or prolong their therapeutic activity and adverse reactions. When idelalisib is co-
administered with other medicinal products, the Summary of Product Characteristics (SmPC) for 
the other product must be consulted for the recommendations regarding co-administration with 
CYP3A4 inhibitors. 
Concomitant treatment of idelalisib with CYP3A substrates with serious and/or life-threatening 
adverse reactions (e.g., alfuzosin, amiodarone, cisapride, pimozide, quinidine, ergotamine, 
dihydroergotamine, quetiapine, lovastatin, simvastatin, sildenafil, midazolam, triazolam) should be 
avoided and alternative medicinal products that are less sensitive to CYP3A4 inhibition should be 
used if possible. 
 
Obinutuzumab 
Patients who experience infusion-related temperature elevations of > 38.5°C (> 101.3°F) or other 
minor infusion-related symptoms may be treated symptomatically with acetaminophen/paracetamol 
(≥ 500 mg) and/or H1 and H2 histamine-receptor antagonists (e.g., diphenhydramine, 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, and/or corticosteroids) as clinically 
indicated according to standard clinical practice. For patients enrolled on obinutuzumab-containing 
regimens, it is recommended that corticosteroids (e.g., 100 mg of IV prednisolone or equivalent) be 
given as premedication within 12 hours of, but at least 60 minutes prior to, the obinutuzumab 
infusion on Cycle 1 Day 1. After the first obinutuzumab infusion, additional glucocorticoids are 
allowed at the investigator’s discretion. For patients who did not experience infusion-related 
symptoms with their previous infusion, premedication at subsequent infusions may be omitted at 
the investigator’s discretion. 
Infusion reaction prophylaxis with medications (e.g., acetaminophen/paracetamol, antihistamines, 
and/or corticosteroids) may be instituted at any point in the study if it is determined to be in the best 
interest of the patient on the basis of the observation of IRRs in patients already enrolled in the 
study. Patients with Grade 3 hypotension or fever must be premedicated prior to retreatment. 


 
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Patients with hypotension requiring vasopressor support or with Grade 3 wheezing, hypoxia, or 
generalized urticaria must be permanently discontinued from study treatment. 
 
Use of the following therapies is prohibited during the study: 
• 
Cytotoxic chemotherapy 
• 
Radiotherapy 
• 
Immunotherapy including immunosuppressive therapy 
• 
Radioimmunotherapy 
• 
Hormone therapy (other than contraceptives, hormone-replacement therapy, or megestrol 
acetate) 
• 
Biologic agents (other than hematopoietic growth factors, which are allowed if clinically 
indicated and used in accordance with instructions provided in the package inserts).  
• 
Any therapy intended for the treatment of lymphoma  
 
Patients who require the use of any of these agents will be discontinued from all study treatment.  
 
13.11. Warnings 
 
Idelalisib 
WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, 
PNEUMONITIS, INFECTIONS, and INTESTINAL PERFORATION 
 
• 
Fatal and/or serious hepatotoxicity occurred in 16% to 18% of idelalisib-treated patients. 
Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue 
idelalisib as recommended (see paragraph 13.12). 
• 
Fatal and/or serious and severe diarrhea or colitis occurred in 14% to 20% of idelalisib-treated 
patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or 
discontinue idelalisib as recommended (see paragraph 13.12). 
• 
Fatal and/or serious pneumonitis occurred in 4% of idelalisib-treated patients. Monitor for 
pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue idelalisib as 
recommended (see paragraph 13.12). 
• 
Fatal and/or serious infections occurred in 21% to 48% of idelalisib-treated patients. Monitor 
for signs and symptoms of infection. Interrupt idelalisib if infection is suspected (see paragraph 
13.12). 
• 
Fatal and serious intestinal perforation can occur in idelalisib -treated patients across clinical 
trials. Discontinue idelalisib for intestinal perforation (see paragraph 13.12). 
 
Obinutuzumab 
WARNING: HEPATITIS B VIRUS REACTIVATION and PROGRESSIVE MULTIFOCAL 
LEUKOENCEPHALOPATHY 
 
• 
Hepatitis B Virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic 
failure, and death, can occur in patients receiving CD20-directed cytolytic antibodies, including 
obinutuzumab. Screen all patients for HBV infection before treatment initiation. Monitor HBV-
positive patients during and after treatment with obinutuzumab. Discontinue obinutuzumab and 
concomitant medications in the event of HBV reactivation (see paragraphs 13.5 and 13.12). 
• 
Progressive Multifocal Leukoencephalopathy (PML) including fatal PML, can occur in patients 
receiving obinutuzumab (see paragraphs 13.5 and 13.12). 
 
13.12. Dose modification and Toxicity Management  
 
Idelalisib 


 
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See Table and paragraphs below for dose modification instructions for specific toxicities related to 
idelalisib. For other severe or life-threatening toxicities related to idelalisib, withhold drug until 
toxicity is resolved. If resuming idelalisib after interruption for other severe or life- threatening 
toxicities, reduce the dose to 100 mg twice daily. Discontinue idelalisib permanently for recurrence 
of other severe or life-threatening idelalisib-related toxicity upon rechallenge. 
No dose modification is required for lymphocytosis, which has been observed in some patients 
taking idelalisib. This observed lymphocytosis is a pharmacodynamic effect and should not be 
considered progressive disease in the absence of other clinical findings. 
Dose Modifications for Toxicities Due to Zydelig  
Pneumonitis 
Any symptomatic pneumonitis 
 
Discontinue Zydelig in patients with any severity of symptomatic pneumonitis 
ALT/AST 
>3-5 × ULN 
>5-20 × ULN 
>20 × ULN 
 
Maintain Zydelig 
dose. Monitor at 
least weekly until 
<1 x ULN. 
Withhold Zydelig. 
Monitor at least weekly until 
ALT/AST are <1 x ULN, then may 
resume Zydelig at 100 mg BID. 
Discontinue Zydelig 
permanently. 
Bilirubin 
>1.5-3 × ULN 
>3-10 × ULN 
>10 × ULN 
 
Maintain Zydelig 
dose. Monitor at 
least weekly until 
<1 x ULN. 
Withhold Zydelig. Monitor at least 
weekly until bilirubin is <1 x ULN, 
then may resume Zydelig at 100 
mg BID. 
Discontinue Zydelig 
permanently. 
Diarrhea* 
Moderate diarrhea 
Severe diarrhea or 
hospitalization 
Life-threatening diarrhea 
 
Maintain Zydelig 
dose. Monitor at 
least weekly until 
resolved. 
Withhold Zydelig. Monitor at least 
weekly until resolved, then may 
resume Zydelig at 100 mg BID. 
Discontinue Zydelig 
permanently. 
Neutropenia 
ANC 1.0 to <1.5 
·109/L 
ANC 0.5 to <1.0 ·109/L 
ANC <0.5 ·109/L 
 
Maintain Zydelig 
dose. 
Maintain Zydelig dose. Monitor 
ANC at least weekly. 
Interrupt Zydelig. Monitor ANC at 
least weekly until ANC ≥0.5 Gi/L, 
then may resume Zydelig at 100 
mg BID. 
Thrombocytopenia Platelets 50 to <75 
·109/L 
Platelets 25 to <50 ·109/L 
Platelets <25 ·109/L 
 
Maintain Zydelig 
dose. 
Maintain Zydelig dose. Monitor 
platelet counts at least weekly. 
Interrupt Zydelig. Monitor platelet 
count at least weekly. May 
resume Zydelig at 100 mg BID 
when platelets ≥25 Gi/L. 
Infections 
Grade 3 or higher sepsis or pneumonia 
 
Interrupt Zydelig until infection has resolved. 
Evidence of CMV infection or viremia 
Interrupt Zydelig in patients with evidence of active CMV infection of any grade or 
viremia (positive PCR or antigen test) until the viremia has resolved. If Zydelig is 
resumed, monitor patients by PCR or antigen test for CMV reactivation at least monthly. 
 
Evidence of PJP infection 
 
Interrupt Zydelig in patients with suspected PJP infection of any grade. Permanently 
discontinue Zydelig if PJP infection is confirmed. 


 
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Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BID, twice daily; ULN, 
upper limit of normal; CMV, cytomegalovirus; PCR: polymerase chain reaction; PJP: Pneumocystis jirovecii 
pneumonia 
*Moderate diarrhea: increase of 4–6 stools per day over baseline; severe diarrhea: increase of ≥7 stools per 
day over baseline. 
 
Serious Infections 
Monitor patients on idelalisib for signs and symptoms of infection, and interrupt idelalisib for Grade 
3 or higher infection. 
Serious and fatal infections have occurred with idelalisib, including opportunistic infections such as 
Pneumocystis jirovecii pneumonia (PJP) and cytomegalovirus (CMV). These infections have most 
frequently occurred the first 6 months of idelalisib treatment. 
All subjects will receive trimethoprim-sulfamethoxazole or other established for PJP throughout the 
treatment with idelalisib. Prophylaxis should continue until the CD4+ T-cell count is documented 
>200 cells/μl following the end of treatment. Interrupt idelalisib in patients with suspected PJP 
infection of any grade, and permanently discontinue idelalisib if PJP infection of any grade is 
confirmed. 
Subjects have to be monitored each 15 days starting from day 1 for CMV throughout the course of 
idelalisib treatment (CMV PCR or antigen test). If unequivocal clinical or laboratory evidence of 
CMV infection is present, the subject has to discontinue idelalisb until the viremia has resolved and 
udergo effective antiviral treatment according to established clinical guidelines. 
If idelalisb is subsequently resumed, patients should be monitored by PCR or antigen test for CMV 
reactivation at least monthly. 
 
Patients should be monitored for respiratory signs and symptoms throughout treatment. Patients 
should be advised to report new respiratory symptoms promptly. 
 
Hepatoxicity 
Withhold idelalisib in the event of a Grade 3 or 4 aminotransferase elevation (ALT/AST ≥5 ULN). 
Once values have returned to Grade 1 or below (ALT/AST ≤3 ULN), resume idelalisib at 100 mg 
twice daily. 
If the event dose not recur, the dose can be escalated to 150 mg twice daily after consulting with 
the Medical Monitor. If the event recurs, withhold until return to Grade 1 or below, after which re-
initiation may be considered after consulting with the Medical Monitor. 
Avoid concurrent use of idelalisib with other drugs that may cause liver toxicity. 
 
