Conditions: Follicular Lymphoma Small Lymphocytic Lymphoma Lymphoplasmacytic Lymphoma Marginal Zone Lymphoma
Keywords: indolent Non-Hodgkin Lymphoma Non-Hodgkin Lymphoma iNHL NHL GS-1101 CAL-101 PI3K Phosphatidylinositol 3-kinase Follicular Lymphoma (FL) Small lymphocytic lymphoma (SLL) Lymphoplasmacytoid lymphoma (LPL) Marginal zone lymphoma (MZL)
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 125
Healthy volunteers: no

Brief summary:
The primary objective will be to assess the overall response rate and to evaluate the efficacy and safety of idelalisib (IDELA; GS-1101) in participants with previously treated indolent Non-Hodgkin Lymphoma (iNHL) that is refractory both to rituximab and to alkylating-agent-containing chemotherapy.

Eligible participants will initiate oral therapy with idelalisib at a starting dose of 150 mg taken twice per day. Treatment with idelalisib can continue in compliant participants as long as the study is still ongoing and the participants appear to be benefiting from treatment with acceptable safety.

Detailed description:

Arms:
arm 1: Treatment with idelalisib will be continued until tumor progression or development of unacceptable toxicity.

Interventions: intervention 1: Idelalisib
Intervention descriptions: intervention 1: Idelalisib 150 mg tablet administered orally twice daily

Protocol document:
Prot_001.pdf: 
CLINICAL PROTOCOL
Protocol Number 101-09
A Phase 2 Study to Assess the Efficacy and Safety of Idelalisib in 
Subjects with Indolent B-Cell Non-Hodgkin Lymphomas Refractory 
to Rituximab and Alkylating Agents
Version 9.0
Release Date: 05 September 2017
Gilead Sciences, Inc.
199 East Blaine Street
Seattle, WA 98102, USA
Notice of Proprietary Information: This document contains confidential information belonging to 
Gilead Sciences, Inc. This material is the property of Gilead Sciences, Inc. and must not be 
disclosed or used except as authorized in writing by Gilead Sciences, Inc. In the event of an 
actual or suspected breach of this obligation, Gilead Sciences, Inc. should be notified promptly.


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PROTOCOL IDENTIFIERS AND SPONSOR STUDY PERSONNEL
Project Code
Idelalisib
Therapeutic Area
Oncology
Study Sponsor Substance Identifier
Idelalisib (CAL-101/GS-1101)
IND Number
EudraCT Number
101,254
2010-022155-33
Included in clinical trials.gov Database
Yes
Protocol Number
101-09
Protocol Version 9.0 Date
05 September 2017
Protocol Phase
Phase 2
Protocol Title
A Phase 2 Study to Assess the Efficacy and Safety 
of idelalisib in Subjects with Indolent B-Cell 
Non-Hodgkin Lymphomas Refractory to Rituximab 
and Alkylating Agents
Study Sponsor Medical Monitor
Gilead Sciences, Inc.
199 East Blaine Street
Seattle, WA 98102, USA
Telephone: 
Facsimile: 
E-mail: 
Study Sponsor Clinical Program 
Manager
Gilead Sciences, Inc.
199 East Blaine Street
Seattle, WA 98102, USA
Telephone: 
Facsimile: 
E-mail: 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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PRINCIPAL INVESTIGATOR AGREEMENT AND SIGNATURE
By signing this document, the principal investigator confirms – on behalf of the 
investigator’s institution – that the study will be conducted in accordance with the protocol; 
generally accepted standards of Good Clinical Practice (GCP); and all applicable laws, rules, and 
regulations relating to the conduct of the clinical study.
Principal Investigator Signature
Date
Institution


PPDPPD
PPD
Protocol I 01-09 
Version 9.0 
SPONSOR PROTOCOL APPROVAL SIGNATURES 
Final 
By signing this document, the sponsor's representatives confirm that this study will be conducted 
in compliance with the protocol; accepted standards of GCP; and all applicable laws, mles, and 
regulations relating to the conduct of the study. They also attest that data will be generated, 
documented, and reported consistent with the protocol; GCP; and relevant laws, rules, and 
regulations. 
--I 
J 
Associate Director, Clinical Research, Oncology 
Gilead Sciences, Inc. 
Clinical Program Manager 
Gilead Sciences, Inc. 
CONFIDENTIAL 
Page4 
Date 
05 September 201 7 


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................5
LIST OF IN-TEXT TABLES........................................................................................................................................9
LIST OF IN-TEXT FIGURES ......................................................................................................................................9
ABBREVIATIONS AND IDENTIFICATION OF TERMS ......................................................................................10
1.
OVERVIEW .......................................................................................................................................................14
1.1.
Background ............................................................................................................................................14
1.2.
Study Design..........................................................................................................................................15
2.
INTRODUCTION ..............................................................................................................................................17
2.1.
Disease Background – Indolent Non-Hodgkin Lymphoma ...................................................................17
2.2.
Role of Phosphatidylinositol 3-Kinases in Tumor Pathogenesis............................................................19
2.3.
Development of Idelalisib......................................................................................................................20
2.4.
Nonclinical Characterization of Idelalisib..............................................................................................20
2.4.1.
Drug Substance and Formulation.........................................................................................20
2.4.2.
Efficacy Pharmacology ........................................................................................................20
2.4.3.
Safety Pharmacology............................................................................................................22
2.4.4.
Pharmacokinetics and Drug Metabolism..............................................................................24
2.4.5.
Toxicology ...........................................................................................................................25
2.5.
Clinical Experience with Idelalisib ........................................................................................................26
2.5.1.
Phase 1 Single- and Multiple-Dose Study in Healthy Volunteers 
(Study 101-01) .....................................................................................................................27
2.5.2.
Phase 1 Safety and Pharmacodynamic Study in Subjects with Allergic 
Rhinitis (Study 101-04)........................................................................................................27
2.5.3.
Phase 1 Study Evaluating Food-Effect, Drug-Drug Interactions, and 
Metabolism in Healthy Volunteers (Study 101-05) .............................................................28
2.5.4.
Phase 1 Study in Subjects with Relapsed or Refractory Hematologic 
Malignancies (Study 101-02)...............................................................................................29
2.6.
Summary and Conclusions.....................................................................................................................31
3.
OBJECTIVES AND ENDPOINTS ....................................................................................................................32
3.1.
Primary Objective ..................................................................................................................................32
3.2.
Secondary Objectives.............................................................................................................................32
3.3.
Primary Endpoint ...................................................................................................................................32
3.4.
Secondary Endpoints..............................................................................................................................32
3.5.
Rationale for Endpoint Selection ...........................................................................................................33
3.5.1.
Antitumor Activity ...............................................................................................................33
3.5.2.
Changes in Health-Related Quality of Life ..........................................................................34
3.5.3.
Changes in Performance Status............................................................................................35
3.5.4.
Pharmacodynamic Activity..................................................................................................35
3.5.5.
Safety....................................................................................................................................36
3.5.6.
Study Drug Administration and Compliance .......................................................................36
3.5.7.
Pharmacokinetics .................................................................................................................36
4.
SUBJECT SELECTION.....................................................................................................................................38
4.1.
Subject Selection Criteria.......................................................................................................................38
4.1.1.
Inclusion Criteria..................................................................................................................38
4.1.2.
Exclusion Criteria.................................................................................................................41
4.2.
Enrollment Criteria Rationale ................................................................................................................42
5.
ENROLLMENT AND STUDY MANAGEMENT PROCEDURES .................................................................43


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5.1.
Number of Subjects................................................................................................................................43
5.2.
Subject Recruitment...............................................................................................................................43
5.3.
Subject Compensation for Participation.................................................................................................43
5.4.
Enrollment of Subjects Without Prior Treatment with Bendamustine...................................................44
5.5.
Interactive Web Response System .........................................................................................................44
6.
TREATMENTS..................................................................................................................................................45
6.1.
Study Drug .............................................................................................................................................45
6.1.1.
Description ...........................................................................................................................45
6.1.2.
Packaging .............................................................................................................................45
6.1.3.
Source...................................................................................................................................45
6.1.4.
Storage and Stability ............................................................................................................46
6.1.5.
Dispensing............................................................................................................................46
6.1.6.
Return...................................................................................................................................46
6.1.7.
Accountability......................................................................................................................46
6.1.8.
Overdose Precautions...........................................................................................................47
6.1.9.
Inadvertent Exposure and Spill Precautions.........................................................................47
6.2.
Study Drug Administration ....................................................................................................................47
6.2.1.
Dosing Instructions ..............................................................................................................47
6.2.2.
Dosing Schedule...................................................................................................................47
6.2.3.
Dose Levels..........................................................................................................................48
6.2.4.
Safety Monitoring and Recommendations for Dose Modification.......................................48
6.2.5.
Management of Specific Adverse Events.............................................................................51
6.2.6.
Hematological and Immunological Events...........................................................................56
6.2.7.
Infectious Events..................................................................................................................57
6.2.8.
Secondary Malignancies.......................................................................................................57
6.2.9.
Ultraviolet Exposure ............................................................................................................58
6.2.10.
Further Safety Information...................................................................................................58
6.2.11.
Duration of Therapy.............................................................................................................58
6.3.
Concomitant and Supportive Therapy....................................................................................................58
6.3.1.
Anticancer or Experimental Therapies Other than Idelalisib ...............................................58
6.3.2.
Antiemetics ..........................................................................................................................59
6.3.3.
Granulocyte Colony-Stimulating Factors and Erythropoietin..............................................59
6.3.4.
Corticosteroids .....................................................................................................................59
6.3.5.
Drugs that Inhibit/Induce CYP3A-Dependent Metabolism..................................................59
6.3.6.
Drugs that Undergo CYP3A-Dependent Metabolism..........................................................60
6.3.7.
Immunization .......................................................................................................................60
6.3.8.
Surgery .................................................................................................................................60
6.3.9.
Diet.......................................................................................................................................60
6.4.
Study Treatment Rationale.....................................................................................................................60
7.
SCHEDULE OF EVENTS AND PROCEDURES.............................................................................................62
7.1.
Schedule of Events.................................................................................................................................62
7.2.
Explanation of Study Visits....................................................................................................................66
7.2.1.
Visit 1 and Screening Period (Clinic Visit)..........................................................................66
7.2.2.
Visit 2 (Day 1) (Clinic Visit)................................................................................................68
7.2.3.
Visit 3 (Day 15) (Laboratory Visit)......................................................................................69
7.2.4.
Visit 4 (Day 29) (Clinic Visit)..............................................................................................69
7.2.5.
Visit 5 (Day 43) (Laboratory Visit)......................................................................................71
7.2.6.
Visit 6 (Day 57) (Clinic and Radiology Visit) .....................................................................71
7.2.7.
Visit 7 (Day 71) (Laboratory Visit)......................................................................................73
7.2.8.
Visit 8 (Day 85) (Clinic Visit)..............................................................................................73
7.2.9.
Visit 9 (Day 113) (Clinic and Radiology Visit) ...................................................................73
7.2.10.
Visit 10 (Day 141) (Clinic Visit)..........................................................................................75
7.2.11.
Visit 11 (Day 169) (Clinic and Radiology Visit) .................................................................76


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7.2.12.
Visits 12 and 14 (Days 211 and 295) (Clinic Visits)............................................................77
7.2.13.
Visits 13, 15, etc. (Days 253, 337, and Every 12 Weeks) 
(Clinic and Radiology Visit) ................................................................................................77
7.2.14.
End-of-Treatment Visit (Clinic Visit) ..................................................................................79
7.2.15.
Immediate Post-Treatment Safety Follow-up.......................................................................80
7.2.16.
Long-Term Follow-up..........................................................................................................80
7.3.
Sample Storage.......................................................................................................................................80
7.4.
Blood Collection ....................................................................................................................................80
7.5.
Study Parameter Selection Rationale .....................................................................................................81
8.
ACTIVITY AND SAFETY ASSESSMENTS ...................................................................................................82
8.1.
Tumor Size Assessments........................................................................................................................82
8.1.1.
Timing of Assessments ........................................................................................................82
8.1.2.
Method of Assessment .........................................................................................................82
8.1.3.
Identification of Index and Non-Index Tumor Lesions at Baseline .....................................82
8.1.4.
Follow-up of Index and Non-Index Tumor Lesions.............................................................84
8.1.5.
Definitions of Tumor Response and Progression.................................................................85
8.2.
Adverse Event Assessments...................................................................................................................88
8.2.1.
Adverse Event Definitions ...................................................................................................88
8.2.2.
Eliciting Adverse Event Information....................................................................................91
8.2.3.
Adverse Event Recording.....................................................................................................91
8.2.4.
Describing Adverse Event Relationship to Study Drug .......................................................92
8.2.5.
Grading of Severity of Adverse Event .................................................................................92
8.2.6.
Follow-up of Unresolved Adverse Events............................................................................93
8.2.7.
Adverse Event Reporting Period..........................................................................................93
8.2.8.
Site Adverse Event Reporting Requirements .......................................................................93
8.2.9.
Study Sponsor Adverse Event Reporting Requirements......................................................95
8.3.
Special Situation Reporting Requirements.............................................................................................95
8.3.1.
Definitions of Special Situations..........................................................................................95
8.3.2.
Pregnancy.............................................................................................................................96
8.3.3.
Instructions for Reporting Special Situations.......................................................................97
9.
WITHDRAWAL OF SUBJECTS.......................................................................................................................98
10.
STATISTICS AND DATA MANAGEMENT...................................................................................................99
10.1.
Statistical Basis for Proposed Sample Size ............................................................................................99
10.2. Analysis Sets..........................................................................................................................................99
10.2.1.
Intent-to-Treat Analysis Set .................................................................................................99
10.2.2.
Per-Protocol Analysis Set.....................................................................................................99
10.2.3.
Pharmacodynamic/Pharmacokinetic Analysis Sets..............................................................99
10.3.
Analysis Plan........................................................................................................................................100
10.3.1.
General Considerations ......................................................................................................100
10.3.2.
Subject Disposition and Characteristics .............................................................................100
10.3.3.
Protocol Deviations............................................................................................................100
10.3.4.
Prior and Concomitant Medication Use .............................................................................100
10.3.5.
Antitumor Activity and Efficacy........................................................................................101
10.3.6.
Health-Related Quality of Life...........................................................................................102
10.3.7.
Performance Status.............................................................................................................102
10.3.8.
Pharmacodynamic Endpoints.............................................................................................102
10.3.9.
Safety Parameters...............................................................................................................102
10.3.10.
Study Treatment Administration and Compliance .............................................................105
10.3.11.
Pharmacokinetics ...............................................................................................................105
10.4.
Interim and Final Analyses ..................................................................................................................105
10.4.1.
Interim Analysis .................................................................................................................105
10.4.2.
Final Analysis.....................................................................................................................106


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10.5.
Data Management and Quality Assurance ...........................................................................................106
10.6.
Statistical and Data Management Rationale.........................................................................................106
11.
STUDY COMMITTEES ..................................................................................................................................108
11.1.
Study Steering Committee ...................................................................................................................108
11.2.
Independent Review Committee ..........................................................................................................108
12.
OBLIGATIONS OF THE INVESTIGATOR AND SPONSOR ......................................................................109
12.1.
Compliance with Ethical and Regulatory Guidelines...........................................................................109
12.2.
Institutional Review Board/Institutional Ethics Committee.................................................................109
12.3.
Informed Consent.................................................................................................................................110
12.4.
Case Report Forms...............................................................................................................................110
12.5.
Study Records ......................................................................................................................................111
12.6.
Retention of Records and Samples.......................................................................................................111
12.7.
Confidentiality .....................................................................................................................................112
12.8.
Financial Disclosure.............................................................................................................................112
12.9.
Monitoring and Auditing......................................................................................................................112
12.10. Termination of the Study......................................................................................................................113
12.11. Public Notification of Study Conduct ..................................................................................................113
12.12. Dissemination of Results......................................................................................................................113
12.13. Communication with Regulatory Authorities ......................................................................................114
13.
RISK-BENEFIT CONSIDERATIONS ............................................................................................................115
13.1.
Potential Risks and Mitigating Factors ................................................................................................115
13.1.1.
Potential Risks Based on Nonclinical and Clinical Idelalisib Metabolism 
Data....................................................................................................................................115
13.1.2.
Potential Risks Based on Nonclinical and Clinical Idelalisib Toxicology 
Data....................................................................................................................................115
13.1.3.
Potential Risks Based on Prior Clinical Experience with Idelalisib...................................115
13.1.4.
Potential Reproductive Risks .............................................................................................116
13.1.5.
General Medical Risks .......................................................................................................116
13.1.6.
Other Potential Risks and Discomforts ..............................................................................117
13.1.7.
Potential Data Confidentiality Risks ..................................................................................117
13.2.
Potential Benefits .................................................................................................................................118
14.
BIBLIOGRAPHY.............................................................................................................................................119
15.
APPENDICES ..................................................................................................................................................127
Appendix A.
Ann Arbor Lymphoma Staging System ...............................................................................128
Appendix B.
Follicular Lymphoma International Prognostic Index..........................................................129
Appendix C.
Functional Assessment of Cancer Therapy: Lymphoma (FACT-Lym) ...............................130
Appendix D.
Performance Status Scoring Systems ...................................................................................133


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LIST OF IN-TEXT TABLES
Table 1.
Required Screening Laboratory Values..................................................................................40
Table 2.
Idelalisib Dose Level Information..........................................................................................48
Table 3.
Recommended and Required Actions Based on Type and Severity of Adverse Event 
or Laboratory Abnormality.....................................................................................................49
Table 4.
Schedule of Events Overview.................................................................................................63
Table 5.
Procedures and Assessments at Visit 1 (During Screening Period)........................................67
Table 6.
Procedures and Assessments at Visit 2 (Day 1) .....................................................................68
Table 7.
Procedures and Assessments at Visit 3 (Day 15) ...................................................................69
Table 8.
Procedures and Assessments at Visit 4 (Day 29) ...................................................................70
Table 9.
Procedures and Assessments at Visit 5 (Day 43) ...................................................................71
Table 10.
Procedures and Assessments at Visit 6 (Day 57) ...................................................................72
Table 11.
Procedures and Assessments at Visit 7 (Day 71) ...................................................................73
Table 12.
Procedures and Assessments at Visit 8 (Day 85) ...................................................................73
Table 13.
Procedures and Assessments at Visit 9 (Day 113) .................................................................74
Table 14.
Procedures and Assessments at Visit 10 (Day 141) ...............................................................75
Table 15.
Procedures and Assessments at Visit 11 (Day 169) ...............................................................76
Table 16.
Procedures and Assessments at Visits 12 and 14 (Days 211 and 295)...................................77
Table 17.
Procedures and Assessments at Visits 13, 15, etc. (Days 253, 337, and Every 12 
Weeks)....................................................................................................................................78
Table 18.
Procedures and Assessments at End-of-Treatment Visit........................................................79
Table 19.
Blood Drawing Requirements Through Visit 15 (Week 48)..................................................81
Table 20.
Relationship of Study Drug to Adverse Event .......................................................................92
Table 21.
Grading of Adverse Event Severity........................................................................................93
Table 22.
Site Reporting Requirements for Adverse Events ..................................................................94
LIST OF IN-TEXT FIGURES
Figure 1.
Kaplan-Meier Time to Diarrhea or Colitis .............................................................................53


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ABBREVIATIONS AND IDENTIFICATION OF TERMS
-HCG
Beta human chorionic gonadotropin
ABCG2
Adenosine triphosphate-binding cassette sub-family G member 2 (see also BCRP)
ALL
Acute lymphocytic leukemia
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AML
Acute myelogenous leukemia
ANC
Absolute neutrophil count
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
AKT
AKT (a serine/threonine protein kinase)
AUC
Area under the concentration-time curve
ATC
Anatomical-Therapeutic-Chemical (drug coding system)
BAFF
B-cell activating factor belonging to the tumor necrosis factor family
BCR
B-cell receptor
BCRP
Breast cancer resistance protein (see also ABCG2)
BFU-e
Erythroid blast-forming units
BID
Twice per day
BTK
Bruton tyrosine kinase
CAL-101
Former product code name for GS-1101 and idelalisib
CD40
Antigen expressed on the surface of immune cells
CD-ROM
Compact disc read-only memory
CRF
Case report form
CFR
United States Code of Federal Regulations
CCL
Chemokine (C-C motif) ligand
CHOP
Cyclophosphamide, doxorubicin, vincristine, and prednisone
CI
Confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CLL
Chronic lymphocytic leukemia
cGMP
Current Good Manufacturing Practices
CK
Creatine kinase
Cmax
Maximum concentration
CMV
Cytomegalovirus
CR
Complete response
CRO
Contract research organization
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
Trough concentration
CVP
Cyclophosphamide, vincristine, and prednisone
CXCL
Chemokine (C-X-C motif) ligand


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CXCR
Chemokine (C-X-C motif) receptor
CYP
Cytochrome P450 enzyme
DLBCL
Diffuse large B-cell lymphoma
DNA
Deoxyribonucleic acid
DNP-KLH
Dinitrophenol-keyhole limpet hemocyanin
DOR
Duration of response
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDC
Electronic data capture
ELISA
Enzyme-linked immunosorbent assay
EMA
European Medicines Agency
FACT-Lym
Functional Assessment of Cancer Therapy: Lymphoma
FDA
United States Food and Drug Administration
FDAMA
Food and Drug Modernization Act
FDG
Fluorodeoxyglucose 
FL
Follicular lymphoma
FLIPI
Follicular Lymphoma International Prognostic Index
GCP
Good Clinical Practices
G-CSF
Granulocyte colony-stimulating factor
GGT
Gamma-glutamyltransferase
GLP
Good Laboratory Practices
GM-CSF
Granulocyte-macrophage colony-stimulating factor
GS-1101
Gilead product code for idelalisib
HBV
Hepatitis B virus
HCV
Hepatitis C virus
hERG
Human ether-à-go-go-related gene
HIV
Human immunodeficiency virus
HRQL
Health-related quality of life
IC50
Concentration inducing 50% inhibition
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
Ig
Immunoglobulin
IND
Investigational New Drug (application)
iNHL
Indolent non-Hodgkin lymphoma
INR
International normalized ratio
ITT
Intention to treat
IRB/IEC
Institutional review board/independent ethics committee
IRC
Independent review committee
IWRS
Interactive web response system
K2-EDTA
Potassium-ethylenediaminetetraacetic acid


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LC-MS/MS
Liquid chromatography with tandem mass spectrometry
LDH
Lactate dehydrogenase
LLN
Lower limit of normal
LPL
Lymphoplasmacytoid lymphoma
MAA
Marketing Authorization Application
MTD
Maximum tolerated dose
MCL
Mantle cell lymphoma
MedDRA
Medical Dictionary for Regulatory Activities
MM
Multiple myeloma
MRI
Magnetic resonance imaging
MZL
Marginal zone lymphoma
NDA
New drug application
NE
Not evaluable
NHL
Non-Hodgkin lymphoma
NOAEL
No-observed-adverse-effect level
NOEL
No-observed-effect level
OAT
Organic anion transporter
OCT
Organic cation transporter
ORR
Overall response rate
OS
Overall survival
PARP
Poly (ADP-ribose) polymerase
PBMC
Peripheral blood mononuclear cell  
PD
Progressive disease
PIP3
Phosphatidylinositiol (3,4,5)-trisphosphate
PET
Positron-emission tomography
PFS
Progression-free survival
PI3K
Phosphatidylinositol 3-kinase
PI3K
Phosphatidylinositol 3-kinase p110isoform
PJP
Pneumocystis jirovecii pneumonia (PJP)
PR
Partial response
PRO
Subject-reported outcome
PT
Prothrombin time
PTEN
Phosphatase and tensin homolog (tumor suppressor)
PVA
Polyvinyl alcohol
QD
Once per day
QTcB
Cardiac QT interval corrected for heart rate by the method of Bazett
QTcF
Cardiac QT interval corrected by for heart rate by the method of Fridericia
R-CHOP
Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone
RNA
Ribonucleic acid
R-CVP
Rituximab, cyclophosphamide, vincristine, and prednisone
SSAD
Study sponsor awareness day


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SSC
Study steering committee
SHIP
Inositol polyphosphate 5-phosphatase
SD
Stable disease
SLL
Small lymphocytic lymphoma
SPD
Sum of the product of the diameters (of nodal or tumor masses)
SPEP
Serum protein electrophoresis
t1/2
Half-life
Tmax
Time of maximum concentration
TTF
Time to treatment failure
TTR
Time to response
UGT
Uridine 5'-diphospho-glucuronosyltransferase
ULN
Upper limit of normal
WHO
World Health Organization 
WHODRUG
World Health Organization Drug Dictionary
WM
Waldenström macroglobulinemia


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1.
OVERVIEW
1.1.
Background
Non-Hodgkin lymphomas (NHL) comprise the most common hematological malignancies. 
Among the variants of these cancers are indolent NHL (iNHL) subtypes that are slowly 
progressive over time. These disorders are characterized by lymphadenopathy that is frequently
disturbing for subjects and can sometimes induce life-threatening organ dysfunction. Subjects 
may have B symptoms (fevers, night sweats, and/or weight loss) and fatigue. The goal of therapy 
is to induce tumor regression and delay tumor progression in order to control disease-related 
complications. Subjects are given sequential treatments with chemotherapeutic and 
immunotherapeutic agents to ameliorate bothersome adenopathy and symptoms. Despite use of 
agents with differing mechanisms of action, progressive resistance to treatment develops. New 
therapies with novel mechanisms of action are needed to offer additional treatment options for 
subjects with iNHL who are experiencing symptoms due to disease progression.
Phosphatidylinositol 3-kinases (PI3K) are a family of enzymes that are involved in proliferation, 
migration, and survival for many cell types. Among several isoforms of the enzyme is 
phosphatidylinositol 3-kinase p110δ (PI3Kδ), which is expressed in B-lymphocytes. 
Gilead Sciences, Inc., a pharmaceutical company located in Seattle, WA, has developed novel 
drugs that can suppress tumor growth by selectively inhibiting PI3Kδ activity. These efforts led 
to identification of idelalisib (GS-1101; formerly known as CAL-101), a 415-Dalton, orally 
bioavailable, new chemical entity with potential clinical utility in the treatment of cancers. In 
vitro studies in cultured lymphoma cells demonstrate that idelalisib abrogates PI3Kδ signaling 
and impairs malignant B-cell survival.
Nonclinical safety testing has supported clinical development of idelalisib. Safety pharmacology 
studies show no adverse effects on cardiopulmonary and neurological functioning. Toxicology 
studies in rats and dogs through 13 weeks indicate generally good tolerability at doses and 
exposures in excess of those to be used in humans and provide information regarding signals to 
be monitored in the clinic. Consistent with the pharmacological activity of idelalisib, lymphoid 
cell depletion is evident in lymphoid organs of rats and dogs. Bone marrow is a target organ in 
rats, while liver is a target organ in dogs. idelalisib does not show genotoxicity in a standard 
battery of nonclinical genotoxicity studies.
Results from an initial Phase 1 study indicated that idelalisib is well tolerated when administered 
to healthy subjects at doses through 400 mg (the highest dose level tested). This same study also 
showed that idelalisib is generally well tolerated when administered to healthy subjects at doses 
through 200 mg twice per day (BID) (the highest dose level tested). When assessed over 7 days 
in a Phase 1b study in subjects with allergic rhinitis, idelalisib 100 mg BID was also well 
tolerated; in this study, idelalisib showed clinical and pharmacodynamic activity, attenuating
adverse responses to allergenic challenge and decreasing markers of inflammation.


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Idelalisib has also been evaluated in a Phase 1 sequential dose-ranging study evaluating 
once per day (QD) or BID dosing in 191 subjects with lymphoid malignancies including iNHL, 
mantle cell lymphoma (MCL), and chronic lymphocytic leukemia (CLL). The drug has been
symptomatically well tolerated at dose levels through 350 mg BID (the highest dose tested) with 
several subjects receiving the drug for >2 years. Monitorable, reversible elevations of hepatic 
transaminases have been observed in some subjects but no maximum tolerated dose (MTD) has 
been apparent within the tested dose range. Among 34 participating subjects with relapsed or 
refractory iNHL receiving idelalisib at doses ≥100 mg BID, 20 partial responses have been 
observed, resulting in a response rate of 59% among subjects with this lymphoma subtype. 
Substantial activity has also been observed in CLL and MCL. The collective safety, 
pharmacokinetic, and response data have supported selection of 150 mg BID as an appropriate 
starting dosing regimen for Phase 2 evaluation. For additional or updated information, please 
refer to the current version of the Investigator’s Brochure.
1.2.
Study Design
Idelalisib (Zydelig®) was approved in the United States on July 23, 2014 and in the 
European Union on September 18, 2014. Refer to local labeling for the approved indication 
statements.
This protocol describes a Phase 2, open-label, single-arm, 2-stage, efficacy, safety, and 
pharmacodynamic study of idelalisib in subjects with previously treated iNHL that is refractory 
both to rituximab and to alkylating-agent-containing chemotherapy.
Eligible subjects will initiate oral therapy with idelalisib at a starting dose of 150 mg BID given 
continuously. Treatment with idelalisib will continue until tumor progression or unacceptable 
toxicity. Subjects will be followed in the clinic at 2-week intervals through the first 12 weeks of 
treatment, at 4-week intervals from 12 to 24 weeks of treatment, at 6-week intervals from 
24 to 48 weeks of treatment, and at 12-week intervals thereafter. Tumor response will be 
evaluated at baseline; at 8, 16, and 24 weeks of therapy; and every 12 weeks thereafter according 
to standard criteria. The responses will be assessed by both the investigator and an 
independent review committee (IRC).
The primary objective will be to assess the overall response rate (ORR). Secondary objectives 
will include determination of duration of response (DOR), lymph node response rate, changes in 
tumor size, time to response (TTR), progression-free survival (PFS) and overall survival (OS). 
The findings of the IRC will be considered primary for analyses of ORR, DOR and other tumor 
control endpoints. Evaluation of health-related quality of life (HRQL) as reported by subjects 
completing the Functional Assessment of Cancer Therapy: Lymphoma (FACT-Lym) and 
assessment of changes in performance status are also planned. To support the clinical findings, 
measurement of concentrations of circulating chemokines and cytokines that are reflective of 
disease activity will be performed. The safety, compliance, and pharmacokinetic profiles of 
idelalisib will also be assessed.
The study will evaluate the null hypothesis that the IRC-reviewed ORR is ≤20% against the 
alternative hypothesis that it is ≥39% (ie, ≥~40%). The study will be conducted in 2 stages using 
Simon’s optimal 2-stage design. In Stage 1 of the study, 31 subjects will be enrolled; 


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if ≥9 of these Stage 1 subjects have a tumor response, then the study will continue. In Stage 2, a 
further 69 subjects will be enrolled. With a total intended sample size of 100 subjects, the study 
provides a power of >0.90 to achieve a 1-sided significance level of 0.005 and will provide an 
ample safety database. The final study analysis will be performed when all enrolled subjects 
have completed efficacy, safety, and other assessments through at least 24 weeks of evaluation.
It is planned that study subjects will be enrolled at investigational sites in North America and 
Europe. Enrollment is planned to occur over ≤18 months, subject follow-up will continue 
through ≥6 months, and analysis and reporting will be completed over ~6 months thereafter.
This study is being conducted in support of idelalisib registration. If positive efficacy and safety 
results are observed, it is intended that the findings would provide the initial basis for regulatory 
approval of idelalisib as treatment for subjects with iNHL that is refractory to rituximab and to 
alkylating-agent-containing chemotherapy.


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2.
INTRODUCTION
2.1.
Disease Background – Indolent Non-Hodgkin Lymphoma
NHL comprises a diverse group of malignancies arising in lymphoid tissue. The neoplasms 
represent a progressive clonal expansion of B cells, T cells, or natural killer cells arising from the 
accumulation of genetic lesions that affect proto-oncogenes or tumor suppressor genes, resulting 
in cell immortalization {Friedberg 2008b}. A B-cell origin is documented in 80-85% of cases. 
Chromosomal translocations that reduce lymphocyte apoptosis are typical. In the United States, 
NHL is the sixth most common cancer; it is estimated that during the year 2010, 
~66,000 new subjects were diagnosed and ~20,000 subjects died of NHL {Jemal 2010}. In 
Europe, it is anticipated that ~74,000 new cases occured, leading to ~31,000 deaths {Ferlay 
2010}. As mortality due to other causes has declined, the incidence of lymphoma has increased; 
almost exclusively a disease of adulthood, diagnosis most commonly occurs during in subjects 
between 50 and 70 years of age {Friedberg 2008b}.
Of the B-cell NHLs, 4 subtypes (follicular lymphoma [FL], small lymphocytic lymphoma [SLL], 
lymphoplasmacytoid lymphoma [LPL] - with or without Waldenström macroglobulinemia
[WM], and marginal zone lymphoma [MZL]) have differing pathological features {Campo 
2011}, but are generally included among those characterized as indolent in nature because they 
have common clinical presentations, show a slowly progressive natural history, and generally 
require similar treatments {Pileri 2004}. Subjects with iNHL typical present with painless and 
gradually progressive peripheral adenopathy {Friedberg 2008b, Salles 2007}. Some subjects 
may experience primary extra-nodal involvement or B symptoms (ie, temperature > 38°C, night 
sweats, or weight loss > 10% from baseline within 6 months). As the disease advances, fatigue is 
often noted. Bone marrow involvement is common and may result in cytopenias. Subjects with 
iNHL commonly have splenomegaly and hepatomegaly. Elevated serum levels of lactate 
dehydrogenase (LDH) reflect general tumor burden. Abnormal transaminase values may indicate
hepatic involvement or chronic lymphoma-related inflammation.
Computed tomography (CT) or magnetic resonance imaging (MRI) scans of the neck, chest, 
abdomen, and pelvis, as well as bone marrow aspirate and biopsy, are employed to stage iNHL
{Zelenetz 2010}. Positron-emission tomography (PET) is sometimes used to identify occult sites 
of disease in subjects who appear to have localized iNHL based on CT and bone marrow biopsy
{Seam 2007}. The Ann Arbor staging system categorizes subjects by whether they have single 
sites of involvement (Stage 1), ≥2 sites of disease on the same side of the diaphragm (Stage 2), 
sites of disease on both side of the diaphragm (Stage 3), or disseminated disease (Stage 4) {Lister 
1989} (Appendix A). For follicular iNHL, the Follicular Lymphoma International Prognostic 
Index (FLIPI) has been developed to define outcomes {Solal-Celigny 2004} (Appendix B). The 
FLIPI characterizes subjects in terms of 5 adverse prognostic factors; age >60 years, Ann Arbor 
stage III-IV, hemoglobin<12 g/dL, number of nodal areas >4, and serum LDH above normal. 
Subjects are scored as low risk (≤1 factor), intermediate risk (2 factors), or high risk (≥3 factors). 
While a protracted course is common in iNHL, life expectancy varies by the types of factors 
represented in the FLIPI score; median survival is ~4 to >10 years from diagnosis depending 
upon such prognostic characteristics {Solal-Celigny 2004}. Subjects are at risk of transformation 


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of iNHL to aggressive, diffuse, large B-cell lymphoma (DLBCL) at a rate of 2 to 3% per year
{Bastion 1997, Montoto 2007}; such transformation is usually associated with a poor clinical 
outcome.
Radiation therapy to involved sites is the most common treatment for the infrequent subjects 
with localized iNHL (Stage 1 or non-bulky Stage 2 disease) {Wilder 2001}, {Tsang 2005}. 
Systemic therapy is considered for the majority of subjects with iNHL, in whom extensive 
lymphoma (Stage 2 bulky, Stage 3, or Stage 4 disease) is present {Zelenetz 2010}. Watchful 
waiting is possible but subjects are generally treated if they have lymphoma-related symptoms or 
end-organ dysfunction, bulky disease, cytopenias, persistent disease progression, or a strong 
preference for immediate therapy. Because iNHL requiring systemic therapy is essentially 
incurable and subjects may be older and have comorbidities, the goal of therapy is primarily to 
alleviate lymphoma-related symptoms and prolong progression-free interval.
For older or infirm subjects, single-agent rituximab (Rituxan®) or alkylating agents such as 
cyclophosphamide or chlorambucil may be administered {Zelenetz 2010}. Most subjects receive 
chemoimmunotherapy in which rituximab is given together with cyclophosphamide, 
doxorubicin, vincristine, and prednisone (R-CHOP) {Buske 2009, Hiddemann 2005} or 
cyclophosphamide, vincristine, prednisone (R-CVP) {Marcus 2005, Marcus 2008}. Alternative 
regimens includes rituximab with the alkylating agent, bendamustine, or fludarabine- or 
mitoxantrone-based therapy that may include an alkylating agent {Herold 2007, Zinzani 2004}. 
Meta-analysis data from randomized trials indicate that the addition of rituximab to 
chemotherapy not only improves tumor control but also extends overall survival (OS) in 
previously untreated subjects {Schulz 2007}. Based on controlled trials, rituximab has formal 
regulatory approval for use as a component of front-line chemoimmunotherapy of iNHL. In 
addition, maintenance or consolidation therapy with rituximab or yttrium90-ibritumomab tiuxetan 
(Zevalin®) has been shown to prolong PFS {Morschhauser 2008, van Oers 2007, Vidal 2009}.
Despite the chemosensitivity of iNHL to front-line therapy, existing systemic therapies for iNHL 
are not curative. Some subjects will be refractory to initial therapy and most subjects will 
ultimately relapse. Several treatments have received regulatory approval in the United States 
and/or Europe for treatment of refractory or relapsed disease, including rituximab, 
yttrium90-ibritumomab tiuxetan, iodine131-tositumomab (Bexxar®), and bendamustine
(Treanda). The principal support for use in these settings has comprised non-randomized 
single-arm trials that have focused on documenting treatment-related tumor responses in 
populations of subjects with disease that has become resistant to either alkylating agents or 
rituximab immunotherapy {Cheung 2009, Ferrucci 2010, Fisher 2005, Friedberg 2008a, Horning 
2005, Johnston 2010, Kahl 2010, Kaminski 2000, Kaminski 2005, Kaminski 2001, Maloney 
1997, McLaughlin 1998, Piro 1999, Schilder 2004, Vose 2000, Witzig 2002}. 
Yttrium90-ibritumomab tiuxetan and iodine131-tositumomab use has been limited because of 
medical and practical restrictions on the use of these agents; these drugs are contraindicated in 
subjects with substantial pre-existing myelotoxicity or bone marrow lymphoma involvement and 
their use is constrained by the complexity of dosimetry calculations and drug preparation, the 
need for administration by specifically trained clinicians at specially equipped sites, protracted 
Grade 3-4 hematological toxicity that commonly results in infectious complications and impedes
subsequent therapy, and long-term risks of hypothyroidism.