Severe Diarrhea/Colitis 
Withhold idelalisib for diarrhea of Grade 3 or 4. Once diarrhea has returned to Grade 1 or below, 
resume idelalisib at 100 mg daily. If the diarrhea does not recur, the dose can be re-escalated to 
150 mg twice daily after consulting with the Medical Monitor. 
Avoid concurrent use of idelalisib and other drugs that cause diarrhea. 
 
Intestinal Perforation 
Fatal and serious intestinal perforation occurred in idelalisib-treated patients. At the time of 
perforation, some patients had moderate to severe diarrhea. Advise patients to promptly report any 
new or worsening abdominal pain, chills, fever, nausea, or vomiting. Discontinue idelalisib 
permanently in patients who experience intestinal perforation. 
 
Pneumonititis 
Fatal and serious pneumonitis occurred in patients treated with idelalisib. Clinical manifestations 
included interstitial infiltrates and organizing pneumonia. Time to onset of pneumonitis ranges from 
<1 to 15 months. Monitor patients on idelalisib for pulmonary symptoms. In patients taking 
idelalisib who present with pulmonary symptoms such as cough, dyspnea, hypoxia, interstitial 
infiltrates on a radiologic exam, or a decline by more than 5% in oxygen saturation, withhold 


 
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idelalisib until the etiology has been determined. If symptomatic pneumonitis or organizing 
pneumonia is diagnosed, initiate appropriate treatment with corticosteroids. 
Once pneumonitis has resolved and if re-treatment is deemed eligible for Medical Monitor, 
resumption of treatment at 100 mg twice daily can be considered. 
 
Severe cutaneous reactions 
Fatal cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have 
occurred in patients treated with idelalisib. If SJS or TEN is suspected, interrupt idelalisib until the 
etiology of the reaction has been determined. If SJS or TEN is confirmed, permanently discontinue 
idelalisib.  
Other severe or life-threatening (Grade ≥3) cutaneous reactions, including dermatitis exfoliative, 
rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash papular, rash 
pruritic, exfoliative rash, and skin disorder, have been reported in idelalisib-treated patients. 
Monitor patients for the development of severe cutaneous reactions and withhold idelalisib Once 
cutaneous reaction has returned to Grade 1 or below, resume idelalisib at 100 mg twice daily. If 
reaction do not recur, the dose can be re-escalated to 150 mg twice daily after consulting with the 
Medical Monitor. 
 
Anaphylaxis 
Serious allergic reactions, including anaphylaxis, have been reported in patients on idelalisib. In 
patients who develop serious allergic reactions, discontinue idelalisib permanently and institute 
appropriate supportive measures. 
 
For more details, please refer to Appendix E or the IB. 
 
Obinutuzumab 
There will be no obinutuzumab dose modification in this study. Consider treatment interruption if 
patients experience an infection, Grade 3 or 4 cytopenia, or a ≥ Grade 2 non-hematologic toxicity. 
Any NCI CTCAE (v. 5.0) toxicity Grade ≥ 3 in severity that is deemed related to obinutuzumab 
treatment will require interruption of study treatment until resolution to Grade ≤ 2 or ≥ 80% of 
baseline, whichever is lower.  
Resumption of obinutuzumab treatment may be considered in patients with resolution of toxicities 
to Grade ≤ 1 within 2 weeks at the discretion of the investigator, after consultation with the Medical 
Monitor. Failure of such toxicities to resolve after 2-week delay in study treatment will require 
permanent discontinuation of obinutuzumab. 
Continuation of study treatment following dose delays beyond 2 weeks will require consultation 
with and approval of the Medical Monitor based on an assessment of the benefit-risk analysis of 
continuing to delay study treatment. 
Patients in whom toxicities have not resolved (i.e., to Grade ≤ 1 or ≥ 80% of baseline) may have 
their study treatment delayed by up to 2 weeks. If all study drug−related toxicities have resolved to 
Grade≤ 1 or ≥ 80% of baseline, the patient may resume idelalisib and obinutuzumab dosing on the 
regular every−28−day schedule.  
Patients who do not fulfill the criteria for dosing after the additional 2 weeks have elapsed may be 
discontinued from study treatment and be followed for safety outcomes. Exceptions on the basis of 
ongoing clinical benefit may be allowed following a careful assessment and discussion of risk 
versus benefit with the patient by the investigator and approval from the Medical Monitor. In 
addition, delay of therapy because of toxicities not attributed to study drug may not require 
discontinuation and will be discussed with the Medical Monitor. 
 
Progressive Multifocal Leukoencephalopathy 
A “black-box” warning for obinutuzumab states that JC viral infection (including fatal) that resulted 
in PML with destructive infection of oligodendrocytes of the CNS white matte have been reported in 
patients treated with anti-CD20 therapies, including rituximab and obinutuzumab. The diagnosis of 


 
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PML should be considered in any patient presenting with new-onset neurologic manifestations. 
The symptoms of PML are unspecific and can vary depending on the affected region of the brain. 
Motor involvement with corticospinal tract findings, sensory involvement, cerebellar deficits, and 
visual field defects are common. 
Some syndromes regarded as cortical (e.g., aphasia or visual-spatial disorientation) can occur. 
Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and 
lumbar puncture (cerebrospinal fluid testing for JC viral DNA). 
Therapy with obinutuzumab should be withheld during the investigation of potential PML and 
permanently discontinued in case of confirmed PML. Discontinuation or reduction of any 
concomitant chemotherapy or immunosuppressive therapy should also be considered. The patient 
should be referred to a neurologist for the diagnosis and management of PML. 
 
Management of Infusion Reactions (IRRs) 
Obinutuzumab can cause severe and life-threatening infusion reactions, mostly on Day 1 of 
obinutuzumab infusion. Infusion reactions can also occur with subsequent infusions. Symptoms 
may include hypotension, tachycardia, dyspnea, and respiratory symptoms (e.g., bronchospasm, 
larynx and throat irritation, wheezing, laryngeal edema). The most frequently reported symptoms 
include nausea, fatigue, chest discomfort, dyspnea, dizziness, vomiting, diarrhea, rash, 
hypertension, hypotension, flushing, headache, pyrexia, and chills. Patient premedication for IRRs 
is highly recommended (see paragraph 13.4.2) 
 
If a patient experiences an infusion reaction of any grade during infusion, adjust the infusion as 
follows: 
− 
Grade 4 (life-threatening): Stop infusion immediately and permanently discontinue 
obinutuzumab therapy. 
− 
Grade 3 (severe): Interrupt infusion and manage symptoms. Upon resolution of symptoms, 
consider restarting obinutuzumab infusion at no more than half the previous rate (the rate 
being used at the time that the infusion reaction occurred) and, if patient does not experience 
any further infusion reaction symptoms, infusion rate escalation may resume at the increments 
and intervals as appropriate for the treatment cycle dose. Permanently discontinue treatment if 
patients experience a Grade 3 infusion-related symptom at rechallenge. 
− 
Grade 1–2 (mild to moderate): Reduce infusion rate or interrupt infusion and treat symptoms. 
Upon resolution of symptoms, continue or resume infusion and, if patient does not experience 
any further infusion reaction symptoms, infusion rate escalation may resume at the increments 
and intervals as appropriate for the treatment cycle dose. 
 
For patients with preexisting cardiac or pulmonary conditions, monitor more frequently throughout 
the infusion and the post-infusion period since they may be at greater risk of experiencing more 
severe reactions. Hypotension may occur as part of the obinutuzumab infusion reaction. Consider 
withholding antihypertensive treatments for 12 hours prior to, during each obinutuzumab infusion, 
and for the first hour after administration until blood pressure is stable. For patients at increased 
risk of hypertensive crisis, consider the benefits versus the risks of withholding their 
antihypertensive medication as is suggested here. 
 
Hypersensitivity Reactions Including Serum Sickness 
Hypersensitivity reactions have been reported in patients treated with obinutuzumab. Signs of 
immediate-onset hypersensitivity included dyspnea, bronchospasm, hypotension, urticaria and 
tachycardia. Late-onset hypersensitivity diagnosed as serum sickness has also been reported, with 
symptoms that include chest pain, diffuse arthralgia and fever. Hypersensitivity reactions may be 
difficult to clinically distinguish from infusion related reactions. However, hypersensitivity very rarely 
occurs with the first infusion and, when observed, often occurs after previous exposure. If a 
hypersensitivity reaction is suspected during or after an infusion, the infusion must be stopped, and 


 
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treatment permanently discontinued. Patients with known hypersensitivity reactions to 
obinutuzumab, including serum sickness, must not be retreated. 
 
Tumor Lysis Syndrome (TLS) 
Tumor lysis syndrome (TLS), including fatal cases, has been reported in patients receiving 
obinutuzumab. During the initial days of obinutuzumab treatment, monitor the laboratory 
parameters of patients considered at risk for TLS. For treatment of TLS, correct electrolyte 
abnormalities, monitor renal function and fluid balance, and administer supportive care, including 
dialysis as indicated. Refer to paragraph 13.5. 
 
Infections 
Fatal and serious bacterial, fungal, and new or reactivated viral infections can occur during and 
following obinutuzumab therapy. Patients with a history of recurring or chronic infections may be at 
increased risk of infection. 
A “black-box” warning for obinutuzumab states that reactivation of hepatitis B as well as other 
serious viral infections (e.g., infections caused by cytomegalovirus, Varicella zoster virus, herpes 
simplex virus, JC virus, and HCV) that were new, reactivated, or exacerbated have been reported 
with the B cell−depleting antibody rituximab mainly in patients who had received the drug in 
combination with chemotherapy or as part of a hematopoietic SCT. The risk of such infections with 
obinutuzumab is unknown. 
 
Thrombocytopenia 
Monitor all patients frequently for thrombocytopenia and hemorrhagic events, especially during the 
first cycle. In patients with Grade 3 or 4 thrombocytopenia, monitor platelet counts more frequently 
until resolution and consider subsequent dose delays of obinutuzumab. Transfusion of blood 
products (i.e., platelet transfusion) may be necessary. Consider withholding concomitant 
medications, which may increase bleeding risk (platelet inhibitors, anticoagulants), especially 
during the first cycle. 
In the event of severe thrombocytopenia (platelet count < 10,000/μL) and/or symptomatic bleeding 
(irrespective of platelet count) in patients who are not receiving concomitant anticoagulants or 
platelet inhibitors: Hold obinutuzumab until thrombocytopenia or symptomatic bleeding resolves. If 
Cycle 1 Day 8 is delayed, then skip Day 8 and administer Day 15 as previously scheduled (if 
thrombocytopenia or symptomatic bleeding has resolved). If Cycle 1 Day 15 is delayed, then skip 
Day 15 dosing and administer Cycle 2 Day 1 of obinutuzumab as scheduled (if thrombocytopenia 
or symptomatic bleeding has resolved). 
In the event of thrombocytopenia with platelet count < 20,000/μL and/or symptomatic bleeding 
(irrespective of platelet count) in patients who are receiving concomitant anticoagulants or platelet 
inhibitors: 
− 
Hold obinutuzumab until thrombocytopenia or symptomatic bleeding resolves. If Cycle 1 Day 8 
is delayed, then skip Day 8 and administer Day 15 as previously scheduled (if 
thrombocytopenia or symptomatic bleeding has resolved). If Cycle 1 Day 15 is delayed, then 
skip Day 15 dosing and administer Cycle 2 Day 1 of obinutuzumab as scheduled (if 
thrombocytopenia or symptomatic bleeding has resolved). 
− 
For patients who are on LMWH or NOACs, when platelet count < 20,000/μL develops, reduce 
the dose of LMWH or NOACs used. 
− 
For patients who are on platelet inhibitors when thrombocytopenia with platelet count < 
20,000/μL develops, consideration should be given to temporarily pausing the use of platelet 
inhibitors. 
 
Neutropenia 
Severe and life-threatening neutropenia, including febrile neutropenia, has been reported during 
treatment with obinutuzumab. Monitor patients with Grade 3 to 4 neutropenia frequently with 
regular laboratory tests until resolution. Anticipate, evaluate, and treat any symptoms or signs of 


 
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developing infection. Consider administration of granulocyte colony-stimulating factors (GCSF) in 
patients with Grade 3 or 4 neutropenia. 
Consider dose delays in the case of Grade 3 or 4 neutropenia. Patients with severe and long 
lasting (> 1 week) neutropenia are strongly recommended to receive antimicrobial prophylaxis until 
resolution of neutropenia to Grade 1 or 2. Consider antiviral and antifungal prophylaxis. 
In the event of febrile neutropenia or neutropenia with infection, hold obinutuzumab until febrile 
neutropenia or neutropenia with infection resolves. 
− 
If Cycle 1 Day 8 is delayed long enough that the patient is approaching Day 15, then skip Day 
8 and administer Day 15 as previously scheduled (if infection or fever has resolved) 
− 
If Cycle 1 Day 15 is delayed long enough that the patient approaching Cycle 2, then skip Day 
15 dosing and administer Cycle 2 Day 1 as scheduled (if infection or fever has resolved). 
 
Neutropenia can also be of late onset (occurring more than 28 days after completion of treatment) 
and/or prolonged (lasting longer than 28 days). 
 
For more details please refer to Appendix F or drug IB. 
 
14. REMOVAL OF SUBJECTS FROM TREATMENT AND/OR STUDY 
14.1. Discontinuation from study treatment 
A patient should discontinue treatment if any of the following occurs: 
• 
completed treatment as per protocol 
• 
unacceptable toxicity that does not allow to give the protocol treatment 
• 
progression, relapse or death at anytime 
• 
refusal of the patient to further cooperate (at any time and for any reasons) 
• 
investigator’s decision that the protocol treatment is not anymore in the best interest of the 
patient 
 
Subject study participation may be ended due to any of the following reasons: 
• 
Initiation of anti-neoplastic therapy in the absence of progression 
• 
Disease progression 
• 
Withdrawal of consent 
• 
Significant subject noncompliance with study drug administration, study procedures, or 
study requirements 
• 
Investigator’s decision to remove the subject from the study, in consultation with the 
Medical Monitor 
• 
Pregnancy 
• 
The subject is lost to follow-up 
• 
Death 
 
Discontinuation of the study at the request of the Sponsor, a regulatory agency, or an independent 
ethics committee (IEC). 
Patients who discontinue treatment for any cause will continue to be followed for two years for OS. 
All subjects will be followed until study completion unless consent to do so is specifically withdrawn 
by the subject. 
Study drug may be discontinued in the following instances, in consultation with the Medical 
Monitor: 
• 
Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree. Following resolution of intercurrent illness, the subject 
may resume study dosing at the discretion of the investigator 
• 
Unacceptable toxicity, or toxicity that, in the judgment of the investigator, compromises the 
ability to continue study-specific procedures or is considered to not be in the subject’s best 
interest 


 
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• 
Objective evidence based of PD 
• 
Subject request to discontinue for any reason 
• 
Subject noncompliance 
• 
Pregnancy during the study 
 
14.2. Withdrawal of subjects from the study  
• 
Circumstances that lead to premature withdrawal of a patient from the trial must be reported 
by the investigator on the appropriate CRF page. 
• 
Criteria for subject withdrawal include (but are not limited to): 
- death,  
- toxicity  
- violation of inclusion criteria 
- lost to follow up 
• 
Subject study participation may be ended due to any of the following reasons: 
- Initiation of anti-neoplastic therapy in the absence of progression 
- Disease progression 
- Withdrawal of consent 
- Significant subject noncompliance with study drug administration, study procedures, or 
study requirements 
- Investigator’s decision to remove the subject from the study, in consultation with the 
Medical Monitor 
• 
Pregnancy 
• 
The subject is lost to follow-up 
• 
Death 
• 
Discontinuation of the study at the request of Sponsor, a regulatory agency, or an 
institutional review board or independent ethics committee (IRB/IEC) 
 
14.3. Withdrawal of Consent 
Patients are free to withdraw from the study at any time without prejudice to their treatment. When 
a patient decides to withdraw from the study, she/he should always be contacted in order to obtain 
information about the reason for withdrawal and to record any adverse events. When possible, the 
patient should return for a study visit at the time of, or soon after withdrawal, and the relevant 
assessments should be performed.  
If the patient explicitly states his/her wish not to contribute further data to the study, the assigned 
FIL Study Coordinator should be informed, and the withdrawal of consent should be documented 
by the investigator in the patient’s case report form. Information from subsequent ambulatory visits, 
laboratory or instrumental assessments and any other information on the patient status after 
consent withdrawal won’t be collected in the data base or used for analysis However, both clinical 
data collected until patient’s withdrawal as well as the data coming from the central review will still 
be considered as available for the study analysis. 
 
14.4. Patients Lost to Follow up 
Every effort will be made to contact patients who fail to return for scheduled visits. A patient is 
considered lost to follow-up if no information has been obtained when the last patient has 
completed the clinical phase of the study. During this time site investigator must document 
attempts to contact the patient either by phone or letter. 
 
14.5. Premature termination of the study 
The sponsor reserves the right to stop the trial at any time, in accordance with the DSMB. The 
investigators will be informed of this decision in writing. 
The same applies to any investigator willing to discontinue his/her participation to the trial. The 
investigator must immediately inform the sponsor in writing of this decision.


 
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15. STUDY PROCEDURES TIMEPOINTS 
15.1. Screening period 
within 28 days prior to Study Cycle 1 Day 1 
All subjects will be screened for study eligibility including: 
• Confirmed relapsed/refractory FL* 
* Histological centralized review is compulsory for start of treatment, but the local pathology 
report is sufficient for patient enrollment 
• Medical History; 
• Physical Examination; 
• Height, Weight; 
• ECOG; 
• Vital Signs; 
• B symptoms; 
• Hematology including Hemoglobin, Platelets, White blood cell count (WBC) with differential; 
• Blood chemistry including creatinine, total bilirubin, LDH, AST, ALT, serum proteins with 
electrophoresis, immunoglobulin levels; 
• Electrocardiogram;  
• LVEF by either bi-dimensional echocardiogram or cardiac scintigraphy (MUGA); 
• Measurable lesion assessment on CT scan of neck, chest, abdomen and pelvis, to be 
performed with and without contrast; 
• FDG-PET scan (mandatory) 
• Pregnancy test (if applicable); 
• A bone marrow biopsy with immunohistochemical evaluation; 
• Local molecular evaluation of BCL-2 rearrangement on marrow blood; 
• Viral tests including HIV, HBsAg, HBsAb, HBcAb, HBV DNA and HCV (HCV RNA required for 
patient who are HCV antibody positive); 
• Monitoring for CMV infection; 
• Concomitant medications. 
 
15.2. Treatment period (Induction) 
Before each course of chemotherapy (within 24 hours prior to Day 1): 
• Physical Examination, including weight; 
• ECOG; 
• Vital Signs; 
• B-symptoms; 
• Hematology including Hemoglobin, Platelets, White blood cell count (WBC) with differential; 
• Blood chemistry including creatinine, total bilirubin, LDH, AST, ALT, serum proteins with 
electrophoresis, immunoglobulin levels; 
• AE assessment; 
• Pregnancy test (if applicable); 
• Concomitant medications. 
 
At days 8 and 15 during the first cycle:  
• Vital Signs; 
• Hematology including Hemoglobin, Platelets, White blood cell count (WBC) and neutrophils; 
• Blood chemistry including creatinine, total bilirubin, LDH, AST, ALT; 
• AE assessment 
 
15.3. Assessment for restaging 
after III* course and at EOI: 


 
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• Measurable lesion assessment on CT scan of neck, chest, abdomen and pelvis, to be 
performed with and without contrast; 
• FDG-PET scan (mandatory);  
• Bone marrow biopsy only if positive at baseline. 
 