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Other approaches that may be attempted off-label include alkylating agent monotherapy, 
alkylating-agent-based combination therapy (CVP, CHOP), or administration of purine 
analogues (fludarabine, cladribine) {Zelenetz 2010}. Similarly, subjects may be treated off-label 
with bortezomib (Velcade®) or lenalidomide (Revlimid®) {Di Bella 2010, Goy 2005, Witzig 
2009}.
Due to the acquisition of drug resistance, progressively less activity is observed, particularly 
when administering previously used therapies; the disease course is characterized by a 
continuous decrease in the quality and the duration of tumor response with each subsequent 
treatment {Salles 2007}. Subjects face the burden of cumulative myelosuppressive toxicity, a 
problem that has been documented with fludarabine {Janikova 2009} and commonly limits 
continued therapy with cytotoxic agents such as bendamustine {Friedberg 2008a, Kahl 2010}. In 
addition, there is a well-document risk of myelodysplasia and/or acute myelogenous leukemia 
associated with use of alkylating agents, doxorubicin, fludarabine, iodine131-tositumomab, and 
Y90-ibritumomab tiuxetan {Friedberg 2006}. Consequently, new therapies with novel 
mechanisms of action are needed to offer additional treatment options for subjects with iNHL. 
The need is especially acute in those subjects whose disease has become refractory to existing 
chemoimmunotherapeutic approaches, particularly in those with lymphoma that is refractory to
both rituximab and alkylating agents.
2.2.
Role of Phosphatidylinositol 3-Kinases in Tumor Pathogenesis
Class I PI3Ks are a family of intracellular signaling proteins that are essential components of 
migratory, proliferative, survival, and differentiation pathways in many cell types, including 
those of hematopoietic origin [reviewed in {Okkenhaug 2003b}]. These enzymes consist of a 
regulatory subunit (designated p50, p55, p85, or p101) and a catalytic subunit (designated p110α, 
p110β, p110δ, or p110γ). Upon PI3K activation, p110 generates the key lipid second messenger 
phosphatidylinositiol (3,4,5)-trisphosphate (PIP3) through phosphorylation of the 3 position of 
the inositol head group of phospholipids present in the cell membrane. PIP3 acts as a binding site 
for recruitment and activation of numerous intracellular signaling enzymes. The most important 
of these is the serine/threonine kinase, AKT, which mediates a positive pleotropic effect on cell 
survival, proliferation, growth, and metabolism {Engelman 2006}. Also important in 
B lymphocytes is the Bruton tyrosine kinase (BTK), that plays an essential role in antigen 
receptor signaling. The activity of PI3K is opposed by lipid phosphatases that include
phosphatase and tensin homolog (PTEN), a known tumor suppressor that is expressed in all cells 
and inositol polyphosphate 5-phosphatase (SHIP), an enzyme that is expressed in hematopoietic 
cells.
PI3Kshows an expression pattern that is largely restricted to cells of hematopoietic origin 
{Vanhaesebroeck 2005}. Mice deficient in PI3Khave no gross abnormalities, are fertile, 
fecund, and live a normal life span without an increased susceptibility to infections {Okkenhaug 
2003a}. However, effects on intracellular signaling, proliferation, migration, and differentiation 
have been observed in cells of myeloid and lymphoid lineages {Sujobert 2005}. In particular, the 
B-lymphocyte population in these animals shows a decrease in maturation, diminished receptor-
induced proliferation, and increased susceptibility to apoptotic cell death.


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The converse situation exists in B-cell malignancies. In this circumstance, B-cell receptor 
activation and/or stimulation by proliferation and survival factors present in lymph node and 
bone marrow microenvironments aberrantly elevate PI3K signaling {Bernal 2001, Munk 
Pedersen 2004, Petlickovski 2005}. Genetic and pharmacological interventions have shown that 
factors such as antigen, CD40 ligand, BAFF, CXCL12, and CXCL13 all stimulate B-cell 
proliferation and survival via a PI3K-dependent pathway {Durand 2009, Lannutti 2011, 
Okkenhaug 2002}. A survey of multiple lymphoma cell lines showed uniform expression of 
PI3Kand in many cases constitutive activation of the PI3K pathway as indicated by expression 
of phosphorylated AKT {Lannutti 2011}. Collectively, these data have supported targeting 
PI3Kin subjects with B-cell malignancies to decrease aberrant lymphocyte activation and 
function, reduce excessive lymphocyte proliferation, and enhance apoptosis of transformed B 
cells.
2.3.
Development of Idelalisib
Knowledge of the critical importance of PI3Kδ in B-cell biology and neoplasia has encouraged
the development of drugs to inhibit this enzyme as a therapy for lymphoid malignancy. 
Gilead Sciences, a pharmaceutical company located in Seattle, WA, USA, has used 
high-throughput screening to identify novel agents that selectively inhibit PI3Kfunction.
Chemical optimization, pharmacological characterization, and toxicological evaluation have led 
to identification of idelalisib, an orally bioavailable, new chemical entity that potently blocks 
PI3Kactivity and diminishes lymphoma growth and survival.
2.4.
Nonclinical Characterization of Idelalisib
2.4.1.
Drug Substance and Formulation
Idelalisib is a fluorinated quinazolinone with 1 stereogenic center. Idelalisib is the S enantiomer. 
The compound has no known structural similarity to existing drugs. The drug substance is a 
white to off-white, crystalline powder with a chemical formula of C22H18FN7O, 
a molecular weight of ~415 Daltons, and low aqueous solubility. Idelalisib is orally bioavailable. 
For toxicological and clinical testing, Idelalisib has been manufactured and formulated according 
to current Good Manufacturing Practices (cGMP).
2.4.2.
Efficacy Pharmacology
Nonclinical efficacy pharmacology data in enzyme-based and cell-based systems indicate that 
idelalisib is a potent inhibitor of PI3Kbut that its selectivity spares other PI3K isoforms and 
other kinases. Testing in nonclinical models of lymphoid neoplasia confirm the importance of the 
PI3Kδ pathway in these tumor types, and document idelalisib activity in suppressing in the 
growth and survival of these malignancies.
2.4.2.1.
Potency and Selectivity
In in vitro assays evaluating PI3K enzymatic activity, idelalisib potently inhibited PI3K, with 
an IC50 value of 2.5 nM. By contrast, IC50 values for the effects of idelalisib on PI3K, PI3K, 
and PI3Kwere 820, 565, and 89 nM respectively, indicating a selectivity of idelalisib for PI3K


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that is 40- to 300-fold greater than for other PI3K Class I family members. When assessing 
IC50 values relative to Class II, III, and IV PI3K enzymes, idelalisib showed 400- to 4000-fold 
greater activity for Class I PI3Kinhibition. In vitro selectivity was further demonstrated by 
evaluation of activity against the comprehensive panel of 402 kinases in the Ambit KinomeScan; 
idelalisib at 10 μM (0.42 μg/mL) inhibited PI3K enzymes but showed no activity against other 
enzymes.
Potency and selectivity have been confirmed in cell-based in vitro assays. In human whole blood, 
idelalisib potently inhibited basophil activation via a PI3Kδ-dependent pathway, with an
EC50 of 62 nM; by contrast, inhibition of basophil activation via a PI3K-dependent pathway 
showed an EC50 of 4,456 nM. idelalisib also showed potent in vitro inhibition of PI3Kδ-mediated 
processes in other cell types; activation of human B-cell proliferation via the B-cell receptor, 
neutrophil degranulation in response to bacterial peptide, and stimulation of human T-cell 
proliferation via the T-cell receptor were inhibited with respective EC50 values of 
8 nM, 119 nM, and 932 nM. By contrast, when examining PI3Kα- or PI3Kβ-mediated 
phosphorylation of AKT in primary mouse fibroblasts, idelalisib showed EC50 values of 
> 20 µM and 1900 nM, thus substantiating the lack of idelalisib effect on signaling via these 
PI3K isoforms.
2.4.2.2.
Activity in Models of Lymphoid Malignancy
Evaluation of the PI3K expression pattern in lymphoid malignancies has supported use of 
idelalisib to target PI3Kδ as therapeutic approach to these cancers {Lannutti 2011}. In fresh
isolates from human subjects, primary B-cell acute lymphocytic leukemia (ALL) cells and CLL 
cells showed high levels of PI3Kδ and PI3Krelative to those seen in normal peripheral blood 
mononuclear cells (PBMCs). By contrast, PI3Kα and PI3Kβ were only variably expressed. 
Similarly, a panel of cell lines representing a variety of B-cell malignancies, including B-cell 
ALL, FL, MCL, and DLBCL, showed consistent high-level expression of PI3Kδ. There appeared 
to be functional consequences of this over-expression; in primary B-cell ALL, CLL, and MCL 
tumor cells and in leukemia and lymphoma cell lines, phosphorylated AKT was constitutively 
present when assessed by flow cytometry or Western blot analysis. These data demonstrate that 
PI3Kδ is highly expressed in B-cell malignancies and that constitutive PI3K pathway activation 
is a common event in B-cell tumors.
Primary CLL and MCL subject samples and B-cell ALL, FL, and DLBCL cell lines that were 
positive for phosphorylated AKT expression have been used to evaluate the effect of PI3Kδ 
inhibition by idelalisib {Herman 2010, Lannutti 2011}. In primary cells, idelalisib treatment 
induced a dose-dependent reduction in phosphorylated AKT with EC50 values of <100 nM in all 
samples evaluated. In cell lines, EC50 values of 0.1 to 1.0 μM were observed, confirming a 
central role for PI3Kδ in constitutive PI3K signaling in malignant B cells, and the activity of 
idelalisib in suppressing this pathway.
To evaluate the role of PI3Kδ in mediating signals from the tumor microenvironment, primary 
tumor cells and cell lines were pretreated with increasing concentrations of idelalisib or vehicle 
and then stimulated with CXCL13 (CXCR5 activation), CXCL12 (CXCR4 activation), anti-IgM 
(B-cell receptor [BCR] activation), BAFF (BAFFR activation) or soluble CD40 ligand


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(CD40 activation) {Lannutti 2011}. Activation via any of these pathways could be inhibited by 
idelalisib at EC50 values of <100 nM, suggesting that idelalisib can interrupt signals from the 
tumor microenvironment that are essential for the expansion, homing, and survival of malignant 
B cells and that promote resistance to conventional drug therapy.
The tumoricidal activity of idelalisib has also been documented in preclinical models of 
lymphoid malignancy. When primary CLL cells were incubated with idelalisib at a concentration 
of 10 μM for 96 hours, median [range] cell survival was 36% [26-78%] relative to 
vehicle-treated cells. In B-cell ALL, FL, DLBCL, and MCL cell lines, concentration-dependent 
cell killing was uniformly observed during 72-hour incubations with idelalisib at concentrations 
of 0.1 to 5 M. Tumor cell killing by idelalisib were associated with 3- to 5-fold increases in 
Annexin-V staining, and 2- to 8-fold increases in cleaved caspase 3 and cleaved
Poly (ADP-ribose) polymerase (PARP) expression, providing documentation of drug-induced 
apoptosis {Lannutti 2011, May 2008}.
2.4.3.
Safety Pharmacology
In vitro and in vivo safety pharmacology studies with idelalisib demonstrate a generally 
favorable non-clinical safety profile. These studies indicate that the drug may slow bone marrow 
progenitor proliferation and differentiation and that it has expected effects on B-cell response to 
antigen challenge. However, the data indicated that idelalisib is unlikely to cause serious 
off-target effects or adverse effects on critical organ systems. Idelalisib has no meaningful effect 
on the human ether-à-go-go-related gene (hERG) channel, indicating that idelalisib would not be 
expected to induce clinical QT prolongation.
The drug has also proved well tolerated in standard in vivo Good Laboratory Practice (GLP) 
studies of pharmacological safety. A functional observation battery in rats revealed no adverse 
effects on behavior or on autonomic, neuromuscular, or sensorimotor function. In a 
cardiopulmonary function study in awake, telemeterized male beagle dogs, single doses of 
idelalisib induced no meaningful abnormalities in pulmonary, cardiovascular, arterial blood gas, 
or electrocardiographic (ECG) (including QT interval) parameters. In an assessment of bacterial 
challenge in rats, idelalisib enhanced, rather than impaired, the phagocytic host clearance of 
staphylococcal bacteria.
2.4.3.1.
In Vitro Evaluation of Off-Target Effects
To assess the potential for adverse off-target effects, idelalisib was evaluated against primary 
molecular targets in radioligand displacement assays. These assays measure functional binding 
interactions for 68 cell proteins that include G-protein-coupled receptors, ion channels, receptor 
tyrosine kinases, steroid receptors, and transporters. Idelalisib at concentration of 10 μM (4.2 µg/mL) 
did not significantly inhibit binding of any of the radioligands tested. When taken together with 
the efficacy pharmacology data, these results support the selectivity of idelalisib.
The effect of idelalisib on human ether-à-go-go-related gene (hERG) channel activity was 
investigated. Testing was performed using a rubidium flux-based method in HEK293 cells stably 
transfected with hERG. No significant hERG inhibition was observed at idelalisib concentrations 
through 50 µM (21 µg/mL) (the highest concentration tested), indicating that idelalisib would not 
be expected to induce clinical QT prolongation.


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Potential inhibitory effects of idelalisib on bone marrow function were assessed. Rat-derived 
bone marrow cultures were evaluated for erythroid precursors by flow cytometry and 
quantification of erythroid blast-forming units (BFU-e). Idelalisib did not significantly inhibit 
erythroid differentiation at 0.1 or 1 μM (0.04 or 0.42 µg/mL), either in the presence or absence of 
erythropoietin. At a concentration of 10 μM (4.2 µg/mL), idelalisib decreased progression of 
erythroid differentiation, and at concentrations of 10 and 100 M (4.2 and 42 µg/mL), idelalisib
decreased BFU-e values, both in the presence or absence of erythropoietin. Potential idelalisib
effects on human bone marrow were assessed in bone marrow cultures derived from healthy 
volunteers. When evaluated by flow cytometry and colony-forming assays, idelalisib across a 
range of concentrations from 0.1 to 50 μ(0.04 to 21 µg/mL) showed concentration-dependent 
effects on erythroid, myeloid, and megakaryocytic differentiation in the presence or absence of 
erythropoietin. While idelalisib is not cytotoxic to bone marrow, these data suggest that idelalisib may 
suppress generation of red cells, neutrophils, and platelets when administered at supratherapeutic doses.
2.4.3.2.
In Vivo Evaluation for Immune, Neurologic, and Cardiopulmonary Effects
To evaluate effects on T-cell-independent, B-cell immunization, rats were inoculated with sheep 
red blood cells at 4 hours after beginning a 10-day course of idelalisib at doses of 1, 3, 10, 30, 
and 150 mg/kg BID. When assessed at 7 and 10 days after antigen challenge, idelalisib at lower 
doses of 1 or 3 mg/kg BID did not impede IgM or IgG antibody response. However, rats 
receiving higher idelalisib doses of 10, 30, and 150 mg/kg BID showed no IgM or IgG antibody 
responses at these same timepoints. In an alternative assessment of its effects on primary 
antibody response, idelalisib at a dose of 60 mg/kg BID was administered to rats for 3 days 
before and for 14 days after antigen challenge with dinitrophenol-keyhole limpet hemocyanin 
(DNP-KLH). When assessed at 7, 10, and 14 days after antigen challenge, idelalisib
administration dampened IgM and IgG antibody responses. In a similar assessment of secondary 
antibody response, rats who had shown a primary antibody response to DNP-KLH challenge 
18 weeks previously underwent a DNP-KLH rechallenge at 4 hours after beginning a 7-day 
course of idelalisib at a dose of 60 mg/kg BID. When assessed 8 days after rechallenge, idelalisib
was associated with nearly complete suppression of secondary IgM and IgG antibody responses
to DNP-KLH. Collectively, these data suggest that high doses of idelalisib may be associated 
with blunting of primary and secondary B-cell-mediated antibody responses to immunization.
In an assessment of host response to bacterial challenge, idelalisib at doses of 
30, 60, and 120 mg/kg was administered 1 hour before and 12, 24, and 36 hours after inoculation 
of Staphylococcus aureus into the inguinal region of male rats. At 48 hours post-infection, 
colony counts from groin abscesses showed dose-dependent inhibition of staphylococcal 
colonies by 65 to 85% among idelalisib-treated animals relative to control animals. By contrast, 
the positive control – dexamethasone at 2 mg/kg – increased bacterial colony counts by 
351% relative to the vehicle control. Thus, idelalisib appeared to enhance, rather than impair, the 
phagocytic host clearance of bacteria in this model.
Idelalisib has also proved well tolerated in standard in vivo Good Laboratory Practices (GLP) 
studies of pharmacological safety. A functional observation battery in Sprague-Dawley rats 
dosed with a single oral dose at idelalisib dose levels of 50, 100, or 150 mg/kg revealed no 
adverse effects on behavior or on autonomic, neuromuscular, or sensorimotor function at any 
dose level. In a cardiopulmonary function study in awake telemeterized male beagle dogs, single 


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doses of idelalisib by oral gavage at dose levels of 1, 5, and 20 mg/kg induced no meaningful 
changes in pulmonary, cardiovascular, arterial blood gas, or electrocardiographic (ECG) 
(including QT interval) parameters.
2.4.4.
Pharmacokinetics and Drug Metabolism
Consistent with the moderate to high bioavailability seen in nonclinical species, idelalisib shows 
high permeability across human Caco-2 cell monolayers. At lower concentrations, the reverse 
permeability at low concentration exceeds forward permeability, indicating efflux driven by 
transporters (eg., human P-glycoprotein [MDR1] and breast cancer resistance protein [BCRP]); 
idelalisib is a substrate for the efflux transporters MDR1 and BCRP; however, the permeability 
increases in a concentration-dependent manner, resulting in a lower efflux ratio at higher, 
clinically relevant concentrations of idelalisib. 
Idelalisib exhibits moderately high plasma protein binding in mouse, rat, dog, and human. In dog 
and human plasma, the protein binding is concentration-independent between 1 and 20 µM. 
Protein binding in human plasma is slightly higher than in mouse, rat, and dog plasma, which 
have comparable free fractions. In human plasma, idelalisib and GS-563117 
(a metabolite of idelalisib) have an average free fraction of ~16% and ~12%, respectively.
After oral administration of [14C]idelalisib to rats and dogs, radioactivity is widely distributed, 
but relatively excluded from bone, brain, spinal cord, and eye lens in rats and from brain and 
eyes in dogs. In rats, the radioactivity declines steadily and most tissues have undetectable levels 
by 72 hours post dose. In bile duct-cannulated rats and dogs, ≥ 69% of radioactivity is recovered 
in bile and urine, indicating high absorption of idelalisib in vivo.
In hepatic tissues from nonclinical species, idelalisib is primarily metabolized by 
aldehyde oxidase, with some involvement of CYP3A and UGT1A4. In vitro metabolism in dog 
and human yields 3 primary oxidative metabolites and 5 primary glucuronides. Of these, the 
oxidative product GS-563117 is the predominant metabolite in vitro and in vivo. In preclinical
species, plasma levels of GS-563117 are below those of idelalisib. In humans, GS-563117
(only circulating metabolite) plasma levels exceed those of idelalisib. After oral administration 
of [14C]idelalisib to rats and dogs, biliary excretion appears to be the major route of elimination 
of idelalisib and its metabolites as the majority of radioactivity is found in feces or bile and little 
in urine.
Idelalisib is substrate for the efflux transporters MDR1 and BCRP, but not a substrate for the 
renal transporters OCT2, OAT1, and OAT3 or the hepatic uptake transporters OATP1B1 and 
OATP1B3. GS-563117 is a substrate for MDR1 and BCRP, but not a substrate for OATP1B1 
and OATP1B3.
Idelalisib is not an inhibitor of CYP1A, CYP2B6, CYP2C9, and CYP2D6, and at concentrations 
above those observed clinically, is an inhibitor of CYP2C8 (IC50 = 13 µM), CYP2C19 
(IC50 = 76 µM), and CYP3A (IC50 = 44 µM). GS-563117 is not an inhibitor of CYP1A, 
CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6, and a reversible and time dependent 
inhibitor of CYP3A (IC50 = 3.1 µM), (KI = 0.18 µM, kinact = 0.033 min-1 with midazolam as the 
probe substrate).


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In vitro, idelalisib is not an inhibitor of the transporters BCRP, OCT2, OAT1, and OAT3, and is
an inhibitor of MDR1 (IC50 = 7.7 µM), OATP1B1 (IC50 = 10.1 µM), OATP1B3 (IC50 = 7.0 µM), 
and, at concentrations above those observed clinically, of glucuronosyltransferase UGT1A1 
(IC50 = 42.0 µM). GS-563117 is not an inhibitor of MDR1, BCRP, OATP1B1, OATP1B3, 
OAT1, OAT3, and OCT2, and at concentrations above those observed clinically, an inhibitor of 
UGT1A1 (IC50 = 16.8 µM).
Idelalisib does not activate human AhR or induce CYP1A2 (mRNA or activity) at clinically 
relevant concentrations. Idelalisib is a weak activator of human PXR (EC50 = 18 µM) and shows 
similarly weak potency as an inducer of CYP3A4, CYP2C8, CYP2C9, UGT1A1, and MDR1 
(by mRNA). Approximately 2-fold weaker induction of CYP2B6 activity and mRNA suggests 
weak activation of CAR. GS-563117 shows no induction of CYP1A2, CYP2B6, CYP2C8, 
CYP2C9, CYP3A, UGT1A1, UGT1A4, MDR1, and aldehyde oxidase at clinically relevant 
concentrations.
Any potential clinical implications of these metabolism studies are being evaluated in a formal 
drug-drug interaction study (GS-US-313-0130) which is evaluating the effect of idelalisib on 
cytochrome P450 3A and the drug transporters P-gp, OATP1B1, and OATP1B3. 
Study GS-US-313-0130 will also evaluate the impact of an inducer of metabolizing enzymes and 
transporters (rifampin) on the PK of idelalisib in healthy human subjects. Preliminary findings 
from this study are presented in Section 2.5.3.
2.4.5.
Toxicology
A comprehensive package of nonclinical studies has been conducted and provides a toxicological 
profile of idelalisib in support of the treatment of adults with advanced cancer. The following 
toxicology studies have been conducted to assess the safety of idelalisib: single-dose 
(in rats and dogs) and repeat-dose oral toxicity studies (up to 26 weeks in rats and up to 
39 weeks in dogs), in vitro and in vivo genotoxicity studies, and developmental and reproductive 
toxicity studies (fertility and embryo-fetal development in rats).
Once daily administration of idelalisib was associated with B-cell depletion in numerous 
lymphoid organs in rats and dogs, consistent with the known pharmacology of PI3Kδ inhibition 
{So 2012}. All changes were partially or completely reversible following a 4-week recovery 
period. Serum transaminase elevations were noted in the dog in both the 28-day and 13-week 
studies at doses ≥7.5 mg/kg/day. Peak elevations occurred approximately 4 weeks following 
initiation of dosing and resolved completely with continued dosing. No evidence of chronic 
hepatic injury was noted in either the 13- or 39-week studies at dose levels up to 7.5 mg/kg/day 
(Day 272 AUC0-t 17.1 µg∙hr/mL). In an investigative pharmacology study, a further 
characterization of the pattern of serum transaminase changes associated with administration of 
15 mg/kg/day of idelalisib to dogs confirmed hepatic adaptation to the effect. In this study, mean 
serum ALT/AST values peaked at approximately Day 24 to Day 27 and resolved spontaneously 
as the dogs continued on idelalisib through the end of the study on Day 44.
Decreased testes weights were observed in GLP repeat dose studies in rats and dogs. Decreased 
testicular weights were noted in all studies. A male fertility in rats study indicated that there was 
no impact on fertiliy or reproductive potential following daily dosing for 10-weeks prior to 


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100 mg/kg/day. Spermatogenic assessment of idelalisib treated animals was similar to controls. 
Changes in testicular weight in repeat dose studies are suspected to be associated with fluid 
production and/or tubular contraction and not a degenerative effect.
Pregnant female rats were administered idelalisib in a standard embryo-fetal development 
toxicity study at oral doses up to 150 mg/kg/day. Idelalisib was shown to be embryo lethal and 
teratogenic in rats at ≥ 75 mg/kg/day (Gestation Day 17 AUC0-t 251 µg hr/mL). Dose-dependent 
developmental findings included decreased fetal viability, increased early and late resorptions, 
and decreased mean fetal body weights. Dose-dependent external malformations included short 
tails and complete tail loss. Additional external malformations were single instances of 
hydrocephaly and microphthalmia, occurring in separate fetuses from different litters.
Idelalisib was negative for mutagenic potential in a bacterial reverse-mutation test and negative 
for inducing chromosomal aberrations in cultured human peripheral blood lymphocytes. 
Idelalisib has shown some evidence of inducing micronuclei in this in vivo test system when 
tested at high dose levels, up to the standard limit of 2000 mg/kg. However, based on the 
mechanism of action of PI3Ks and their role as intracellular signaling proteins essential to 
migratory, proliferative, survival, and differentiation pathways, idelalisib may cause a small 
increase in micronucleated erythrocytes by mechanisms unrelated to the inherent genotoxicity of 
the compound {Tweats 2007}. These data suggest that idelalisib is not genotoxic.
Coadministration of cyclophosphamide with idelalisib did not appear to exacerbate the 
myelosuppressive effects of cyclophosphamide. Idelalisib did not impair bacterial clearance in a 
rat S. aureus abscess model.
A phototoxicity study yielded inconclusive results for the assessment of idelalisib due to 
cytotoxicity observed in the assay. However, the predominant oxidative metabolite, GS-563117, 
was determined to be toxic only in the presence of ultraviolet A (UVA) light.
2.5.
Clinical Experience with Idelalisib
Idelalisib has undergone extensive early clinical evaluation in a series of Phase 1 studies in 
healthy volunteers and subjects. Studies in healthy subjects have provided information on drug 
safety; pharmacokinetics; food effects; the potential for drug interactions with CYP3A inhibitors; 
and idelalisib absorption, metabolism and excretion {Webb 2010}. A Phase 1 study in subjects 
with allergic rhinitis has offered additional safety information and confirmed the expected 
immunomodulatory pharmacological effects of the drug. A Phase 1 study in subjects with 
lymphoid malignancies has extended safety and pharmacokinetic observations; documented the 
clinical and pharmacodynamic activity of idelalisib in subjects with iNHL, MCL, and CLL; and 
provided dosing information in support of further development {Furman 2010, Kahl 2010}.
Reference the Investigator Brochure for updated information regarding clinical experience with 
idelalisib.


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2.5.1.
Phase 1 Single- and Multiple-Dose Study in Healthy Volunteers
(Study 101-01)
This first-in-human study was performed to evaluate the safety, pharmacokinetics, and 
pharmacodynamics of idelalisib. Five cohorts of healthy male subjects were enrolled to receive 
sequentially higher single doses of idelalisib at dose levels of 17, 50, 125, 250, or 400 mg. 
Subsequently, 3 cohorts of healthy male subjects were enrolled to receive sequentially higher 
multiple doses of idelalisib given over 7 days at 50 mg BID, 100 mg BID, or 200 mg BID. 
Within each cohort, 2 subjects were randomized to placebo and 6 subjects to idelalisib.
A total of 8 cohorts or 64 subjects were enrolled to the trial, as planned. Idelalisib treatment was 
well tolerated. There were no serious or severe adverse events. A maculopapular skin rash 
affecting the trunk and extremities was observed in 3/6 subjects who received idelalisib at 
200 mg BID for 7 days. The rash resolved spontaneously 5 to 11 days later. Drug rechallenge in 
2 of these subjects resulted in recurrence in 1 subject who received 200 mg BID for 5 days and in 
no recurrence in 1 subject dosed at 100 mg BID for 7 days. The rechallenge rash was also 
maculopapular in nature and resolved over 10 days during treatment with topical corticosteroids. 
Skin biopsies showed spongeotic dermatitis with perivascular infiltrates containing 
lymphohistiocytes and eosinophils. The data suggested that the rash represented a delayed-type
hypersensitivity reaction. There were no other adverse events that were suggestive of a causal 
relationship with idelalisib treatment. No clinically significant abnormal findings were observed 
in vital signs, ECGs, or clinical laboratory tests.
Pharmacokinetic results indicated that idelalisib appeared rapidly in plasma with a median 
Tmax of 1 to 1.5 hours. Cmax and AUC increased in a less-than-dose-proportional manner and
mean t1/2 values were across the dose range were 6.5 to 9.8 hours.
An ex-vivo pharmacodynamic evaluation was performed on whole blood in subjects receiving
200 mg BID. Anti-FCR1 was used to activate basophils via the PI3Kδ pathway. Idelalisib
administration was associated with inhibition of basophil activation as measured by CD63 
surface expression.
2.5.2.
Phase 1 Safety and Pharmacodynamic Study in Subjects with Allergic 
Rhinitis (Study 101-04)
This randomized, double-blind, placebo-controlled, 2-period crossover study was designed to 
evaluate the safety, clinical, and pharmacodynamic effects of idelalisib in male subjects with 
allergic rhinitis. Subjects with documented allergy to grass pollen upon screening allergen 
exposure were randomized to placebo or idelalisib at a dose of 100 mg BID for 7 days. On the 
last day of dosing, subjects were exposed to allergen in an environmental chamber for 4 hours. 
During the allergen challenge, symptoms, nasal airflow, and nasal secretions were measured. 
Following a 2-week washout period, subjects received the alternative treatment for 7 days and 
again underwent allergen challenge and evaluation.


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Altogether, 41 male subjects were enrolled and 39 subjects completed the study. One subject 
withdrew for personal reasons and 1 subject receiving placebo was withdrawn after having 
elevations in muscle-derived enzymes following strenuous exercise. Idelalisib was well tolerated.
Two subjects reported mild adverse events that were not considered to be related to study drug. 
No rash was observed. There were no clinically significant laboratory abnormalities.
Idelalisib treatment led to statistically significant reductions in the primary efficacy endpoint of 
total nasal symptom score. Significant reductions were also achieved in total symptom score, 
nasal airflow, and nasal secretion weight. An ex-vivo pharmacodynamic evaluation was 
performed on whole blood collected on Day 1. In response to grass antigen, basophil activation 
was assessed by measurement of % CD63+/CCR3+ cells using flow cytometry. Idelalisib
administration induced significant inhibition of basophil activation with mean post-dose 
decreases of 76% at 1.5 hours and 66% at 3 hours. By contrast, placebo had no effect.
2.5.3.
Phase 1 Study Evaluating Food-Effect, Drug-Drug Interactions, and 
Metabolism in Healthy Volunteers (Study 101-05)
This 3-period crossover study was designed to evaluate food effects on idelalisib
pharmacokinetics, assess the effect of ketoconazole (a potent CYP3A inhibitor) on idelalisib
pharmacokinetics, and to evaluate idelalisib absorption, metabolism and excretion after a 
single oral or intravenous microdose of [14C]idelalisib. In the first period, subjects received a 
single 400-mg idelalisib dose in either fasting or fed states; subjects dosed in the fasting state 
also received an oral microdose of [14C]idelalisib. In the second period, subjects received a 
single 400 mg idelalisib dose in either fasting or fed states, alternate to the condition during the 
first period; subjects dosed in the fasting state also received an intravenous microdose of 
[14C]idelalisib. In the third period, all subjects received ketoconazole 400 mg QD for 4 days and 
on the fourth day also received a single 400-mg idelalisib dose in the fasting state.
Twelve subjects were enrolled and 11 subjects completed the study. One subject had 
musculoskeletal pain and muscle-related increases in serum creatine kinase (CK), ALT, and AST 
and was discontinued prior to the third study period. Idelalisib treatment was well tolerated
throughout the study and no idelalisib-related adverse events or laboratory abnormalities were 
noted.
Compared to fasted dosing, ingestion of a high-fat, high-calorie meal just prior to administration 
of idelalisib increased the median Tmax from 0.75 hours to 3 hours without altering mean Cmax. 
The aggregate effect was a modest increase of 1.4-fold in mean AUC, which is not considered to 
be clinically relevant; thus, idelalisib may be given with or without food.
Idelalisib is metabolized in humans primarily by aldehyde oxidase, with some involvement of 
CYP3A4 and UGT1A4. Accordingly, when idelalisib was administered following 4 days of 
ketoconazole dosing, moderate increases in mean idelalisib Cmax and AUC values of 
30% and 80%, respectively, which is not considered to be clinically relevant and suggesting that 
idelalisib is a weak CYP3A substrate. GS-563117 is formed from idelalisib primarily via 
aldehyde oxidase.


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The 14C-labeled idelalisib human mass balance results showed that the drug has a moderate to 
high oral bioavailability. Idelalisib is eliminated mainly via hepatic metabolism and biliary 
excretion in the feces (~78% of dose); recovery in urine was < 15%. GS-563117 was the only 
circulating metabolite observed in human plasma and was also observed in urine and feces.
Preliminary results from the drug interaction/probe Study GS-US-313-0130 indicate that 
idelalisib does not affect the pharmacokinetics of substrates of Pgp, BCRP, OATP1B1 or 
OATP1B3 transporters. Idelalisib is not expected to affect the exposures of coadministered 
agents via transporter mediated interactions.
The exposures (AUC) of probe CYP3A substrate, midazolam, increased ~5-fold upon 
coadministration with idelalisib, driven by reversible and time-dependent CYP3A inhibition by 
GS-563117, the only circulating metabolite of idelalisib. Coadministration of the highly potent 
CYP3A inducer rifampin resulted in a ~75% reduction in idelalisib systemic exposures, likely 
driven by a higher relative contribution to CYP3A to overall idelalisib clearance under the 
induced state.
2.5.4.
Phase 1 Study in Subjects with Relapsed or Refractory Hematologic 
Malignancies (Study 101-02)
This Phase 1 dose-ranging study was designed to investigate the safety, pharmacokinetics, 
pharmacodynamics, and clinical activity of idelalisib in subjects with relapsed or refractory 
hematologic malignancies {Furman 2010, Kahl 2010}. Dose-ranging has been performed across 
progressively higher dose levels in sequential cohorts of 3 to 6 subjects with B-cell NHL or CLL.
During the study, expansion of cohorts has also permitted evaluation in subjects with AML and 
multiple myeloma (MM). Single-agent idelalisib has been administered at starting dose levels of 
50 mg BID, 100 mg BID, 150 mg BID, 200 mg BID, 350 mg BID and 300 mg QD. Patients have 
received idelalisib continuously and have been evaluated in cycles of 28 days. Idelalisib
administration has been continued until the earliest of disease progression, intolerable toxicity, or 
completion of 12 cycles of therapy (with the potential for more prolonged therapy on an 
extension protocol thereafter). The severity of adverse events and laboratory abnormalities have 
been graded using the Common Terminology Criteria for Adverse Events (CTCAE), 
Version 3.0. Pharmacokinetics have been obtained through 6 hours after dosing on Days 1 and 
28 of idelalisib treatment. Pharmacodynamic assessment at baseline and during treatment have 
included evaluations of plasma chemokines and cytokines in all subjects and AKT activity in 
subjects with CLL. Antitumor activity has been assessed using standard criteria {Cheson 2007, 
Hallek 2008}. Response assessments have been performed after Cycles 1 and 2 and after every 
2 cycles thereafter.
Study 101-02 has completed enrollment. A total of 191 subjects were enrolled to the study at 
dose levels of 50 mg BID (n=17), 150 mg QD (n = 16), 100 mg BID (n=25), 
150 mg BID (n=45), 200 mg BID (n=35), 350 mg BID (n=17), and 300 mg QD (n=19). An 
additional cohort was also enrolled to receive IDELA 150 mg BID in 28 day cycles (21 days on 
IDELA/7 days off [n=17]). Patient characteristics were as follows: males/females n=139
(73%)/52 (27%) with median age of 64.5 [range 32-91] years. Diagnoses included: CLL, n=54
(28%); iNHL, n=64 (34%); aggressive NHL (MCL and DLBCL), n=49 (26%); AML, n=12 (6%);


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and MM, n=12 (6%). Categorization of disease by response to the last prior therapy included: 
refractory, n=111 (58%); relapsed, n=79 (42%); and unknown, n=1 (1%). The median [range] 
number of prior therapies was 5 [1-14]. Among subjects with iNHL and CLL, the majority had 
received prior rituximab and prior alkylating agent therapy.
Adverse events were usually mild to moderate and not clearly idelalisib-related. Among 
Grade ≥3 adverse events, pneumonias and diarrhea were notable. Pneumonia was observed in 
23 (12%) subjects, primarily in subjects with CLL. In most instances, these findings 
wereconsidered bacterial in origin, based either on culture results or on response to conventional 
antibiotics. Grade ≥3 adverse events of diarrhea were seen in 11 subjects (5.6%). Other 
Grade ≥3 events have included rash in 3 (1.6%) subjects. The relative contributions of 
disease-related factors, toxicity from prior therapies or ongoing supportive care, and idelalisib to 
these events was not clear.
Grade ≥3 hematological laboratory abnormalities included neutropenia, n=46 (24%); 
thrombocytopenia, n=27, (14%), anemia, n=14 (7.3%), and lymphopenia 13 (6.8%); with 
12 subjects (6.3%) having febrile neutropenia. The occurrence of these events was greater in 
subjects with leukemia, particularly in those with pre-existing hematological abnormalities due 
to disease or prior therapy, commonly making attribution of these events to idelalisib uncertain.
Consistent with the observations in the 28-day dog toxicology study, reversible 
Grade ≥3 ALT/AST elevations occurred in 28 (15%) subjects and have been attributed to 
idelalisib. Onset generally occurred 2 to 16 weeks after idelalisib initiation and resolution was
usually seen 2 to 6 weeks after idelalisib interruption. After resolution of ALT/AST changes, 
14 subjects were rechallenged at the same or a reduced dose of idelalisib and 9 (64%) of these 
subjectswere able to resume treatment without recurrence of transaminase elevations. 
Two (1.0%) subjects had elevations in bilirubin, both of whom had confounding factors 
(recent history of biliary obstruction or concomitant use of potentially hepatotoxic medications)
so that a causal relationship to idelalisib could not be established.
Pharmacokinetic analyses indicated that the increase in Cmax and AUC0-6h with dose was less 
than dose-proportional, with modest increases above the dose level of 150 mg BID.
Pharmacodynamic data supported drug activity. In subjects with NHL, plasma concentrations of 
chemokines CCL22 and CCL17 were elevated at baseline and showed significant decreases 
within 1 cycle of idelalisib treatment (p<0.001 for both comparisons). Flow cytometry of CLL 
cells from subjects showed that idelalisib reduced constitutive expression of phosphorylated 
AKT to background levels when measured after 1 week of treatment (p<0.0001), demonstrating 
pharmacodynamic inhibition of activated PI3K signaling. Plasma concentrations of chemokines 
CCL3, CCL4, and CXCL13 were elevated in CLL subjects at baseline and decreased 
significantly within 1 cycle of idelalisib administration (p<0.001 for all comparisons).
Tumor reductions meeting antitumor response criteria were not observed in subjects with 
AML or MM. One of 11 subjects with DLBCL achieved a PR. In 104 subjects with iNHL and 
MCL, idelalisib induced PRs at all dose levels, with respective ORRs in enrolled subjects of 
29/64 (45%) for iNHL and 16/40 (40%) for MCL. The median DOR was not been reached in 
subjects with iNHL; 19 subjects continued to receive idelalisb in a long-term extension study. 