Patients who achieve a response less than stable disease after first restaging or at EOI are 
considered out of treatment and will be shifted to survival follow up 
*Within 7 days before cycle IV day 1 
 
Clinical and Laboratory CMV infections monitoring: Every two weeks starting from C1D1. 
Prophylaxis for PJP: all patients will receive PJP prophylaxis during idelalisib treatment and for 2 to 
6 months after stopping treatment; patients have to be monitored for respiratory signs and 
symptoms. 
 
15.4. EOT phase 
at 4-6 weeks after last treatment administration 
• Physical Examination; 
• ECOG; 
• Vital Signs; 
• Hematology including Hemoglobin, Platelets, White blood cell count (WBC) with differential; 
• Blood chemistry including creatinine, total bilirubin, LDH, AST, ALT, serum proteins with 
electrophoresis, immunoglobulin levels; 
• Pregnancy test (if applicable); 
• Electrocardiogram;  
• LVEF by either bi-dimensional echocardiogram or cardiac scintigraphy (MUGA); 
• Measurable lesion assessment on CT scan of neck, chest, abdomen and pelvis, to be 
performed with and without contrast (unless the subject already has had per-protocol 
assessments ≤4 weeks prior); 
• FDG-PET scan (mandatory) unless the subject already has had per-protocol scan ≤4 weeks 
prior; 
• Bone marrow biopsy only if positive at baseline; 
• Molecular evaluation of BCL-2 rearrangement on marrow blood only if positive at baseline; 
• Drug accountability 
• AEs assessment 
• Recording of concomitant medications. 
 
Subjects lost to follow up should be recorded as such on the eCRF. All subjects who discontinue 
study treatment, including those who refuse to return for a final visit, should be contacted for a list 
of antineoplastic therapies received after discontinuation of study treatment. 
 
15.5. Maintenance period 
every 3 months for the first year and every 4 months for the second year 
Maintenance phase begins after the end of induction and continues until 2 years or PD 
documentation or unacceptable toxicity, whichever comes first only for patients who achieve at 
least PR at EOT. 
• Physical Examination; 
• ECOG; 
• Vital Signs; 
• Clinical Laboratory Evaluations; 
• CT scan of neck, chest, abdomen and pelvis, to be performed with and without contrast 
(counting months with a ±7 days range from EOT imaging evaluation); 


 
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• FDG-PET scans during maintenance are optional and will be performed at clinician discretion 
only if in accordance to the site clinical practice. 
 
15.6. Follow up period 
(every 6 months) 
− 
For patients in SD at the EOI restaging (ie for patients who not continue with maintenance 
phase). 
− 
For patients in SD, PR or CR at the end of maintenance phase. 
The follow up phase continues until 2 years, PD or a new anti-lymphoma therapy, whichever 
comes first. If any of the above occurs, patients will enter the survival follow up period till the 
completion of two years globally. 
• Physical Examination; 
• ECOG; 
• Vital Signs; 
• Pregnancy test (if applicable); 
• Clinical Laboratory Evaluations; 
• FDG-PET and CT scan of neck, chest, abdomen and pelvis, to be performed with and without 
contrast (counting months with a ±7 days range from EOT imaging evaluation); 
• FDG-PET scans during follow-up are optional and will be performed at clinician discretion only if 
in accordance to the site clinical practice. 
 
15.7. Survival Follow up 
For patients in PD or for patients who start a new anti-lymphoma treatment. Every 3 months until 2 
years (counting follow up phase too if applicable) or until study closure whichever comes first. 
Survival follow up can be performed with a telephone contact too and the investigator must report: 
disease status, patients’ status (dead or alive and date of death, new anti-lymphoma therapy). 
 
15.8. Early withdrawn (EW) 
discontinuation from study treatment 
• Physical Examination; 
• ECOG; 
• Vital Signs; 
• Hematology including Hemoglobin, Platelets, White blood cell count (WBC) with differential; 
• Blood chemistry including creatinine, total bilirubin, LDH, AST, ALT, serum proteins with 
electrophoresis, immunoglobulin levels; 
• Pregnancy test (if applicable); 
• Electrocardiograms;  
• LVEF by either bi-dimensional echocardiogram or cardiac scintigraphy (MUGA); 
• Measurable lesion assessment on CT scan of neck, chest, abdomen and pelvis, to be 
performed with and without contrast unless the subject already has had per-protocol scan ≤4 
weeks prior; 
• FDG-PET scan (mandatory) unless the subject already has had per-protocol scan ≤4 weeks 
prior; 
• Drug accountability 
• AEs assessment 
• Recording of concomitant medications. 


 
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Page 41 of 64 
15.9. Schedule of assessments 
  
 
Screening 
Treatment (Induction) 
Restaging after 3 
cycles, EOI, EOT, EW 
Maintenanceg 
FUe 
OS- FU 
Cycle 1 
Cycle 2-6 
-28 to D1 
D1 
D8 
D15 
D1 
D8 
D15 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Weight  
X 
X 
X 
X 
X 
 
 
 
 
 
 
Physical exam 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
Pregnancy test 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
Vital signs 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
ECOG 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
Hematology 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
Chemistry 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
Virology 
X 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
 
 
X h 
 
 
 
Tumor biopsy b 
X 
 
 
 
 
 
 
 
 
 
 
CT of neck, chest, 
abdomen, pelvis 
X 
 
 
 
 
 
 
X f 
X f 
X f 
 
FDG-PET 
X 
 
 
 
 
 
 
X f 
X f 
X f 
 
LVEF 
measurement 
X 
 
 
 
 
 
 
X h 
 
 
 
BM biopsy 
X 
 
 
 
 
 
 
X a 
X a 
X a 
 
BCL-2 
rearrangement 
X 
 
 
 
 
 
 
X ah 
 
 
 
B symptoms 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
Idelalisib 
 
BID 
 
 
 
 
Obinutuzumab 
 
X 
X 
X 
X 
 
 
 
X g 
 
 
CMV monitoring c 
X 
 
 
X 
X 
 
X 
 
 
 
 


 
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Page 42 of 64 
 
Screening 
Treatment (Induction) 
Restaging after 3 
cycles, EOI, EOT, EW 
Maintenanceg 
FUe 
OS- FU 
Cycle 1 
Cycle 2-6 
-28 to D1 
D1 
D8 
D15 
D1 
D8 
D15 
 
 
 
 
PJP prophylaxis d 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Survival follow up 
contact 
 
 
 
 
 
 
 
 
 
 
X 
Concomitant 
medications 
Recorded from screening through 30 days after the last dose of treatment. 
 
 
Adverse 
event 
reporting 
 
Recorded from first dose of study drug through 30 days after the last dose of 
treatment. 
 
 
Serious 
adverse 
event 
Reported from signing of the informed consent from through last patient last visit 
 
 
a only if positive at baseline/previous assessment;  
b Histological centralized review is compulsory for treatment start, but the local pathology report is sufficient for patient enollment; 
c Every two weeks starting from C1D1; 
d All patients will receive prophylaxis for PJP during idelalisib treatment and for 2 to 6 months after stopping treatment; patients have to be monitored for 
respiratory signs and symptoms; 
e Every 6 months for 2 years only for CR, PR or SD patients at the end of treatment until PD, unacceptable toxicity or a new anti-lymphoma therapy; 
f FDG-PET scan is mandatory at baseline, after induction cycle 3, at the EOI, at the end of treatment after 2 years of maintenance or in case of early 
withdrawal (EOT) and at relapse/progression, unless the subject already has had per-protocol scan ≤4 weeks prior; all additional PET scans (every 3 months 
during the first year of maintenance, every 4 months during the second year of maintenance and during follow-up) are optional and will be done at clinician 
discretion only if in accordance to the site clinical practice; 
g obinutuzumab on day 1 every two months, procedures every 3 months for first year and every 4 months for the second year; 
h only EOI and EOT. 
 


 
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16. SAFETY MEASUREMENTS AND PARAMETERS 
16.1. Safety measurements 
All patients who have received at least one dose of study medication will be considered the 
Analysis Population and will be evaluated for toxicity from the time of their first drug administration. 
When toxicity occurs, it should be graded according to the NCI Common Toxicity Criteria, version 
5.0. 
 
16.2. Safety parameters 
Adverse Events (AE) 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. This includes any occurrence 
that is new in onset or aggravated in severity or frequency from the baseline condition. 
An overdose, accidental or intentional, whether or not it is associated with an AE, or abuse, 
withdrawal, sensitivity or toxicity to an investigational product should be reported as an AE. If an 
overdose is associated with an AE, the overdose and adverse event should be reported as 
separate terms. 
 
Serious Adverse Events (SAE) 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
• 
Results in death  
• 
Is life-threatening (the term "life-threatening" in the definition of "serious" refers to an event 
in which the patient was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it were more severe)  
• 
Requires inpatient hospitalization or prolongation of existing hospitalization (hospitalization 
is defined as an inpatient admission, regardless of length of stay) 
• 
Results in persistent or significant disability/incapacity  
• 
Is a congenital anomaly/birth defect 
• 
Is a medically significant event 
• 
Is a suspected transmission of any infectious agent via a medicinal product. 
 
Important medical events are defined as those occurrences that may not be immediately life 
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above. Medical 
and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriated in other situations, such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the outcomes listed in the definition above. 
The term “severe” is a measure of intensity, thus a severe AE is not necessarily serious. For 
example, “nausea of several hours” duration may be severe but may not be clinically serious. 
 
Events not considered to be SAEs are hospitalizations for: 
• 
A standard procedure for protocol therapy administration.  However, hospitalization or 
prolonged hospitalization for a complication of therapy administration will be reported as an 
SAE.  
• 
Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition. 
• 
The administration of blood or platelet transfusion as routine treatment of studied indication.  
However, hospitalization or prolonged hospitalization for a complication of such transfusion 
remains a reportable SAE. 


 
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• 
A procedure for protocol/disease-related investigations (e.g., surgery, scans, endoscopy, 
sampling for laboratory tests, bone marrow sampling). However, hospitalization or 
prolonged hospitalization for a complication of such procedures remains a reportable SAE. 
• 
Hospitalization or prolongation of hospitalization for technical, practical, or social reasons, in 
absence of an AE. 
• 
A procedure that is planned (i.e., planned prior to starting of treatment on study); must be 
documented in the source document and the CRF.  Hospitalization or prolonged 
hospitalization for a complication remains a reportable SAE. 
• 
An elective treatment of a pre-existing condition unrelated to the studied indication. 
 
If an AE is considered serious, both the AE page/screen of the CRF and the SAE Report Form on 
www.drugvigilance.filinf.it must be completed. 
For each SAE, the Investigator will provide information on severity, start and stop dates, 
relationship to IP, action taken regarding IP, and outcome. 
 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
An unlisted adverse event, the nature or severity of which is not consistent with the applicable 
product information. For an investigational drug, the expectedness of an adverse event will be 
determined by whether or not it is listed in the Investigator's Brochure of experimental drug. For 
drugs with a marketing authorization, the expectedness of an adverse event will be determined by 
whether or not it is listed in the SmPC. 
 
Severity 
The intensity of the toxicities, AE or SAE will be graded by the investigator according to the 
Common Terminology Criteria for Adverse Events (CTCAE) grading system version 5.0 in the 
toxicity categories that have recommended grading. 
AEs not listed on this grading system will be graded according to the five-point system below: 
 
Mild (grade 1)  
 
Discomfort noticed but no disruption of normal daily activity 
Moderate (grade 2) 
 
Discomfort sufficient to reduce or affect normal daily activity 
Severe (grade 3) 
 
Incapacitating with inability to work or perform normal daily  
 
 
 
 
activity 
Life-threatening (grade 4) 
Substantial risk of dying at time of event 
Death (grade 5) 
 
Fatal 
 
Causality 
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 related. An adverse event that is not related to the use of the investigational product. 
• 
Unlikely/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. 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). 
• 
Definite/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 drug(s), concomitant 
disease(s). The relationship in time is very suggestive (e.g., it is confirmed by dechallenge 
and rechallenge). 
• 
Not assessable: there is insufficient or incomplete evidence to make a clinical judgement of 
the causal relationship. 


 
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16.3. Serious Adverse Events reporting rules 
All events that meet one or more criteria of seriousness (see above) occurred after the informed 
consent signature until the end of the study or early withdrawal for any cause, regardless of the 
relationship to the study treatment, will be reported as SAE. 
After this time, SAE that occurs, during the follow-up period, if considered related to the study 
medication, will be reported. 
Whenever possible, symptoms should be grouped as a single syndrome or diagnosis. The 
investigator should specify the date of onset, intensity, action taken regarding trial medication, 
corrective therapy given, outcome of all SAEs and his opinion as to whether the SAE can be 
related to the study drugs. 
General SAE reporting rules:  
• 
Any episode of any grade of toxicities, which meets one of the seriousness criteria, must be 
reported as “Serious Adverse Event” in the appropriate SAE form. 
• 
Signs, symptoms and physical findings indicative of lymphoma or progression of lymphoma 
are not to be reported as “Serious Adverse Event”. 
• 
“Alopecia” toxicity (any grade) will never be reported as “Serious Adverse Event”. 
 
All AEs that occur from the first dose of study drug administration up to 30 days following the last 
dose of investigational product will be reported.  
All SAEs that occur between the study informed consent signature and until the LPLV will be 
notified to the sponsor, using the FIL Serious Adverse Event reporting rules. The sponsor will 
evaluate any safety information that is spontaneously reported by an investigator beyond the time 
frame specified in the protocol. 
 
All AEs and SAEs, regardless of seriousness, severity, or presumed relationship to study therapy, 
must be recorded in the CRF in accordance to the CTCAE criteria v 5.0. They must be recorded 
using medical terminology (MedDRA version 21.1).  
 
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide.  
 
Obligations of the Investigator 
Investigators must record also 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.  
Investigators must submit reports of all SAEs, regardless of attribution to the Sponsor within 24 
hours of learning of the events.  
For initial SAE investigators should record all case details that can be gathered on a SAE form that 
must be completed directly online through the FIL web site: www.drugvigilance.filinf.it  
 
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 as soon as it becomes available and/or upon request. 
The Investigator(s) must keep copies of all SAE information on file. All SAEs that have not resolved 
upon discontinuation of the patient’s participation in the study must be followed until either the 
event resolves completely, stabilizes/resolves with sequelae, or returns to baseline (if a baseline 
value is available). 
 
The FIL Pharmacovigilance will supply Gilead Sciences and F. Hoffmann-La Roche AG 
[Pharmaceutical Company] with a copy of all SAEs which involve exposure to a Gilead Sciences 
and F. Hoffmann-La Roche AG product within 24 hours of being made aware of the event 
regardless of whether or not the event is listed in the reference document (e.g. IB, SmPC). 


 
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The FIL Pharmacovigilance will provide Gilead Sciences and F. Hoffmann-La Roche AG with a 
copy of the development safety update report (DSUR) at the time of submission to the Regulatory 
Authority and Ethics Committees.   
 
CONTACT DETAILS FOR PHARMACOVIGILANCE 
Name: Elena Borgo, FIL Pharmacovigilance Department 
: +39 0131 033 156        
Fax: +39 0131 263455 
 
Email: drugvigilance@filinf.it  
Website: www.drugvigilance.filinf.it  
 
Adverse Events of Special Interest (Immediately Reportable to the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event). 
Adverse events of special interest for this study include the following: 
• 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 by Hy’s law and based on the 
following observations: 
– 
Treatment-emergent ALT or AST > 3 x baseline value in combination with total bilirubin > 2 
x ULN (of which ≥ 35% is direct bilirubin) 
– 
Treatment-emergent ALT or AST > 3 x baseline value in combination with clinical jaundice 
• Suspected transmission of an infectious agent by the study treatment, 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 any of the study treatment components is suspected. 
• TLS of any grade, irrespective of causality 
• Second malignancies. 
 
Obligations of the Sponsor 
The Sponsor will inform relevant Regulatory Authorities and Ethics Committees: 
− 
Of all relevant information about serious unexpected adverse events suspected to be related 
to the study drugs 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 be subsequently be submitted within an additional eight days 
− 
Of all other serious unexpected events suspected to be related to the study drugs as soon as 
possible, but within a maximum of fifteen days of first knowledge by the investigator. 
 
16.4. Pregnancy 
Females of Childbearing Potential 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female subject occurring while the subject is on study drug are considered 
events to be reported immediately to FIL Pharmacovigilance on the appropriate Pregnancy Form: 
 
e-mail: drugvigilance@filinf.it  
Fax: +39.0131.263455  
 
If the subject is on study drug, the study drug is to be discontinued immediately. 
The exposure of any pregnant female (e.g. caregiver or pharmacist) to study drug is also an 
immediately reportable event. 
The female should be referred to an obstetrician/gynecologist preferably one experienced in 
reproductive toxicity for further evaluation and counseling. 
The Investigator will follow the female subject until completion of the pregnancy and must notify FIL 
immediately about the outcome of the pregnancy (either normal or abnormal outcome). 


 
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If the outcome of the pregnancy was abnormal (i.e., spontaneous or therapeutic abortion) the 
Investigator should report the abnormal outcome as a SAE within 24 hours of the Investigator’s 
knowledge of the event through www.drugvigilance.filinf.it. 
All neonatal deaths that occur within 30 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 30 days that the Investigator(s) suspects is 
related to the in-utero exposure to the study drug should also be reported to FIL within 24 hours of 
the Investigator’s knowledge of the event through www.drugvigilance.filinf.it. 
 
Male patients 
If a female partner of a male patient taking study drug becomes pregnant, the male patient taking 
study drug should notify the Investigator, and the pregnant female partner should be advised to call 
her healthcare provider immediately. 
If a pregnancy related event is reported in a female partner of a male subject, the investigator 
should determine whether the female partner is willing to release her medical information to FIL 
Pharmacovigilance and allow the pregnancy related event to be followed-up to completion. 
 
16.5. Follow up of AEs and SAEs 
Any SAE should be monitored until they are resolved or are clearly determined to be due to a 
patient’s stable or chronic condition or underlying condition. Any additional information known after 
the event has been initially reported should be sent to the FIL as soon as information becomes 
available via www.drugvigilance.filinf.it. 
All AEs must be documented, and the outcome must be followed-up until the return to normal or 
consolidation of the patient’s condition. 
Subjects withdrawn from the study due to any AE will be followed at least until the outcome is 
determined even if it implies that the follow-up continues after the patient has left the trial. 
 
16.6. Product Quality Complaint Handling  
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have an 
impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of subjects, investigators, 
and the sponsor, and are mandated by regulatory agencies worldwide.  
 
Procedures 
All initial PQCs must be reported to Gilead Sciences/F. Hoffmann-La Roche AG by the study-site 
personnel within 24 hours after being made aware of the event. 
If the defect is combined with a SAE, the investigational staff must report the PQC to Gilead 
Sciences/F. Hoffmann-La Roche AG according to the SAE reporting timelines.  A sample of the 
suspected product should be maintained for further investigation if requested by Gilead 
Sciences/F. Hoffmann-La Roche AG. 
 
17. 
STATISTICAL CONSIDERATIONS 
 
17.1. Sample size  
Optimal Simon's two-stage design [32]  has been  be used to calculate the sample size. 
The null hypothesis that the true response rate is 55% (response rate of idelalisib single agent) [6] 
will be tested against a one-sided alternative response rate of 75% (response of obinutuzumab in 
combination) [23]. Last available clinical response will be considered for patients who will 
permanently discontinue for any cause both drugs of the experimental combination before the 
completion of the 6th cycle (planned duration of induction phase).  
For the first stage, the accrual will be suspended when 15 patients will have started experimental 
therapy. If there are 9 or fewer responses in these 15 patients, the study will be stopped. 
Otherwise, enrollment will be reopened until 28 additional patients will start experimental therapy   
for a total of 43. The null hypothesis will be rejected if 29 or more responses are observed in 43 
patients. 


 
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This design yields a type I error rate of 5% and power of 80% when the true response rate is 75%. 
 