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The median [range] DOR was 2.7 months [1 month to 8 months] in subjects with MCL; 
6 MCL subjects contined to receive idelalisib in a long-term extension study.
In subjects with CLL, idelalisib reduced lymphadenopathy in almost all subjects; 
44/54 (81.5%) achieved a lymph node response (≥50% reduction in target nodal lesions). An 
initial increase in peripheral absolute lymphocyte counts of >50% from baseline was observed 
some subjects; increases were maximal during the first 2 cycles and decreased thereafter; the 
pattern suggested drug-mediated lymphocyte redistribution. In 54 subjects with CLL, 
39/54 (72%) achieved a PR (includes PR with lymphocytosis). The median DOR was not 
reached; 23 subjects continued to receive idelalisb in a long-term extension study.
2.6.
Summary and Conclusions
Based on the collective data regarding the natural history of iNHL, current therapies for iNHL, 
and the nonclinical and clinical information regarding idelalisib, it is concluded that:

iNHL is a serious, disabling, and potentially life-threatening disorder that requires sequential 
treatment with agents that provide alternative mechanisms of tumor control. Development of 
a therapy that can address disease pathogenesis with a new mechanism of action would 
address unmet medical need, particularly when applied in subjects with disease that is 
refractory to rituximab and alkylating agents.

PI3Kδ over-expression plays an important role in iNHL biology. Further evaluation of 
idelalisib as a potential treatment for iNHL has sound scientific rationale founded on 
knowledge of its actions to selectively abrogate PI3Kδ activity and to inhibit lymphoma 
growth and survival in nonclinical models of lymphoid malignancy. These data are supported 
by clinical documentation of inhibition of PI3Kδ signaling in subjects with CLL participating 
in Phase 1 studies.

The safety of advancing idelalisib into the proposed study is well supported by safety 
pharmacology and toxicology studies and by Phase 1 safety data obtained in healthy 
volunteers and subjects with lymphoid cancers.

The potential for clinical efficacy of idelalisib in subjects with previously treated iNHL has 
been demonstrated in Phase 1 studies involving subjects with similar characteristics as are 
expected in this trial; these efficacy data in subjects with iNHL are supported by the 
observation of substantial antitumor activity in subjects with MCL and CLL.

The dosing regimen planned for this study builds on dose-response and 
exposure-relationships observed in Phase 1 studies of idelalisib.

Given the seriousness of iNHL and the aggregate potential benefits considered in the context 
of potential risks, further development of idelalisib in this Phase 2 clinical trial is justified.


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3.
OBJECTIVES AND ENDPOINTS
3.1.
Primary Objective

To evaluate tumor regression as determined by ORR in subjects receiving idelalisib for 
treatment of iNHL refractory to rituximab and alkylating agents
3.2.
Secondary Objectives

To determine the onset, magnitude, and duration of tumor control and of treatment success in 
subjects receiving idelalisib

To characterize HRQL as reported by subjects with iNHL receiving idelalisib

To evaluate the effects of idelalisib on subject performance status

To assess the pharmacodynamic effects of idelalisib

To evaluate idelalisib treatment administration and compliance with idelalisib therapy

To describe the safety profile of idelalisib

To characterize idelalisib plasma exposure over time
 
3.3.
Primary Endpoint

ORR – defined as the proportion of subjects who achieve a confirmed complete response 
(CR) or partial response (PR; or MR for subjects with WM) during idelalisib treatment; 
response definitions will be based on standard criteria {Cheson 2007}
3.4.
Secondary Endpoints

DOR – defined as the interval from the first documentation of CR or PR (or minor response 
(MR) for subjects with WM) to the earlier of the first documentation of disease progression 
or death from any cause

Lymph node response rate (LNR) – defined as the proportion of subjects who achieve a 
≥50% decrease from baseline in the sum of the products of the greatest perpendicular 
diameters (SPD) of index lymph nodes

TTR – defined as the interval from the start of idelalisib treatment to the first documentation 
of CR or PR (or MR for subjects with WM)
PPD


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
PFS – defined as the interval from the start of idelalisib treatment to the earlier of the first 
documentation of disease progression or death from any cause

Overall Survival (OS) – defined as the interval from randomization to death from any cause

Changes in HRQL as reported by subjects using the FACT-Lym (Appendix C)

Changes in performance status as documented using the Karnofsky performance criteria 
(Appendix D)

Changes in the plasma concentrations of disease-associated chemokines and cytokines

Overall safety profile of idelalisib characterized by the type, frequency, severity, timing, and 
relationship to study therapy of any adverse events or abnormalities of physical findings, 
laboratory tests, or ECGs; drug discontinuations due to adverse events; or serious adverse 
events

Study drug administration as assessed by prescribing records and compliance as assessed by 
quantification of used and unused drug

Idelalisib trough and peak plasma concentrations assessed pre-dose and 1.5 hours post-dose
3.5.
Rationale for Endpoint Selection
The proposed endpoints have been chosen based on relevance to the pathophysiology and
clinical manifestations of iNHL, the known pharmacology of idelalisib, and the goals of the 
study in documenting idelalisib benefit:risk. All of the endpoints have been employed in prior 
studies in iNHL and can be evaluated with acceptable reliability and accuracy.
3.5.1.
Antitumor Activity
Assessments of changes in tumor size using radiographic imaging techniques are routinely used
in determining therapeutic effect and disease course in subjects with iNHL {Cheson 2007}. In 
addition, because subjects are being treated until tumor progression, repeated radiographic tumor 
assessment must be performed in order to define the proper duration of treatment for each study 
participant.
Characterization of ORR and changes in tumor size are necessary for confirming idelalisib drug 
effect and the potential for drug-related benefit. Lymphoma-related nodal enlargement is a major 
cause of subject discomfort and can cause organ dysfunction. Shrinking lymphadenopathy is an 
important therapeutic goal for improving subject well-being and relieving obstructive symptoms. 
Given that the natural history of iNHL is inexorable nodal growth, reductions in tumor extent 
during therapy provide strong evidence of idelalisib pharmacological activity. In addition, 
because of the association of lymph node size and subject symptoms, it can be inferred that
PPD


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drug-mediated reductions in pathological nodal enlargement are reasonably likely to predict 
clinical benefit, thus meeting a regulatory standard for drug approval {U.S. Department of 
Health and Human Services Food and Drug Administration Center for Drug Evaluation and 
Research (CDER) Center for Biologics Evaluation and Research (CBER) 2007}.
Determinations of DOR and TTR are important in characterizing the rapidity of achieving tumor 
shrinkage and the duration of tumor control. PFS conveys longitudinal information regarding 
tumor control for both subjects who meet response criteria and those who do not. To ensure 
consistency of reporting relative to prior results, standard radiographic response and progression 
criteria {Cheson 2007} will be used to evaluate the ability of idelalisib to induce tumor shrinkage 
and extend tumor control. The timing of radiographic tumor assessments is consistent with the 
approach used in the recent registration-directed study of bendamustine in subjects with 
rituximab-refractory iNHL {Kahl 2010}. Evaluation of response and progression information by 
both investigators and the IRC will provide additional assurance regarding the accuracy of 
response assessments.
3.5.2.
Changes in Health-Related Quality of Life
Direct patient reporting of outcomes using standardized methods has become an increasingly 
important component of therapeutic assessment. Evaluation of patient-reported outcomes (PROs) 
is particularly relevant in subjects who cannot be cured of disease {Reeve 2007}. PRO 
questionnaires have been previously used in iNHL to predict treatment outcome, to characterize 
the symptomatic effects of therapeutic tumor control, to assess subject perceptions of benefit and 
risk, and to assess outcomes in long-term survivors of lymphoma therapy {Crespi 2010, Mols 
2007, Smith 2009, Webb 2010}.
In this study, it is postulated that idelalisib-mediated tumor control will be correlated with 
changes in HRQL and that assessments of the drug’s safety profile will be supported by HRQL 
evaluations. The FACT-Lym (Appendix C) has been selected to evaluate such outcomes for the 
study. The FACT-Lym comprises a general HRQL measure for subjects receiving cancer 
treatment that yields a total score and subscales for physical, functional, social/family and 
emotional well-being {Cella 1993} and a diagnosis-specific measure for subjects with NHL 
{Cella 2005}. The FACT-Lym was developed to assess concerns (eg, nodal swelling, fevers, 
night sweats, weight loss, fatigue, infection) specifically relevant to lymphoma subjects. FACT 
instruments have documented psychometric properties {Brucker 2005, Cella 1993}, {Cella 2005, 
Victorson 2008} and have been shown to differentiate subjects with active NHL from those who 
are in disease remission {Smith 2009}.
The FACT-Lym instrument is available in appropriate languages for this study. FACT-Lym data 
will be obtained in at baseline and during each investigational clinic visit during treatment. 
Having FACT-Lym data concurrent with tumor response information will allow an evaluation of 
the potential relationship between tumor response and symptomatic changes as reported by 
subjects. To avoid biasing HRQL results, the FACT-Lym will be administered at each visit 
before other procedures are performed and before any study information is conveyed to the 
subject.


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3.5.3.
Changes in Performance Status
Performance status in subjects with iNHL is predictive of treatment outcome and provides an 
integrated assessment of subject well-being before, during, and after treatment {Lim 2008, 
Thieblemont 2008, Winkelmann 2011}. Ideally, performance status assessments may indicate 
how drug efficacy and toxicity affect subject functioning.
In this study, it is conjectured that idelalisib-mediated tumor control will be correlated with 
changes in performance status and that assessments of the drug’s safety profile might be 
supported by performance status evaluations. The well-established, reliable, and validated 
Karnofsky performance score {Karnofsky 1949, Schag 1984, Yates 1980} (see Appendix D) will 
be employed in the trial for characterization of the subject population and repeated assessment of 
performance status.
3.5.4.
Pharmacodynamic Activity
In lymphoma, disease-related perturbations in inflammatory status can be clinically overt; 
subjects often develop bothersome B symptoms (fevers, night sweats, and weight loss) that are 
characteristic of excessive systemic inflammation {Friedberg 2008b, Salles 2007}. Consistent 
with such disease manifestations, chemokines
and cytokines that are markers of aberrant B-cell trafficking or perturbations in inflammation are 
overexpressed by iNHL tissues and circulate in plasma; in Phase 1 studies it has been confirmed 
that plasma concentrations of such biomarkers are circulating in abnormally high quantities in 
subjects with iNHL and CLL {Furman 2010, Kahl 2010}. Thus, it is hypothesized that drug-
mediated changes in these biomarkers provide direct evidence of mechanism-specific drug 
effects on PI3Kδ activity or indirectly document drug effects on overall tumor cell volume. In 
either case, improvements in these pharmacodynamic measures provide corroborative evidence 
in support of idelalisib pharmacological activity. In addition, it is possible that disease-or 
inflammation-related biomarkers may provide corollary information relating to the adverse 
lymphoma-specific effects of idelalisib on the liver; such data might allow better prediction of 
which subjects might be most susceptible to ALT/AST elevations during idelalisib treatment.
Based on these considerations, this study will evaluate circulating concentrations of relevant 
chemokines and cytokines with a particular focus on CCL7, CCL17, CCL22, CXCL12, 
CXCL13, interleukin-6, tumor necrosis factor-α, and C-reactive protein. In addition serum 
markers of iron metabolism (eg, hepcidin, iron, ferritin, transferrin) that that might provide 
markers linking lymphoma-related inflammation with perturbations of liver iron and sensitivity
to liver injury will be evaluated {Ferrucci 2010, Nemeth 2003}. Appropriate methods for the 
measurement of circulating biomarkers have been determined. Clinically validated assays 
(eg, enzyme-linked immunosorbent assays [ELISAs]) will be used to measure circulating 
concentrations of chemokines and cytokines at baseline and during the course of idelalisib
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3.5.5.
Safety
In defining the therapeutic activity of a drug in a particular clinical setting, it is imperative that 
its safety profile be fully characterized. As is conventional in all clinical studies, proper 
description of each adverse event or laboratory abnormality requires an understanding of the 
type, incidence, timing, severity, and relatedness to study drug. In this study, particular focus will 
be placed on monitoring for adverse events and laboratory abnormalities that were encountered 
in the prior toxicology studies and clinical experience with idelalisib. Safety parameters of 
specific interest include those relating to infection, colitis, rash, liver injury, and bone marrow 
dysfunction. Particular scrutiny will be applied to adverse events causing interruption or 
discontinuation of idelalisib and to serious adverse events requiring rapid regulatory reporting.
In addition, the protocol will evaluate the potential for adverse effects of chronic idelalisib
administration on normal lymphocyte number; the absolute number of CD4+, CD8+, 
CD16/CD56+ and CD19+ cells will be assessed by flow cytometry. Serum concentrations of 
IgA, IgE, IgG, and IgM will be followed at baseline and during protocol therapy.
For consistency of interpretation, adverse events will be coded using the standard 
Medical Dictionary for Regulatory Activities (MedDRA), and the severity adverse events and 
laboratory abnormalities will be graded using the well-defined CTCAE, Version 3.0. Standard 
definitions for seriousness will be applied (see Section 8.2.1.2).
3.5.6.
Study Drug Administration and Compliance
Evaluation of study drug administration and compliance provides context for assessments of 
safety, pharmacokinetics, and pharmacological activity. Evaluations of treatment administration 
and modifications from planned therapy document the influence of treatment-emergent 
adverse events on prescribing practice. Compliance assessment offers a general indication of 
subjects’ acceptance of therapy, integrating factors of tolerability, palatability, and convenience.
In this study, information regarding planned treatment and modification from planned treatment 
(eg, dose reductions and interruptions) will be kept. The compliance of the subject will be 
verified by accounting for used and unused drug.
3.5.7.
Pharmacokinetics
Given the intent of this protocol to assess longer-term dosing, collection of plasma for idelalisib
concentrations is important for evaluating the steady-state maintenance of exposure over time. 
These data may allow correlations of exposure with measures of efficacy and toxicity. For this 
evaluation, limited plasma sampling will be performed every 4 weeks in all study subjects during 
the first 12 weeks of treatment. Based on existing clinical data, this 12-week duration of 
sampling provides acute and steady-state exposure information over a period in which antitumor 
activity and pharmacodynamic effects are evident and in which potential drug toxicity may 
occur. Samples will be collected pre-dose and 1.5 hours post-dose relative to the morning 
administration of idelalisib. This approach will provide information regarding trough plasma 
concentrations and will describe drug absorption as characterized by the approximate maximum 
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4.
SUBJECT SELECTION
4.1.
Subject Selection Criteria
This clinical trial can fulfill its objectives only if appropriate participants are enrolled. The 
following eligibility criteria are designed to select subjects for whom study participation is 
considered appropriate. All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a particular subject. Eligibility 
criteria may not be waived by the investigator and conformance to the eligibility criteria is 
subject to review in the case of a Good Clinical Practice (GCP) or a regulatory authority audit. 
Any questions regarding a subject’s eligibility should be discussed with the study sponsor 
medical expert prior to enrollment.
4.1.1.
Inclusion Criteria
Subjects must meet all of the following conditions to be eligible for enrollment into the study:
1) Age ≥18 years.
2) Karnofsky performance score of ≥60 (Eastern Cooperative Oncology Group [ECOG]
performance score of 0, 1, or 2) (see Appendix D).
3) Histologically confirmed diagnosis of B-cell iNHL, with histological subtype limited to the 
following based on criteria established by the World Health Organization 
(WHO 2008 classification of tumors of haematopoietic and lymphoid tissues:

Follicular lymphoma (FL) Grade 1, 2, or 3a

Small lymphocytic lymphoma (SLL) with absolute lymphocyte count < 5 x 109/L at the 
time of diagnosis and on baseline laboratory assessment performed within 4 weeks prior 
to the start of study drug administration

Lymphoplasmacytic lymphoma (LPL), with or without associated 
Waldenstroms Macroglobulinemia (WM)

Marginal zone lymphoma (MZL) (splenic, nodal, or extra-nodal)
4) Histological materials documenting diagnosis of lymphoma available for review. 
Note: Central pathology confirmation of diagnosis will be performed in this study. However, 
a subject may be enrolled without waiting for confirmation of histological diagnosis on 
condition that pathological materials are known to be available for review.
5) Presence of radiographically measurable lymphadenopathy or extranodal lymphoid 
malignancy (defined as the presence of ≥1 lesion that measures ≥2.0 cm in the longest 
dimension [LD] and 1.0 cm in the longest perpendicular dimension [LPD] as assessed by 
CT or MRI).


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6) Prior treatment with ≥2 prior chemotherapy- or immunotherapy-based regimens for iNHL.
7) Prior treatment with rituximab and with an alkylating agent 
(eg, bendamustine, cyclophosphamide, ifosfamide, chlorambucil, melphalan, busulfan,
nitrosoureas) for iNHL.
8) Lymphoma that is refractory to rituximab and to an alkylating agent. Refractoriness is 
defined as:

Rituximab (without chemotherapy):
Lack of a CR or PR during rituximab therapy comprising ≥4 doses of ≥375 mg/m2
given weekly, or
Occurrence of progressive disease (PD) within 6 months of the completion of a 
regimen of rituximab therapy comprising ≥4 doses of ≥375 mg/m2 given weekly, or
Occurrence of PD during rituximab maintenance therapy or within 6 months of 
completion of rituximab maintenance therapy

Rituximab (with chemotherapy): 
Lack of a CR or PR during rituximab-containing therapy comprising ≥2 doses of 
≥375 mg/m2, or
Occurrence of progressive disease (PD) within 6 months of the completion of a 
regimen of rituximab-containing therapy comprising ≥2 doses of ≥375 mg/m2, or
Occurrence of PD during rituximab maintenance therapy or within 6 months of 
completion of rituximab maintenance therapy

Alkylating agent (administered with or without rituximab):
Lack of a CR or PR during alkylating-agent-containing therapy comprising 
≥2 cycles of treatment, or
Occurrence of PD within 6 months of the completion of a regimen of 
alkylating-agent-containing chemotherapy comprising ≥2 cycles of treatment
Note: Review of subject treatment records will be performed to ensure that subjects 
enrolled to the study meet the definition of rituximab- and alkylating-agent refractoriness 
that has been established for this trial. 
9) Discontinuation of all other therapies (including radiotherapy or chemotherapy) for the 
treatment of iNHL 3 weeks before initiation of study treatment (Visit 2).


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10) All acute toxic effects of any prior antitumor therapy resolved to Grade 1 before initiation 
of study treatment (Visit 2) (with the exception of alopecia [Grade 2 permitted], 
neurotoxicity [Grade 2 permitted], or bone marrow parameters noted in Table 1
[Grade 2 permitted]).
11) Required baseline laboratory data (within 4 weeks prior to start of study drug administration)
as shown in Table 1. Note: Confirmation should be performed for out-of-range values to 
determine if the abnormality is real or artifactual. Values used to establish eligibility 
should be obtained within the screening period, and should generally be the most recent 
measurement obtained.
Table 1.
Required Screening Laboratory Values
Organ System
Parameter
Required Value
Bone marrow
ANC
1.0 x 109/L
Platelets
50 x 109/L
Hemoglobin
80 g/L (8.0 g/dL or 4.9 mmol/L)
Hepatic
Serum total bilirubin
1.5 x ULN (unless elevated due to Gilbert’s syndrome)
Serum ALT
2.5 x ULN
Serum AST
Renal
Serum creatinine
<1.5 x ULN
Pregnancy
Serum -HCG (for females of 
childbearing potential)
Negative
Infection
HIV
Negative antibody
HBV
Negative HBsAg (if serology positive for infection)
HCV
Negative viral RNA (if serology positive for infection)
Abbreviations: ANC, absolute neutrophil count; ULN, upper limit of normal ; ALT, alanine aminotransferase; 
AST, spartate aminotransferase; -HCG, beta human chorionic gonadotropin; HIV , human immunodeficiency virus; 
HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; RNA, ribonucleic acid
12) For men and women of childbearing potential (ie, subjects who are not postmenopausal or 
surgically sterile), willingness to abstain from sexual intercourse or employ an effective
method of contraception during the study drug administration and follow-up periods. 
Note: The definition of effective contraception will be based on the judgment of the 
investigator.
13) Willingness and ability to provide written informed consent and to comply with scheduled 
visits, drug administration plan, imaging studies and contrast dye administration, laboratory 
tests, other study procedures, and study restrictions. Note: Psychological, social, familial, or 
geographical factors that might preclude adequate study participation should be 
considered.


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14) Evidence of a personally signed informed consent indicating that the subject is aware of the 
neoplastic nature of the disease and has been informed of the procedures to be followed, the 
experimental nature of the therapy, alternatives, potential benefits, possible side effects, 
potential risks and discomforts, and other pertinent aspects of study participation.
15) In the judgment of the investigator, participation in the protocol offers acceptable benefit:risk 
when considering current iNHL disease status, medical condition, and the potential benefits 
and risks of alternative treatments for iNHL.
4.1.2.
Exclusion Criteria
The presence of any of the following conditions will exclude a subject from study enrollment:
1) Central nervous system or leptomeningeal lymphoma.
2) Known histological transformation from iNHL to diffuse large B-cell lymphoma.
Note: Biopsy documentation of the absence or presence of transformation is not required.
3) History of a non-lymphoma malignancy except for the following: adequately treated local 
basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial 
bladder cancer, localized prostate cancer, other adequately treated Stage 1 or 2 cancer 
currently in complete remission, or any other cancer that has been in complete remission for 
≥5 years.
4) Evidence of ongoing systemic bacterial, fungal, or viral infection (excluding viral 
upper respiratory tract infections) at the time of initiation of study treatment (Visit 2). 
Note: Subjects with localized fungal infections of skin or nails are eligible. Subjects may 
be receiving prophylactic antiviral or antibacterial therapies at the discretion of the 
investigator. For subjects who are at substantial risk of an infection (eg, influenza) that 
may be prevented by immunization, consideration should be given to providing the vaccine 
prior to initiation of protocol therapy.
5) Pregnancy or breastfeeding.
6) Ongoing alcohol or drug addiction.
7) Known history of drug-induced liver injury, chronic active HCV, chronic active HBV, 
alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, ongoing 
extrahepatic obstruction caused by stones, cirrhosis of the liver or portal hypertension.
8) History of prior allogeneic bone marrow progenitor cell or solid organ transplantation.
9) Ongoing immunosuppressive therapy, including systemic corticosteroids.
Note: Subjects may be using topical or inhaled corticosteroids.
10) Prior therapy with idelalisib
11) Exposure to another investigational drug within 3 weeks prior to start of study treatment.


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12) Concurrent participation in another therapeutic treatment trial.
13) Prior or ongoing clinically significant illness, medical condition, surgical history, physical 
finding, ECG finding, or laboratory abnormality that, in the investigator’s opinion, could 
affect the safety of the subject; alter the absorption, distribution, metabolism or excretion of 
the study drug; or impair the assessment of study results.
4.2.
Enrollment Criteria Rationale
The eligibility criteria are designed to limit enrollment to subjects who clearly have iNHL and 
who are sufficiently well to safely participate in study procedures and provide interpretable 
results. The requirement of measurable lymphadenopathy ensures that subjects have lymphoma 
that justifies therapy and can adequately be assessed for evidence of drug activity. Prior therapy 
provisions are intended to define a population that has already received available therapies with 
well-defined activity and is appropriate for inclusion in a study evaluating an investigational 
drug. Existing agents have shown activity in subjects who have disease resistant to either 
immunotherapeutic or chemotherapeutic agents, but not both. This study will evaluate idelalisib
in a population of particular medical need, ie, those subjects whose disease has become 
refractory to both rituximab and alkylating agents. In delineating this population, definitions 
have been used that build on those employed in past studies {Kahl 2010, Witzig 2002}. Central 
reviews of lymphoma diagnosis and refractory status provide additional context for the validity 
of study results.
Subjects must not have serious prior or concomitant conditions or therapies that would 
compromise safety, compliance, or evaluation. Severe comorbid conditions 
(eg, hepatic dysfunction) may mask, exacerbate, or confound the interpretation of adverse effects 
of idelalisib and therefore subjects with such medical disorders are excluded. Pregnancy testing 
and restrictions on eligibility relating to reproductive potential, pregnancy, and breastfeeding are 
important because idelalisib is a new chemical entity and adverse effects relating to fertility, 
pregnancy, or drug transmission via breast milk are possible.
To minimize missing data and premature discontinuations, subjects should have sufficient 
psychological and social resources to comply with study procedures and restrictions. Consistent 
with GCP guidelines, subjects must provide informed consent before initiation of any study 
procedures.


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5.
ENROLLMENT AND STUDY MANAGEMENT PROCEDURES
5.1.
Number of Subjects
The primary analysis will be based upon the intention-to-treat (ITT) principle. However, as many 
as 120 subjects may be enrolled in order to ensure enrollment of 100 subjects who have a 
documented diagnosis of lymphoma, who have confirmed refractory disease, and who can be 
evaluated for tumor response with baseline and on-study scans (ideally through the planned 
24-week, follow-up tumor assessment). Thus, if an eligibility criterion or protocol violation 
occurs that substantially impairs evaluation of safety and activity in a study participant, or if a 
study participant does not undergo both a baseline and on-study tumor assessment, another 
subject can be enrolled to complete accrual of the planned number of evaluable subjects. The 
decision to accrue replacement subjects will be made by the study sponsor medical expert.
5.2.
Subject Recruitment
Study candidates comprise subjects with iNHL who are being followed at the specified study 
sites or are referred to the study sites. Subjects will be enrolled from investigational sites in 
North America and Europe. The site principal investigator, designated sub-investigators, or other 
designees will discuss the possibility of participation directly with subjects who may be 
appropriate candidates for the study.
A description of the protocol will be posted on the ClinicalTrials.gov website.
5.3.
Subject Compensation for Participation
For subjects requesting such assistance, reasonable reimbursements for the costs of travel 
required to participate in this study will be provided by the study sponsor. To receive payment 
for travel, subjects will need to submit the original travel receipts to the research study staff at 
the investigational site.
 
However, other than medical care that may be provided, subjects will not be paid for 
participation in the study. Payments for such items as lost wages, disability, discomfort due to 
injury, or meals obtained while waiting at the clinical research center will not be provided.
Through the informed consent process, study candidates will be notified that their insurance 
company could be charged for standard care that is a component of this research study and that 
subjects may be responsible for co-payments and deductible payments that are typical for their 
insurance coverage.
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5.4.
Enrollment of Subjects Without Prior Treatment with Bendamustine
Given the increasing relevance of bendamustine as a component of treatment for subjects with 
iNHL {Friedberg 2008a, Kahl 2010, Robinson 2008}, the number of subjects that have not 
received prior bendamustine (given alone or in combination with other agents) will be limited to 
no more than 50 of the total enrolled.
5.5.
Interactive Web Response System
An interactive web response system (IWRS) will be employed to manage screening, enrollment, 
dose modifications, off-treatment, and other activities during the conduct of the trial. The IWRS 
will use this information to maintain a central log documenting screening, to manage enrollment 
and dose modifications, to assess current inventories of study drug, and to initiate any necessary 
resupply of study drug. In addition, the IWRS will gate accrual of subjects without prior 
treatment with bendamustine (see Section 5.4).


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6.
TREATMENTS
6.1.
Study Drug
6.1.1.
Description
Idelalisib is manufactured according to current Good Manufacturing Practices (cGMP). The 
study drug is provided in tablets intended for oral administration. Each tablet contains 
100 or 150 mg of the active study drug substance. Inactive excipients present in the formulation 
are microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, sodium starch 
glycolate, and magnesium stearate. The 100 mg tablets are orange, and the 150 mg tablets are 
pink. The yellow coating contains yellow iron oxide, polyethylene glycol, talc, polyvinyl alcohol 
(PVA) and titanium dioxide. The orange coating contains FD&C Yellow #6/Sunset Yellow FCF 
Aluminum Lake, polyethylene glycol, talc, PVA and titanium dioxide. The pink coating contains 
red iron oxide, polyethylene glycol, talc, PVA and titanium oxide. Details regarding the shape, 
size and color of each tablet dosage form will be provided in the pharmacy manual for the study.
6.1.2.
Packaging
Idelalisib will be packaged in bottles containing 60 or 64 tablets. A label will be affixed to each 
bottle and will contain the following information translated into the official language(s) of the 
countries in which the clinical trials will be conducted:

Sponsor name and address

Protocol identifier

Description of contents, including dose strength and fill count

Caution statement (includes “keep out of reach of children” statement)

Storage conditions

Manufacture date and retest date

Lot number
6.1.3.
Source
Idelalisib will be supplied free of charge by the study sponsor. The IWRS will provide the site 
staff with information regarding the study drug tablet strength to be dispensed to that subject and 
instructions for dosing. Any questions or concerns regarding study drug supply should be 
referred to the study sponsor clinical project manager.


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6.1.4.
Storage and Stability
Bottles containing tablets of idelalisib will be stored at controlled room temperature 
(15 to 30°C). While stability of tablets stored at controlled room temperature has been 
confirmed, brief excursions to temperatures up to 40°C or down to -20°C (eg, during shipping) 
will not adversely affect the drug. Stability data at the start of study will support the use of the 
drug product for ≥12 months. The clinical site will be updated as more stability data become 
available.
6.1.5.
Dispensing
The clinic pharmacist or an alternative qualified person will be responsible for dispensing study 
medication. It is planned that drug will be dispensed at 4-week intervals through the first 
24 weeks of treatment and at 12-week intervals thereafter. A modest overage will be supplied 
such that subjects have sufficient drug in case of loss, spillage, or necessary deviations in 
scheduling clinic returns (eg, due to inclement weather, holidays, etc). Tablets should be kept in 
the original bottles provided.
6.1.6.
Return
Subjects should return all unused study medication to the study site at each applicable study visit.
6.1.7.
Accountability
The disposition all idelalisib study drug 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.
The investigator and/or the responsible site personnel must maintain accurate records of the 
receipt of all study drug shipped by the study sponsor 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 and the date, quantity and lot number of the study drug dispensed.
The study drug supply should be retrieved from subjects at the end of each dosing interval. The 
quantity of study drug and the date returned by the subject should be recorded in the study drug 
accountability records. All returned study drug should be retained for review by the study site 
monitor prior to destruction.
Depending upon the decision of the study sponsor, remaining unused study drug supply will be 
returned to the study sponsor or its designee after the study is completed or will be discarded or 
destroyed at the clinical site. If the study drug is discarded or destroyed at the clinical site, 


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standard institutional policy should be followed. Records documenting the date of study drug 
shipping or destruction, relevant lot numbers, and amount shipped or destroyed should be 
maintained.
6.1.8.
Overdose Precautions
For this protocol, an overdose is defined as administration of >700 mg of idelalisib in a single 
day. In a subject who experiences an overdose of this magnitude, idelalisib administration should 
be temporarily interrupted. If the overdose ingestion is recent and substantial, and if there are no 
medical contraindications, use of gastric lavage or induction of emesis may be considered. 
Observation for any symptomatic side effects should be instituted, and vital signs and 
biochemical and hematological parameters should be followed closely (consistent with the 
protocol or more frequently, as needed). Appropriate supportive management to mitigate adverse 
effects should be initiated.
The study sponsor medical expert should be contacted if an overdose occurs. Under applicable 
regulations, overdosing may result in a serious adverse event and may require reporting 
accordingly (see Sections 8.2.1.2 and 8.2.8).
6.1.9.
Inadvertent Exposure and Spill Precautions
Based on available data from nonclinical studies, idelalisib does not appear to be acutely toxic, 
genotoxic, or irritative at levels that are likely to result from inadvertent exposure to the contents 
of broken capsules or tablets. Personnel handling the drug should use reasonable precautions to 
avoid eye contact, skin contact, inhalation, or ingestion of the study drug product. For further 
information regarding inadvertent exposure and spill precautions, please consult the idelalisib
investigator brochure.
6.2.
Study Drug Administration
6.2.1.
Dosing Instructions
The prescribed dose of idelalisib should be taken orally. At each dose administration, the tablet
number corresponding to the appropriate dose of idelalisib is to be swallowed whole with 
100 to 200 mL (~ 4 to 8 ounces) of water. Subjects should be instructed not to bite or chew on 
the tablets. In case of breakage of the tablets in the oral cavity, additional water should be taken
as a rinse.
Idelalisib may be taken with or without food. There are no known dietary restrictions related to 
idelalisib use. No specific premedications or supporting medications are required in conjunction 
with idelalisib administration.
6.2.2.
Dosing Schedule
Idelalisib will be taken on BID schedule at approximately the same times each day. Ideally doses 
should be taken at ~12-hour intervals (eg, at ~7 AM and at ~7 PM). While it is realized that 
variations in dosing schedule may occur in the outsubject setting, the prescribed regimen 
(12-hour dosing intervals) should be followed as closely as possible, especially in the clinic.