17.2. Safety monitoring and stopping rules 
In order to monitor the safety of the treatment in small cohorts of patients, the Bayesian approach 
of Thall, et al. [33], as extended by Thall and Sung [34], for monitoring toxicity will be used. We 
have planned the monitoring of toxicity to ensure that the proportion of patients with non-
hematological toxicity defined as any non-hematological toxicity of grade 3 or higher after 3 and 6 
cycles of induction was not higher than an acceptable level of 25%. The prior probability of toxicity 
(25%) is modeled by a beta distribution [Beta (0.5,1.5)]. We will stop the enrolment in the 
experimental cohort if the posterior probability of the treatment being more toxic than expected is 
greater than 90%. Patients will be monitored, without suspending the enrollment, according to the 
following stopping boundaries for toxicity in cohorts of five patients as per assessment every 3 
cycles: 
 
Patients Enrolled 
Stop the enrollment in the cohort if the relevant toxicities are 
greater or equal to: 
5 
3 
10 
5 
15 
7 
20 
9 
25 
10 
30 
12 
35 
13 
40 
15 
 
Demographics and patients’ characteristics will be summarized by descriptive statistics. Point 
estimates of efficacy and toxicity will be provided with 95% confidence intervals. Overall response 
rate will be calculated as the sum of complete and partial response rates. Time-to event endpoints 
(progression free survival, overall survival) will be estimated by the Kaplan-Meier method. For the 
safety analyses, frequency of toxicities will be reported by type and grade according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0).  
 
17.3. Statistical analysis plan 
Analysis population 
Both efficacy and safety analyses will be conducted on all patients receiving at least one dose of 
planned therapy. 
Adverse Events 
All adverse events will be listed. The focus of AE summarization will be on treatment-emergent 
adverse events. A treatment-emergent adverse event is defined as an AE that occurs or worsens 
in the period from the first dose of study drugs to 30 days after the last dose of study drug. AEs 
that occur before the first dose of study treatment or >30 days after the subject has been 
discontinued from study treatment will be included in data listings. 
AEs will be classified using MedDRA version 21.1 with descriptions by System Organ Class, High-
Level Group Term, High-Level Term, Preferred Term, and Lower-Level Term. The severity of 
adverse events will be graded by the investigator according to the CTCAE, Version 5.0, whenever 
possible. If a CTCAE criterion does not exist for a specific type of adverse event, the grade 
corresponding to the appropriate adjective will be used by the investigator to describe the 
maximum intensity of the adverse event: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), 
Grade 4 (life threatening), or Grade 5 (fatal). The relationship of the AE to the study drug will be 
categorized as related or unrelated. 
A subject who reports multiple treatment emergent AEs within the same Preferred Term (or 
System Organ Class) is counted only once for that Preferred Term (or System Organ Class) using 
the worst severity grade. 
AE descriptions will be presented by decreasing frequency for a given System Organ Class and 
Preferred Term. 


 
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Separate listings and summaries will be prepared for the following types of treatment-emergent 
adverse events: 
• Study-drug-related (idelalisib or obinutuzumab) adverse events 
• AEs that are Grade ≥3 in severity 
• AEs leading to study drug interruption and/or dose modification 
• AEs leading to study drug (idelalisib or obinutuzumab) discontinuation 
• SAE (with categorization of the primary reason that the adverse event is considered serious, 
e.g., death, hospitalization, etc) 
 
18. INDEPENDENT DATA SAFETY MONITORING BOARD (DMSB) 
The FIL on its own initiative and responsibility set up an independent external DSMB. The DSMB 
consist in Experts independent from the sponsor. 
The aim of the DSMB is to assess, at intervals (every 3 cycles) during the course of the trial, the 
progress of the trial, the trial safety data and the trial outcome data with a view to recommending 
whether the trial should continue, be modified or be terminated. 
 
The DSMB will be composed by: 
• 
Three independent clinicians with expertise in the treatment of FL 
• 
The biostatistician of the study 
• 
An independent statistician with expertise in the methodology of clinical trials and data 
analysis. 
 
Roles of DSMB (suggested, not exclusive): 
• 
To monitor evidence for treatment harm (toxicity). 
• 
To decide whether to recommend changes to the protocol.  
• 
To decide whether to recommend that the trial continues to recruit participants or whether 
recruitment should be terminated. 
• 
To review final analysis of the data. 
• 
To discuss final data with PI and the sponsor. 
Timing of Analyses 
Interim Analyses 
The DSMB will have access to serious adverse events requiring expedited reporting and will be 
provided with accumulating safety data on a regular basis. An interim safety review will be 
conducted by the DSMB at ~3 months after the first subject is enrolled. Thereafter, interim safety 
reviews will be performed by the DSMB at intervals of ~3 months, according to the availability of 
the safety monitoring results; the specific frequency of these reviews will depend upon the rate at 
which the trial is enrolled, the nature of any emerging safety signals, and monitoring 
recommendations from the DSMB. At each review, all available safety data will be summarized 
and evaluated. The analyses will offer opportunities to assess early for evidence of substantial 
clinical benefit. 
Planned meetings: 
Three face-to-face meetings that include preparation, working time during the meeting, transport 
time and writing reports. 
Three call conferences that include preparation, working time during the meeting, transport time 
and writing reports. 
 
Following each review, each meeting and each call conference, the DSMB will prepare a report 
and may recommend changes in the conduct of the trial. 
 
19. INDEPENDENT EXTERNAL PATHOLOGY REVIEW 
An independent pathologist panel will review the lymph node/tumor biopsy, as well as any 
available bone marrow biopsy or other diagnostic material for upfront confirmation of the diagnosis 
of cases classified by local pathologist as FL. The investigative site must submit the requested 
samples as part of the screening phase to allow for a histological review. Histological centralized 
review is compulsory for treatment start, but the local pathology report is sufficient for patient 


 
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enrollment A confirmation of diagnosis of FL will be made by an expert pathologist and his staff 
The review process will be organized according to the procedures described in Appendix D.  
 
20. 
GOOD CLINICAL PRACTICE, QUALITY CONTROL AND QUALITY 
ASSURANCE 
20.1. Monitoring, Audits and Inspections 
During the study the monitoring will be prevalently made by e-mail and telephone. The field monitor 
will visit the site, when needed, mainly in presence of data incongruity, to check the completeness 
of patient records, the accuracy of entries on the CRFs, the adherence to the protocol and to Good 
Clinical Practice and the progress of enrolment. Key study personnel must be available to assist 
the field monitor during these visits. 
The investigator must maintain source documents for each patient in the study, consisting of case 
and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by the 
patient (a signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. FIL Safety Monitoring standards require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria, documentation of 
SAEs, and the recording of data that will be used for all primary and safety variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the study-
specific monitoring plan. No information in source documents about the identity of the patients will 
be disclosed. 
 
20.2. Investigator(s) responsibilities 
Investigator responsibilities are set out in the ICH guideline for Good Clinical Practice. The 
investigator must give the monitor access to relevant records to confirm the above.   
The Investigator(s) is responsible for keeping a record of all patients who sign an Informed 
Consent Form and are screened for entry into the study. For those patients who fail screening the 
reason(s) for exclusion must be recorded in the patient’s source documents. 
No procedure/assessment/measurement/test other than those outlined here, or in the schedule of 
study assessments, is to be performed without the prior written approval of Principal Investigator, 
or unless deemed by the investigator(s) as necessary for the patient’s medical care. Investigator(s) 
and/or authorized designee(s) must enter study data onto electronic CRFs supplied by FIL. The 
data on the CRF will be recorded in an anonymous manner to protect the patient’s identity by using 
a unique identifier that will prevent personal identifiable information. 
The Investigator(s), or a designated member of the Investigators’ staff, must be available at some 
time during monitoring visits to review data and resolve any queries and to allow direct access to 
the patient’s records (e.g., medical records, office charts, hospital charts, and study related charts) 
for source data verification. The CRFs must be completed as soon as possible after the patient’s 
visit, but no later than prior to each monitoring visit and be made available to the FIL 
representative(s) so that the accuracy and completeness may be checked. 
 
 
21. 
ETHICAL AND REGULATORY STANDARDS 
21.1. Independent Ethics Committee Review Approval  
This study will be conducted according to the Declaration of Helsinki Ethical Principles for Medical 
Research Involving Human Patients (see: http://www.wma.net/e/policy/b3.html for more 
information). The review of this protocol by the IEC and the performance of all aspects of the study, 
including the methods used for obtaining informed consent, must also be in accordance with 
principles enunciated in the declaration, as well as ICH Guidelines, Title 21 of the Code of Federal 
Regulations (CFR), Part 50 Protection of Human Patients and Part 56 Institutional Review Boards. 
Before implementing this study, the protocol, the proposed informed consent form and other 
information to patients, must be reviewed by a properly constituted IEC. A signed and dated 
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FIL before the study initiation. The names and occupations of the chairman and the members of 
the IEC must be supplied to FIL. 
The FIL as sponsor of the study, together with site Investigator(s), will be responsible for preparing 
documents, where ever applicable, for submission to the relevant IEC and obtaining written 
approval for this study. The approval will be obtained prior to the initiation of the study. 
A copy of the IEC approval for the protocol and the Informed Consent is to be provided to FIL and 
site Investigator(s). The approval for both the protocol and informed consent must specify the date 
of approval, protocol number and version, or amendment number. 
The Investigator(s) is responsible for notifying the FIL Safety Monitoring Office and the IEC of any 
serious deviations from the protocol, or anything else that may involve added risk to patients. 
Any advertisements used to recruit patients for the study must be reviewed and approved by FIL 
and the IEC prior to use. 
Before the start of the study, the FIL will provide the IEC with current and complete copies of the 
following documents: 
1. final protocol and, if applicable, amendments 
2. informed consent form (and any other written materials to be provided to the subjects) 
3. Investigator’s Brochure (or equivalent information) and amendments 
4. information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable 
5. investigator’s curriculum vitae or equivalent information (unless not required, as 
documented by IEC) 
6. any other documents that the IEC requests to fulfil its obligation. 
 