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At specified clinic visits, the study drug will be administered in the clinic with dosing 
appropriately timed relative to blood sampling for idelalisib pharmacokinetics. As detailed in 
Section 7.2, clinic staff should record peri-dosing food intake and idelalisib administration 
information, including the exact clock time of each dose, for doses of study drug administered in 
the clinic or hospital. Thereafter, subjects will be given an adequate supply of tablets to take at 
home.
6.2.3.
Dose Levels
Idelalisib dose levels and tablet numbers are shown in Table 2 below. The starting dose level will 
be 150 mg BID. Lower dose levels are provided in case a subject requires idelalisib dose 
reduction.
Table 2.
Idelalisib Dose Level Information
Dose Level
Dosing Regimen
Tablet Strength
Tablet Number Per Dose
Starting
150 mg BID
150 mg
1
-1
100 mg BID
100 mg
1
Abbreviation: BID, 2 times per day
Subjects should be followed closely for adverse events or laboratory abnormalities that might 
indicate idelalisib-related toxicity. Recommendations for idelalisib dose modification are 
provided in Section 6.2.4. If a subject experiences an idelalisib-related adverse event requiring 
dose modification during the course of idelalisib therapy, then study drug administration should 
be held, as necessary, until the adverse event resolves or stabilizes to an acceptable degree. 
Thereafter, idelalisib may be reinstituted, but the dose of idelalisib should be reduced by 1 dose 
level; successive adjustments to progressively lower dose levels can be made. If the subject 
cannot tolerate idelalisib at Dose Level -1 (100 mg BID) then the subject should be discontinued 
from study drug therapy.
After a dose is reduced, the dose need not be re-escalated, even if there is minimal or no toxicity 
with the reduced dose. However, if the subject tolerates a reduced dose of idelalisib for 
≥4 weeks then the idelalisib dose may be increased to the next higher dose level, at the 
discretion of the investigator. Such re-escalation may be particularly warranted if further 
evaluation reveals that the adverse event that led to the dose reduction was not study 
drug-related. Successive adjustments to progressively higher dose levels can be made at 4-week 
intervals. The starting dose level (150 mg BID) should not be exceeded.
6.2.4.
Safety Monitoring and Recommendations for Dose Modification
Subjects must be monitored closely for adverse events or laboratory abnormalities during the 
course of the study. Reference should be made to the CTCAE, Version 3.0 for grading the 
severity of adverse events and laboratory abnormalities 
(refer to http://ctep.info.nih.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf


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Based on Phase 1 clinical experience with idelalisib adverse events potentially attributable to 
idelalisib have included rash, colitis/diarrhea, pneumonitis, and hepatic laboratory abnormalities. 
While myelosuppression is not a prominent toxicity of idelalisib in previous experience, dose 
modification provisions for subjects experiencing neutropenia or thrombocytopenia are provided 
as a precaution. Recommendations for dose modification based on the type and severity of 
adverse events or laboratory abnormalities are provided in Table 3 and suggestions for 
evaluation and management of specific adverse events are also noted thereafter. Whenever 
possible, any dose adjustment of idelalisib should be discussed between the investigator and the 
study sponsor medical expert prior to implementation.
Table 3.
Recommended and Required Actions Based on Type and Severity of 
Adverse Event or Laboratory Abnormality
NCI CTCAE Grade
Recommendation
Idelalisib
HEMATOLOGICAL ADVERSE EVENTS
Neutropenia
Grade 2 neutropenia
Maintain current dose level and schedule.
Grade 3 neutropenia
Maintain current dose level and schedule.
Required: Monitor blood counts at least weekly until ANC Grade 2.
Grade 4 neutropenia
(or occurrence of 
neutropenic fever 
or infection)
Required: Interrupt idelalisib dosing. Monitor blood counts at least weekly until ANC 
Grade 2.
May resume idelalisib at lower dose when ANC is ≤ Grade 3.
Thrombocytopenia
Grade 3
Maintain current dose level and schedule.
Grade 4
Required: Withhold idelalisib for bruising or bleeding until Grade 3.
May resume idelalisib at initial or lower dose level at investigator discretion.
NON-HEMATOLOGICAL ADVERSE EVENTS
Rash
Grade 1
Maintain current dose level and schedule.
Grade 2
Maintain current dose level and schedule.
Grade ≥3 
Required: Withhold idelalisib until Grade 1.
May resume at lower dose level or discontinue idelalisib at investigator discretion.
Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis
Any Grade
Required: Discontinue idelalisib. Institute systemic immunosuppression per 
institutional standards.


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NCI CTCAE Grade
Recommendation
Idelalisib
Gastrointestinal Inflammation/Diarrhea/Colitis
Any Grade
Provide anti-diarrheal agent (eg, loperamide), ensure good hydration status and 
maintain current idelalisib dose level and schedule.
Required: Obtain history of onset and duration of diarrhea, including description of 
number of stools and stool composition (eg, watery, bloody, nocturnal), travel history, 
dietary changes and a medication review to identify possible diarrheogenic agents.
Perform physical examination including assessment for fever, dizziness, abdominal 
pain/cramping and weakness (ie, evaluate for sepsis, bowel obstruction, dehydration).
Grade 2
Provide anti-diarrheal agent (eg, loperamide). Consider addition of anti-inflammatory 
agent (eg, sulfasalazine, budesonide). Ensure good hydration status and maintain current 
idelalisib dose level and schedule.
Grade ≥3 (or persistent 
Grade 2 without clear 
etiology)
Provide anti-diarrheal agent (eg, loperamide). 
Consider addition of anti-inflammatory agent (eg, sulfasalazine, budesonide).
Required: Withhold idelalisib until Grade 1 Resume at lower dose level or 
discontinue idelalisib at investigator discretion.
Hepatic Adverse Events (elevations in ALT, AST, or bilirubin)
Grade 1
(ALT/AST3xULN)
(Bilirubin1.5xULN)
Maintain current dose level and schedule.
Grade 2
(ALT/AST>3-5xULN)
(Bilirubin>1.5-3xULN)
Maintain current dose level and schedule. Monitor ALT, AST, ALP,
and bilirubin at least 1x per week.
Grade 3
(ALT/AST>5-20xULN)
(Bilirubin>3-10xULN)
Withhold idelalisib. Monitor ALT, AST, ALP, and bilirubin at least 1x per week until 
all abnormalities are Grade 1. If bilirubin abnormality was Grade <3, resume idelalisib 
at same dose level. If bilirubin abnormality was Grade 3, resume at lower dose level.
Grade 4
(ALT/AST>20xULN)
(Bilirubin>10xULN)
Required: Withhold idelalisib. Monitor ALT, AST, ALP, and bilirubin at least 1x per 
week until all abnormalities are Grade 1. If bilirubin abnormality was Grade <4, 
resume idelalisib at lower dose level. If bilirubin abnormality was Grade 4, discontinue 
idelalisib.
Pneumonitis (with new onset or worsening of baseline dyspnea, cough or hypoxia without obvious infectious cause)
Grade 1 (asymptomatic)
Required: Withhold idelalisib until resolution to baseline. May resume at lower dose 
level or discontinue at investigator discretion.
Grade ≥ 2
Required: Discontinue idelalisib permanently in subjects with any severity of 
symptomatic pneumonitis and institute therapy as clinically appropriate.
Pneumocystis jirovecii pneumonia (PJP)
Any Grade
Required: Discontinue idelalisib
Organizing Pneumonia
Any Grade
Required: Discontinue idelalisib permanently.


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NCI CTCAE Grade
Recommendation
Idelalisib
CMV infection/Reactivationa
Any Grade
Required: Interrupt idelalisib upon unequivocal clinical or laboratory evidence of 
CMV infection and initiate treatment according to established clinical guidelines.  If the 
benefits of resuming idelalisib are judged to outweigh the risks, consideration should be 
given to administering pre-emptive CMV therapy.
Other Nonhematological Adverse Events
Grade 2
Maintain current dose level and schedule.
Grade 3
Withhold idelalisib until Grade 1. Resume idelalisib at initial or lower dose level or 
discontinue idelalisib at investigator discretion.
a
CMV should be diagnosed using clinical or laboratory criteria per established institutional standard
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST= aspartate aminotransferase, 
CTCAE=Common Terminology Criteria for Adverse Events, G-CSF=granulocyte colony-stimulating factor, 
NCI=National Cancer Institute, ULN=upper limit of normal
When there is a dose modification, the IWRS should be notified. In addition, the subject should 
be notified of the change in dose and the appropriate clinic staff should instruct the subject about 
the revised number of study medication tablets to be used per dose according to the new dose 
level. Any questions regarding dose modification should be referred to the study sponsor medical 
expert.
6.2.5.
Management of Specific Adverse Events
6.2.5.1.
Dermatological Events
Subjects receiving idelalisib with ≥Grade 3 rash have generally presented with a maculopapular 
rash on the trunk and extremities that is occasionally associated with fever and/or pruritus and 
responded to treatment with diphenhydramine and/or topical or oral corticosteroids. 
For subjects who develop a severe rash for which an underlying etiology cannot be identified 
(e.g., infection, co-suspect drug), study drug should be interrupted. Resumption of study drug 
should be considered once rash resolves.
Severe cutaneous reactions, including fatal events of Stevens-Johnson syndrome (SJS) and 
toxic epidermal necrolysis (TEN), have been reported in subjects receiving idelalisib. 
Assessment of potential causal association between idelalisib and the occurrence of SJS or TEN 
has been confounded by the coadministration of antineoplastic agents (e.g., bendamustine, 
rituximab) and/or other concomitant medications known to be associated with SJS or TEN 
(e.g., allopurinol). If SJS or TEN is suspected, idelalisib and all coadministered medications 
associated with SJS or TEN should be interrupted and the subject treated accordingly. 
Subjects should be monitored for the development of SJS, TEN, or other severe cutaneous 
reactions and idelalisib treatment should be discontinued if such events occur.


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6.2.5.2.
Gastrointestinal Events
Isolated cases of gastrointestinal inflammation (eg, stomatitis, colitis, cecitis) have been noted in 
subjects receiving idelalisib. Rare cases of gastrointestinal perforation have occurred, generally 
in the setting of occult carcinoma, mesenteric embolus or diverticular disease. Discontinuation of 
idelalisib is required in subjects who experience bowel perforation.
Cholangitis manifest as hyperbilirubinemia out of proportion to serum transaminase elevations 
has been observed. While disease-related factors, neutropenia, toxicity from prior therapies, 
effects of ongoing supportive care, or pre-existing cholelithiasis may have initiated such events, 
it is possible that idelalisib played a contributory role. In such subjects, rechallenge with 
idelalisib has been possible and has not been associated with other severe adverse events. 
Subjects who have developed evidence of enteritis during idelalisib therapy have been 
successfully treated with antidiarrheals (eg, loperamide) and with enteric steroidal 
(eg, budesonide) or non-steroidal (eg sulfasalazine [Azulfidine®]) anti-inflammatory agents and 
have been able to continue or resume idelalisib.
For study subjects who develop severe abdominal pain the possibility of a bowel obstruction or 
perforation should be considered. Appropriate clinical and radiographic examination should be 
performed and supportive care or surgical intervention should be considered. 
For subjects who develop persistent diarrhea, causes related to concomitant medications or 
gastrointestinal infections such as Clostridium difficile (particularly for patients recently treated 
with broad spectrum antibiotics), Shigella, Campylobacter, Yersinia and CMV should be 
considered and treated if appropriate. Depending upon the clinical circumstances, endoscopy and 
biopsy, with bacterial and viral IHC staining should be considered. In the event that an infectious 
cause is not identified, an antimotility agent (eg, loperamide) may lessen symptoms and 
intervention with enteric steroidal (eg, budesonide) or non-steroidal (eg, sulfasalazine) 
anti-inflammatory agents should be considered. In such subjects, rechallenge with idelalisib at a 
lower dose level has resulted in recurrence of symptoms in some but not all subjects and has not 
been associated with other severe adverse events.
6.2.5.2.1.
Investigation for Idelalisib Late Onset or Severe Diarrhea/Colitis 
Among idelalisib-treated patients who reported diarrhea or colitis, the median time to onset of 
any grade diarrhea or colitis was 1.9 months (range, 0.0–29.8), of grade 1 or 2 was 1.5 months 
(range, 0.0–15.2) and of grade 3 or 4 was 7.1 months (range, 0.5–29.8). Kaplan–Meier curves of 
time to onset of diarrhea or colitis are shown for all idelalisib-treated patients in Figure 1 {Coutre 
2015}.


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Figure 1.
Kaplan-Meier Time to Diarrhea or Colitis
Idelalisib-associated severe diarrhea responds poorly to antimotility agents however, median 
time to resolution ranged between 1 week and 1 month across trials following interruption of 
idelalisib treatment and, in some instances, initiation of corticosteroid treatment 
{Gilead Sciences Inc 2014}.
6.2.5.2.2.
Evaluation for Gastrointestinal Events/Colitis 
For Grade 2 colitis and diarrhea (unless clinical diagnosis is established from medical history and 
physical examination), the following testing is required:

Stool culture for routine pathogens (Salmonella, Shigella, Campylobacter species, 
Clostridium difficile toxin, Rotavirus, Cytomegalovirus, Adenovirus)

Stool for Ova and Parasites (Cryptosporidium parvum, Isospora belli, Enterocytozoon 
bieneusi, Septata intestinalis, Strongyloides, Microsporidia, Entamoeba histolytica, 
Cyclospora), Giardia antigen

For grade ≥ 3 or persistent grade 2 colitis or diarrhea without clear etiology 
(eg, clostridium difficile enterocolitis), endoscopy with biopsy is required. All biopsy 
samples should include immunohistochemistry (IHC) and PCR for CMV, Adenovirus.
6.2.5.2.3.
Differentiation Between Small-Bowel and Large-Bowel Diarrhea
Differentiation between small-bowel and large-bowel diarrhea: may be possible on a clinical 
basis. If unclear, consider upper and lower tract endoscopy with biopsy.
PPD


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
Small bowel diarrhea is characterized by large volume diarrhea (more than one per day), 
possible associated dehydration weight loss and paraumbilical pain. Consider an endoscopic 
small-bowel biopsy and evaluate other etiologies such as celiac disease.

Large-bowel diarrhea may present with lower pelvic pain, tenesmus, generally smaller stool 
volume with gross blood frquently found in the stool. Condsider a colonoscopic evaluation 
and biopsy.
6.2.5.3.
Hepatic Events
Transaminase Elevations: Consistent with observations in a dog toxicology study, reversible 
asymptomatic ALT/AST increases were also observed early in the idelalisib program in phase 1 
studies (101-02 and 101-07) in subjects with hematologic malignancies. Transaminase elevations 
generally occurred within 4 to 12 weeks of drug initiation, and resolved spontaneously over a 
period of 2 to 4 weeks with drug being continued for Grade 1 and 2 elevations and drug withheld 
for Grade 3 or 4 elevations until resolution. These early observations have been consistent with 
the ongoing experience with idelalisib treatment and transaminase elevations are now well 
characterized as most frequently asymptomatic, transient and occurring within the first 3 months 
of treatment.
Grade 1 or 2 elevations commonly resolve despite continued idelalisib treatment and 
Grade 3 or 4 elevations can be managed by temporarily withholding idelalisib. Successful 
rechallenge after resolution at either the same or lower dose level of idelalisib has been achieved 
in the majority of subjects. There has been no evidence of impaired synthetic function. Close 
monitoring of hepatic laboratory tests during therapy is important to allow for appropriate 
idelalisib interruption and reinstitution so that subjects may continue with study drug treatment.
6.2.5.4.
Pulmonary Events
Documented bacterial, fungal, viral, and pneumocystis pneumonias have been observed in 
patients receiving idelalisib, primarily in patients with CLL. Some study subjects receiving 
idelalisib alone or in combination have developed evidence of pneumonitis and organizing 
pneumonia, respectively, without documented pulmonary infection. 
Given the potential for infectious or drug-related adverse events, clinicians should be particularly 
observant for evidence of respiratory events in subjects participating in this trial. Subjects should 
be evaluated who describe pulmonary symptoms (eg, dyspnea on exertion, cough, 
shortness of breath); manifest a decline from baseline of 5% in oxygen saturation, or 
demonstrate evidence of pulmonary inflammation (eg, focal or diffuse interstitial pattern or 
ground-glass opacities on chest CT). Potential bacterial, fungal, or viral etiologies should be 
assessed. Noninfectious etiologies such as pulmonary edema or thromboembolism should also be 
considered.
As appropriate for the clinical situation and culture results, subjects should be treated empirically 
or given specific antibiotics, antifungals, or antiviral agents for a cultured organism. Supportive 
care, including oxygen or mechanical ventilation, should be provided as necessary.


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For subjects with suspected Grade 1 pneumonitis, withhold idelalisib until resolution to baseline. 
Upon resolution to baseline, idelalisib may be resumed at a lower dose level or discontinued at 
investigator discretion. For subjects with Grade ≥2 pneumonitis (eg, new onset or worsening of 
baseline cough, dyspenea, hypoxia and/or a diffuse interstitial pattern or ground-glass opacities 
on chest imaging without obvious infectious etiology), idelalisib must be discontinued
permanently and therapy initiated as clinically appropriate.
Cases of organizing pneumonia, some with fatal outcome, have occurred with idelalisib. In 
subjects presenting with serious lung events, idelalisib should be interrupted and the subject 
assessed for an explanatory etiology. If organizing pneumonia is diagnosed, treatment with 
idelalisib should be permanently discontinued and the subject treated accordingly.
6.2.5.5.
Pregnancy, Lactation, and Reproduction
Idelalisib has induced embryo lethality and teratogenicity when administered to pregnant female 
rats at maternally toxic doses. However, definitive reproductive toxicology studies in animals 
have not yet been performed and the specific effects of idelalisib on human embryogenesis or 
fetal development are unknown. Whether idelalisib is excreted in human breast milk is unknown.
General toxicology studies of idelalisib in rats and dogs indicated dose-dependent reductions in 
testicular weights, with persistent minimal to mild degeneration of the seminiferous tubules and 
decreased spermatozoa in rats and hypospermatogenesis in dogs. The implications of these 
testicular changes for animal or human fertility are unknown.
Given the potential risks to a fetus or infant as a result of exposure to idelalisib, women of 
reproductive potential entering this study must have a negative serum pregnancy test at baseline 
and must not be breastfeeding. Males and females of childbearing potential should abstain from 
sexual intercourse or use an effective form of contraception during the course of the study and 
for 90 days following the last dose of study drug. If a female study participant becomes pregnant 
or decides to breastfeed during the course of the study, all study therapy must be discontinued. 
PJP Prophylaxis
Trimethoprim sulfamethoxazole is rated a Pregnancy category C agent. In rats, oral doses of 
533 mg/kg or 200 mg/kg produced teratologic effects manifested mainly as cleft palates.
One survey found no congenital abnormalities in 35 children whose mothers had received oral
sulfamethoxazole and trimethoprim at the time of conception or shortly thereafter. Because 
sulfamethoxazole and trimethoprim may interfere with folic acid metabolism it should be used 
during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Dapsone is rated a Pregnancy Category C agent. Extensive, but uncontrolled experience and 
two published surveys on the use of Dapsone in pregnant women have not shown that Dapsone 
increases the risk of fetal abnormalities if administered during all trimesters of pregnancy or can 
affect reproduction capacity. Because of the lack of animal studies or controlled human 
experience, Dapsone should be given to a pregnant woman only if clearly needed. Dapsone is 
excreted in breast milk in substantial amounts. Hemolytic reactions can occur in neonates. 
Because of the potential for tumorgenicity shown for Dapsone in animal studies a decision 
should be made whether to discontinue nursing or discontinue the drug taking into account the 
importance of drug to the mother.


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Atovaquone is rated a Pregnancy Category C agent. Atovaquone is teratogenic and did not cause 
reproductive toxicity in rats at plasma concentrations up to 2 to 3 times the estimated human 
exposure. Atovaquone can cause maternal toxicity in rabbits at plasma concentrations that were 
approximately one half the estimated human exposure. Mean fetal body lengths and weights were 
decreased and there were higher numbers of early resorption and post-implantation loss per dam. It is 
not clear whether these effects are caused by atovaquone directly or are secondary to maternal 
toxicity. Concentrations of atovaquone in rabbit fetuses averaged 30% of the concurrent maternal 
plasma concentrations. There are no adequate and well-controlled studies in pregnant women. 
Atovaquone should be used during pregnancy only if the potential benefit justifies the potential risk 
to the fetus. It is not known whether atovaquone is excreted into human milk. Because many drugs 
are excreted into human milk, caution should be exercised when Atovaquone is administered to a 
nursing woman. In a rat study, atovaquone concentrations in the milk were 30% of the concurrent 
atovaquone concentrations in the maternal plasma.
Aerosolized Pentamidine (NebuPent) is a Pregnancy Category C agent. There are no adequate and 
well controlled studies of NebuPent in pregnant women. One literature report indicated that 
intravenously administered pentamidine in pregnant rats at 4 mg/kg/day was embryolethal; 
teratogenicity was not observed in this study. It is unknown whether pentamidine administered via 
the aerosolized route crosses the placenta at clinically significant concentrations. It is not known 
whether NebuPent can cause fetal harm when administered to a pregnant woman. NebuPent should 
be given to a pregnant woman only if clearly needed. It is not known whether NebuPent is excreted 
in human milk. NebuPent should not be given to a nursing mother unless the potential benefits are 
judged to outweigh the unknown risks.
6.2.6.
Hematological and Immunological Events
In the Phase 1 experience with idelalisib in patients with NHL and CLL, subjects with Grade 3 
neutropenia, anemia, and/or thrombocytopenia were enrolled to clinical trials. Decreased levels 
of neutrophil counts, hemoglobin, or platelet counts during idelalisib administration were largely 
due to minor fluctuations in these parameters among subjects with pre-existing hematological 
abnormalities due to disease or prior therapy. Thus, idelalisib did not appear to induce overt 
myelosuppression. Obvious patterns of drug-mediated reductions in circulating CD4+ 
lymphocyte counts or suppression of serum IgG levels were also not observed.
Treatment-emergent Grade 3 or 4 neutropenia events including those accompanied by fever or 
infection have occurred in subjects treated with idelalisib, most commonly in the context of 
myelosuppressive agents such as bendamustine. For subjects who develop ANC 
0.5 to < 1.0 Gi/L, blood counts should be monitored at least weekly. For subjects who develop 
ANC < 0.5 Gi/L, idelalisib should be interrupted and blood counts monitored at least weekly 
until ANC is ≥ 0.5 Gi/L, at which point, idelalisib dosing may be resumed at 100 mg BID.
Management of neutropenia, including administration of G-CSF should be per established 
clinical guidelines and institutional standard of care.


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6.2.7.
Infectious Events
Patients with lymphoid cancers receiving idelalisib have developed serious and fatal infections 
during therapy. Opportunistic infections, most notably Pneumocystis jirovecii pneumonia (PJP) 
and CMV infection, have most frequently occurred within the first 6 months of treatment with 
idelalisib and are increased in the context of concurrent myelosuppressive therapy such as 
bendamustine.
Subjects must receive trimethoprim-sulfamethoxazole or other established prophylaxis for PJP
throughout the course of idelalisib treatment. Prophylaxis will continue for a period of 2 to 
6 months after idelalisib discontinuation.  The duration of prophylaxis should be based on 
clinical judgment and may take into account risk factors such as concomitant corticosteroid 
treatment and prolonged neutropenia after idelalisib treatment ends. Subjects must permanently 
discontinue idelalisib upon diagnosis of PJP.
CMV surveillance for active disease (quantitative PCR or PP65 antigen) must be conducted 
approximately every 4 weeks throughout the course of idelalisib treatment. CMV viral load 
testing should be performed from the same specimen type whenever possible and caution should 
be exercised when comparing CMV viral load results across different testing centers. If 
unequivocal clinical or laboratory evidence of CMV infection is present, the subject must 
interrupt idelalisib treatment and undergo effective antiviral treatment according to established 
clinical guidelines. If the benefits of resuming idelalisib are judged to outweight the risks, 
consideration should be given to administering pre-emptive CMV therapy.
In high-risk subjects (history of recurrent infection, allogeneic transplant, treatment with 
alemtuzumab, hypogammaglobulinemia) other infection prophylaxis should be considered per 
consensus guidelines. Administration of intravenous immunoglobulin is permitted per standard 
institutional practice {Raanani 2009}. For subjects who develop an infection, appropriate 
medical therapy should be instituted in a timely manner.
6.2.8.
Secondary Malignancies
Subjects receiving idelalisib for CLL or iNHL have developed pre-malignant and secondary 
malignant diseases, such as basal cell carcinoma, myelodysplastic syndrome, myeloproliferative 
disorders, and more aggressive lymphoid malignancies (eg, have had Richter transformation). 
Generally this has occurred in subjects who have received multiple previous lines of therapy and 
when idelalisib is combined with other therapies such as rituximab or bendamustine. The specific 
association of the therapeutic agents with these types of events has not been determined.
There are reports of pre-malignant and malignant diseases that have developed in subjects who 
have been treated with bendamustine, including myelodysplastic syndrome, myeloproliferative 
disorders, acute myeloid leukemia, and bronchial carcinoma. The specific association of the 
therapeutic agents with these types of events has not been determined.


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6.2.9.
Ultraviolet Exposure
In vitro studies indicate enhanced cytotoxicity when embryonic murine fibroblasts treated with 
GS-563117 (the major metabolite of idelalisib) are simultaneously exposed to ultraviolet light. 
While nonclinical findings suggest the hypothetical potential for phototoxicity in humans, 
available clinical data do not reveal a photosafety concern. Although specific clinical correlates 
for these nonclinical data are not available, investigators and study subjects should be observant 
for the possibility that study participants may have exaggerated sunburn reactions 
(eg, burning, erythema, exudation, vesicles, blistering, edema) involving areas of skin exposed to 
ultraviolet light.
6.2.10.
Further Safety Information
Further safety information regarding the study drug may be found in the investigator brochure 
for idelalisib. 
6.2.11.
Duration of Therapy
Subjects may continue receiving idelalisib until the occurrence of any events requiring treatment 
discontinuation as defined in Section 9.
6.3.
Concomitant and Supportive Therapy
To the extent possible, administration of any prescription or over-the-counter drug products other 
than study medication should be minimized during the study period. Subjects should be 
discouraged from use of street drugs, herbal remedies, self-prescribed drugs, tobacco products, or 
excessive alcohol at any time during the clinical study of idelalisib.
If considered necessary for the subject’s well-being, drugs for concomitant medical conditions or 
for symptom management may be given at the discretion of the investigator. The decision to 
authorize the use of any drug other than study drug should take into account subject safety, the 
medical need, the potential for drug interactions, the possibility for masking symptoms of a more 
significant underlying event, and whether use of the drug will compromise the outcome or 
integrity of the study.
Subjects should be instructed about the importance of the need to inform the clinic staff of the 
use of any drugs or remedies (whether prescribed, over-the-counter, or illicit) before and during 
the course of the study. Any concomitant drugs taken by a subject during the course of the study 
and the reason for use should be recorded on the case report forms (CRFs).
Information regarding use or restrictions on specific concomitant medications, dietary measures, 
or other interventions is provided below.
6.3.1.
Anticancer or Experimental Therapies Other than Idelalisib
No other anticancer therapies (including chemotherapy, radiation, antibody therapy, 
immunotherapy, or other experimental therapies) of any kind are permitted while the subject is 
receiving study treatment with idelalisib. Subjects are not allowed to participate concurrently in 
any other therapeutic clinical study.


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6.3.2.
Antiemetics
Nausea and/or vomiting have not been commonly observed with idelalisib in prior studies. 
However, subjects who experience nausea or vomiting while on study therapy may receive 
antiemetics based on the judgment of the treating physician and local institutional practices. At 
the occurrence of persistent nausea or vomiting of severity grade 1, it is suggested that the 
subject receive an oral or transdermal serotonin antagonist (eg, dolasetron, granisetron, 
ondansetron, tropisetron, palonosetron). Other classes of antiemetic medications that may be 
employed include dopamine antagonists or benzodiazepines. If possible, systemic corticosteroids 
should be avoided (see Section 6.3.4).
6.3.3.
Granulocyte Colony-Stimulating Factors and Erythropoietin
Granulocyte-macrophage colony-stimulating factor (GM-CSF) should not be administered given 
the potential for GM-CSF-related inflammatory symptoms. Granulocyte colony-stimulating 
factor (G-CSF) agents and erythropoietic agents (eg, erythropoietin or darbepoetin) may be 
administered per institutional standard. Such use should be particularly considered if providing 
hematopoietic support might help to maintain idelalisib therapy. Reference should be made to the 
American Society of Clinical Oncology guidelines {Rizzo 2008, Smith 2006}.
6.3.4.
Corticosteroids
Subjects may receive topical or inhaled corticosteroids while on study. The use of systemic 
corticosteroids is discouraged because their potential antineoplastic activity in subjects with 
iNHL may confound interpretation of idelalisib-mediated antitumor effects. However, subjects 
who develop severe or life-threatening conditions that may be alleviated by systemic 
corticosteroid therapy are permitted to receive such drugs and are not required to discontinue 
study participation.
6.3.5.
Drugs that Inhibit/Induce CYP3A-Dependent Metabolism
Idelalisib is metabolized to its major metabolite GS-563117 via aldehyde oxidase and 
cytochrome P450 3A (CYP3A). Idelalisib also undergoes minor metabolism by 
UDP-glucoronosyltransferase 1-4 (UGT1A4). The AUC of idelalisib was increased 1.8-fold 
when idelalisib was coadministered with a strong CYP3A inhibitor. Therefore, if subjects are 
taking concomitant strong CYP3A inhibitors, the subject should be monitored closely for signs 
of idelalisib toxicity and the dose modifications for adverse reactions should be followed in the 
event of toxicity (see Table 3).
Additionally, idelalisib exposures are approximately 75% lower when coadministered with 
rifampin, a highly potent inducer of CYP3A. Therefore, avoid coadministration of strong 
inducers of CYP3A (rifampin, carbamazepine, phenytoin, and St. John’s wort) with idelalisib.


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6.3.6.
Drugs that Undergo CYP3A-Dependent Metabolism
The metabolite of idelaisib, GS-563117, is a reversible and time-dependent inhibitor of CYP3A; 
accordingly coadministration of idelalisib with midazolam, a probe CYP3A substrate, resulted in 
a ~5-fold increase in midazolam systemic exposure (AUC), indicating that idelalisib is a strong 
inhibitor of CYP3A. Coadministration of CYP3A substrates with idelalisib may result in an 
increase in their systemic exposures (eg, antiarrhythmics, calcium channel blockers, 
benzodiazepines, certain HMG-CoA reductase inhibitors, phosphodiesterase-5 (PDE5) 
inhibitors, warfarin). Avoid coadministration of drugs that are highly dependent on CYP3A for 
clearance and for which elevated plasma concentrations are associated with serious and/or 
life-threatening events, including narrow therapeutic index CYP3A substrates
(eg, alfentanil, cyclosporine, sirolimus, tacrolimus, cisapride, pimozide, fentanyl, quinidine,
ergotamine, dihydroergotamine, astemizole, terfenadine) with idelalisib.
6.3.7.
Immunization
Because of its actions to inhibit PI3Kδ-dependent B-cell function, high doses of idelalisib can 
impair primary or secondary responses to immunization in animals (see Section 2.4.3.2). The 
specific clinical relevance of these nonclinical findings is unknown. However, for subjects who 
are at substantial risk of an infection (eg, influenza) that may be prevented by immunization, 
consideration should be given to providing the vaccine prior to initiation of treatment with 
idelalisib.
6.3.8.
Surgery
There are no known effects of idelalisib on coagulation or wound healing. Pending receipt of 
additional information, idelalisib may be continued in the peri-procedural period in subjects who 
require surgery or invasive procedures.
6.3.9.
Diet
There are no specific dietary restrictions in the study. Idelalisib may be taken with or without 
food.
6.4.
Study Treatment Rationale
Selection of the idelalisib treatment regimen (including starting dose level, dose-modification 
levels, schedule, duration, and conditions of administration) for this study has been based on 
primarily on safety, exposure and activity profiles from previous Phase 1 clinical studies 
involving healthy volunteers, subjects with allergic rhinitis, and subjects with refractory/relapsed 
lymphoid malignancies. The following information was considered:

Idelalisib was symptomatically well tolerated in subjects with lymphoid malignancies 
receiving dose levels of 50 mg BID through 350 mg BID (the highest dose level tested). 
Monitorable, reversible transaminase elevations were observed in some subjects with iNHL 
but dose-dependency could not be clearly established and no MTD was apparent over this 
dose range.


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
Increases in idelalisib plasma Cmax, AUC, and Ctrough values were less than dose-proportional 
in subjects with lymphoid malignancies; the dose-exposure evaluation indicated modest 
increases in plasma exposure at dose levels >150 mg BID. Thus, administration of idelalisib
doses higher than 150 mg BID does not appear warranted given that no attendant gains in 
exposure would be expected. In Phase 1 studies, the mean plasma t1/2 of idelalisib was 
~6.5 to 9.8 hours across dose levels.

In an allergic rhinitis study, idelalisib induced statistically significant improvements in 
clinical and pharmacodynamic endpoints when administered at 100 mg BID over 7 days. 
These data support the pharmacological relevance of idelalisib-mediated PI3Kδ inhibition 
when administered at a dose-level approximating that to be used in this Phase 2 study.

A positive correlation was noted between idelalisib dose and improvement in 
lymphadenopathy in subjects with B-cell malignancies, with near-maximal effect was 
apparent at 150 mg BID. Thus, treatment with a idelalisib dose of 150 mg BID is considered 
appropriate. 

The idelalisib dose modification provisions described in the protocol are designed to balance 
a primary concern for subject safety with the potential for observing pharmacological and 
antitumor activity in circumstances under which a subject experiencing an adverse event may 
still be able to continue on therapy at a lower idelalisib dose level. The enhanced monitoring 
to be performed and the actions to be taken in response to toxicity are based on experience 
with interruption, dose-modification, rechallenge, and re-escalation already piloted in 
idelalisib Phase 1 trials. In addition, idelalisib antitumor activity has been observed in the 
Phase 1 studies across all dose levels tested, including doses in the range of the modified 
Dose Levels -1 (100 mg BID) planned for this protocol. Thus, use of these lower dose levels 
to accommodate individual subject tolerability in this protocol is justified because subjects 
receiving such idelalisib dose levels still have the potential for benefit.

Treatment until the occurrence of disease progression or unacceptable toxicity is appropriate 
to obtain information regarding drug safety during chronic administration. Prolonged therapy 
also offers study participants the potential for maximum benefit from treatment.

The changes in exposure observed when administering idelalisib after a high-fat, high-calorie 
meal are modest (~40% increase in mean AUC with no change in mean Cmax). Thus, 
idelalisib can be administered with or without food.

Overdose is defined as administration of >700 mg of idelalisib in a single day because this 
dose is >2 times the planned starting dose of 150 mg BID and exceeds the maximum 
administered dose of 350 mg BID that has been shown to be generally well tolerated in the 
existing Phase 1 experience.


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7.
SCHEDULE OF EVENTS AND PROCEDURES
7.1.
Schedule of Events
An overview of the proposed procedures and types and timing of data to be collected and 
recorded in the study is provided in Table 4 below. Detailed information regarding activities to 
be performed at each visit is provided in Section 7.2, below.


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Table 4.
Schedule of Events Overview
Period
Screen
Treatment
Follow-up
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16+
End of 
Treatment
Immediate
post-
treatment
Long-
term
Week
-4
0
2
4
6
8
10
12
16
20
24
30
36
42
48
Q4 
Weeks
Q12
Weeks
Study Day
Within
-28
Days
1
15
29
43
57
71
85
113
141
169
211
253
295
337
Visit 
Window
±2
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±7
±7
±7
±7
Informed 
consent
X
Medical 
history
X
Histopatholo
gy review
X
Serum 
virology
X
Coagulation
X
Urinalysis
X
β-HCG
X
HRQL –
FACT-Lym
X
X
X
X
X
X
X
X
X
X
X
X
Study drug 
return/
accounting 
X
X
X
X
X
X
X
X
X
X
Adverse 
eventsd,e
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Performance 
status
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PPD


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Period
Screen
Treatment
Follow-up
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16+
End of 
Treatment
Immediate
post-
treatment
Long-
term
Week
-4
0
2
4
6
8
10
12
16
20
24
30
36
42
48
Q4 
Weeks
Q12
Weeks
Study Day
Within
-28
Days
1
15
29
43
57
71
85
113
141
169
211
253
295
337
Visit 
Window
±2
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±7
±7
±7
±7
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum 
chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pharmacody
namics
X
X
X
X
X
X
X
X
X
X
X
X
X
Drug 
dispensing
X
X
X
X
X
X
X
X
X
X
Physical
examination
X
X
X
12-lead ECG
X
X
X
Immuno-
phenotyping
X
X
X
X
X
X
X
X
Serum
immuno-
globulins
X
X
X
X
X
X
X
X
Radiology
assessments 
(CT/MRI)
X
X
X
X
X
X
X
X
Bone 
marrow 
biopsy/
aspiratea
X
Xa
Xa
Xa
Xa
Xa
Xa
SPEP (IgM 
monoclonal 
protein)b
X
X
X
X
X
X
X
X


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Period
Screen
Treatment
Follow-up
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16+
End of 
Treatment
Immediate
post-
treatment
Long-
term
Week
-4
0
2
4
6
8
10
12
16
20
24
30
36
42
48
Q4 
Weeks
Q12
Weeks
Study Day
Within
-28
Days
1
15
29
43
57
71
85
113
141
169
211
253
295
337
Visit 
Window
±2
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±7
±7
±7
±7
Idelalisib 
dosing in 
clinic
X
X
X
X
Limited 
pharmaco-
kinetics
X
X
X
X
Monthly 
CMV testing
X
X
Immune-
monitoring 
labs
X
X
Study Procedures and Timingc
a
Required at screening. If disease present at baseline, to be performed post-baseline to confirm response category in subjects with potential CR by radiological assessments. If 
the baseline bone marrow biopsy/aspirate does not show lymphoma involvement, it is not necessary to obtain a follow-up bone marrow biopsy/aspirate to establish CR.
b
For subjects with WM only, performed locally per standard of care.
c
For detailed information regarding activities to be performed at each visit, see Section 7.2.
d
Assessment of Diarrhea/Colitis: obtain history of onset and duration of diarrhea, including description of number of stools and stool composition (eg, watery, bloody, 
nocturnal), travel history, dietary changes and a medication review to identify possible diarrheogenic agents.
e
Assessment of Diarrhea/Colitis: perform physical examination including assessment for fever, dizziness, abdominal pain/cramping, and weakness (ie, evaluate for sepsis, 
bowel obstruction, dehydration).
Abbreviations: -HCG, beta human chorionic gonadotropin; HRQL, health-related quality of life; FACT-Lym, Functional Assessment of Cancer Therapy-Lymphoma; 
ECG, electrocardiogram; CT, computed tomography; LPL, lymphoplasmacytoid lymphoma; WM, Waldenstroms Macroglobulinemia, MRI, magnetic resonance imaging; 
SPEP, serum protein electrophoresis; CR, complete response
PPD


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7.2.
Explanation of Study Visits
The specific assessments to be performed at each visit are detailed below.
For visits at which HRQL results are obtained, it is important that the subject be administered the 
FACT-Lym before any other procedures are performed and before any study-related information 
is communicated to the subject; this is necessary to avoid biasing the HRQL responses provided 
by the subject. Once the subjects had completed the HRQL assessments, the remaining 
procedures may be performed.
At visits involving idelalisib administration and pharmacokinetic sampling in the clinic, care 
should be taken to perform procedures with the appropriate timing relative to idelalisib
administration. The actual sample collection times of pharmacokinetic blood specimens should 
be recorded. If a heparinized venous catheter is placed for sample collection in order to avoid 
repeated needle sticks, at least 2 mL of blood should be removed and discarded prior to each 
sample collection in order to avoid heparin contamination of the sample.
At visits designated as laboratory only visits (Visits 3, 5, and 7), subjects will have laboratory 
assessments that may be performed at the investigational site or at an accredited local laboratory 
or clinic that is convenient for the subject/caregiver. If blood is collected at a local laboratory, 
samples are not to be analyzed at the local laboratory. For these visits, subjects and/or caregivers 
will be provided with central laboratory kits that will contain materials necessary for the 
collection and shipment of the laboratory samples by the local laboratory clinic to the central 
laboratory.
CT or MRI imaging of the neck, chest, abdomen, and pelvis will be performed as a component of 
tumor assessments throughout the study; the same method of assessment (CT or MRI) and the 
same technique should be used to characterize each identified and reported lesion at baseline and 
while on study.
7.2.1.
Visit 1 and Screening Period (Clinic Visit)
The initial screening visit is designated as Visit 1. At Visit 1, the investigator must inform each 
prospective study participant of the nature of the study, explain the potential risks, and obtain 
written informed consent from the study candidate and/or legal guardian prior to performing any 
study-related screening procedures. Once the informed consent document has been signed, the 
subject may undergo the screening procedures.
In order to optimize scheduling convenience for the subject and for the investigational staff, 
screening procedures may be performed over as many days as necessary provided that screening 
is completed within 4 weeks prior to initiation of treatment.
The tests and evaluations outline in Table 5 will be performed at Visit 1 or during the screening 
period prior to study enrollment and initiation of study treatment.