During the study the FIL according with site investigators will send the following documents to the 
IEC for their review and approval, where appropriate: 
1. protocol amendments 
2. revision(s) to informed consent form and any other written materials to be provided to 
subjects 
3. revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable 
4. Investigator’s Brochure amendments or new edition(s) 
5. summaries of the status of the study (at least annually or at intervals stipulated in guidelines 
of the IEC) 
6. reports of adverse events that are serious, unexpected and associated with the 
investigational drug 
7. new information that may affect adversely the safety of the subjects or the conduct of the 
study 
8. deviations from or changes to the protocol to eliminate immediate hazards to the subjects 
9. report of deaths of subjects under the investigator's care 
10. notification if a new investigator is responsible for the study at the site 
11. any other requirements of the IEC     
  
21.2. Protocol Amendments Approval 
Any amendment to this protocol that seems appropriate, as the study progresses will be submitted 
to the IEC for written approval before the implementation of the amended version. The written 
signed approval from the IEC should refer specifically to the investigator(s) and to the protocol 
number and title and mention any amendment numbers that are applicable. Amendments that are 
administrative in nature do not require IEC approval but will be submitted to the IEC for information 
purposes. 
 
22. ADMINISTRATIVE PROCEDURES 
22.1. Curriculum vitae 
An updated copy of the curriculum vitae of each investigator and sub-investigator will be provided 
to the FIL Start Up prior to the beginning of the study. 
 
22.2. Confidentiality agreement 


 
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All goods, materials, information (oral or written) and unpublished documentation provided to the 
investigators (or any company acting on their behalf), inclusive of this study, the patient case report 
forms are the exclusive property of FIL. 
They may not be given or disclosed by the investigator or by any person within his authority either 
in part or in totality to any unauthorized person without the prior written formal consent of FIL. 
It is specified that the submission of this study and other necessary documentation to the Ethics 
Review Committee or a like body is expressly permitted, the Ethics Committee members having 
the same obligation of confidentiality. 
The investigator shall consider as confidential and shall take all necessary measures to ensure that 
there is no breach of confidentiality in respect of all information accumulated, acquired or deduced 
in the course of the trial, other than that information to be disclosed by law. 
 
22.3. Record retention in investigating centers 
The investigator must maintain all study records, patient files and other source data for the 
maximum period of time permitted by the hospital, institution or private practice. 
However national regulations should be taken into account, the longest time having to be 
considered. 
For trials performed in the European Community, the investigator is required to arrange for the 
retention of the patient identification codes according to the applicable laws and regulations on 
Clinical Trials. 
Any center will notify the sponsor before destroying any data or records. 
 
22.4. Ownership of data and use of the study results 
The sponsor has the ownership of all data and results collected during this study. In consequence 
the sponsor reserves the right to use the data of the present study, either in the form of case report 
forms (or copies of these), or in the form of a report, with or without comments and with or without 
analysis, in order to submit them to the health authorities of any country. 
 
22.5. Authorship 
The first results of the trial will be published after complete data collection and evaluation of the 
primary endpoint. Partial or preliminary results can be published beforehand. Publication is to be 
initiated by the chairmen in charge of the study with approval of coordinators. 
Any publication in the form of a lecture, poster or article must be before approved by the Scientific 
Committee of FIL. 
The authors will be proposed (according to the updated FIL publication rules) by the chairmen in 
charge of the study, approved by coordinators and finally decided by the Steering Committee of the 
study. 
All study data and publications are the property of the FIL.  
 
22.6. Insurance coverage 
The Investigator-sponsor of the Study must ensure that adequate insurance coverage is available 
to the patients, in accordance with the ICH Guidelines of Good Clinical Practice. Such coverage 
must extend to all damages deriving from the study, to the Protocol Study exclusion of those 
attributable to wilful 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 Global SE has been 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. 
 
22.7. Protocol amendments procedures 
It is specified that the appendices attached to this study and referred to in the main text of this 
study, form an integral part of the study. 


 
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No changes or amendments to this study may be made by the investigator or by the sponsor after 
the study has been agreed to and signed by both parties unless such change(s) or amendment(s) 
have been fully discussed and agreed upon by the investigator and the FIL.  
Any change agreed upon will be recorded in writing, the written amendment will be signed by the 
investigator and by the sponsor and the signed amendment will be appended to this study. 
Approval/advice of amendments by Ethics Review Committee and Competent Authorities are 
required prior to their implementation, unless there are overriding safety reasons. 
If the change or deviation increases risk to the study population, or adversely affects the validity of 
the clinical investigation or the subject's rights, full approval/advice must be obtained prior to 
implementation. For changes that do not involve increased risk or affect the validity of the 
investigation or the subject's rights, approval / advice may be obtained by expedited review, where 
applicable. 
In some instances, an amendment may require a change to a consent form. The investigator must 
receive approval/advice of the revised consent form prior to implementation of the change. In 
addition, changes to the case report forms, if required, will be incorporated in the amendment. 
 
23. DATA HANDLING AND RECORD KEEPING 
23.1. Data/documents 
The investigator(s) must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the study drug, that is copies of CRFs and source documents original 
documents, data, and records (e.g., hospital records; clinical and office charts; laboratory notes; 
memoranda; patient’s diaries or evaluation checklists; pharmacy dispensing records; recorded data 
from automated instruments; copies or transcriptions certified after verification as being accurate 
copies; microfiches; photographic negatives, microfilm, or magnetic media; x-rays; patient files) 
and records kept at the pharmacy, at the laboratories, and at medico-technical departments 
involved in the clinical study are complete, accurate, filed and retained. 
 
23.2. Data Management 
Data will be entered into the clinical database as per FIL SOPs. These data will be electronically 
verified through use of on-line checks during data entry, and through programmed edit checks 
specified by the clinical team. Discrepancies in the data will be brought to the attention of the 
clinical team, and investigational site personnel, if necessary, in the form of a Data Clarification 
Form (DCF) or a query. Resolutions to these issues will be reflected in the database. An audit trail 
within the system will track all changes made to the data. 
 
23.3. Retention of Records 
The investigator(s) must maintain records of all study documents and supporting information 
relating to the conduct of the study. This documentation includes, but is not limited to, protocols, 
case report forms, advertising for patient participation, adverse event reports, patient source data, 
correspondence with health authorities and IECs, informed consent forms, investigator(s) curricula 
vitae, monitor visit logs, laboratory reference ranges, laboratory certification or quality control 
procedures and laboratory director curriculum vitae. Patient files and other source data must be 
kept for the maximum period of time permitted by the hospital, institution or private practice 
specified below. The study monitor must be consulted if the investigator(s) wishes to assign the 
study files to someone else, remove them to another location or is unable to retain them for a 
specified period. The investigator(s) must retain study records for the time period according to local 
laws or requirements, whichever is longer. The monitor will inform the investigator(s) of the dates 
for retention. All study documents should be made available if required by relevant health 
authorities.  
 
24. PRIVACY OF PERSONAL DATA 
The collection and processing of personal data from subjects enrolled in this study will be limited to 
those data that are necessary to investigate the efficacy, safety, quality, and utility of the 
investigational product(s) used in this study. These data must be collected and processed with 


 
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adequate precautions to ensure confidentiality and compliance with applicable data privacy 
protection laws and regulations. 
The investigator-sponsor ensures that the personal data will be: 
1. processed fairly and lawfully 
2. collected for specified, explicit, and legitimate purposes and not further processed in a way 
incompatible with these purposes 
3. adequate, relevant, and not excessive in relation to said purposes 
4. accurate and, where necessary, kept current 
Explicit consent for the processing of personal data will be obtained from the participating subject 
before collection of data. Such consent should also address the transfer of the data to other 
entities and to other countries. The subject has the right to request through the investigator access 
to his/her personal data and the right to request rectification of any data that are not correct or 
complete. Reasonable steps should be taken to respond to such a request, taking into 
consideration the nature of the request, the conditions of the study, and the applicable laws and 
regulations. 
Patients will be registered in the study via web site prior to any study related procedure and after 
signing informed consent. 
The name of the patient will not be asked for not recorded at the Data Center. A sequential 
identification number will be automatically attributed to each patient registered in the trial. This 
number will identify and must be included on all case report form. 


 
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25. REFERENCES 
 
1.  
Rummel MJ, Al-Batran SE, Kim S-Z et al. Bendamustine plus rituximab is effective and has 
a favorable toxicity profile in the treatment of mantle cell and low-grade non-Hodgkin’s 
lymphoma. J. Clin. Oncol. 2005; 23(15):3383–9. 
2.  
Robinson KS, Williams ME, van der Jagt RH et al. Phase II multicenter study of 
bendamustine plus rituximab in patients with relapsed indolent B-cell and mantle cell non-
Hodgkin’s lymphoma. J. Clin. Oncol. 2008; 26(27):4473–9. 
3.  
Kahl BS, Bartlett NL, Leonard JP et al. Bendamustine is effective therapy in patients with 
rituximab-refractory, indolent B-cell non-Hodgkin lymphoma: results from a Multicenter 
Study. Cancer 2010; 116(1):106–14. 
4.  
Cheson BD, Wendtner C-M, Pieper A et al. Optimal use of bendamustine in chronic 
lymphocytic leukemia, non-Hodgkin lymphomas, and multiple myeloma: treatment 
recommendations from an international consensus panel. Clin. Lymphoma. Myeloma Leuk. 
2010; 10(1):21–7. 
5.  
Sehn LH, Chua NS, Mayer J et al. GADOLIN: Primary results from a phase III study of 
obinutuzumab plus bendamustine compared with bendamustine alone in patients with 
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Gopal AK, Kahl BS, de Vos S et al. PI3Kδ inhibition by idelalisib in patients with relapsed 
indolent lymphoma. N. Engl. J. Med. 2014; 370(11):1008–18. 
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Leonard JP, Jung S-H, Johnson J et al. Randomized Trial of Lenalidomide Alone Versus 
Lenalidomide Plus Rituximab in Patients With Recurrent Follicular Lymphoma: CALGB 
50401 (Alliance). J. Clin. Oncol. 2015; 33(31):3635–40. 
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Flinn I, Oki Y, Patel M et al. a Phase 1 Evaluation of Duvelisib (IPI-145), a PI3K-δ,γ Inhibitor, 
in Patients with Relapsed/Refractory iNHL. Blood 2014; 124(21):802 LP-802. 
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Bartlett NL, LaPlant BR, Qi J et al. Ibrutinib Monotherapy in Relapsed/Refractory Follicular 
Lymphoma (FL): Preliminary Results of a Phase 2 Consortium (P2C) Trial. Blood 2014; 
124(21):800 LP-800. 
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Gerecitano JF, Roberts AW, Seymour JF et al. A Phase 1 Study of Venetoclax (ABT-199 / 
GDC-0199) Monotherapy in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma. 
Blood 2015; 126(23):254 LP-254. 
11.  
Advani RH, Flinn I, Sharman JP et al. Two doses of polatuzumab vedotin (PoV, anti-CD79b 
antibody-drug conjugate) in patients (pts) with relapsed/refractory (RR) follicular lymphoma 
(FL): Durable responses at lower dose level. J. Clin. Oncol. 2015; 33(15_suppl):8503. 
12.  
van Besien K, Loberiza FR, Bajorunaite R et al. Comparison of autologous and allogeneic 
hematopoietic stem cell transplantation for follicular lymphoma. Blood 2003; 102(10):3521 
LP-3529. 
13.  
Rezvani AR, Storer B, Maris M et al. Nonmyeloablative allogeneic hematopoietic cell 
transplantation in relapsed, refractory, and transformed indolent non-Hodgkin’s lymphoma. 
J. Clin. Oncol. 2008; 26(2):211–7. 
14.  
Khouri IF, Saliba RM, Erwin WD et al. Nonmyeloablative allogeneic transplantation with or 
without 90yttrium ibritumomab tiuxetan is potentially curative for relapsed follicular 
lymphoma: 12-year results. Blood 2012; 119(26):6373–8. 
15.  
Schouten HC, Qian W, Kvaloy S et al. High-dose therapy improves progression-free survival 
and survival in relapsed follicular non-Hodgkin’s lymphoma: results from the randomized 
European CUP trial. J. Clin. Oncol. 2003; 21(21):3918–27. 
16.  
Rohatiner AZS, Nadler L, Davies AJ et al. Myeloablative therapy with autologous bone 
marrow transplantation for follicular lymphoma at the time of second or subsequent 
remission: long-term follow-up. J. Clin. Oncol. 2007; 25(18):2554–9. 
17.  
Sebban C, Mounier N, Brousse N et al. Standard chemotherapy with interferon compared 
with CHOP followed by high-dose therapy with autologous stem cell transplantation in 
untreated patients with advanced follicular lymphoma: the GELF-94 randomized study from 
the Groupe d’Etude des Lymphomes de. Blood 2006; 108(8):2540–4. 
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Puri KD, Gold MR. Selective inhibitors of phosphoinositide 3-kinase delta: modulators of B-


 
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cell function with potential for treating autoimmune inflammatory diseases and B-cell 
malignancies. Front. Immunol. 2012; 3:256. 
19.  
Vanhaesebroeck B, Welham MJ, Kotani K et al. P110delta, a novel phosphoinositide 3-
kinase in leukocytes. Proc. Natl. Acad. Sci. U. S. A. 1997; 94(9):4330–5. 
20.  
Eyre TA, Osborne WL, Gallop-Evans E et al. Results of a multicentre UK-wide 
compassionate use programme evaluating the efficacy of idelalisib monotherapy in 
relapsed, refractory follicular lymphoma. Br. J. Haematol. 2018; 181(4):555–559. 
21.  
de Vos S, Wagner-Johnston ND, Coutre SE et al. Combinations of idelalisib with rituximab 
and/or bendamustine in patients with recurrent indolent non-Hodgkin lymphoma. Blood Adv. 
2016; 1(2):122–131. 
22.  
Cheson BD, Pfistner B, Juweid ME et al. Revised response criteria for malignant lymphoma. 
J. Clin. Oncol. 2007; 25(5):579–586. 
23.  
Sehn LH, Chua N, Mayer J et al. Obinutuzumab plus bendamustine versus bendamustine 
monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma 
(GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol. 
2016; 17(8):1081–1093. 
24.  
Marcus R, Davies A, Ando K et al. Obinutuzumab for the First-Line Treatment of Follicular 
Lymphoma. N. Engl. J. Med. 2017; 377(14):1331–1344. 
25.  
Tuscano JM, Dutia M, Chee K et al. Lenalidomide plus rituximab can produce durable 
clinical responses in patients with relapsed or refractory, indolent non-Hodgkin lymphoma. 
Br. J. Haematol. 2014; 165(3):375–81. 
26.  
Salles GA, Morschhauser F, Solal-Céligny P et al. Obinutuzumab (GA101) in patients with 
relapsed/refractory indolent non-Hodgkin lymphoma: results from the phase II GAUGUIN 
study. J. Clin. Oncol. 2013; 31(23):2920–6. 
27.  
Radford J, Davies A, Cartron G et al. Obinutuzumab (GA101) plus CHOP or FC in 
relapsed/refractory follicular lymphoma: results of the GAUDI study (BO21000). Blood 2013; 
122(7):1137–43. 
28.  
Cheson BD, Fisher RI, Barrington SF et al. Recommendations for initial evaluation, staging, 
and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano 
classification. J. Clin. Oncol. 2014; 32(27):3059–3068. 
29.  
Smith TJ, Bohlke K, Lyman GH et al. Recommendations for the Use of WBC Growth 
Factors: American Society of Clinical Oncology Clinical Practice Guideline Update. J. Clin. 
Oncol. 2015; 33(28):3199–3212. 
30.  
Aapro MS, Bohlius J, Cameron DA et al. 2010 update of EORTC guidelines for the use of 
granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced 
febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. 
Eur. J. Cancer 2011; 47(1):8–32. 
31.  
Klastersky J, de Naurois J, Rolston K et al. Management of febrile neutropaenia: ESMO 
Clinical Practice Guidelines. Ann. Oncol. 2016; 27(suppl 5):v111–v118. 
32.  
Simon R. Optimal two-stage designs for phase II clinical trials. Control. Clin. Trials 1989; 
10(1):1–10. 
33.  
Thall PF, Simon RM, Estey EH. Bayesian sequential monitoring designs for single-arm 
clinical trials with multiple outcomes. Stat. Med. 1995; 14(4):357–79. 
34.  
Thall PF, Sung HG. Some extensions and applications of a Bayesian strategy for monitoring 
multiple outcomes in clinical trials. Stat. Med. 1998; 17(14):1563–80. 
 
 


 
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26. APPENDICES  
 
APPENDIX A: ECOG PERFORMANCE STATUS 
SOURCE: Oken MM et al, Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. 
 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed 
or chair 
5 
Dead 


 
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APPENDIX B: COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (CTCAE) 
 
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 5.0. 
Click on CTCAE, version 5.0 to download the document in pdf. 
 
 
 


 
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APPENDIX C: Response assessment by CT and PET scans  
SOURCE: Cheson et al., J Clin Oncol. 2014 Sep 20;32(27):3059-68 [28]. 
 
 


 
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APPENDIX D:  PATHOLOGY REVIEW GUIDELINES 
 
Every center participating to the study will provide the central laboratory with material used to 
perform local diagnosis of FL relapsed, or that used for the more recent biopsy in the case of 
refractory patients. The investigative site must submit the requested samples as part of the 
screening phase to allow for an upfront histological review. Central review is mandatory to start 
treatment, even if patients can be entered in the study according to local diagnosis. 
 
Samples shipment will be set up by FIL. 
For each patient, a formalin-fixed paraffin embedded (FFPE) tissue block should be provided to the 
central laboratory. Sites are encouraged to provide a block, since some nuclear antigens to be 
tested are labile, and the risk for false negative results on cut sections is high. 
The block will be promptly returned to the local site upon completion of the central review process.  
In the case a block is absolutely not available, the site can choose one on the two following 
options: 
a) to send 20 unstained sections; 
b) to send one H&E or GIEMSA stained slide from each block, and all immunostains 
performed for local diagnosis plus 15 unstained sections. The institution’s H&E, GIEMSA 
and immunostains will be returned promptly after the review is done. 
In both cases, an anonymized copy of the local diagnostic reports, including the description, the 
final diagnosis, and the immunohistochemical and/or flow cytometry results and molecular results, 
if done, are also to be also provided. 
Tests to be performed at central laboratory 
Standard panel: 
CD20, CD5, CD10, BCL6, IRF4/MUM1, CD23, BCL2 (if negative with monoclonal antibody 124, to 
be tested also with E17 and SP66), LMO2, MYC, P53 and KI-67. 
Differential diagnosis: 
In the case of problems of differential diagnosis with marginal lymphoma, IRTA1 and MNDA will be 
also assessed. 
Special cases: 
In some particular types of FL cases, it could be difficult rendering a definite diagnosis relying on 
the results of the above reported tests: in these cases, FISH analysis (e.g., disease presenting with 
IRF4 rearrangement or double hits) and/or molecular assessments (e.g., TP53 mutations or Ig 
rearrangement) will be done.  
Central diagnosis review FIL laboratory: 
Prof. Stefano Pileri, Dr. Valentina Tabanelli, Dr. Stefano Fiori 
Unità di Diagnosi Emolinfopatologica 
Building IEO1, 1° piano 
IEO - Istituto Europeo di Oncologia 
via Ripamonti 435, Milano 
Phone: +39 02 57489522 
Fax: +39 02 94379320 
Email: stefano.pileri@ieo.it; unita.emolinfopatologia@ieo.it 
The laboratory has entered into an agreement with FIL to carry out the centralized review of the 
samples of patients registered in the trial. 


 
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APPENDIX E:  REFERENCE SAFETY INFORMATION FOR IDELALISIB 
Serious Expected Terms Associated with idelalisib Coded by MedDRA version 21.1) 
IB edition 19 of 27 September 2018. 
 
 
 
 
 
 
 
 
 
 
 
 


 
MD01-01_I01_PRDS00 
 
 
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APPENDIX F:  REFERENCE SAFETY INFORMATION FOR OBINUTUZUMAB 
(Serious Expected Terms Associated with obinutuzumab Coded by MedDRA version 21.1) 
IB edition 13; study pool = 3745 patients; Data cut-off date = 14 Mar 2018  
 
 
 
 


 
MD01-01_I01_PRDS00 
 
 
FIL_GAUDEALIS, version n. 2.0 of May 29, 2019 
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