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Table 5.
Procedures and Assessments at Visit 1 (During Screening Period)
Assessment or Procedure
Explanation
Informed consent
To be obtained before any screening procedures are initiated (unless procedures are
performed as standard of care prior to informed consent)
Medical history
Including relevant information regarding iNHL histology, iNHL history, current 
iNHL Ann Arbor staging, current FLIPI score, reasons for treatment, prior therapies 
for iNHL, documentation that iNHL is refractory to rituximab and alkylating agents, 
and past history of hepatobiliary disease
Concomitant medications
Recording of ongoing concomitant medication use
Histopathology review
Transmission of histopathology materials for confirmation of iNHL. Results not 
required for enrollment.
Performance status
Using Karnofsky performance status criteria and ECOG for study inclusion criteria 
(see Appendix D)
Physical examination
Including height, weight, evidence of palpable lymphadenopathy, hepatomegaly, 
and/or splenomegaly
Vital signs
Including weight, temperature, resting systolic and diastolic blood pressure while 
sitting, resting heart rate while sitting
12-lead ECG
To be obtained while subject is resting in the supine position
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Serum virology
Including HBV antigen, HCV antibody, HIV antibody, CMV serology; if HBV 
antigen or HCV antibody are positive, subjects must be evaluated for the presence of 
circulating HBV or HCV viral RNA
Coagulation
aPTT, PT
Urinalysis
Dipstick for pH, protein, glucose, blood, nitrite, leukocytes
β-HCG
Women of childbearing potential only
SPEP
Including serum IgM monoclonal protein level
(subjects with WM only; performed locally per standard of care)
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be performed within 
28 days prior to initiation of study treatment at Visit 2; the same method of 
assessment (CT or MRI) and the same technique should be used to characterize each 
identified and reported lesion at baseline and while on study
Bone marrow biopsy and 
aspirate
Required to assess presence or absence of bone marrow involvement with lymphoma; 
may be omitted if already performed within 6 weeks prior to initiation of study 
treatment
Abbreviations: NHL, indolent non-Hodgkin lymphoma; FLIPI, Follicular Lymphoma International Prognostic Index; 
ECOG, Eastern Cooperative Oncology Group; ECG, electrocardiogram; ALT, alanine aminotransferase; 
AST, aspartate aminotransferase; ALP, alkaline phosphatase; GGT, gamma-glutamyltransferase; LDH, lactate dehydrogenase; 
HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; CMV, cytomegalovirus; RNA, ribonucleic 
acid; aPTT, activated partial thromboplastin time; PT, partial thromboplastin time; -HCG, beta human chorionic gonadotropin; 
SPEP, serum protein electrophoresis; Ig, immunoglobulin; LPL, lymphoplasmacytoid lymphoma;
WM, Waldenstroms Macroglobulinemia, CT, computed tomography; MRI, magnetic resonance imaging


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7.2.2.
Visit 2 (Day 1) (Clinic Visit)
Subjects will be medically assessed to determine if they still meet eligibility criteria and can 
initiate study treatment. The procedures outlined in Table 6 will be performed at Visit 2 (Day 1).
Table 6.
Procedures and Assessments at Visit 2 (Day 1)
Assessment or Procedure
Explanation
Pre-Dose Procedures and Assessments
FACT-Lym
HRQL instrument (Appendix C) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
Adverse events
Recording of adverse events occurring since the initiation of the screening period
Concomitant medications
Recording of concomitant medication use since the initiation of the screening period
Performance status
Using Karnofsky performance status criteria (see Appendix D)
Vital signs
Including weight, temperature, resting systolic and diastolic blood pressure while sitting, 
resting heart rate while sitting
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils,basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, 
total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, 
triglycerides
Circulating cells for 
immuno-phenotyping
Including quantitation of absolute number of CD4+, CD8+, CD16/CD56+ and CD19+ 
cells by flow cytometry
Serum immunoglobulins
Including quantitative levels of IgA, IgE, IgG, and IgM
Pharmacodynamic markers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording of 
the date and actual clock time of the last meal [if any] and of the date and actual clock 
time of blood collection)
Idelalisib Administration
Idelalisib administration
First dose of idelalisib study drug to be administered to the subject (with recording of the 
date and actual clock time of the idelalisib administration)
Post-Dose Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours
(± 5 minutes) after idelalisib administration
(with recording of the date and actual clock time of blood collection)
Drug dispensing
Dispensing of 4-week supply of idelalisib study drug to the subject with instructions for 
self-administration at home
Instruction regarding dosing 
at next full clinic visit
Instruction to the subject that the morning dose of idelalisib should not be taken on the day 
of Visit 4.
Abbreviations: FACT-Lym, Functional Assessment of Cancer Therapy; Lymphoma HRQL, health-related quality of life; 
ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; GGT, gamma-glutamyltransferase; 
LDH, lactate dehydrogenase; Ig, immunoglobulin; DNA, deoxyribonucleic acid; RNA, ribonucleic acid
PPD
PPD


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7.2.3.
Visit 3 (Day 15) (Laboratory Visit)
The procedures outlined in Table 7 will be performed at Visit 3 (Day 15 [±2 days]).
Table 7.
Procedures and Assessments at Visit 3 (Day 15)
Assessment or Procedure
Explanation
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including ALT, AST, ALP, GGT, total bilirubin, LDH
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; 
GGT, gamma-glutamyltransferase; LDH, lactate dehydrogenase
7.2.4.
Visit 4 (Day 29) (Clinic Visit)
The procedures outlined in Table 8 will be performed at Visit 4 (Day 29 [±2 days]).


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Table 8.
Procedures and Assessments at Visit 4 (Day 29)
Assessment or Procedure
Explanation
Pre-Dose Procedures and Assessments
FACT-Lym
HRQL instrument (Appendix C) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 2
Concomitant medications
Recording of concomitant medication used since Visit 2
Performance status
Using Karnofsky performance status criteria (see Appendix D)
Compliance
Counting returned study drug. Recording of the date and actual clock time of the last 
prior subject self-administration of idelalisib (should be the prior evening dose) and 
whether that dose of idelalisib was taken within 1 hour after a meal
Vital signs
Including weight, temperature, resting systolic and diastolic blood pressure while 
sitting, resting heart rate while sitting
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Pharmacodynamic markers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording 
of the date and actual clock time of the last meal [if any] and of the date and actual 
clock time of blood collection)
Idelalisib Administration
Idelalisib administration
Dose of idelalisib study drug to be administered to the subject (with recording of the 
date and actual clock time of idelalisib administration)
Post-Dose Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours
(± 5 minutes) after idelalisib administration (with recording of the date and actual 
clock time of blood collection)
Drug dispensing
Dispensing of 4-week supply of idelalisib study drug to the subject with instructions 
for self-administration at home
Instruction regarding 
dosing at next full clinic 
visit
Instruction to the subject that the morning dose of idelalisib should not be taken on 
the day of Visit 6.
Scheduling of Visit 6 
radiology assessment
CT or MRI imaging of chest, abdomen, and pelvis to be scheduled for Visit 6; the 
same method of assessment (CT or MRI) should be used as was used at baseline
Abbreviations: FACT-Lym, Functional Assessment of Cancer Therapy: Lymphoma; HRQL, health-related quality of life; 
ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; GGT, gamma-glutamyltransferase; 
LDH, lactate dehydrogenase; CT, computed tomography; MRI, magnetic resonance imaging
PPD


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7.2.5.
Visit 5 (Day 43) (Laboratory Visit)
The procedures outlined in Table 9 will be performed at Visit 5 (Day 43 [±2 days]).
Table 9.
Procedures and Assessments at Visit 5 (Day 43)
Assessment or Procedure
Explanation
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including ALT, AST, ALP, GGT, total bilirubin, LDH
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; 
GGT, gamma-glutamyltransferase; LDH, lactate dehydrogenase
7.2.6.
Visit 6 (Day 57) (Clinic and Radiology Visit)
The procedures outlined in Table 10 will be performed at Visit 6 (Day 57 [±2 days]).


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Table 10.
Procedures and Assessments at Visit 6 (Day 57)
Assessment or Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis on day of visit or within 1 week 
prior to the visit; the same method of assessment (CT or MRI) should be used as was used 
at baseline and the assessment should be done even if study drug has been interrupted.
Pre-Dose Procedures and Assessments
FACT-Lym
HRQL instrument (Appendix C) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 4
Concomitant medications
Recording of concomitant medication used since Visit 4
Performance status
Using Karnofsky performance status criteria (see Appendix D)
Compliance
Counting returned study drug. Recording of the date and actual clock time of the last prior 
subject self-administration of idelalisib (should be the prior evening dose) and whether 
that dose of idelalisib was taken within 1 hour after a meal
Vital signs
Including weight, temperature, resting systolic and diastolic blood pressure while sitting, 
resting heart rate while sitting
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, 
total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, 
triglycerides
Pharmacodynamic markers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Circulating cells for 
immuno-phenotyping
Including quantitation of absolute number of CD4+, CD8+, CD16/CD56+ and CD19+ 
cells by flow cytometry
Serum immunoglobulins
Including quantitative levels of IgA, IgE, IgG, and IgM
SPEP
Including serum IgM monoclonal protein level
(subjects with WM only; performed locally per standard of care)
Bone marrow biopsy and 
aspirate
To be performed post-baseline to confirm response category in subjects with potential CR 
by radiological assessments. If the baseline bone marrow biopsy/aspirate did not show 
lymphoma involvement, it is not necessary to obtain a follow-up bone marrow 
biopsy/aspirate to establish CR.
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics
(with recording of the date and actual clock time of the last meal [if any] and of the date 
and actual clock time of blood collection)
Idelalisib Administration
Idelalisib administration
Dose of idelalisib study drug to be administered to the subject (with recording of the date 
and actual clock time of idelalisib administration)
Post-Dose Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours 
(±5 minutes) after idelalisib administration (with recording of the date and actual clock 
time of blood collection)
Drug dispensing
Dispensing of 4-week supply of idelalisib study drug to the subject with instructions for 
self-administration at home
Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging; FACT-Lym, Functional Assessment of Cancer 
Therapy: Lymphoma; HRQL, health-related quality of life; ALT, alanine aminotransferase; AST, aspartate aminotransferase; 
ALP, alkaline phosphatase; GGT, gamma-glutamyltransferase; LDH, lactate dehydrogenase; Ig, immunoglobulin; 
SPES, serum protein electrophoresis; LPL, lymphomplasmacytoid lymphoma; WM- Waldenstroms Macroglobulinemia, 
CR, complete response


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7.2.7.
Visit 7 (Day 71) (Laboratory Visit)
The procedures outlined in Table 11 will be performed at Visit 7 (Day 71 [±2 days]).
Table 11.
Procedures and Assessments at Visit 7 (Day 71)
Assessment or Procedure
Explanation
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including ALT, AST, ALP, GGT, total bilirubin, LDH
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; 
GGT, gamma-glutamyltransferase; LDH, lactate dehydrogenase
7.2.8.
Visit 8 (Day 85) (Clinic Visit)
The procedures outlined in Table 12 will be performed at Visit 8 (Day 85 [±2 days]).
Table 12.
Procedures and Assessments at Visit 8 (Day 85)
Assessment or Procedure
Explanation
Pre-Dose Procedures and Assessments
FACT-Lym
HRQL instrument (Appendix C) to be administered before any other procedures are performed 
and before any study-related information is communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 6
Concomitant medications
Recording of concomitant medication used since Visit 6
Performance status
Using Karnofsky performance status criteria (see Appendix D)
Compliance
Counting returned study drug. Recording of the date and actual clock time of the last prior 
subject self-administration of idelalisib (should be the prior evening dose) and whether that 
dose of idelalisib was taken within 1 hour after a meal
Vital signs
Including weight, temperature, resting systolic and diastolic blood pressure while sitting, 
resting heart rate while sitting
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, 
triglycerides
Pharmacodynamic markers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Drug dispensing
Dispensing of 4-week supply of idelalisib study drug to the subject with instructions for self-
administration at home
Instruction regarding dosing at 
next full clinic visit
Instruction to the subject that the morning dose of idelalisib should not be taken on the day of 
Visit 9.
Scheduling of Visit 9 
radiology assessment
CT or MRI imaging of chest, abdomen, and pelvis to be scheduled for the Visit 9 radiology 
assessment; the same method of assessment (CT or MRI) should be used as was used at 
baseline
Abbreviations: FACT-Lym, Functional Assessment of Cancer Therapy: Lymphoma; HRQL, health-related quality of life; 
ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; GGT, gamma-glutamyltransferase; 
LDH, lactate dehydrogenase; CT, computed tomography; MRI, magnetic resonance imaging
7.2.9.
Visit 9 (Day 113) (Clinic and Radiology Visit)
The procedures outlined in Table 13 will be performed at Visit 9 (Day 113 [±3 days]).


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Table 13.
Procedures and Assessments at Visit 9 (Day 113)
Assessment or Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis on day of visit or within 1 week prior 
to the visit; the same method of assessment (CT or MRI) should be used as was used at baseline
Pre-Dose Procedures and Assessments
FACT-Lym
HRQL instrument (Appendix C) to be administered before any other procedures are performed 
and before any study-related information is communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 8
Concomitant medications
Recording of concomitant medication used since Visit 8
Performance status
Using Karnofsky performance status criteria (see Appendix D)
Compliance
Counting returned study drug. Recording of the date and actual clock time of the last prior 
subject self-administration of idelalisib (should be the prior evening dose) and whether that 
dose of idelalisib was taken within 1 hour after a meal
Physical examination
Including height, weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Vital signs
Including weight, temperature, resting systolic and diastolic blood pressure while sitting, 
resting heart rate while sitting
12-lead ECG
To be obtained while subject is resting in the supine position
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, 
triglycerides
Pharmacodynamic markers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Circulating cells for immuno-
phenotyping
Including quantitation of absolute number of CD4+, CD8+, CD16/CD56+ and CD19+ cells by 
flow cytometry
Serum immunoglobulins
Including quantitative levels of IgA, IgE, IgG, and IgM
SPEP
Including serum IgM monoclonal protein level (subjects with WM only; performed locally per
standard of care)
Bone marrow biopsy and 
aspirate
To be performed post-baseline to confirm response category in subjects with potential CR by 
radiological assessments. If the baseline bone marrow biopsy/aspirate did not show lymphoma 
involvement, it is not necessary to obtain a follow-up bone marrow biopsy/aspirate to establish 
CR.
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording of the 
date and actual clock time of the last meal [if any] and of the date and actual clock time of 
blood collection)
Idelalisib Administration
Idelalisib administration
Dose of idelalisib study drug to be administered to the subject (with recording of the date and 
actual clock time of idelalisib administration)
Post-Dose Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours (±5 minutes)
after idelalisib administration (with recording of the date and actual clock time of blood 
collection)
Drug dispensing
Dispensing of 4-week supply of idelalisib study drug to the subject with instructions for self-
administration at home
Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging; FACT-Lym, Functional Assessment of Cancer 
Therapy: Lymphoma; HRQL, health-related quality of life; ECG, electrocardiogram; ALT, alanine aminotransferase; 
AST, aspartate aminotransferase; ALP, alkaline phosphatase; GGT, gamma-glutamyltransferase; LDH, lactate dehydrogenase; 
Ig, immunoglobulin; SPEP, serum protein electrophoresis; LPL, lymphoplasmacytoid lymphoma, 
WM, Waldenstroms Macroglobulinemia; CR, complete response;


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7.2.10.
Visit 10 (Day 141) (Clinic Visit)
The procedures outlined in Table 14 will be performed at Visit 10 (Day 141 [±3 days])
Table 14.
Procedures and Assessments at Visit 10 (Day 141)
Assessment or Procedure
Explanation
FACT-Lym
HRQL instrument (Appendix C) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
Adverse events 
Recording of adverse events occurring since prior visit
Concomitant medications
Recording of concomitant medication used since prior visit
Performance status
Using Karnofsky performance status criteria (see Appendix D)
Compliance
Counting returned study drug. Recording of the date and actual clock time of the last 
prior subject self-administration of idelalisib (should be the prior evening dose) and 
whether that dose of idelalisib was taken within 1 hour after a meal
Vital signs
Including weight, temperature, resting systolic and diastolic blood pressure while 
sitting, resting heart rate while sitting
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Pharmacodynamic markers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Drug dispensing
Dispensing of 4-week supply of idelalisib study drug to the subject with instructions 
for self-administration at home
Scheduling of Visit 11 
radiology assessment
CT or MRI imaging of chest, abdomen, and pelvis to be scheduled for Visit 11; the 
same method of assessment (CT or MRI) should be used as was used at baseline
Abbreviations: FACT-Lym, Functional Assessment of Cancer Therapy: Lymphoma; HRQL, health-related quality of life 
ALT; alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; GGT, gamma-glutamyltransferase; 
LDH, lactate dehydrogenase; CT, computed tomography; MRI, magnetic resonance imaging


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7.2.11.
Visit 11 (Day 169) (Clinic and Radiology Visit)
The procedures outlined in Table 15 will be performed at Visit 11 (Day 169 [±3 days]).
Table 15.
Procedures and Assessments at Visit 11 (Day 169)
Assessment or Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis on day of visit or within 
1 week prior to the visit; the same method of assessment (CT or MRI) should be used 
as was used at baseline
During-Visit Assessments and Procedures
FACT-Lym
HRQL instrument (Appendix C) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
Adverse events 
Recording of adverse events occurring since prior visit
Concomitant medications
Recording of concomitant medication used since prior visit
Performance status
Using Karnofsky performance status criteria (see Appendix D)
Compliance
Counting returned study drug
Vital signs
Including weight, temperature, resting systolic and diastolic blood pressure while 
sitting, resting heart rate while sitting
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Pharmacodynamic markers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Circulating cells for 
immuno-phenotyping
Including quantitation of absolute number of CD4+, CD8+, CD16/CD56+ and 
CD19+ cells by flow cytometry
Serum immunoglobulins
Including quantitative levels of IgA, IgE, IgG, and IgM
SPEP
Including serum IgM monoclonal protein level (subjects with WM only; performed 
locally per standard of care)
Bone marrow biopsy and 
aspirate
To be performed post-baseline to confirm response category in subjects with potential 
CR by radiological assessments. If the baseline bone marrow biopsy/aspirate did not 
show lymphoma involvement, it is not necessary to obtain a follow-up bone marrow 
biopsy/aspirate to establish CR.
Drug dispensing
Dispensing of 12-week supply of idelalisib study drug to the subject with instructions 
for self-administration at home
Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging; FACT-Lym , Functional Assessment of Cancer 
Therapy: Lymphoma; HRQL, health-related quality of life ; ALT, alanine aminotransferase; AST, aspartate aminotransferase; 
ALP, alkaline phosphatase; GGT, gamma-glutamyltransferase; LDH, lactate dehydrogenase; CR = complete response; 
Ig, immunoglobulin; SPEP, serum protein electrophoresis; LPL, lymphoplasmacytoid lymphoma, 
WM, Waldenstroms Macroglobulinemia; CR, complete response


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7.2.12.
Visits 12 and 14 (Days 211 and 295) (Clinic Visits)
The procedures outlined in Table 16 will be performed at Visits 12 and 14
(Days 211] and 295 [±3 days])
Table 16.
Procedures and Assessments at Visits 12 and 14 (Days 211 and 295)
Assessment or Procedure
Explanation
FACT-Lym
HRQL instrument (Appendix C) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
Adverse events 
Recording of adverse events occurring since prior visit
Concomitant medications
Recording of concomitant medication used since prior visit
Performance status
Using Karnofsky performance status criteria (see Appendix D)
Vital signs
Including weight, temperature, resting systolic and diastolic blood pressure while 
sitting, resting heart rate while sitting
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Pharmacodynamic markers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Scheduling of next-visit 
radiology assessment
CT or MRI imaging of chest, abdomen, and pelvis to be scheduled to occur within 
1 week prior to the next clinic visits (Visits 13 and 15); the same method of 
assessment (CT or MRI) should be used as was used at baseline
Abbreviations: FACT-Lym, Functional Assessment of Cancer Therapy: Lymphoma; HRQL, health-related quality of life ; 
ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; GGT, gamma-glutamyltransferase; 
LDH, lactate dehydrogenase; CT, computed tomography; MRI, magnetic resonance imaging
7.2.13.
Visits 13, 15, etc. (Days 253, 337, and Every 12 Weeks)
(Clinic and Radiology Visit)
The procedures outlined in Table 17 will be performed at Visit 13 (Day 253 [±3 days]) and at
Visit 15, etc. (Days 337 and every 12 weeks thereafter [±7 Days]).


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Table 17.
Procedures and Assessments at Visits 13, 15, etc. (Days 253, 337, and 
Every 12 Weeks)
Assessment or Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis on day of visit or within 1 week 
prior to the visit; the same method of assessment (CT or MRI) should be used as was used 
at baseline
During-Visit Assessments and Procedures
FACT-Lym
HRQL instrument (Appendix C) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
Adverse eventsa, b
Recording of adverse events occurring since prior visit
Concomitant medications
Recording of concomitant medication used since prior visit
Performance status
Using Karnofsky performance status criteria (see Appendix D)
Compliance
Counting of returned study drug
Vital signs
Including weight, temperature, resting systolic and diastolic blood pressure while sitting, 
resting heart rate while sitting
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, 
total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, 
triglycerides
Pharmacodynamic markers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Circulating cells for 
immuno-phenotyping
Including quantitation of absolute number of CD4+, CD8+, CD16/CD56+ and CD19+ 
cells by flow cytometry
Serum immunoglobulins
Including quantitative levels of IgA, IgE, IgG, and IgM
SPEP
Including serum IgM monoclonal protein level (subjects with WM only; performed locally 
per standard of care)
Bone marrow biopsy and 
aspirate
To be performed post-baseline to confirm response category in subjects with potential CR 
by radiological assessments. If the baseline bone marrow biopsy/aspirate did not show 
lymphoma involvement, it is not necessary to obtain a follow-up bone marrow 
biopsy/aspirate to establish CR.
Drug dispensing
Dispensing of12-week supply of idelalisib study drug to the subject with instructions for 
self-administration at home
Scheduling of next-visit 
radiology assessment
CT or MRI imaging of chest, abdomen, and pelvis to be scheduled to occur within 1 week 
prior to the next clinic visit (Visit 15 and every 12 weeks therafter); the same method of 
assessment (CT or MRI) should be used as was used at baseline
Monthly CMV Testing
CMV surveillance must be conducted approximately every 4 weeks.
Immune-monitoring Labs

Lymphocyte subset panel using flow cytometry (immunophenotyping)

Quantitative immunoglobulins: IgG, IgM, IgA

Serum CH50 level
a
Assessment of Diarrhea/Colitis: obtain history of onset and duration of diarrhea, including description of number of stools 
and stool composition (eg, watery, bloody, nocturnal), travel history, dietary changes and a medication review to identify 
possible diarrheogenic agents.
b
Assessment of Diarrhea/Colitis: perform physical examination including assessment for fever, dizziness, abdominal 
pain/cramping, and weakness (ie, evaluate for sepsis, bowel obstruction, dehydration).
Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging; FACT-Lym, Functional Assessment of Cancer 
Therapy: Lymphoma; HRQL, health-related quality of life; ALT, alanine aminotransferase; AST, aspartate aminotransferase; 
ALP, alkaline phosphatase; GGT, gamma-glutamyltransferase; LDH, lactate dehydrogenase; Ig, immunoglobulin; 
SPEP, serum protein electrophoresis; LPL, lymphoplasmacytoid lymphoma, WM, Waldenstroms Macroglobulinemia; 
CR, complete response


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7.2.14.
End-of-Treatment Visit (Clinic Visit)
At the time of discontinuation from the treatment, the subject should have the following 
procedures and assessments performed. The radiology assessment should be obtained if the last 
radiology assessment was >4 weeks from the end-of-treatment visit. ECG and laboratory 
evaluations should be obtained if these had not been obtained within the preceding 2 weeks.
Table 18.
Procedures and Assessments at End-of-Treatment Visit
Assessment or Procedure
Explanation
Radiology assessmenta
CT or MRI imaging of neck, chest, abdomen, and pelvis; the same method of assessment 
(CT or MRI) should be used as was used at baseline
Adverse events c,d
Recording of adverse events occurring since prior visit; if a clinically significant adverse 
event or abnormal result is observed that is not resolved by the end-of treatment visit, 
repeat evaluations should be performed to document resolution or stabilization of the 
abnormality
Concomitant medications
Recording of concomitant medication used since prior visit
Performance status
Using Karnofsky performance status criteria (see Appendix D)
Physical examination
Including evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly
Compliance
Counting of used and unused study drug since last compliance assessment and return of all 
study drug
Vital signs
Including weight, temperature, resting systolic and diastolic blood pressure while sitting, 
resting heart rate while sitting
12-lead ECGb
To be obtained while subject is resting in the supine position
Hematologyb
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistryb
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, 
total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, 
triglycerides
SPEPb
Including serum IgM monoclonal protein level (subjects with WM only; performed locally
per standard of care)
Pharmacodynamic markersb
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Circulating cells for 
immuno-phenotypingb
Including quantitation of absolute number of CD4+, CD8+, CD16/CD56+ and CD19+ 
cells by flow cytometry
Serum immunoglobulinsb
Including quantitative levels of IgA, IgE, IgG, and IgM
Monthly CMV Testinge
CMV surveillance must be conducted approximately every 4 weeks. 
Immune-monitoring labs

Lymphocyte subset panel using flow cytometry (immunophenotyping)

Quantitative immunoglobulins: IgG, IgM, IgA

Serum CH50 level
a
The radiology assessment should be obtained if the last radiology assessment was >4 weeks from the end-of-treatment visit.
b
ECG and laboratory evaluations should be obtained if these had not been obtained within the preceding 2 weeks.
c
Assessment of Diarrhea/Colitis: obtain history of onset and duration of diarrhea, including description of number of stools 
and stool composition (eg, watery, bloody, nocturnal), travel history, dietary changes and a medication review to identify 
possible diarrheogenic agents.
d
Assessment of Diarrhea/Colitis: perform physical examination including assessment for fever, dizziness, abdominal 
pain/cramping, and weakness (ie, evaluate for sepsis, bowel obstruction, dehydration).
e
Unless already performed within 4 weeks of the End of Treatment visit.
Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging; ECG, electrocardiogram; 
ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; GGT, gamma-glutamyltransferase; 
LDH, lactate dehydrogenase; SPEP, serum protein electrophoreis; LPL, lymphoplasmacytoid lymphoma, 
WM, Waldenstroms Macroglobulinemia; Ig, immunoglobulin


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7.2.15.
Immediate Post-Treatment Safety Follow-up
After the last dose of study treatment subjects should be followed for any drug-related adverse 
events and/or ongoing serious adverse events until those events have resolved or become stable, 
whichever occurs later. Follow-up may be obtained in person or by telephone contact.
7.2.16.
Long-Term Follow-up
Long-term post-treatment follow-up will be obtained for all subjects, including those who 
prematurely withdraw from study treatment.
The long-term post-treatment follow-up will be conducted (as measured from the last dose of 
study drug) at ~6-month intervals during Year 1 and Year 2, and at ~12-month intervals during 
Years 3, 4, and 5. Data on subject survival, date of disease progression if processgion occurred 
after the end-of-treatment, post-idelalisib therapies for iNHL, and occurrence of new 
non-iNHL-related health problems (eg, chronic hepatic abnormalities, endocrine disorders, renal 
dysfunction, etc) will be collected from all subjects who receive 1 dose of study drug. The 
information will be gathered during a routine clinic visit or other contact with the subject, or via 
telephone. These data will be collected in the source documents (eg, subject medical record) and 
transcribed into the electronic case report form. Any unsuccessful efforts to contact the subject
(eg, dates of unanswered phone calls, return of certified letter sent to subject’s home, etc) will be 
documented.
7.3.
Sample Storage
 
 
 
 
 
7.4.
Blood Collection
Computations of blood drawing requirements for this study are shown in Table 19. The 
maximum amount of blood to be drawn at a visit is ≤82 mL and the total amount of blood to be 
drawn over the initial 52-week study period (including the 4-week screening period and through 
Week 48 of the study) is ~379 mL. For a 40-kg person (the smallest participant expected to 
enroll in the study), this equates to maximum blood volume per body weight per visit 
of ~2.1 mL/kg and a total blood volume per body weight per average 6-week period of 
~1.1 mL/kg. These quantities of blood are within accepted limits of 3.0 mL/kg of body weight 
for a single blood draw and 7.0 mL/kg of body weight for any 6-week period 
[National Institutes of Health 2003].
Specific details regarding blood sample collection and processing requirements will be provided 
separately in the central laboratory manual.
PPD


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Table 19.
Blood Drawing Requirements Through Visit 15 (Week 48)
Test
Sample 
Type
Tube
Type
Blood 
Per Tube
(mL)
Tubes (n)
Blood Volume (mL)
Maximum 
Per Visit
Total in 
Studya
Maximum 
Per Visit
Total in 
Studya
Hematology
Plasma
K2-EDTA
3
1
15
3
45
Serum chemistry 
(including -HCG)
Serum
Clot
5
1
15
5
75
Coagulation
Plasma
Citrate
4
1
1
4
4
Serum virology
Serum
Clot
9
1
1
9
9
Pharmacodynamic
markers
Plasma
K2-EDTA
5
1
11
5
55
Serum
Clot
5
1
11
5
55
Circulating cells for 
immuno-phenotyping
Plasma
K2-EDTA
4
1
6
4
24
Serum 
immunoglobulins
Serum
Clot
5
1
6
5
30
Idelalisib
pharmacokinetics 
(limited, all subjects)
Plasma
K2-EDTA
2
2
8
4
16
Total
82
369
a
Computed for initial 52-week period (considering 4 weeks for screening and 48 weeks on study)
Abbreviations: -HCG, beta human chorionic gonadotropin; K2-EDTA, potassium-ethylenediaminetetraacetic acid; 
DNA, deoxyribonucleic acid; RNA, ribonucleic acid
Serum and plasma may be retained for subjects who have provided specific informed consent for 
sample banking.
7.5.
Study Parameter Selection Rationale
The planned study assessments and timing have been selected as appropriate for screening of 
subjects, for determination of idelalisib-related or disease-related toxicities, for dose 
modification during the study, for characterization of drug exposure and desired pharmacological 
effects, and for evaluation of drug activity. The scheduling of testing is designed to collect a 
complete safety and pharmacology data set while maintaining subject tolerance of study 
procedures. The planned schedule of tumor assessments is consistent with expected rate of 
changes and appropriately balances precise measurement of tumor control with the expense and 
subject inconvenience associated with radiological procedures. For discussion of the rationale for 
endpoint selection, see Section 3.5.
PPD
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8.
ACTIVITY AND SAFETY ASSESSMENTS
8.1.
Tumor Size Assessments
The determination of iNHL response and progression will be based on standardized criteria 
{Cheson 2007, Owen 2013}. Treatment decisions by the investigator will be based on these 
assessments.
8.1.1.
Timing of Assessments
During screening, imaging-based tumor assessments should be performed within 28 days prior to 
the start of treatment. On-study tumor assessments should be performed at ~8- to 12-week 
intervals as dictated by the study protocol. An end-of-treatment tumor assessment (if the subject
withdraws from the study for reasons other than tumor progression on a routine imaging/scan) 
should be performed if the last assessment was performed >4 weeks prior to end-of-treatment 
visit.
8.1.2.
Method of Assessment
Imaging-based evaluation is preferred to evaluation by clinical examination. CT or MRI scans 
are the required methods for tumor assessments. PET scanning will not be a required component 
of response assessment in this study. Clinical palpation, chest x-ray, ultrasound, endoscopy, 
laparoscopy, radionuclide scan, or tumor markers will not be considered for response 
assessment.
The same method of assessment and the same technique (eg, scan type, scanner, subject position, 
dose of contrast, injection/scan interval) should be used to characterize each identified and 
reported lesion at baseline and during study treatment and follow-up. CT or MRI of the neck, 
chest, abdomen, and pelvis should be performed with cuts of ≤10 mm in slice thickness 
contiguously.
All relevant clinical and radiographic information required to make each tumor status assessment 
must be made available for source verification and for submission to the IRC (see Section 11.2).
For subjects with WM, serum Monoclonal IgM as assessed by SPEP will only be considered if 
baseline total serum IgM quantitation by nephelometry is not available. The same laboratory 
method for IgM assessment within a given subject should be used throughout the study.
8.1.3.
Identification of Index and Non-Index Tumor Lesions at Baseline
At baseline, tumor lesions will be categorized as index lesions or non-index lesions as described 
below.
Up to 6 lesions (eg, lymph nodes, liver or spleen nodules, and/or other circumscribed 
extra-nodal masses) should be selected as index lesions that will be used to quantitate the status 
of the disease during study treatment. Ideally, the index lesions should be located in disparate 
regions of the body and include mediastinal and retroperitoneal areas of disease whenever these 
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Index lesions will be measured and recorded at baseline and at the stipulated intervals during 
treatment. The cross-sectional dimensions (the largest cross-sectional diameter, ie, the 
longest diameter [LD] × the longest perpendicular diameter [LPD]) will be recorded (in cm) for 
each index lesion. The product of the perpendicular diameters (PPD) will be calculated. The 
PPDs and the sum of the products (SPDs) for all index lesions will be calculated and recorded. 
The baseline SPDs will be used as references by which objective tumor response will be 
characterized during treatment. The nadir SPD and nadir LDs of individual lesions will be used 
as references by which objective tumor progression will be characterized during treatment. All 
PPD and SPD measurements will be reported in centimeters squared.
8.1.3.1.
Index Lesions
8.1.3.1.1.
Nodal Index Lesions
A nodal mass may be selected as a nodal index lesion if it is both abnormal and measurable at 
baseline. A lymph node lesion is considered abnormal if it has a single diameter that is 1.0 cm 
and is considered measurable if it has 2 perpendicular diameters that can be accurately measured 
in cross section with the LD being 1.0 cm and the LPD also being 1.0 cm.
Abnormal, measurable nodal lesions will be subcategorized as either large or small.

Large nodal lesions have an LD that is >1.5 cm and an LPD that is 1.0 cm.

Small nodal lesions have an LD that is >1.0 cm and 1.5 cm and an LPD that is >1.0 cm.
Index lesions measuring >1.5 cm in the LD, regardless of the measurement of the LPD, will be 
prioritized during baseline index lesion selection.
8.1.3.1.2.
Extra-Nodal Index Lesions
An extra-nodal mass may be selected as an index lesion if it is both abnormal and measurable at 
baseline. An extra-nodal mass of any size is considered abnormal. It is considered measurable if 
it has 2 perpendicular diameters that can be accurately measured in cross section with the LD 
being 1.0 cm and the LPD also being ≥1.0 cm.
8.1.3.2.
Non-Index Lesions
Any other measurable and abnormal nodal or extra-nodal lesions not selected for quantitation as 
index lesions may be considered non-index lesions. In addition, non-measurable evidence of 
iNHL such as nodal lesions or extra-nodal lesions with both diameters < 1.0 cm, bone lesions, 
leptomeningeal disease, ascites, pleural or pericardial effusions, lymphangitis of the skin or lung, 
abdominal masses that are not confirmed and followed by imaging techniques, cystic lesions, 
previously irradiated lesions, or lesions with artifacts may be considered as non-index disease.
The presence or absence of non-index disease should be recorded at baseline and at the stipulated 
intervals during treatment. If present at baseline, up to 6 non-index lesions should be recorded. 
The non-index disease at baseline will be used as a general reference to further characterize 


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regression or progression of lymphoma during assessments of the objective tumor response 
during treatment. Measurements are not required and these lesions should be followed as 
“present” or “absent”.
8.1.4.
Follow-up of Index and Non-Index Tumor Lesions
8.1.4.1.
Nodal Lesions
At follow-up time points, the LDs for individual lesions and the SPD of all nodal index lesions 
will be considered. Because nodal index lesions that have one or both diameters 
>0 cm and 1.0 cm cannot be reliably measured, a default value of 1.0 cm will be assigned for 
each diameter that meets these criteria and the resulting PPD will be used in SPD calculations. 
Based on this convention, a CR may be achieved even if an SPD value is >0 cm2.
New or enlarging nodal lesions that are still 1.0 cm by 1.0 cm will not be considered to 
represent recurrent or progressive disease. A new node that measures >1.5 cm in any diameter or 
a new node that measures >1.0 cm to 1.5 cm in the LD and measures >1.0 cm in the LPD will 
be considered progressive disease.
In cases in which a large lymph node mass has split into multiple components, all 
subcomponents regardless of size will be used in calculating the SPD. Progression of the lesion 
will be based on the SPD of all sub-components. Lesion sub-components will have PPDs 
calculated. Similarly, lesion sub-components that are visible but neither abnormal nor 
measurable will have the default PPD of 1.0 cm2 (1.0 cm 1.0 cm) used in calculating the SPD.
If lesions merge, a boundary between the lesions will be established so the LD of each individual 
lesion can continue to be measured. If the lesions have merged in a way that they can no longer 
be separated by this boundary, the newly merged lesion will be measured bi-dimensionally.
8.1.4.2.
Extra-nodal Lesions
At follow-up time points, the LDs of each single extra-nodal lesion and the SPD of all 
extra-nodal index lesions will be considered. Because extra-nodal index lesions that have one or 
both diameters 1.0 cm and >0 cm cannot be reliably measured, a default value of 1.0 cm will be 
assigned for each diameter that meets these criteria and the resulting PPD will be used in SPD 
calculations. If an extra-nodal lesion is no longer clearly visible, it will be considered resolved 
and its PPD will be defined as 0 cm2.
If an extra-nodal lesion that had resolved (ie, had a PPD of 0 cm2) subsequently reappears, the 
subject will be considered to have progressive disease. A new extra-nodal lesion of any size that 
appears at a site that was not previously involved with lymphoma and is discernable to the 
radiologist by CT scan will be considered progressive disease.


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8.1.5.
Definitions of Tumor Response and Progression
Responses will be categorized as CR, PR, minor response (MR) for subjects with WM only, 
stable disease (SD), or progressive disease (PD). In addition, a response category of not 
evaluable (NE) is provided for situations in which there is inadequate information to otherwise 
categorize response status. A response category of no disease (ND) is included for situations in 
which there is no evidence of tumor either at baseline or on treatment.
The best overall response will be determined. The best overall response is the best response 
recorded from the start of treatment until progressive disease/recurrence (taking as reference for 
PD the smallest measurements recorded since treatment started). Subjects with NE or ND will be 
counted as failures in the analyses of tumor response. Where imaging data are available, these 
data will supersede physical examination data in determining tumor status.
8.1.5.1.
Response Categories
8.1.5.1.1.
Complete Response
To satisfy criteria for complete response (CR), all of the following criteria must be met:

No evidence of new disease

Regression of all index nodal and extra-nodal masses to normal size (≤1.5 cm in the LD for 
nodes that were considered large at baseline and ≤1.0 cm in the LD for nodes that were 
considered small at baseline) (see Section 8.1.3.1.1 for definitions of large and small nodes)

Regression to normal of all nodal non-index disease and disappearance of all detectable 
non-nodal, non-index disease

Normal spleen and liver size by imaging studies, no hepatic or splenic lymphoma nodules, 
and no new organ enlargements

Morphologically negative bone marrow based on an adequate unilateral core biopsy 
(>20 mm unilateral core); if the sample is indeterminate by morphology, it should be 
negative by immunohistochemistry

If PET performed (not required), no evidence of residual disease

If the subject has WM, disappearance of monoclonal protein by immunofixation
8.1.5.1.2.
Partial Response
To satisfy criteria for partial response (PR), all of the following criteria must be met except for
subjects with WM as noted below:

No evidence of new disease


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
A 50% decrease from baseline in the SPD of the index nodal and extra-nodal lesions 
(eg, splenic or hepatic nodules)

No increase in the size of non-index nodes or non-measurable disease

No increase in the size of the liver or spleen and no new organ enlargements.

Persistence of bone marrow involvement in a subject who meets other criteria for CR based 
on the disappearance of all nodal and extra-nodal masses

If PET performed (not required):
Typically FDG-avid lymphoma: if no pretreatment PET scan or if the PET scan was 
positive before therapy, the on-treatment PET is positive in 1 previously involved site.
Variably FDG-avid lymphoma/FDG-avidity unknown: if no pretreatment PET scan or if 
the pretreatment PET scan was negative for lymphoma, CT criteria should be used in 
assessing the tumor during treatment. If the PET scan was positive before therapy, the 
on-treatment PET is positive in 1 previously involved site.

For subjects with WM
50% decrease from baseline in monoclonal IgM concentration by SPEP or total serum 
IgM quantitation by nephelometry
Any decrease from baseline in the SPD of the index nodal and extral-nodal lesions 
(eg, splenic or hepatic nodules)
8.1.5.1.3.
Minor Response (WM only)
To satisfy criteria for MR, the following criteria must be met: 

A ≥25% but <50% decrease from baseline in either monoclonal IgM concentration by SPEP
or total serum IgM quantitation by nephelometry

No increase from baseline in the SPD of the index nodal and extra-nodal lesions 
(eg, splenic or hepatic nodules)

No increase in the size of non-index nodes or non-measurable disease

No increase in the size of the liver or spleen and no new organ enlargements
8.1.5.1.4.
Stable Disease
To satisfy criteria for stable disease (SD), all of the following criteria must be met:

No evidence of new disease


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
Neither sufficient tumor shrinkage from baseline to qualify for PR nor sufficient evidence of 
tumor growth to qualify for PD

If the subject has WM, neither a sufficient decrease from baseline in either monoclonal IgM 
concentration by SPEP or total serum IgM quantitation by nephelometry to qualify for MR or 
PR nor a sufficient increase from nadir in either monoclonal IgM concentration by SPEP or 
total serum IgM quantitation by nephelometry to qualify for PD
8.1.5.1.5.
Progressive Disease
The occurrence of any of the following events indicates progressive disease (PD):

Evidence of any new disease that was not present at baseline:
A new node that measures >1.5 cm in any diameter
A new node that measures >1.0 cm to 1.5 cm in the LD and >1.0 cm in the LPD
Reappearance of an extra-nodal lesion that had resolved (ie, had previously been assigned 
a PPD of 0 cm2)
A new extranodal lesion of any size
New non-index disease (eg, effusions, ascites, or other organ abnormalities) of any size 
unequivocally attributable to lymphoma (usually requires PET, biopsy, cytology, or other 
non-radiologic confirmation to confirm disease attributable to lymphoma). 
Note: Isolated new effusions, ascites, or bone lesions are not sufficient evidence alone 
of PD unless histologically confirmed. In subjects with no prior history of pulmonary 
lymphoma, new lung nodules identified by CT are usually benign. Thus, a declaration 
of PD should not be made if this is the only manifestation of an apparently new lesion.

Evidence of worsening of nodal or extra-nodal index lesions:
Increase from the nadir by 50% in the SPD of index lesions
Increase from the nadir by 50% in the LD of an individual node or extra-nodal mass that 
now has an LD of >1.5 cm and an LPD of > 1.0 cm

Unequivocal increase in the size of non-index lesions or non-measurable disease 
(eg, pleural effusions or bone lesions)

An unequivocal increase in the size of the liver, spleen or other organ

If PET performed (not required):
The appearance of any new lesion compatible with lymphoma with confirmation by other 
radiographic or histological modalities.
The reappearance of any activity in a pre-existent lesion that meets size criteria for a new 
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
If the subject has WM, a 25% increase from the nadir in either monoclonal IgM 
concentration by SPEP or total serum IgM quantitation by nephelometry (with confirmation 
by a repeat measurement). An absolute increase of at least 0.5 gram/dL is required to define 
progression.
Note: If there is uncertainty regarding whether there is true progression, the subject may 
continue study treatment and remain under close observation (eg, evaluated at 
4-week intervals). If subsequent evaluations suggest that the subject is experiencing 
progression, then the date of progression should be the timepoint at which progression was 
first identified.
8.1.5.1.6.
Non-Evaluable
In a subject who does not have evidence of PD, the occurrence of any of the following conditions 
indicates a response status of NE:

There are no images or inadequate or missing images.

For subjects with WM, on-study monoclonal IgM concentration by serum protein 
electrophoresis (SPEP) or total serum IgM quantitation by nephelometry is missing in a 
subject with baseline IgM available. If the baseline IgM value is missing, IgM will not be 
considered for the on-study disease assessments.
Note: A time-point will be considered to have a response of NE if any index lesion is missing. 
PD may be assigned at any time point regardless of the extent of missing index or non-index 
lesions. Missing non-index lesions will not impact the ability to assess for response or disease 
progression.
8.1.5.1.7.
No Disease
In a subject who does not have evidence of PD, the occurrence of all of the following conditions 
indicates a response status of ND:

Index disease absent at both baseline and on-treatment

Non-index disease absent at both baseline and on-treatment

Enlargement of the liver and spleen absent at both baseline and on-treatment
8.2.
Adverse Event Assessments
8.2.1.
Adverse Event Definitions
8.2.1.1.
Adverse Events
By convention, an adverse event is any untoward medical occurrence in a trial subject who is 
administered a drug or biologic (medicinal product) or who is using a medical device; the event 
does not necessarily have a causal relationship with study drug administration or usage. An 
adverse event can therefore be any unfavorable and unintended sign (including an abnormal 


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laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product. For 
this protocol, untoward medical occurrences that should be reported as adverse events include 
the following:

All adverse events that are suspected to be due to study drug 

All reactions from medication abuse, withdrawal, sensitivity, or toxicity

Apparently unrelated illnesses, including the worsening of a preexisting illness

Injury or accidents. Note that if a medical condition is known to have caused the injury or 
accident (a fall secondary to dizziness), the medical condition (dizziness) and the accident 
(fall) should be reported as 2 separate adverse events.

Abnormalities in physiological testing or physical examination findings that require clinical 
intervention or further investigation (beyond ordering a repeat [confirmatory] test).

Laboratory or ECG abnormalities that require clinical intervention or further investigation 
(beyond ordering a repeat [confirmatory] test) unless they are associated with an already 
reported clinical event. Laboratory abnormalities associated with a clinical event 
(eg, elevated liver enzymes in a subject with jaundice) should be captured in the source 
documents. Laboratory abnormalities not requiring clinical intervention or further 
investigation will be captured as part of overall laboratory monitoring, and should not be 
reported as adverse events.

A preexisting condition (eg, allergic rhinitis) must be noted on the appropriate baseline CRF 
but should not be reported as an adverse event unless the condition worsens or episodes 
increase in frequency during the adverse event reporting period. Diagnostic and therapeutic 
non-invasive and invasive procedures, such as surgery, should not be reported as adverse
events. However, the medical condition for which the procedure was performed should be 
reported if it meets the definition of an adverse event. For example, an acute appendicitis that 
begins during the adverse event reporting period should be reported as the adverse event and 
the resulting appendectomy should be recorded in the source documents. If a surgical 
procedure was planned prior to entry into the trial, and the surgery is not performed because 
of a worsening of a baseline condition, this should not be reported as an adverse event. 
Note that, as described in Section 8.2.1.2, any in-patient hospitalization occurring as the 
consequence of an adverse event during the study period should be reported as a serious 
adverse event.

Each adverse event is to be classified as serious or nonserious.
8.2.1.2.
Serious Adverse Events
A serious adverse event is an untoward medical occurrence, regardless of whether or not it is 
considered related to the study medication, which results in:

Death (ie, all deaths on treatment or within 30 days after last study drug administration), 
excluding deaths due to disease progression. Deaths occurring later than 30 days following 
the last dose need not be reported as serious adverse events unless they are a result of an 
event that started within the time frame covered by the on-study definition. The reported 


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adverse event should be the event that caused the death. Death is the outcome of this 
serious adverse event. In addition, any adverse event resulting in death that occurs 
subsequent to the adverse event-reporting period and that the investigator assesses as 
possibly related to the study drug should also be reported as serious.

Life-threatening situation (ie, with an immediate risk of death from the event as it occurred). 
It does not include an event that, had it occurred in a more serious form, might have caused 
death.

In-patient hospitalization or prolongation of existing hospitalization
(excluding hospitalizations for administration of the study drug, procedures required by the 
study protocol, or tumor-related diagnostic procedures; other planned hospitalizations; or 
hospitalizations related only to progression of disease). Treatments in the emergency room 
for procedures such as hydration that do not require admitting the subject to the hospital are 
not considered as serious.

Persistent or significant disability/incapacity

Congenital anomaly/birth defect

Any other adverse event that the investigator or the sponsor judges to be serious or which is 
defined as serious by the regulatory agency in the local country. Medical judgment should be 
exercised in deciding whether a reaction is serious in other situations. Important adverse 
reactions that are not immediately life-threatening or do not result in death or hospitalization 
but may jeopardize the subject or may require medical or surgical intervention to prevent any 
of the outcomes listed above should be considered serious. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment administration in an emergency 
room or at home, new cancers or blood dyscrasias, or convulsions that do not result in 
insubject hospitalization, or the development of drug dependency or drug abuse.

An event needs not be reported as a serious adverse event if it exclusively represents a 
relapse or an expected change or progression of the baseline malignant disease.
8.2.1.3.
Unexpected Adverse Events
Unexpected adverse events are defined as those events that were not previously reported with 
study drug as referenced in the protocol, investigator brochure, consent form, or package insert, 
or that are symptomatically and pathophysiologically related to a known toxicity but differ 
because of greater severity or specificity. For example, under this definition, hepatic necrosis 
would be unexpected (by virtue of greater severity) if the investigator brochure only referred to 
elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral 
vasculitis would be unexpected (by virtue of greater specificity) if the investigator brochure only 
listed cerebral vascular accidents. “Unexpected,” as used in this definition, refers to an adverse 
drug experience that has not been previously observed (eg, included in the investigator brochure, 
study protocol, informed consent document, or package insert) rather than from the perspective 
of such experience not being anticipated from the pharmacological properties of the 
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The investigator brochure provides a summary of the safety profile of idelalisib based on a 
review of the available safety data from studies in healthy volunteers and in subjects with cancer. 
Consistent with the definitions outlined in this section, the study sponsor will consider the 
information provided in the investigator brochure when determining whether a drug-related 
serious adverse event is unexpected. In making this determination, the study sponsor will 
consider the uniqueness, type, severity, and specificity of the event relative to past events of 
similar nature, recognizing that an event that might be considered expected in a subject with one 
condition might be considered unexpected in a subject with another condition. This assessment 
will be used in determining the need for expedited regulatory reporting.
8.2.2.
Eliciting Adverse Event Information
The investigator is to report all directly observed adverse events and all adverse events 
spontaneously reported by the study subject. In addition, each study subject will be questioned 
about adverse events at each scheduled clinic visit or during each telephone contact with the 
subject following initiation of study treatment. The type of question asked should be open-ended, 
eg, "Have you had any new health problems?” or a similar type of query.
8.2.3.
Adverse Event Recording
All adverse events (both serious and nonserious) that occur in subjects during the adverse event 
reporting period must be recorded, whether or not the event is considered drug related. If the 
subject is a screen failure, then only adverse events related to study procedures should be 
recorded. In addition, any known untoward event that occurs subsequent to the adverse event 
reporting period that the investigator assesses as possibly related to the investigational 
drug/product should also be recorded as an adverse event.
All adverse events are to be recorded in the source documents and on the CRF using concise 
medical terminology; whenever possible terms contained in MedDRA should be employed. In 
addition, the following information should be recorded:

Indication of whether the event is serious or nonserious (see Section 8.2.1.2)

Relationship to study drug (see Section 8.2.4)

Severity of the event (see Section 8.2.5)

Onset date and time

Resolution date and time, or date and time of death 

Action taken

Outcome of the event
Classification of the event as serious or nonserious determines the reporting procedures to be 
followed.


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8.2.4.
Describing Adverse Event Relationship to Study Drug
Based on the considerations outlined in Table 20 below, an evaluation of whether an adverse 
event can be attributed to the study drug should be provided.
Table 20.
Relationship of Study Drug to Adverse Event
Relationship
Description
Definite
A clinical event in which a relationship to the use of the study drug seems definite because of such 
factors as consistency with known effects of the drug; a clear temporal association with the use of 
the drug; lack of alternative explanations for the event; improvement upon withdrawal of the drug 
(de-challenge); and recurrence upon resumption of the drug (rechallenge).
Probable
A clinical event in which a relationship to the study drug seems probable because of such factors 
as consistency with known effects of the drug; a reasonable temporal association with the use of 
the drug; lack of alternative explanations for the event; and improvement upon withdrawal of the 
drug (de-challenge).
Possible
A clinical event with a reasonable temporal association with administration of the study drug, and 
that is not likely to be explained by concurrent disease or other drugs or chemicals. Information on 
drug withdrawal may be lacking.
Unlikely
A clinical event with a temporal relationship to study drug administration that makes a causal 
relationship improbable and for which other factors suggesting an alternative etiology exist. Such 
factors might include a known relationship of the adverse event to a concomitant drug, past 
medical history of a similar event, the subject’s disease state, intercurrent illness, or environmental 
factors.
Unrelated
A clinical event in which a relationship to the study drug seems improbable because of factors 
such as inconsistency with known effects of the study drug; lack of a temporal association with 
study drug administration; lack of association of the event with study drug withdrawal or 
rechallenge; and/or presence of alternative explanations for the event. Alternative explanations 
might include a known relationship of the adverse event to a concomitant drug, past medical 
history of a similar event, the subject’s disease state, intercurrent illness, or environmental factors.
8.2.5.
Grading of Severity of Adverse Event
The severity of adverse events will be graded using the CTCAE, Version 3.0
(refer to http://ctep.info.nih.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf). 
For each episode, the highest severity grade attained should be reported
If a CTCAE criterion does not exist, the investigator should use the grade or adjectives: 
Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or 
Grade 5 (fatal) to describe the maximum intensity of the adverse event. For purposes of 
consistency with the CTCAE, these intensity grades are defined in Table 21.


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Table 21.
Grading of Adverse Event Severity
Grade
Adjective
Description
Grade 1
Mild
Sign or symptom is present, but it is easily tolerated, is not expected to have a 
clinically significant effect on the subject’s overall health and well-being, does not 
interfere with the subject’s usual function, and is not likely to require medical 
attention.
Grade 2
Moderate
Sign or symptom causes interference with usual activity or affect clinical status, and 
may require medical intervention.
Grade 3
Severe
Sign or symptom is incapacitating or significantly affects clinical status and likely 
requires medical intervention and/or close follow-up.
Grade 4
Life-threatening
Sign or symptom results in a potential threat to life.
Grade 5
Fatal
Sign or symptom results in death.
Note the distinction between the seriousness and the severity of an adverse event. Severe is a 
measure of intensity; thus, a severe reaction is not necessarily a serious reaction. For example, a 
headache may be severe in intensity, but would not be classified as serious unless it met one of 
the criteria for serious events listed in Section 8.2.1.2 above.
8.2.6.
Follow-up of Unresolved Adverse Events
All adverse events should be followed until resolution, the investigator assesses them as chronic 
or stable, or the end-of-treatment visit. All related adverse events should be followed until 
resolution or 30 days following the last dose of study drug. The investigator should use his/her 
discretion in ordering additional tests as necessary to monitor the resolution of such events. 
A subject withdrawn from the study because of an adverse event must be followed by the 
investigator until the clinical outcome from the adverse event is determined.
8.2.7.
Adverse Event Reporting Period
The start of the adverse event reporting for a study subject will coincide with the day the 
informed consent is signed. The end of the adverse-event-reporting period occurs at the 
completion of study treatment or when any ongoing drug-related adverse events and/or 
serious adverse events have resolved or become stable. A longer reporting period applies in the 
case of pregnancy (see Section 8.3.2). Except as part of the long-term follow-up 
(see Section 7.2.16), new adverse events beginning >30 days after the last study treatment will 
not be considered in the safety database.
8.2.8.
Site Adverse Event Reporting Requirements
Classification of an event as serious or nonserious (see Section 8.2.1.2) determines the reporting 
procedures to be followed. Site reporting requirements for adverse events are summarized in 
Table 22, below.


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Table 22.
Site Reporting Requirements for Adverse Events
Classification
Reporting Time
Reporting Action
Within 24 hours
Fax report on designated serious adverse event report form to 
the INC Research Drug Safety Case Manager a, and to the site 
IRB/IEC, as per local IRB/IEC requirements
Within 5 working days
Photocopies of relevant CRFs (eg, adverse event form, 
medical history form, concomitant drug/therapy form) and 
source documentsb (eg, progress notes, nurses’ notes, laboratory 
and diagnostic test results, discharge summaries) to the 
INC Research Drug Safety Case Managera.
Per CRF submission procedure
Record and submit information on appropriate CRFs
Nonserious
Per CRF submission procedure
Record and submit information on appropriate CRFs
a
The INC Research Drug Safety Case Manager serious adverse event telephone number is
 and the 
serious adverse event fax number is 
b
Subject name, address, and other personal identifiers should be obscured.
Abbreviations: IRB/IEC, Institutional Review Board/Independent Ethics Committee; CRF, case report form
For serious adverse events, in addition to completing the adverse event portion of the CRF, the 
serious adverse event report form must also be completed. The serious adverse event report form 
should be signed by the investigator; however, if the investigator is unable to sign at the time of 
the event or within 24 hours, the form should be signed by the clinical staff member reporting the 
serious adverse event (eg, the study coordinator). The serious adverse event report form must be 
faxed to the contract research organization (CRO) (designated as the INC Research Drug Safety 
Case Manager), and to the site IRB/IEC (if required by local regulations) within 24 hours. 
Follow up information to the serious adverse event should be clearly documented as “follow up” 
in the serious adverse event report form and must be faxed to these same parties. All follow up 
serious adverse event report forms for the respective event must be signed by the investigator. 
The subject’s name, address, and other personal identity information should be obscured on any 
source documents (eg, progress notes, nurses’ notes, laboratory and diagnostic test results, 
discharge summaries). Only the subject’s study number, initials or date of birth are to be 
provided. The information in the adverse event portion of the CRF page and the serious adverse 
event report form(s) must match or be reconciled. Where the same data are collected, the forms 
must be completed in a consistent manner. For example, the same adverse event term should be 
used on both forms.
In the rare event that the investigator does not become aware of the occurrence of a 
serious adverse event immediately (for example, if a subject initially seeks treatment elsewhere), 
the investigator is to report the event within 24 hours after learning of it and to document his/her 
first awareness of the adverse event.
The INC Research Drug Safety Case Manager contact information for reporting serious adverse 
events is:
PPD
PPD


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INC Research Drug Safety Case Manager
Serious adverse event telephone number:
Serious adverse event fax number:
8.2.9.
Study Sponsor Adverse Event Reporting Requirements
Gilead Sciences is required to expedite reports to regulatory authorities worldwide relating to 
serious adverse events including events related to study procedures; serious adverse drug 
reactions (SADRs); or suspected, unexpected, serious adverse reactions (SUSARs) consistent 
with relevant legislation or regulations, including the applicable US FDA 
Code of Federal Regulations (CFR), the European Commission Clinical Trials Directive 
(2001/20/EC, and revisions), and other country-specific legislation or regulations.
Each serious adverse event report received from the investigator through INC Research 
Pharmacovigilance will be evaluated by Gilead Sciences Drug Safety and Public Health (DSPH). 
Gilead Sciences DSPH will assess the seriousness of the event, the expectedness of the event, 
and the relationship to participation in the study. For regulatory reporting purposes, expectedness 
will be determined by Gilead Sciences using reference safety information specified in the 
investigator brochure and the event will be classified as related if either the investigator or 
Gilead Sciences determines that the event may be related to the study drug.
Gilead Sciences or its designee will also provide all investigators a safety letter e-mail, fax, or 
overnight mail notifying them of a SUSAR. Investigators will be requested to provide written 
notification of the SUSAR to the IRB/IEC as soon as is practical, consistent with local regulatory 
requirements and local institutional policy.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the Investigator’s Brochure or relevant local label as applicable.
8.3.
Special Situation Reporting Requirements
8.3.1.
Definitions of Special Situations
Special situations include pregnancy; medication error, abuse, misuse, or overdose; and adverse 
reactions associated with product complaints.

Information regarding pregnancy is provided in Section 8.3.2.

A medication error is any preventable event that can cause or lead to inappropriate 
medication use or subject harm while the medication is in the control of a healthcare 
professional, subject, or consumer.

Abuse is defined as persistent, sporadic or intentionally excessive use of a drug by a subject 
when such use is accompanied by harmful physical and/or psychological effects.
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
Misuse is defined as any use of a drug in a way that is not in accordance with the protocol 
instructions or the local prescribing information and may be accompanied by harmful 
physical and/or psychological effects.

An overdose is defined as a dose taken (accidentally or intentionally) exceeding the dose as 
prescribed by the protocol (see Section 6.1.8). In cases of a discrepancy in drug 
accountability, overdose will be established only when it is clear that the subject has taken 
excess doses or the investigator has reason to suspect that the subject has taken the additional 
dose(s).

A product complaint is defined as any written or verbal report arising from potential 
deviations in the manufacture, packaging or distribution of the product.
8.3.2.
Pregnancy
Each female subject should be instructed to discontinue further idelalisib and inform the 
investigator immediately if she becomes pregnant at any time between the initiation of study 
drugs until 30 days after the last use of a study drug.
The investigator should counsel the subject regarding the possible effects of prior investigational 
medicinal product exposure on the fetus and the need to inform the study site of the outcome of 
the pregnancy.
Neither the pregnancy itself nor an induced elective abortion to terminate the pregnancy without 
medical reasons is considered an adverse event; such occurrences should be reported on the 
appropriate pregnancy report forms. However, if the outcome of the pregnancy meets the criteria 
for classification as a serious adverse event (ie, spontaneous abortion, induced abortion due to 
complications, stillbirth, neonatal death, or congenital anomaly [including that in an 
aborted fetus]), the investigator should follow the procedures for reporting serious adverse 
events, ie, report the event to INC Research Pharmacovigilance by telephone and follow up by 
submission of the appropriate adverse event eCRFs (see Section 8.2.8).
Additional information about pregnancy outcomes that are classified as serious adverse events 
includes:

Any spontaneous abortion, including miscarriage and missed abortion will be reported as a 
serious adverse event.

An induced therapeutic abortion to terminate any pregnancy due to complications or other 
medical reasons will be recorded as a serious adverse event. The underlying medical reason 
for this procedure should be recorded as the adverse event term.

All neonatal deaths that occur within 1 month of birth should be reported, without regard to 
causality, as serious adverse events. In addition, any infant death after 1 month that the 
investigator assesses as possibly related to the in utero exposure to the study drug should also 
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
In the case of a live birth, the “normality” of the newborn can be assessed at time of birth 
(ie, there is no required minimum follow-up of a presumably normal infant before the 
Pregnancy Outcome Report eCRF can be completed).

The “normality” of an aborted fetus can be assessed by gross visual inspection unless there 
are pre-abortion laboratory findings suggestive of a congenital anomaly, in which case 
pathologic examination should be requested.
8.3.3.
Instructions for Reporting Special Situations
Information regarding any pregnancy in a study subject or the female partner of a male subject 
must be documented on the Pregnancy Report Form and forwarded to INC Research 
Pharmacovigilance within 24 hours of learning of the pregnancy. Monitoring of the pregnancy in 
both female study subjects and female partner of male study subjects should continue until the 
conclusion of the pregnancy. The outcome of the pregnancy should be reported on the 
Pregnancy Outcome Report Form within 5 days of the conclusion of the pregnancy. If the end of 
the pregnancy occurs after the study has been completed, the outcome should be reported 
directly to Gilead Sciences DSPH (facsimile:
 
e-mail:
Information regarding all other special situations must be documented on the Special Situations 
Report Form and forwarded to INC Research Pharmacovigilance within 24 hours of learning of 
the event.
Along with information regarding the circumstances of the special situation, any clinical 
sequelae occurring in association with that situation should be reported as adverse events or 
serious adverse events according to the reporting requirements for those events 
(see Section 8.2.8). Details of signs or symptoms, clinical management, and outcome should be 
reported, if available.
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9.
WITHDRAWAL OF SUBJECTS
All study participants may receive study drug indefinitely. However:

Any subject has the right to withdraw from the study at any time.

Any subject who experiences progression of disease should be withdrawn from the study 
treatment.

Any subject whose condition substantially changes after entering the study should be 
carefully evaluated by the investigator in consultation with the study sponsor medical expert. 
Such subjects should be withdrawn from study treatment if continuing would place them at 
risk.

Any subject who becomes pregnant should be removed from study treatment.

Any subject who becomes significantly noncompliant with study drug administration, study 
procedures, or study requirements should be withdrawn from study treatment in 
circumstances that increase risk or substantially compromise the interpretation of study 
results.

The investigator, in consultation with the study sponsor medical expert, may withdraw any 
subject from the study treatment, if, in the investigator’s opinion, it is not in the subject’s best 
interest to continue.

Any subject who is unable to tolerate the protocol-described, dose-modified idelalisib
Dose Level -1 of 100 mg BID should be withdrawn from study treatment.

The study sponsor may discontinue the study at any time.

If idelalisib becomes commercially available in the country where the subject is living, the 
study sponsor may transition subjects from study treatment to commercial drug supply
(as allowed by national and local law).
The date the subject is withdrawn from the study and the reason for discontinuation will be 
recorded on the appropriate CRF.
When a subject is withdrawn from study treatment or is permanently removed from study 
treatment (regardless of the reason), all of the evaluations required at the End-of-Treatment visit 
should be performed and any additional evaluations should be completed that may be necessary 
to ensure that the subject is free of untoward effects. The subject should be encouraged to seek 
appropriate follow-up for any continuing health problems.
All subjects receiving 1 dose of study drug will be followed during the immediate 
post-treatment and long-term follow-up assessments unless the subject withdraws consent for 
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10.
STATISTICS AND DATA MANAGEMENT
10.1.
Statistical Basis for Proposed Sample Size
There is no agent currently approved for use in subjects with iNHL that is refractory to both 
rituximab and alkylating agents. Without any therapy, the ORR for iNHL in this situation would 
be negligible. Off-label use of an existing agent (eg, bortezomib or lenalidomide) in this setting 
might be expected to yield an ORR of ~20% at the cost of considerable toxicity {Di Bella 2010, 
Goy 2005, Witzig 2009}. These data suggest that excluding an ORR 20% while targeting an
ORR of ≥40% would be a conservative approach to evaluation of the idelalisib treatment effect
in this population of subjects with refractory malignancy.
Accordingly, the study will test the null hypothesis that the IRC-reviewed ORR is ≤20% against 
the alternative hypothesis that it is ≥39% (ie, ~40%). Using Simon’s optimum 2-stage design
{Simon 1989}, a sample size of 100 subjects provides a power of >0.90 to achieve a 1-sided 
significance level of 0.005 and will provide an ample safety database. Under the Simon’s 2-stage
design, an ORR of 31% (ie, 31 subjects responding of 100 subjects evaluated) will achieve 
this significance level. The exact binomial test will be used in the final analyses because of the 
practical consideration that accrual cannot be limited to exactly 100 subjects and because 
subjects included in the interim analysis (see Section 10.4.1) as nonresponding may be included 
in the final analysis as responding if they experience a late response.
10.2.
Analysis Sets
10.2.1.
Intent-to-Treat Analysis Set
The intent-to-treat (ITT) analysis set will comprise all subjects who receive 1 dose of 
idelalisib. The ITT analysis set will be used in the analyses of ORR, PFS, OS, safety, and study 
drug administration and compliance. The ITT analysis set will be the primary analysis set for all 
the efficacy variables.
DOR and TTR will be analyzed based on all ITT subjects who achieve a CR or PR. LNR will be 
analyzed based on all ITT subjects who have both baseline and ≥1 evaluable post-baseline SPD.
10.2.2.
Per-Protocol Analysis Set
The per-protocol (PP) analysis set will comprise all subjects in the ITT analysis set who have a 
diagnosis of lymphoma, who have documented refractory disease, who have measurable nodal 
disease as determined by the IRC, and who can be evaluated for tumor response with both a 
baseline and 1 on-study tumor evaluations. The PP analysis set will be used in analyses of 
ORR, DOR, TTR, LNR, PFS, and OS.
10.2.3.
Pharmacodynamic/Pharmacokinetic Analysis Sets
The pharmacodynamic/pharmacokinetic (PK/PD) analysis sets include data from subjects in the 
ITT analysis set who have the necessary baseline and on-study measurements to provide 
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10.3.
Analysis Plan
10.3.1.
General Considerations
By-subject listings will be created for important variables from each CRF module. 
Summary tables for continuous variables will contain the following statistics: 
N (number in population), n (number with data), mean, standard deviation, standard error, 
95% CIs on the mean, median, minimum, and maximum. Summary tables for categorical 
variables will include: N, n, percentage, standard error, and 95% CIs on the percentage. Unless 
otherwise indicated, 95% CIs for binary variables will be calculated using the 
binomial distribution. Data will be summarized by visit, as appropriate for the outcome measure. 
Information regarding compliance with efficacy testing and data missingness will be 
documented. Graphical techniques (eg, waterfall plots, Kaplain-Meier curves) will be used when 
such methods are appropriate and informative.
The baseline value used in each analysis will be the last (most recent) pre-treatment value. Data 
from all sites will be pooled for all analyses. Analyses will be based upon the observed data 
unless methods for handling missing data are specified. If there is a significant degree of 
non-normality, analyses may be performed on log-transformed data or nonparametric tests may 
be applied, as appropriate. Unless otherwise specified, all analyses will be 2-sided at the 
0.05 level of significance.
Analyses will be performed using SAS® (Version 9.1 or higher).
10.3.2.
Subject Disposition and Characteristics
A subject listing of all treated subjects will be generated to describe site, subject number, first 
screening date, first treatment date, duration of treatment, analysis sets in which the subject is 
included (ITT, PP, PK/PD) and subject disposition. Subject disposition listings will subjectd be 
provided with the reasons for discontinuing treatment. A table will be created summarizing these 
categories in terms of number and percent for each of the populations defined above.
Subject demographic and baseline characteristics will be listed and summarized. Information 
regarding the diagnosis of iNHL, both as provided by the investigator and as documented by the 
central pathology review, will be summarized and listed.
10.3.3.
Protocol Deviations
Important (major) deviations related to study inclusion or exclusion criteria, conduct of the trial, 
subject management, or subject assessment will be listed and summarized by deviation type.
10.3.4.
Prior and Concomitant Medication Use
Concomitant medications will be coded by means of the World Health Organization Drug 
Dictionary (WHODRUG) dictionary into Anatomical-Therapeutic-Chemical classification 
(ATC) codes. The type and timing of use of specific concomitant medications will be listed and 
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Descriptions of prior medication use will be focused on drugs and regimens used as treatments 
for iNHL. Information on the sequencing and type of prior regimens will be provided. Specific 
attention will be given to the details of prior rituximab and alkylator administration. In addition, 
details regarding response and duration of the last prior antineoplastic therapy before 
administration of idelalisib will be described.
Information regarding the type and use of any supportive medications 
(eg, antiemetics, hematopoietic growth factors) during idelalisib treatment will be described.
10.3.5.
Antitumor Activity and Efficacy
Antitumor activity will be documented by radiographic response category, lymph node response 
rate, and the timing and duration of tumor control. SPD values, the best on-study tumor response, 
TTR, DOR and PFS will be listed for each subject.
Data will be presented for both investigators assessments and the IRC assessments, and the IRC 
assessments will be considered primary. Consistency of evaluation will be summarized by the 
percent agreement/disagreement between the IRC and investigator assessments.
10.3.5.1.
Overall Response Rate
While the Simon optimal 2-stage design has been used to structure the trial, the exact binomial 
test will be used in the final analyses of ORR because of the practical consideration that accrual 
cannot be limited to exactly 100 subjects. The ORR and 95% CI will be presented along with the 
corresponding p-value from the exact binomial test.
10.3.5.2.
Percent Change in Tumor Size
The LNR rate will be summarized with 95% CI based on the exact binomial distribution in the 
ITT and PP analysis sets using both the IRC assessments and investigators assessments. The 
SPD at each assessment will be described. The percent change in tumor size from baseline to 
each subsequent assessment will be summarized. The best percent change from baseline during 
the study will also be summarized. The on-treatment values will be compared with the 
pre-treatment baseline values using paired t-tests.
10.3.5.3.
Time-to-Event Endpoints
Based on the definitions provided in Section 3.4, DOR, PFS, and OS will be described. These 
data will be summarized using Kaplan-Meier methods. The following censoring conventions will 
be applied:

DOR and PFS: Data from surviving, non-progressing subjects will be censored at the earliest 
of the time of initiation of antitumor treatment other than the study treatment or the last time 
that lack of iNHL progression was objectively documented. Data from subjects who progress 
or die after ≥2 consecutive missing tumor assessments will be censored at the last time prior 
to the missing assessments that lack of progression was objectively documented.

OS: Data from surviving subjects will be censored at the last time that the subject was known 
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10.3.6.
Health-Related Quality of Life
The FACT-Lym questionnaire (Appendix C) will be scored as recommended in the user manual 
for the instrument. Data for each subscale (physical well-being; social/family well-being; 
emotional well-being; functional well-being; additional concerns) at each assessment will be 
analyzed. The subscale scores, the composite scores, the individual items in B-symptoms 
(Fever, Night Sweats and Losing Weight) and the change scores from baseline to each 
subsequent assessment will be summarized. The best change from baseline during the study will 
also be summarized.
Data collected from the FACT-Lym instrument will not be reconciled with adverse event or 
laboratory data.
10.3.7.
Performance Status
The Karnofsky performance status scores (Appendix D) at each assessment will be described. 
The change in values from baseline to each subsequent assessment will be summarized. The best 
and worst changes from baseline during the study will also be summarized. On-treatment values 
will be compared with the pre-treatment baseline values using paired t-tests.
10.3.8.
Pharmacodynamic Endpoints
For each pharmacodynamic variable, the concentration at each assessment will be described. The 
change from baseline to each assessment will be summarized. The best change from baseline 
during the study will also be summarized. The on-treatment values will be compared with the 
pre-treatment baseline values using paired t-tests.
10.3.9.
Safety Parameters
10.3.9.1.
Adverse Events
Adverse events will be classified by MedDRA using 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 3.0, whenever possible. If a CTCAE criterion does not exist, 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 investigator-described relationship of the 
adverse event to the study drug will be categorized as ‘definite’, ‘probable’, ‘possible’, 
‘unlikely’, or ‘unrelated’. Adverse events will be considered as treatment related if the causal 
relationship with study drug is recorded as “definite’, ‘probable’ or ‘possible’.
All adverse events will be listed. The focus of safety data summarization will be on 
treatment-emergent adverse events. A treatment-emergent adverse event is defined as an adverse 
event that occurs or worsens in the period extending from the first dose of study drug to 30 days 
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Treatment-emergent adverse events will be summarized. Summary tables will be presented to 
show the number of subjects reporting treatment-emergent adverse events by severity grade and 
corresponding percentages. A subject who reports multiple treatment-emergent adverse events 
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. They will be presented 
in descending freqency by System Organ Class and then in decreasing frequency by
Preferred Term.
Separate listings and summaries will be prepared for treatment-emergent adverse events 
classified as severe or life-threatening (Grade 3 or higher); study-drug-related adverse events; 
adverse events leading to treatment interruption, modification, or discontinuation; and serious 
adverse events.
10.3.9.2.
Clinical Laboratory Tests
Sample collections will be taken either at laboratories associated with each investigational site or 
at laboratories that are located closer to the subject’s home. However, all specimens will be sent 
to a central Covance laboratory for assessment.
All laboratory data will be listed. Summaries of laboratory data will be based on observed data. 
The focus of laboratory data summarization will be on treatment-emergent laboratory 
abnormalities. A treatment-emergent laboratory abnormality is defined as an abnormality that, 
compared to baseline, worsens by ≥1 grade in the period from the first dose of study drug to 
30 days after the last dose of study drug. If baseline data are missing, then any graded 
abnormality (ie, an abnormality that is Grade ≥1 in severity) will be considered 
treatment-emergent. Hematological, serum biochemistry, and urine data will be 
programmatically graded according to CTCAE severity grade, when applicable. For parameters 
for which a CTCAE scale does not exist, reference ranges from the laboratory will be used to 
determine programmatically if a laboratory parameter is below, within, or above the normal 
range for the subject’s age, sex, etc.
Hematological, serum biochemistry, and urine data and their changes from baseline (only for 
continuous laboratory parameters) will be summarized by visit. Summary tables will be 
presented for each relevant assay to show the number of subjects by CTCAE severity grade with 
corresponding percentages. For parameters for which a CTCAE scale does not exist, the
frequency of subjects with values below, within, and above the normal ranges will be 
summarized. Subjects will be characterized only once for a given assay, based on their worst 
severity grade observed during a period of interest (eg, during the study or from baseline to a 
particular visit).
Shift tables for hematology and serum biochemistry will also be presented showing change in 
CTCAE severity grade from baseline to worst grade post-baseline.
For immunophenotyping data, cell count at baseline and at each assessment will be described. 
For immunoglobulin data, the concentrations at baseline and at each assessment will be 
described. Shift tables will be presented showing change in results from baseline 
(normal, low and high [or abnormal]) to each visit (normal, low and high [or abnormal]). In 
addition, the change in values from baseline will be described at each assessment and the worst 
on-treatment changes during the course of the study will be computed.


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10.3.9.3.
Vital Signs
Vital sign data (height, weight, body temperature, systolic and diastolic blood pressures, pulse) 
will be obtained at each investigational site using routine clinical procedures and available 
equipment. Blood pressure parameters will be programmatically flagged as high or low.
Systolic blood pressures ≥140 mmHg and diastolic blood pressures ≥90 mmHg will be classified 
as high, while systolic blood pressures <90 mmHg and diastolic blood pressures < 60 mmHg will 
be categorized as low.
Vital signs obtained during routine safety evaluations will be listed by subject and visit. Blood 
pressure categories will be listed by subject and visit. Vital signs and the changes from baseline 
for each measure will be summarized by visit. A summary of the number and percent of subjects 
by systolic and diastolic blood pressure category (high, normal, low) at each visit will be created.
10.3.9.4.
Electrocardiography
ECG data will be generated from ECG machines at each investigational site using routine 
clinical procedures and available equipment. ECG data will be categorized at the investigational 
sites as normal, abnormal but not clinically significant, or abnormal and clinically significant.
Standard ECG intervals will be determined. The QT interval will be corrected by both the 
Bazett and Fridericia method as follows:

Bazett: QTcB = QT/(RR)1/2

Fridericia: QTcF = QT/(RR)1/3
ECG data will be listed and summarized by visit. Shift tables for 12-lead ECG results 
(normal or abnormal) will be presented to show the change in results from baseline 
(normal or abnormal) to evaluations at on-treatment and end-of-treatment visits 
(normal or abnormal).
The QTc data obtained by using the Bazett and Fridericia corrections will be categorized 
separately into the following classifications and summarized by visit:

QTc interval >450 msec and ≤480 msec

QTc interval >480 msec and ≤500 msec

QTc interval >500 msec
The change of the QTc values obtained by using the Bazett’s and Fridericia’s correction will also 
be categorized separately as follows:

QTc interval increases from baseline by >30 msec and ≤60 msec

QTc interval increases from baseline by >60 msec
QTc data will be presented in shift tables consistent with these categories.


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10.3.10.
Study Treatment Administration and Compliance
Descriptive information will be provided regarding the number of idelalisib doses prescribed, the 
total number of doses taken, the number of days of treatment, and the number and timing of 
prescribed dose reductions and interruptions.
For each subject, idelalisib compliance will be described in terms of the proportion of study drug 
actually taken based on returned pill count relative to the amount that was dispensed (taking into 
account physician-prescribed reductions and interruptions).
10.3.11.
Pharmacokinetics
Limited-sampling idelalisib plasma concentrations collected prior to the morning dose and 
1.5 hours post-morning dose will be summarized by visit. Results will be placed into context 
with pharmacokinetics data from the Phase 1 sub-study.
 
 
 
 
10.4.
Interim and Final Analyses
10.4.1.
Interim Analysis
A single formal interim analysis is planned using Simon’s optimal 2-stage procedure. The 
purpose of this interim analysis is solely to determine if there is a sufficient ORR observed early 
in the study to warrant continuing the study to completion. The interim analysis constitutes a 
futility analysis; it will not be used to stop the trial early for positive efficacy.
In Stage 1 of the study, 31 subjects will be enrolled; if ≥9 Stage 1 subjects have an OR, then the 
study will continue. If <9 Stage 1 subjects have an OR, accrual to the study will be halted. At the 
end of Stage 1, the probability of erroneously proceeding with the study is 0.151 under the
null hypothesis and of erroneously discontinuing the study is 0.091 under the alternative 
hypothesis.
If the required Stage 1 tumor ORR is seen based on investigator assessments, accrual can 
proceed in Stage 2 without interruption. If the required total number of subjects are accrued to 
Stage 1 but follow-up is not sufficiently mature (ie, through the Week 16 radiographic 
evaluation) in all Stage 1 subjects to reasonably assess the Stage 1 ORR, accrual to Stage 2 may 
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proceed while the Stage 1 data are being collated. All available tumor response and progression 
data will be considered at the time of the assessment. At the latest, the interim analysis will occur 
when the last of the Stage 1 subjects has been enrolled and has completed the 16-week tumor 
assessment and these data are available for review.
10.4.2.
Final Analysis
In Stage 2 of the study, it is planned that 69 subjects will be enrolled to achieve the total intended 
sample size of 100 subjects. The final study analysis will be performed when all enrolled subjects 
have completed efficacy, safety, and other assessments through ≥24 weeks of evaluation.
10.5.
Data Management and Quality Assurance
The services of experienced CROs will be retained for data collection and management. 
Electronic data capture will be used to enter the completed CRF data into a study-specific 
electronic database. During the data collection process, automated quality assurance programs 
will be used to identify missing data, selected protocol violations, out-of-range data, and other 
data inconsistencies. Requests for data clarification or correction will be forwarded to the 
investigative site for resolution. CRFs will be provided to the study sponsor for review.
Quality assurance and quality control systems will be implemented and maintained according to 
written standard operating procedures generated by the CROs to ensure that the data are 
generated, recorded, and reported in compliance with the protocol, GCP, and applicable 
regulatory requirements. Data collection and storage systems will provide audit trail, security 
mechanisms, and electronic signature capabilities that meet the requirements of FDA Title 21 of 
the Code of Federal Regulations (CFR) Part 11 regarding electronic records and electronic 
signatures.
Data security will be controlled through appropriate and specific restriction of access only to data 
and systems required by individual users to accomplish their roles in the data management 
process. Individual login and password protections will be employed at study sites, at the CRO, 
and at the study sponsor. The database will exist on physically secured servers. Data backups 
will be done regularly and will be stored in separate facilities. Printed documents relating to the 
study will be secured in locked file cabinets when not under review.
10.6.
Statistical and Data Management Rationale
The proposed sample size of 100 subjects has been established to have high power (> 90%) to 
exclude an uninteresting ORR of ≤20% in favor of a clinically relevant target ORR of 40%. In 
this calculation, the use of subjects as their own controls and omission of a contemporaneous 
untreated control group relies upon knowledge that, in the absence of treatment, the likelihood of 
achieving a ORR for subjects with iNHL refractory to rituximab and alkylating agents is 
extremely low (ie, has a likelihood of essentially 0%) and that even with conventionally 
available off-label treatments, a response rate of ≤20% is anticipated. The target ORR of 
40% has been selected with reference to past experience with treatments for iNHL
(see Section 10.1) and with consideration for the treatment effect that would likely be considered 
clinically meaningful.


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It would have been reasonable to consider performing this trial in a single stage. However, the 
planned 2-stage design takes a more conservative approach by including a futility assessment. 
Permitting Stage 2 accrual while Stage 1 response assessment is ongoing acknowledges the high 
level of idelalisib activity already observed in subjects with relapsed/refractory iNHL, the well 
tolerated safety profile of idelalisib, and the lack of approved alternative therapies for subjects 
with iNHL refractory to both rituximab and alkylating agents. This plan avoids interruptions to 
accrual while observing initial subjects and rapidly provides a sufficiently large safety database 
to support of drug registration.
The proposed analytical techniques are standard and appropriate for the types of data to be 
assessed. Similarly, the data management methods are appropriate to assure the quality, validity, 
and security of the data derived from the study.


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11.
STUDY COMMITTEES
11.1.
Study Steering Committee
A study steering committee (SSC) will be responsible for assisting the sponsor with protocol 
development, review of any study amendments if requested by sponsor, coordination of study 
conduct, interpretation of data, and presentation and publication of study results. The SSC 
comprises the study sponsor medical expert for the study, the study sponsor head of research and 
development, several clinicians with expertise in the care of subjects with iNHL and a 
gastroenterologist/hepatologist. Other specialists may be invited to participate as members of the 
SSC at any time if additional expertise is desired. Academic SSC members may be involved in 
accruing subjects to the study. The study sponsor medical expert serves as the chair of the SSC.
11.2.
Independent Review Committee
An independent review committee (IRC) will be established to provide an objective review of 
radiographic data and pertinent clinical data in order to provide expert interpretation of changes 
in tumor status. The IRC will include independent board-certified radiologists and an 
independent board-certified oncologist, and will be managed by the contracted imaging core 
facility, BioClinica. The specifics of BioClinica’s processes and reading methods will be 
described in an independent review charter developed by BioClinica in conjunction with the 
study sponsor.


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12.
OBLIGATIONS OF THE INVESTIGATOR AND SPONSOR
12.1.
Compliance with Ethical and Regulatory Guidelines
The investigator is responsible for ensuring that the clinical study is performed in accordance 
with the FDA GCP regulations (CFR 21 parts 50, 56, and 312), and the 
International Conference on Harmonisation (ICH) GCP guidance documents.
12.2.
Institutional Review Board/Institutional Ethics Committee
As required by the FDA and other regulatory authorities, the protocol and informed consent 
document will be reviewed and approved by an appropriate IRB/IEC prior to enrollment of 
subjects into the study. By signing the Statement of Investigator Form (FDA Form 1572), the 
investigator assures that approval of the trial protocol will be obtained from the IRB/IEC and that 
all aspects of the IRB/IEC review will be conducted in accordance with current regulations. 
Amendments to the protocol will be subject to the same IRB/IEC review requirements as the 
original protocol. Only changes necessary to eliminate apparent immediate hazards to the 
subjects may be initiated prior to IRB/IEC approval. In that event, the investigator must notify 
the IRB/IEC and study sponsor in writing within 5 working days after implementation. The 
investigator will also promptly notify the IRB/IEC of any serious, unexpected adverse events, or 
any other information that may affect the safe use of the drug during the course of the trial.
A letter documenting the IRB/IEC approval and a list of the names and titles of the IRB/IEC 
members must be received by the study sponsor prior to the initiation of the study. All 
correspondence with the IRB/IEC should be retained in the investigator’s study file.
The investigator shall submit a progress report, at least once yearly, to the IRB/IEC, and must 
provide a copy to the study sponsor. As soon as possible after completion or termination of the 
study, the investigator will submit a final report to the IRB/IEC and to the study sponsor. This 
report should include the dates of initiation and completion of the trial, a description of any 
changes in study procedures or amendments to the protocol, any deviations from the protocol, 
the number and type of subjects evaluated, the number of subjects who discontinued 
(and the reasons for discontinuation), the number of subjects who completed the trial, and the 
results of the trial, including a description of any adverse events. The study sponsor will assist 
the investigator in the preparation of this report, as needed.
If certain aspects of this study require additional IRB/IEC review, or if the study is performed 
under a grant from the United States government, the study sponsor will also submit the protocol 
and informed consent documents to the company’s IRB of record. The study sponsor will be 
responsible for all interactions with the IRB of record, including submission of protocol 
documents, consent forms, and amendments; submission of adverse event reports and annual 
reports; receipt of approval notices; and exchange of other correspondence.


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12.3.
Informed Consent
By signing the Statement of Investigator (FDA Form 1572), the investigator assures that 
informed consent will be obtained from each subject and/or guardian prior to study entry and that 
the informed consent will be obtained in accordance with current regulations.
The investigator will give each subject and/or guardian full and adequate verbal and written 
information regarding the objectives and procedures of the trial and the possible risks involved. 
An informed consent document will be provided to each subject and/or guardian in a language in 
which the subject or guardian is fluent. This information must be provided to the subject or 
guardian prior to undertaking any trial-related procedure. Adequate time should be provided for 
the subject and/or guardian to read the informed consent, to understand the risks and benefits of 
participating in the study, and to ask any questions that the subject and/or guardian may have 
about the study. The subject should be able to ask additional questions as and when needed 
during the conduct of the study. The subject’s signature on the informed consent form should be 
obtained at the investigational site in the presence of the investigator or a qualified representative 
(eg, sub-investigator or study coordinator) and in the presence of a witness.
Each subject or guardian will be given a copy of the signed consent/assent form. The original 
signed informed consent forms will be retained by the investigator with the study records.
The written subject information must not be changed without prior approval by the study sponsor
and the IRB/IEC.
12.4.
Case Report Forms
An electronic CRF (eCRF) is required and must be completed for each enrolled subject, with all 
required study data accurately recorded such that the information matches the data contained in 
medical records (eg, physicians’ notes, nurses’ notes, clinic charts, or other study-specific source 
documents). The eCRFs exist within a Web-based electronic data capture (EDC) system 
managed by the data management CRO for this study. After the investigator or the investigator’s 
designees (eg, research coordinators) have been appropriately trained, they will be given access 
to the EDC system and will enter the data required by the protocol into the EDC system. Any 
change of data will be made via the EDC system, with all changes tracked by the system to 
provide an audit trail.
The investigator must certify that the data are complete and accurate by signing a memo that will 
be sent to him by the data management CRO prior to database lock. This signature serves to 
attest that the information contained in the eCRFs is true. After database lock, the investigator 
will receive a compact disc read-only memory (CD-ROM) or paper copies of the subject data for 
archiving at the investigational site. At all times, the principal investigator has final 
responsibility for the accuracy and authenticity of all clinical data entered onto the eCRFs and/or 
reported to the study sponsor from the investigator’s site.
CRF information is the sole property of the study sponsor. Without written permission from the 
study sponsor, this information should not be made available in any form to third parties
(except for consultants or contractors retained by the study sponsor or authorized representatives 
of appropriate regulatory authorities).


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12.5.
Study Records
During the study, the investigator will maintain adequate and complete records for the study, 
including the identity of all participating subjects (with sufficient information to link clinic 
records and eCRFs), medical records, source document records detailing the progress of the 
study for each subject, laboratory reports, a CD-ROM or paper copy of the data that have been 
captured in the EDC for each subject (electronic equivalents of CRFs), any paper CRFs, signed 
informed consent forms, study drug disposition records, correspondence with the IRB/IEC, 
adverse event reports, and information regarding subject discontinuation and completion of the 
study. Current regulations require the study sponsor (or an authorized designee) to inspect all 
documents and records required to be maintained by the investigator, including but not limited to 
medical records (office, clinic, or hospital) for the subjects enrolled in this trial. These 
regulations also allow the same records to be inspected by authorized representatives of the FDA 
or other regulatory authorities.
12.6.
Retention of Records and Samples
All records and documents pertaining to the study (including but not limited to those outlined 
in Section 12.5 above) will be maintained by the investigator until notification is received from 
the study sponsor that the records no longer need to be retained. This will be for a period of 
at least a) 2 years after approval of the drug in the United States and other countries; 
b) 5 years after non-approval of the New Drug Application (NDA) in the United States, 
Marketing Authorization Application (MAA), or a similar regulatory submission in other 
countries; or c) 2 years after withdrawal of the United States Investigational New Drug (IND)
application or a similar regulatory permission in other countries under which this study was 
conducted.
The investigator must obtain written permission from the study sponsor before disposing of any 
records. In order to avoid any possible errors, the investigator will contact the study sponsor
prior to the destruction of any study records. The investigator will promptly notify the study 
sponsor in the event of accidental loss or destruction of any study records. If the investigator 
relocates, retires, or for any reason withdraws from the study, the study records may be 
transferred to an acceptable designee, such as another investigator, another institution, or to the 
study sponsor.
Biological samples including tissue and blood samples collected as a study procedure or as 
standard of care during study participation will be stored and maintained by the investigator until 
notification is received from Gilead Sciences that the retained samples are no longer required. 
The investigator must obtain written permission from Gilead Sciences before disposing of any 
retained samples. The investigator should promptly notify Gilead Sciences in the event of 
accidental loss or destruction of any study samples. With the permission of Gilead Sciences, the 
retained samples may be transferred to an acceptable designee, such as another investigator, 
another institution, a contract storage site, or to Gilead Sciences.


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12.7.
Confidentiality
Research records will be collected and stored in a manner that protects the confidentiality of 
subject information. The names and identities of all research subjects will be kept in strict 
confidence and will not appear on eCRFs, any paper CRFs, or other records provided to or 
retained by the study sponsor (or its authorized designees). The names and identities of the 
subjects need not be divulged; however, the records must nevertheless be inspected. This will be 
accomplished by blanking out the subject’s name and replacing the name with the subject’s study 
identification number on any record provided to or retained by the study sponsor. The informed 
consent form must include appropriate statements explaining these requirements.
Attention is drawn to the regulations promulgated by the FDA under the Freedom of Information 
Act providing, in part, that information furnished to clinical investigators and the IRB/IEC will 
be kept confidential by the FDA only if maintained in confidence by the clinical investigator and 
the IRB/IEC. By signing this protocol, the investigator affirms to the study sponsor that the 
investigator will maintain, in confidence, information furnished by the study sponsor and will 
divulge such information to the IRB/IEC under an appropriate understanding of confidentiality 
with such board.
12.8.
Financial Disclosure
As necessitated by regulation, the investigator must provide the sponsor with accurate 
information relating to potential financial conflicts of interest (eg, honoraria, stock ownership, 
inventorship, payments, etc). The sponsor will be responsible for summarizing this information 
and reporting it to regulatory agencies in compliance with applicable regulation.
12.9.
Monitoring and Auditing
In accordance with 21 CFR 312.56 and/or relevant ICH guidelines, the study sponsor or a 
designee will periodically inspect all eCRFs (see Section 12.4), study documents, research 
facilities, and clinical laboratory facilities associated with this study at mutually convenient 
times, before, during, and after completion of the study. As stipulated in Subpart D of the 
IND regulations (Responsibilities of Sponsors and Investigators), the monitoring visits provide 
the study sponsor with the opportunity to evaluate the progress of the study; verify the accuracy 
and completeness of data in the eCRFs; ensure that all protocol requirements, applicable FDA 
and other relevant regulations, and investigator’s obligations are being fulfilled; and resolve any 
inconsistencies in the study records. At monitoring visits, the study sponsor or designee may 
inspect all documents and records that must be maintained by the investigator, including but not 
limited to medical records (office, clinic, or hospital) for the subjects in this trial. The 
investigator/institution guarantees direct access to source documents by the study sponsor and 
appropriate regulatory authorities.
The trial site may also be subject to review by the IRB/IEC, to quality assurance audits 
performed by the study sponsor or a designee, and/or to inspection by the FDA and/or other 
regulatory authorities. The IND regulations also require the investigator to allow authorized 
representatives of the FDA to inspect and make copies of the same records.


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It is important that the investigator and relevant institutional personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
12.10.
Termination of the Study
The investigator reserves the right to discontinue the trial prior to inclusion of the intended 
number of subjects or completion of subject follow-up; the study sponsor medical expert must be 
notified before discontinuation of the trial by a study site. The study sponsor also reserves the 
right to discontinue the trial prior to inclusion of the intended number of subjects or completion 
of subject follow-up, but intends only to exercise this right for valid scientific or administrative 
reasons.
After a decision to terminate the study, investigators must contact all subjects who are continuing 
their participation in the study and must do so within a time set by the study sponsor. As directed 
by the study sponsor, all study materials must be collected and all eCRFs completed to the 
greatest extent possible.
12.11.
Public Notification of Study Conduct
Consistent with Section 113 of the Food and Drug Modernization Act of 1997 (FDAMA) and 
with requirements of the International Committee of Medical Journal Editors (ICMJE) as a 
condition of consideration for publication of study results, the study sponsor will be responsible 
for ensuring that this protocol is listed at the ClinicalTrials.gov website and that information at 
the website relating to study design and conduct is appropriately updated during the course of the 
study. In order to facilitate this process, investigators will need to supply the study sponsor with 
appropriate contact information for study site personnel.
12.12.
Dissemination of Results
The information developed during the conduct of this clinical study is considered confidential by 
the study sponsor and must not be revealed by the investigator without permission from the 
sponsor.
To allow for the use of the information derived from this clinical study and to insure compliance 
with current regulations, the investigator is obliged to provide the study sponsor with complete 
test results and all data developed in this study. The study sponsor may make information 
obtained during this study available to further the sponsor’s scientific or business needs or as 
required by law or regulation. In this regard, the study sponsor may provide study information to 
private or public organizations (eg, business partners, collaborators, consultants, CROs, 
investors, other physicians who are conducting similar studies, funding organizations, regulatory 
authorities, or other government authorities). Such information may be publically disclosed as 
deemed necessary by the study sponsor.
The study sponsor intends that the data from this study will be presented and published. In 
collaboration with the SSC, the study sponsor staff, under the direction of the study sponsor
medical expert, will be responsible for preparing presentations and writing manuscripts for 
publication. Investigators will not be allowed to present or publish the data from this study 
without prior agreement from the study sponsor.


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12.13.
Communication with Regulatory Authorities
The study sponsor, working either directly or through collaborators or CROs will assume 
responsibility for regulatory interactions with the FDA, the European Medicines Agency (EMA) 
and/or other regulatory authorities. The study sponsor will maintain an IND for idelalisib in 
support of the study in the United States and will maintain similar regulatory applications with 
other regulatory authorities, as required for conduct of the study. In fulfilling this responsibility, 
the study sponsor (or a designee) will collect, assemble, and communicate all required regulatory 
documents (eg, Form FDA 1572, investigator financial disclosure forms, protocol and 
protocol amendments, investigator brochures, informed consent documents, annual reports) as 
required by regulation. The study sponsor (or a designee) will also assume responsibility for 
adverse event reporting to regulatory authorities as described in Section 8.2.9.


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13.
RISK-BENEFIT CONSIDERATIONS
13.1.
Potential Risks and Mitigating Factors
13.1.1.
Potential Risks Based on Nonclinical and Clinical Idelalisib Metabolism Data
Nonclinical drug metabolism studies show that idelalisib is metabolized primarily via 
aldehyde oxidase, with some involvement of CYP3A. A clinical drug-drug interaction study in 
healthy volunteers showed that orally administered ketoconozole (a potent CYP3A inhibitor) 
increased idelalisib plasma exposure (AUC) 1.8-fold (Section 2.5.3), which is not considered to 
be clinically relevant and suggests idelalisib is a weak CYP3A substrate. Coadministration of 
idelalisib with rifampin, a highly potent inducer of CYP3A, resulted in ~75% lower idelalisib 
exposures. Coadministration of potent inducers of CYP3A with idelalisib should be avoided. 
Coadministration of CYP3A substrates with idelalisib may result in an increase in their systemic 
exposures, due to reversible and time-dependent inhibition of CYP3A by metabolite GS-563117. 
Avoid coadministration of drugs that are highly dependent on CYP3A for clearance and for 
which elevated plasma concentrations are associated with serious and/or life-threatening events, 
including narrow therapeutic index CYP3A substrates, with idelalisib (see Section 6.3.6). The 
investigator is encouraged to contact the study sponsor medical expert to discuss specific drugs 
of concern.
13.1.2.
Potential Risks Based on Nonclinical and Clinical Idelalisib Toxicology Data
In toxicology studies through 28 days in rats and dogs, idelalisib-related effects included
lymphoid depletion (rats and dogs), bone marrow suppression (rats), and hepatotoxicity (dogs). It 
is possible that subjects participating in the current protocol could experience events similar to 
those that occurred in animals.
Mitigating the risks of similar events in humans is the knowledge that these nonclinical effects 
were observed at idelalisib plasma concentrations that are higher than those likely to be achieved 
in this study. In addition, these types of effects are readily monitored clinically and will be 
followed with frequent assessments of subject symptoms and laboratory parameters in the 
current study.
13.1.3.
Potential Risks Based on Prior Clinical Experience with Idelalisib
In single-dose and 7-day multiple dose studies in healthy volunteers and in a 7-day study in 
subjects with allergic rhinitis, idelalisib was generally well tolerated. Healthy volunteer subjects
experienced a maculopapular skin rash consistent with delayed type hypersensitivity reaction 
that recurred on idelalisib rechallenge. In studies evaluating prolonged administration in subjects 
with lymphoid malignancies, adverse events that have been considered potentially related to 
idelalisib have included rash, enteritis, pneumonia/pneumonitis, and elevations of serum ALT 
and AST. It is possible that subjects participating in the current protocol could experience events 
similar to those observed in prior clinical studies.


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Mitigating factors are that such events have generally been recoverable or treatable. A hepatic 
monitoring plan has been introduced into all idelalisib protocols, including the protocol for this 
study. In addition, the doses and expected plasma exposures to be used in the current protocol 
should not exceed those evaluated in prior clinical studies. Frequent monitoring for 
adverse events and laboratory abnormalities is planned in the course of the current study.
13.1.4.
Potential Reproductive Risks
Decreased testes weights were observed in rats and dogs, but no effect on male fertility was 
observed in a rat study. Changes in testicular weight in repeat dose studies are suspected to be 
associated with fluid production and/or tubular contraction and not a degenerative effect.
Idelalisib has induced embryo lethality and teratogenicity when administered to pregnant female 
rats at maternally toxic doses. However, the specific effects of idelalisib on human 
embryogenesis or fetal development are unknown. Whether idelalisib is excreted in human 
breast milk is also unknown.
Mitigating reproductive risks are that many female subjects with iNHL have lost reproductive 
function because they are postmenopausal or because they have received prior therapy that 
disrupts ovarian function; thus, this population is inherently at less risk for new adverse effects 
on reproductive function. Many male subjects with iNHL are beyond the age at which they are 
likely to conceive a child.
However, in view of the status of the current nonclinical data, measures to minimize 
reproductive risk are included in this study. Women of reproductive potential must have a 
negative serum pregnancy test and must not be breastfeeding. If a female study participant
becomes pregnant or decides to breastfeed during the course of the study, idelalisib
administration must be discontinued. Both women and men of reproductive potential are advised 
in the informed consent that they should abstain from sexual intercourse or use an adequate 
method of contraception throughout the duration of their participation in the trial. Study 
candidates are also advised in the informed consent document that the effect of idelalisib on the 
future ability to have children is not known.
13.1.5.
General Medical Risks
It is possible that study subjects may experience new adverse events that have not already been 
observed in studies of idelalisib in animals or humans. It is also possible that study subjects 
might experience better outcomes if they elected to receive an alternative treatment rather than 
receiving idelalisib.
Mitigations for these types of risks are incorporated into the study design, subject eligibility 
criteria, idelalisib administration plan, and monitoring schedule as follows:

Conduct of the study by expert investigators will allow consistency of methods and 
observation, minimizing variability that could compromise subject safety or interpretation of 
study data.


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
Conduct of the study by qualified investigators and experienced monitors, performing the 
study in accordance with GCP, also enhances safety.

The eligibility criteria are designed to identify subjects who have iNHL, are able to safely 
receive systemic treatment, and have the potential for therapeutic benefit.

The planned dosing regimen is supported by safety and exposure data from completed 
nonclinical toxicology studies and from completed Phase 1a studies in healthy volunteers, 
and by evolving information from ongoing Phase 1b/2 studies of idelalisib.

Idelalisib dose modification provisions are incorporated into the drug administration plan for 
subjects experiencing toxicities

Study assessments and timing are appropriate for screening of subjects, for determination of 
idelalisib-related or disease-related toxicities, for dose modification during the study, for 
characterization of drug exposure, for evaluation of drug activity, and for assessment of 
tumor progression

Appropriate guidance regarding discontinuation of subjects from study drug administration is 
provided to minimize harm (Section 9).

The study investigator and the study site and study sponsor medical experts will review 
adverse events experienced by subjects and the study physicians will provide the appropriate 
treatment for these adverse events.

The overall toxicity profile for idelalisib will be reviewed on an ongoing basis by the study 
sponsor, and study investigators will be updated regarding any safety issues that may be 
observed in other preclinical or clinical studies of idelalisib.
13.1.6.
Other Potential Risks and Discomforts
During the course of the study, subjects may experience risks associated with study procedures. 
Such risks might include bruising, bleeding, or infection at blood collection sites; anemia; 
allergic reactions to radiographic contrast dye; radiation exposure during CT scanning; exposure 
of metallic implants to MRI-related magnetic fields; or procedure-related anxiety. 
The possibilities of such risks and potential preventive measures are explained in the informed 
consent form. The potential risks related to radiographic procedures to be performed in the study 
are considered minimal, particularly in this population of subjects with iNHL who would likely
undergo such testing to follow disease status even if they did not participate in the study. 
Subjects can be offered sedative medications to reduce procedure-related anxiety.
13.1.7.
Potential Data Confidentiality Risks
As a consequence of participation in this study, medical and research records that include 
personal subject information will be produced. There is a risk to the subject of loss of medical 
confidentiality due to the existence, review, and communication of these records.


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To mitigate these risks, personal identifiers will be replaced with subject numbers on study 
information communicated outside study sites and the link between personal identifiers and 
subject numbers will not be disclosed, except as required by law. Review of information 
containing personal identifiers will be restricted to authorized personnel from specific 
organizations who have responsibility to protect human subjects involved in research and to 
assess the validity of the data derived from this study. These organizations have been 
prespecified in the informed consent document. Presentation or publication of data will not 
include information that identifies a study subject. Measures to ensure security of study data 
have been incorporated into the data management plan.
13.2.
Potential Benefits
The primary potential benefit to subjects participating in this clinical study is that idelalisib may 
induce a regression of tumors or a prolongation of PFS and/or may induce an improvement in 
iNHL-related symptoms. As a secondary consequence of undergoing study procedures, 
participants will receive a thorough review of their health status and general medical condition 
that may be of value to them.
Factors enhancing the potential for subject benefit are the following:

PI3K over-expression plays an important role in iNHL biology.

Idelalisib has been shown to impede PI3Kδ activity and to inhibit lymphoma cancer cell
growth and survival in nonclinical models of lymphoid malignancy.

At the dose level to be evaluated in this trial, idelalisib has demonstrated substantial clinical 
activity and positive pharmacodynamic effects in subjects with previously treated iNHL and 
CLL, including subjects with refractory disease and other adverse prognostic characteristics.


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14.
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Oncol 2004;22 (13):2654-61.


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15.
APPENDICES
Appendix A.
Ann Arbor Lymphoma Staging System
Appendix B.
Follicular Lymphoma International Prognostic Index
Appendix C.
Functional Assessment of Cancer Therapy: Lymphoma (FACT-Lym)
Appendix D.
Performance Status Scoring Systems


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Appendix A.
Ann Arbor Lymphoma Staging System
Area of Involvement
Stage
Single lymph node group or lymph node region.
1
Two or more node regions on same side of diaphragm
2
Lymph node regions on both sides of the diaphragm 
3
Multiple extra-nodal sites or lymph nodes and extra-nodal sites
4
Additional Anatomic Factors
Designation
Confined  to lymph nodes
N
Site of bulky disease (>10 cm in diameter)
X
Extra-nodal extension or single isolated site of extra-nodal disease
E
Hepatic
H
Lung
L
Bone marrow
M
Spleen
S
Pleura
P
Bone
O
Skin
D
Additional Symptomatic Factors
Designation
No symptoms
A
Symptoms of weight loss >10% within 6 months, fever, night sweats
B


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Appendix B.
Follicular Lymphoma International Prognostic Index
Scoring System
Parameter
Value
Point Score
Age
>60 years of age
1
Ann Arbor stage
Stage III or IV
1
Hemoglobin level
<120 g/L (12.0 g/dL or 6.37 mmol/L)
1
Serum LDH
>ULN
1
Number of Nodal Sites
>5
1
Risk Group by FLIPI Total Point Score
Risk Group
Total Point Score
Low
≤1
Intermediate
2
High
≥3
Abbreviations: LDH, lactate dehydrogenase; ULN, upper limit of normal


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Appendix C.
Functional Assessment of Cancer Therapy: Lymphoma (FACT-Lym)
FA T-L. m (' er ion 4) 
Below i a list of raremem rhar orher people with yom illne 
ha e aid are imponanr. Plea e rirde 
or mark one number per line to indicate your response a it applie 
PHY ICAL WELL-BEI::'IlG 
l"ot 
at aU 
GPI 
I ha\·e a lack of energy ....................................................... 
0 
GPl 
I ha,·e nausea ...................................................................... 
0 
GPJ 
Becau e of my phy ical condition. I ha\'e u·ouble 
meeting the needs of my family ......................................... 
0 
GP4 
I ha\'e pain .............................................................. , ........... 
0 
GPS 
I am bothered by ide effect of treatment ......................... 
0 
-
0 
GP7 
I am forced to spend time in bed ..... , .................................. 
0 
0 IALIFA.l\DLY WELL-BEI:\"G 
l"ot 
at all 
GSI 
I get emotional upport from m family ...... ..... .. ...... .. ... .. .. 
0 
I get tpp r:t from my friend ........ .... . .. .. ...... .. ..... ...... ..... .. .. 
0 
~y famil has a epted m illue 
................... ..... ............ 
0 
GISS 
I am arisfied with family collllllunication about my 
ilh1e .................................................................................. 
0 
I feel clo e to my partner or the person who is my main 
upport) .............................................................................. 
0 
QI 
Regardless ofyour cun-ent level of sexual activiry, please 
answer rile following quesTion. If you prefer nor ro answer ir, 
please mark this box 0 and go to the nexr secTion. 
GS7 
I am ati tied with my ex life ............................................ 
0 
"""""(U~ 
Capynpr. 1911. 1997 
A little 
bit 
AIWit> 
bit 
orne-
Quite 
what 
a bit 
3 
2 
3 
3 
2 
3 
3 
3 
oml'-
Quill' 
what 
a bit 
2 
3 
2 
3 
3 
2 
3 
3 
3 
\ 'et')" 
mu<-b 
4 
4 
4 
4 
4 
4 
4 
, .l'l';\' 
mu<-b 
4 
4 
4 
4 
4 
4 
16Nat"'!!!llbb!r200'l 
...... u 


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FACT-Lym (Vt>r ion 4) 
Pita t' drclt or mark our numbtr per lint to indiratr . ·our l't' pon t' a it applir to tht Jl!!.lll 
day. 
EMOTIONAL WELL-BEil\"G 
::\ot 
A little 
orne-
Quite 
\"er·r 
at aU 
bit 
what 
a bit 
mu~h 
G£1 
I feel ad .............................................................................. 
0 
3 
4 
I am atisfied with how I am oping with my illne .. .. ...... 
0 
4 
I am lo ing hope in the fight against my illne .... ... ... .. ...... 
0 
4 
I feel nerTOl ............................................................... ,....... 
0 
4 
I won; about dying ............................................................. 
0 
4 
3 
4 
FUXCTIO. AL WELL-BEDlG 
'\'ot 
A little 
orne-
Quite 
Yer·r 
at aiJ 
bit 
what 
a bit 
much 
(if! 
I am able to work (include work at home .......................... 
0 
2 
3 
4 
My work in tude work at horne 1 
llfilli.ng..................... 
0 
3 
I am able to enjoy life..... ............ ...... .... ...... ...... .... .... .. . .... ... 
0 
3 
4 
I ha\·e accepted my illne ................................................... 
0 
4 
(if$ 
I am leepiog well ... ........... ...... ... . .... .. . .... ..... . . .. . ....... ... . . .... .. 
0 
3 
Gf6 
I am enjoyi.no the things I l ually do for fun ...................... 
0 
3 
4 
I am content \'-'ith the quality of my life right now.............. 
0 
3 
4 


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FACT -L. m (Ver ion 4) 
Plea e circle or mark one number per line to indicate your re pon e a it applie to the .Jl!!l!1 
day. 
1'\ot 
A littlE' 
at all 
bit 
P2 
I haYe ce11aiu part of my body where I experience pain... 
0 
I am bothered by hm1p or swelling in ce11ain part of 
my body e.g .. ne k. armpit. or groin).............................. 
0 
I am bothered by feYel (episode of high body 
ten1pe1·ature ....................................................................... 
0 
ESJ 
Lnn 
1 
0 
0 
0 
Gal 
0 
Hll 
I haw trouble oncentrating... ... . . .. .. ... ... . ... ... ...... ...... .. .. . . . . .. 
0 
I wony about gettin~ iufe lions......................................... 
0 
I w ny that I might get new symptoms of my illne 
0 
U\17 
I feel isolated from othe because of my illne 
or 
treatment............................................................................. 
0 
I ha,·e emotional up and down ........................................ 
0 
Becat e of my illne . I haYe difficulty planning for the 
future .................................................................................. 
0 
omP-
QuitE' 
wb:ll 
a bit 
3 
2 
3 
3 
3 
3 
3 
3 
3 
3 
3 
2 
3 
2 
3 
3 
3 
3 
, .('t•y 
much 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
16~100 
.... Ja!J 


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Appendix D.
Performance Status Scoring Systems
Karnofsky and ECOG Performance Status Scoring Systems
Karnofsky Performance Status
ECOG Performances Status
General Description
Score
Specific Description
Score
Description
Able to carry on 
normal activity and 
to work; no special 
care needed.
100
Normal; no complaints; no evidence of 
disease.
0
No symptoms, fully active,
able to work.
90
Able to carry on normal activity; minor 
signs or symptoms of disease.
1
Symptomatic, but not spending 
extra time in bed; able to do 
light work.
80
Normal activity with effort; some signs 
or symptoms of disease.
Unable to work; able 
to live at home and 
care for most 
personal needs; 
varying amount of 
assistance needed.
70
Cares for self; unable to carry on 
normal activity or to do active work.
2
In bed less than 50% of the 
time, unable to work, but able 
to care for self.
60
Requires occasional assistance, but is 
able to care for most of personal needs.
50
Requires considerable assistance and 
frequent medical care.
3
In bed more than 50% of the 
time, though not bedridden, 
limited self-care.
Unable to care for 
self; requires 
equivalent of 
institutional or 
hospital care; disease 
may be progressing 
rapidly.
40
Disabled; requires special care and 
assistance.
30
Severely disabled; hospital admission 
is indicated although death not 
imminent.
4
Completely bedridden
20
Very sick; hospital admission 
necessary; active supportive treatment 
necessary.
10
Moribund; fatal processes progressing 
rapidly.
0
Dead
Abbreviations: ECOG, Eastern Cooperative Oncology Group

SAP_000.pdf: 
Study Title: 
Name of Test Drug: 
Study Number: 
Protocol Version: 
Protocol Date: 
Analysis Type: 
Analysis Plan Version: 
Analysis Plan Date: 
Analysis Plan Author: 
~ GILEAU 
STATISTICAL ANALYSIS PLAN 
A Phase 2 Study to Assess the Efficacy and Safety of 
Idelalisib in Subjects with Indolent B-Cell Non-Hodgkin 
Lymphomas Refractory to Rituximab and Alkylating Agents 
Idelalisib (IDELA; GS-1101) 
101-09 
Version 3.0 
23 May, 2013 
Final 
Final Version 1.0 
08 July, 2013 
Daniel Li, Ph.D. 
CONFIDENTIAL AND PROPRIETARY INFORMATION 


Idelalisib (IDELA) Study 101-09 
Statistical Analysis Plan 
TABLE OF CONTENTS 
TABLE OF CONTENTS .... 
LIST OF ABBREVIATIONS 
1. 
INTRODUCTION ................ . 
1.1. 
1.2. 
1.3. 
Study Objectives 
Study Design .................... . 
Sample Size and Power ............... . 
2. 
TYPE OF PLANNED ANALYSIS 
2.1. 
2.2. 
Interim Analysis 
Final Analysis ................................................................... . 
3. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
3.1. 
3.2. 
3.3. 
3.4. 
3.5. 
3.6. 
3.7. 
3.8. 
Analysis Sets ............................................... . 
3.1.1. 
Intent-to-Treat Analysis Set 
3.1.2. 
Per Protocol Analysis Set ............................................... . 
3.1.3. 
Pharmacodynamic/Pharmacokinetic Analysis Sets 
Subject Groups ................................................................................. . 
Treatment Strata ............................... . 
Examination of Subject Subsets 
Multiple Comparisons ...................... . 
Missing Data and Outliers ........................................... . 
Data Handling Conventions and Transformations 
3. 7.1. 
Data Handling for Efficacy Endpoints 
3.7.2. 
Data Handling for Laboratory data ............ . 
Visit Windows .................................................................. . 
3.8.1. 
Definition of Study Day 1 and Baseline 
3.8.2. 
Analysis Windows ............................................................................. . 
3.8.3. 
Selection of Data in the Event of Multiple Records in a Window 
4. 
SUBJECT DISPOSITION 
5. 
6. 
4.1. 
4.2. 
4.3. 
4.4. 
Subject Emollment 
Disposition of Subjects 
Extent of Exposure ................................................... . 
4.3.1. 
Duration of Exposure to Study Drug .............. . 
4.3.2. 
Adherence (Compliance) with Study Drug 
Protocol Deviations .......................................................... . 
BASELINE DATA .......................................................... . 
5.1. 
5.2. 
Demographics and Baseline Characteristics 
Medical History ............................................................ . 
5.2.1. 
Indolent NHL Disease History/Status 
5.2.2. 
General Medical History ............................ . 
EFFICACY ANALYSES .................................................. . 
6.1. 
6.2. 
6.3. 
6.4. 
Definition of the Primary Efficacy Endpoint ........................... . 
Statistical Hypothesis for the Primary Efficacy Endpoint. 
Analysis of the Primary Efficacy Endpoint .............................. . 
Secondary Efficacy Endpoints ............................................ . 
6.4.1. 
Definition of Secondary Efficacy Endpoints .................. . 
Final Version 1.0 
.. 2 
.. 4 
...... 6 
.... 6 
. ..... 7 
. ... 13 
.... 14 
.... 14 
. ... 14 
. ... 15 
. ... 15 
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. ... 15 
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. ... 16 
. ... 16 
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. ... 18 
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.... 20 
.... 20 
.... 20 
. ... 21 
. ... 21 
.... 21 
. ... 21 
. ... 22 
.... 22 
. ... 22 
.... 22 
. ... 23 
. ... 24 
.... 24 
. ... 24 
. ... 25 
. ... 25 
. ... 25 
6.4.2. 
Analysis Methods for Secondary Efficacy Endpoints ............................ . 
. ... 26 
.... 26 
6.4.2.1. 
Duration of Response and Progression-Free Survival 
CONFIDENTIAL 
Page 2 
08 July 2013 


Idelalisib (IDELA) Study 101-09 
Statistical Analysis Plan 
7. 
8. 
6.4.2.2. 
6.4.2.3. 
6.4.2.4. 
6.4.2.5. 
6.4.2.6. 
Lymph Node Response Rate 
Time to Response ...................... . 
Overall survival ............................ . 
Health-Related Quality of Life 
Performance Status. 
SAFETY ANALYSES ............................. . 
7.1. 
7.2. 
7.3. 
7.4. 
7.5. 
7.6. 
7.7. 
7.8. 
Adverse Events and Deaths .......................... . 
7.1.1. 
Adverse Event Dictionary 
7.1.2. 
Adverse Event Severity .............................................. . 
7.1.3. 
Relationship of Adverse Events to Study Drug. 
7.1.4. 
Serious Adverse Events .......................................... . 
7.1.5. 
Treatment-Emergent Adverse Events ........................ . 
7.1.5.1. 
Definition of Treatment-Emergent 
7.1.5.2. 
Incomplete Dates .................................. . 
7.1.6. 
Summaries of Adverse Events and Deaths 
Laboratory Evaluations ....................................................... . 
7.2.1. 
Summaries ofNumeric Laboratory Results ............ . 
7.2.2. 
Summaries of Categorical Laboratory Results 
7.2.3. 
Graded Laboratory Values .............................................................. . 
7.2.3.1. 
Treatment-Emergent Laboratory Abnormalities 
7.2.3.2. 
Summaries ofLaboratory Abnormalities .................. . 
7.2.4. 
Shift in CTCAE Grade Relative to Baseline ...................... . 
7.2.5. 
Transaminase elevations .................................... . 
Vital Signs ................................................ . 
Prior Therapy and Prior Radiation 
Concomitant Medications .................... . 
Electrocardiogram Results ................... . 
7.6.1. 
Corrected QT Intervals. 
7.6.2. 
Investigator Assessment ofECG Readings ................ . 
Physical Examination ..... 
Post Treatment Assessments ........................ . 
PHARMACOKINETIC ANALYSES ........................... . 
8.1. 
8.2. 
Estimation ofPharmacokinetic Parameters 
Statistical Analysis Methods ............................... . 
9. 
PHARMACODYNAMIC ANALYSES 
10. REFERENCES 
11. 
SOFTWARE ............ . 
12. 
SAP REVISION 
13. APPENDICES 
CONFIDENTIAL 
Page 3 
Final Version 1.0 
.... 26 
. ... 27 
. ... 27 
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. .. 30 
... 30 
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. ... 39 
.... 39 
. ... 39 
... .41 
.... 42 
.... 43 
.... 44 
... .45 
08 July 2013 


Idelalisib (IDELA) Study 101-09 
Statistical Analysis Plan 
AE 
ATC 
AUC 
AUCo.n 
AUCo.Jast 
BID 
B:MI 
BOR 
CI 
CR 
CRF 
CSR 
CT 
CTCAE 
Cn-ough 
DNA 
DOR 
ECG 
ECOG 
FACT-Lym 
FDG 
FL 
HLGT 
HLT 
HRQL 
ICH 
iNHL 
IRC 
ITT 
IWRS 
LLQ 
LLT 
LPL 
MedDRA 
MMRM 
MRI 
:tvfZL 
ND 
CONFIDENTIAL 
LIST OF ABBREVIATIONS 
adverse event 
Anatomical-Therapeutic-Chemical (drug coding system) 
area under the curve 
area under the curve for 0- 12 hours 
area under the curve for 0 -last sampling time point 
twice a day 
body mass index 
best overall response 
confidence interval 
complete response 
case report form 
maximum plasma concentration 
clinical study report 
computerized tomography 
Common Tenninology Criteria for Adverse Events 
trough drug concentration 
deoxyribonucleic Acid 
duration of response 
electrocardiogram 
Eastern Cooperative Oncology Group 
Functional Assessment of Cancer Therapy: Lymphoma 
fluorodeoxyglucose 
follicular lymphoma 
high-level group term 
high-level tenn 
health-related quality of life 
International Conference on Harmonisation 
indolent Non-Hodgkin lymphoma 
independent review committee 
intent-to-treat 
interactive web response system 
lower limit of quantification 
low level tenn 
lymphoplasmacytoid lymphoma 
Medical Dictionary for Regulatory Activities 
mixed-effects model repeated measures 
magnetic resonance imaging 
marginal zone lymphoma 
no disease 
Page 4 
Final Version 1.0 
08 July 2013 


Idelalisib (IDELA) Study 101-09 
Statistical Analysis Plan 
Final Version 1.0 
NE 
NHL 
ORR 
OS 
PD 
PET 
PFS 
PK 
pp 
PR 
PT 
QTc 
QTc-B 
QTc-F 
SAE 
SAP 
SD 
SE 
SLL 
StD 
soc 
SPD 
SPEP 
tl/2 
TEAE 
Truax 
TTR 
\VHODRUG 
CONFIDENTIAL 
not evaluable 
non-Hodgkin lymphoma 
overall response rate 
overall survival 
progressive disease 
positron-emission tomography 
progression-free survival 
pharm acokinetic 
per protocol 
partial response 
preferred term 
QT interval corrected 
QT interval corrected for heart rate using Bazett's formula 
QT interval corrected for heart rate using Fridericia' s formula 
serious adverse event 
statistical analysis plan 
stable disease 
standard error 
small lymphocytic lymphoma 
standard deviation 
system organ class 
sum of the products of the perpendicular diameters of measurable index lesions 
serum protein electrophoresis 
half-life 
treatment-emergent adverse event 
time of maximum concentration 
time to response 
World Health Organization Drug Classification Dictionary 
Page 5 
08 July 2013 


Idelalisib (IDELA) Study 101-09 
Statistical Analysis Plan 
Final Version 1.0 
1. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the analyses to be conducted for Gilead 
Sciences, Inc. idelalisib (IDELA) Study 101-09. The final study analysis will be performed 
when all enrolled subjects have completed efficacy, safety, and other assessments through 
::.: 24 weeks of evaluation. 
1.1. 
Study Objectives 
Primary Study Objectives 
• 
To evaluate tumor regression as determined by overall 
response rate (ORR) in subjects receiving IDELA for 
treatment of iNHL refractory to rituximab and alkylating 
agents 
Secondary Study Objectives • 
To determine the onset, magnitude, and duration of 
tumor control and of treatment success in subjects 
receiving IDELA 
CONFIDENTIAL 
• 
To characterize health-related quality of life (HRQL) as 
reported by subjects with iNHL receiving IDELA 
• 
To evaluate the effects of IDELA on subject 
performance status 
• 
To assess the pharmacodynamic effects of IDE LA 
• 
To evaluate IDELA treatment administration and 
compliance with IDELA therapy 
• 
To describe the safety profile of IDELA 
• 
To characterize IDELA plasma exposure over time 
PPD 
Page 6 
08 July 2013 


Idelalisib (IDELA) Study 101-09 
Statistical Analysis Plan 
1.2. 
Study Design 
Design Configuration and 
Subject Population 
Treatment Groups 
CONFIDENTIAL 
Final Version 1.0 
This protocol describes a Phase 2, open-label, single-arm, 2-
stage, efficacy, safety, and pharmacodynamic study of 
IDE LA in subjects with previously treated iNHL that is 
refractory both to rituximab and to alkylating-agent-
containing chemotherapy. 
Eligible subjects will initiate oral therapy with IDELA at a 
starting dose of 150 mg BID given continuously. Treatment 
with IDELA will continue until tumor progression or 
unacceptable toxicity. Subjects will be followed in the clinic 
at 2-week intervals through the first 12 weeks oftreatment, at 
4-week intervals from 12 to 24 weeks of treatment, at 6-week 
intervals from 24 to 48 weeks of treatment, and at 12-week 
intervals thereafter. Tumor response will be evaluated at 
baseline; at 8, 16, and 24 weeks oftherapy; and every 12 
weeks thereafter according to standard criteria. The 
responses will be assessed by both the investigator and an 
independent review committee (IRC). 
The study will be conducted in 2 stages using Simon's 
optimal 2-stage design. In Stage 1 ofthe study, 31 subjects 
will be enrolled; if?:9 ofthese Stage 1 subjects have a tumor 
response, then the study will continue. In Stage 2, a further 
69 subjects will be enrolled. With a total intended sample 
size of 100 subjects, the study has power >0.90 to achieve a 
1-sided significance level of0.005 and will provide an ample 
safety database. 
Starting Dose: 150 mg BID 
Reduced Dose -1: 100 mg, BID 
Reduced Dose -2: 75 mg, BID 
Page 7 
08 July 2013 


Idelalisib (IDELA) Study 101-09 
Statistical Analysis Plan 
Key Eligibility Criteria 
CONFIDENTIAL 
Final Version 1.0 
• 
Age ?: 18 years 
• 
Kamofsky performance score ?: 60 (Eastern Cooperative 
Oncology Group [ECOG] performance score of 0, 1, or 
2) 
• 
Histologically confirmed diagnosis of B-cell iNHL, with 
histological subtype limited to the following based on 
criteria established by the World Health Organization 
(WHO) 2008 classification oftumors ofhaematopoietic 
and lymphoid tissues: 
-Follicular lymphoma (FL) Grade 1, 2, or 3a 
-
Small lymphocytic lymphoma (SLL) with absolute 
lymphocyte count <5 x 109/L at the time of diagnosis 
and on baseline laboratory assessment performed 
within 4 weeks prior to the start of study drug 
administration 
-
Lymphoplasmacytic lymphoma/Waldenstrom 
Macroglobulinemia (LPLIWM) 
-Marginal zone lymphoma (MZL) (splenic, nodal, or 
extra-nodal) 
• 
Histological materials documenting diagnosis of 
lymphoma available for review. Note: Central pathology 
confirmation of diagnosis will be performed in this study. 
However, a subject may be enrolled without waiting for 
confirmation ofhistological diagnosis on condition that 
pathological materials are known to be available for 
revtew. 
• 
Presence of radiographically measurable 
lymphadenopathy or extranodallymphoid malignancy 
(defined as the presence of?: 1lesion that measures~ 2.0 
em in the longest dimension [LD] and~ 1.0 em in the 
longest perpendicular dimension [LPD] as assessed by ?: 
CT or magnetic resonance imaging [MRI]) 
• 
Prior treatment with ?: 2 chemotherapy- or 
immunotherapy-based regimens, or with rituximab/with 
an alkylating agent for iNHL 
• 
Prior treatment with rituximab and with an alkylating 
agent ( eg, bendamustine, cyclophosphamide, ifosfamide, 
chlorambucil, melphalan, busulfan, nitrosoureas) for 
iNHL. 
• 
Lymphoma that is refractory to rituximab and to an 
alkylating agent 
Page 8 
08 July 2013 


Idelalisib (IDELA) Study 101-09 
Statistical Analysis Plan 
Final Version 1.0 
CONFIDENTIAL 
• 
Refractoriness is defined as: 
• 
D Rituximab (without chemotherapy): 
-
Lack of a complete response (CR) or partial response 
(PR) during rituximab therapy comprising 2'4 doses 
of2'375 mg/m2 given weekly, or 
-
Occurrence of progressive disease (PD) within 6 
months of the completion of a regimen ofrituximab 
therapy comprising 2'4 doses of 2'375 mg/m2 given 
weekly, or 
-
Occurrence of PD during rituximab maintenance 
therapy or within 6 months of completion of 
rituximab maintenance therapy 
• 
Rituximab (with chemotherapy): 
-
Lack of a CR or PR during rituximab-containing 
therapy comprising 2'2 doses of 2'375 mg/m2, or 
-
Occurrence ofPD within 6 months ofthe completion 
of a regimen of rituximab-containing therapy 
comprising 2'2 doses of2'375 mg/m2, or 
-
Occurrence of PD during rituximab maintenance 
therapy or within 6 months of completion of 
rituximab maintenance therapy 
• 
Alkylating agent (administered with or without 
rituximab ): 
-
Lack of a CR or PR during alkylating-agent-
containing therapy comprising 2'2 cycles of treatment, 
or 
-
Occurrence ofPD within 6 months ofthe completion 
of a regimen of alkylatingagent-containing 
chemotherapy comprising 2'2 cycles of treatment 
• 
Discontinuation of all other therapies for the treatment of 
iNHL ~ 3 weeks before initiation of study treatment 
(Visit 2). 
• 
All acute toxic effects of any prior antitumor therapy 
resolved to Grade ~ 1 before initiation of study treatment 
(Visit 2) (with the exception of alopecia [Grade ~2 
permitted], neurotoxicity [Grade ~2 permitted], or bone 
marrow parameters noted in Table 1 [Grade ~2 
permitted]). 
• 
Required baseline laboratory data (within 4 weeks prior 
to start of study drug administration) as shown in Table 1 
ofthe study protocol. 
Page 9 
08 July 2013 


Idelalisib (IDELA) Study 101-09 
Statistical Analysis Plan 
Study Periods/Phases 
CONFIDENTIAL 
Final Version 1.0 
This study will consist of 3 study periods. The screening 
period will be 4 weeks or less. The treatment period may 
continue until the occurrence of any events requiring 
treatment discontinuation. The long-term post-treatment 
follow-up period will be from the last dose of study drug up 
to Year 5. 
The study will be conducted in 2 stages using Simon's 
optimal 2-stage design. In Stage 1 ofthe study, 31 subjects 
will be enrolled; if2 9 ofthese Stage 1 subjects have a tumor 
response, then the study will continue. In Stage 2, a further 
69 subjects will be enrolled. The final study analysis will be 
performed when all enrolled subjects have completed 
efficacy, safety, and other assessments through at least 24 
weeks of evaluation. 
Page 10 
08 July 2013 


IDELALISIB Study 101-09 
Statistical Analysis Plan 
Schedule of Assessments 
Period 
Screen 
Visit 
1 
Week 
-4 
Within 
Study Day 
-28 
Days 
Visit Window 
Informed consent 
X 
Medical history 
X 
Histopathology review 
X 
Serum virology 
X 
Coagulation 
X 
Urinalysis 
X 
P-HCG 
X 
~PD 
HRQL -FACT-Lym 
Study drug return/accounting 
Adverse events 
Concomitant medications 
X 
Performance status 
X 
Vital signs 
X 
Hematology 
X 
Serum chemistry 
X 
Pharmacodynamics 
Drug dispensing 
CONFIDENTIAL 
2 
0 
1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
3 
4 
5 
6 
7 
8 
9 
2 
4 
6 
8 
10 
12 
16 
15 
29 
43 
57 
71 
85 
113 
±2 
±2 
±2 
±2 
±2 
±2 
±3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Page 11 
Final Draft Version 1.0 
Treatment 
Follow-up 
10 
11 
12 
13 
14 
15 
16+ 
Imme-
20 
24 
30 
36 
42 
48 
End of 
diate Long-
Q12 
post-
Weeks Treatment 
term 
141 169 
211 
253 
295 
337 
treat-
ment 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
l 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
13 May 2013 


IDELALISIB Study 101-09 
Statistical Analysis Plan 
Period 
Visit 
Week 
Study Day 
Visit Window 
Physical examination 
12-lead ECG 
Immunophenotyping 
Serum immunoglobulins 
Radiology assessments 
(CTIMRI) 
Bone marrow biopsy/aspirate• 
SPEP (IgM monoclonal 
protein) 
Idelalisib dosing in clinic 
LimitedPK 
~PD 
Screen 
1 
-4 
Within 
-28 
Days 
X 
X 
X 
X 
X 
Study Procedures and Timingc 
2 
0 
1 
X 
X 
X 
X 
3 
4 
5 
6 
7 
8 
2 
4 
6 
8 
10 
12 
15 
29 
43 
57 
71 
85 
±2 
±2 
±2 
±2 
±2 
±2 
X 
X 
X 
x· 
X 
X 
X 
X 
X 
Final Draft Version 1.0 
Treatment 
Follow-up 
9 
10 
11 
12 
13 
14 
15 
16+ 
Imme-
16 
20 
24 
30 
36 
42 
48 
End of 
diate Long-
Q12 
post-
Weeks Treatment 
term 
113 141 169 
211 
253 
295 
337 
treat-
ment 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
x· 
x· 
x· 
x· 
x· 
X 
X 
X 
X 
X 
X 
X 
X 
a 
Required at screening. If disease present at baseline, to be performed post-baseline to confirm response category in subjects with potential CR by radiological assessments. If 
the baseline bone marrow biopsy/aspirate does not show lymphoma involvement, it is not necessary to obtain a follow-up bone marrow biopsy/aspirate to establish CR. 
b 
For subjects with LPL only, performed locally per standard of care 
c 
For detailed information regarding activities to be performed at each visit, see Section 7. 2 of study 101-09 protocol. 
Abbreviations: ~-HCG, beta human chorionic gonadotropin; HRQL, health-related quality oflife; FACT-Lym, Functional Assessment of Cancer Therapy- Lymphoma; ECG, 
electrocardiogram; CT, computed tomography; LPL, lymphoplasmacytoidlymphoma; MRI, magnetic resonance imaging; SPEP, serum protein electrophoresis; CR, complete 
response 
CONFIDENTIAL 
Page 12 
13 May 2013 
I 


Idelalisib Study 101-09 
Statistical Analysis Plan 
Randomization 
Site and/or 
Stratum 
Enrollment Limits 
Study Duration 
Final Version 1.0 
No randomization will be performed in the study. 
Study subjects will be enrolled at investigational sites in North 
America and Europe. 
At least 50 subjects with prior bendamustine exposure will be 
enrolled. The IWRS will gate accrual of subjects without prior 
bendamustine treatment. 
All subjects may receive study drug indefinitely unless any of the 
withdrawal criteria (such as withdrawal of consent, experienced an 
adverse event, or tumor progression) indicated in Section 9 of the 
protocol is met. 
Subjects will be followed in the clinic at 2-week intervals through the 
first 12 weeks oftreatment, at 4-week intervals from 12 to 24 weeks 
of treatment, at 6-week intervals from 24 to 48 weeks of treatment, 
and at 12-week intervals thereafter. Tumor response will be evaluated 
at baseline; at 8, 16, and 24 weeks of therapy; and every 12 weeks 
thereafter according to standard criteria. The responses will be 
assessed by both the investigator and an independent review 
committee (IRC), with the IRC-reviewed responses treated as primary 
in the efficacy analyses. 
Enrollment is planned to occur over ::; 15 months; subject follow-up 
will continue through ::=:: 6 months. 
1.3. 
Sample Size and Power 
Planned Sample Size 
Up to 120 subjects may be enrolled in order to ensure enrollment of 
::=:: 100 subjects (31 in Stage 1, and 69 in Stage 2) who have a 
documented diagnosis of lymphoma, who have confirmed 
refractory disease, and who can be evaluated for tumor response 
with baseline and on-study scans (through the planned 24-week, 
follow-up tumor assessment). 
Power Statement 
The null hypothesis that the IRC-reviewed ORR is ::; 20% will be 
tested against the alternative hypothesis that it is ::=:: 39% (ie, ~40% ). 
Using Simon's optimal 2-stage design [Simon 1989], a sample size 
of 100 subjects has power > 0.90 to achieve a 1-sided significance 
level of < 0.005 and will provide an adequate safety database. 
Actual Enrollment 
A total of 125 subjects have been enrolled into this study and this 
and Impact on Power will provide > 0.90 power to test the primary hypothesis. 
CONFIDENTIAL 
Page 13 
05 July 2013 


Idelalisib Study 101-09 
Statistical Analysis Plan 
2. 
TYPE OF PLANNED ANALYSIS 
2.1. 
Interim Analysis 
Final Version 1.0 
A single formal interim analysis is planned under Simon's optimal 2-stage design. The sole 
purpose of this interim analysis is to determine ifthere is a sufficient ORR observed early in 
the study to warrant continuing the study to completion. The interim analysis constitutes a 
futility analysis; it will not be used to stop the trial early for positive efficacy. 
In Stage 1 of the study, 31 subjects will be enrolled. If ~ 9 Stage 1 subjects have a response 
(ie, complete response or partial response), then the study will continue. If < 9 Stage 1 
subjects have a response, accrual to the study will be halted. At the end of Stage 1, the 
probability of erroneously proceeding with the study is 0.151 under the null hypothesis and 
of erroneously discontinuing the study is 0. 091 under the alternative hypothesis. 
If the required Stage 1 tumor ORR is seen based on investigator assessments, accrual can 
proceed in Stage 2 without interruption. If the required total number of subjects are accrued 
to Stage 1 but follow-up is not sufficiently mature (ie, through the Week 16 radiographic 
evaluation) in all Stage 1 subjects to reasonably assess the Stage 1 ORR, accrual to Stage 2 
may proceed while the Stage 1 data are being collated. All available tumor response and 
progression data will be considered at the time of the assessment. At the latest, the interim 
analysis will be performed when the last of the Stage 1 subjects has been enrolled and has 
completed the 16-week tumor assessment and these data are evaluated. 
2.2. 
Final Analysis 
In Stage 2 of the study, it is planned that 69 subjects will be enrolled to achieve the total 
intended sample size of 100 subjects. The final study analysis will be performed when all 
enrolled subjects have completed efficacy, safety, and other assessments through at least 
24 weeks of evaluation. 
CONFIDENTIAL 
Page 14 
05 July 2013 


Idelalisib Study 101-09 
Statistical Analysis Plan 
Final Version 1.0 
3. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
3.1. 
Analysis Sets 
3.1.1. 
Intent-to-Treat Analysis Set 
The intent-to-treat (ITT) analysis set will comprise all subjects who receive ~1 dose of 
IDELA. The ITT analysis set will be used in the analyses of ORR, progression-free survival 
(PFS), overall survival (OS), safety, and study drug administration and compliance. The ITT 
analysis set will be the primary analysis set for all the efficacy variables. 
Duration of response (DOR) and time-to-response (TTR) will be analyzed based on all ITT 
subjects who achieve a CR or PR (including MR for subjects with WM). Lymph node 
response rate (LNR) will be analyzed based on all ITT subjects who have both baseline and 
2::1 evaluable post-baseline tumor assessments. 
3.1.2. 
Per Protocol Analysis Set 
It is anticipated that ITT subjects who meet any of the following criteria will not be included 
in the per protocol (PP) analysis set: 
• 
Do not have a diagnosis of lymphoma or documented refractory disease (refractory to 
both rituximab and an alkylating agent) 
• 
Do not have measurable nodal disease at baseline as determined by the IRC 
• 
Do not have a PFS event (PD or death), and do not have baseline and on-study tumor 
evaluation. 
The PP analysis set will be used in analyses of ORR, DOR, TTR, LNR and PFS. 
3.1.3. 
Phannacodynamic/Phannacokinetic Analysis Sets 
The pharmacodynamic/pharmacokinetic analysis sets include data from subjects in the ITT 
analysis set who have the necessary baseline and on-study measurements to provide 
interpretable results for the specific parameters of interest. 
3.2. 
Subject Groups 
There is only 1 treatment group for this study. 
3.3. 
Treatment Strata 
There is only 1 treatment group for this study and no treatment strata were planned. 
However, given the increasing relevance ofbendamustine as a component of treatment for 
subjects with iNHL, the IWRS will gate ::;so subjects without prior bendamustine treatment. 
CONFIDENTIAL 
Page 15 
05 July 2013 


Idelalisib Study 101-09 
Statistical Analysis Plan 
3.4. 
Examination of Subject Subsets 
Final Version 1.0 
The efficacy endpoints (ORR, DOR, TTR and PFS) will be examined in the following 
subject subsets: 
• 
Refractory to last therapy status (Yes or No) 
• 
Number of prior therapies ( <4 or ~4) 
• 
Number of times refractory to an Alklating Agent (:S: 1 or > 1) 
• 
Number of times refractory to Rituximab (:S: 2 or > 2) 
• 
Refractory to bendamustine (Yes or No) 
• 
Disease subcategory (FL, SLL, WM or MZL ) 
• 
Suite for radioimmunotherapy (Yes or No) 
• 
Bulky status (Longest diameter of baseline lesion <7cm or~ 7cm) 
• 
Gender (Male or Female) 
• 
Age group ( <65 or ~65 years) 
• 
Race (White or Non-White) 
• 
Region (US or Non-US) 
AEs will be examined in the following subject subsets: 
• 
Sex (Male or Female) 
• 
Age group ( <65 or ~65 years) 
• 
Race (White or Non-White) 
• 
Region (US or Non-US) 
3.5. 
Multiple Comparisons 
Not applicable. 
3.6. 
Missing Data and Outliers 
Missing Data 
A missing data point for a given study visit may be due to any of the following reasons: 
CONFIDENTIAL 
Page 16 
05 July 2013 


Idelalisib Study 101-09 
Statistical Analysis Plan 
Final Version 1.0 
• 
A visit occurred in the window but data were not collected or were unusable 
• 
A visit did not occur in the window 
• 
A subject permanently discontinued from the study before reaching the window 
In general, values for missing data will not be imputed unless methods for handling missing 
data are specified. 
Missing data in Functional Assessment of Cancer Therapy: Lymphoma (FACT-Lym) will be 
handled according to the administration and scoring guidelines (Section 6.4.2. 5). 
Outliers 
No data will be excluded from the analyses, including any outliers. 
3. 7. 
Data Handling Conventions and Transformations 
• 
By-subject listings will be presented for subjects in the ITT analysis set and sorted by 
subject number, visit, and time (if applicable). 
• 
Summary tables for continuous variables will contain the following statistics: N 
(number in analysis set), n (number with data), mean, standard deviation (StD), 95% CI, 
median, Q 1, Q3, minimum, and maximum. The same number of decimal places as in the 
raw data will be presented when reporting minimum and maximum, 1 more decimal 
place than in the raw data will be presented when reporting mean, median, Q1 and Q3, 
and 2 more decimal places than in the raw data will be presented when reporting StD and 
95% CI. 
• 
Summary tables for categorical variables for baseline and safety data will include: N, n, 
percentage. The tables for efficacy endpoints will include standard error, and 95% Cis on 
the percentage, where appropriate. Unless otherwise indicated, 95% Cis for binary 
variables will be calculated using the binomial distribution. The denominator for the 
percentages will be the number of subjects in the respective analysis set, unless otherwise 
specified. Missing data will be included as a row in tables where it is appropriate. All 
percentages will be presented as one-decimal point, unless otherwise specified. Percents 
equal to 100 will be presented as 100% and percents will not be presented for zero 
frequencies. 
• 
Data from all sites will be pooled for all analyses. 
• 
Unscheduled visits will only be included in listings and the best or worst post-baseline 
summary. Unscheduled visits will not be included in the by-visit summary tables, unless 
otherwise specified. 
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Statistical Analysis Plan 
Final Version 1.0 
• 
Unless otherwise specified, all analyses will be 2-sided at the 0.05 level of significance. 
• 
For Kaplan-Meier (KM) estimates, the 95% Cis will be calculated using Greenwood's 
formula with (complementary) log-log transformation. 
3.7.1. 
Data Handling for Efficacy Endpoints 
Ifthere is a significant degree of non-normality for a continuous endpoint, analysis may be 
performed on log-transformed data or using nonparametric methods, as appropriate. 
3.7.2. 
Data Handling for Laboratory data 
Laboratory data that are continuous in nature but are less than the lower limit of quantitation 
or above the upper limit of quantitation will be imputed as follows: 
• 
A value that is 1 unit less than the limit of quantitation will be used for calculation of 
descriptive statistics if the data is reported in the form of "<x" (xis considered the limit 
of quantitation). For example, if the values are reported as <50 and <5.0, then values of 
49 and 4.9 will be used for calculation of summary statistics, respectively. However, for 
direct bilirubin, a value of "<0.1" will be treated as 0.05 for calculation of summary 
statistics. 
• 
A value that is 1 unit above the limit of quantitation will be used for calculation of 
descriptive statistics if the data is reported in the form of ">x" (xis considered the limit 
of quantitation). For example, if the values are reported as >50 and >5.0, then values of 
51 and 5.1 will be used for calculation of summary statistics, respectively. 
• 
The limit of quantitation will be used for calculation of descriptive statistics if the data is 
reported in the form of":::; x" or "2:' x" (xis considered as the limit of quantitation). 
3.8. 
Visit Windows 
3.8.1. 
Defmition of Study Day 1 and Baseline 
Study Day 1 is defined as the day of first dose of study medication. 
Baseline is defined as the last observation before the first dose, unless otherwise specified. 
3.8.2. 
Analysis Windows 
For parameters that will be summarized by visit, the nominal visit as recorded on the 
electronic case report form will be used. For parameters assessed at the end of treatment 
(EOT) visit, the assessment results will be assigned to the next scheduled visit where the 
respective data were scheduled to be collected for summary. There will be no additional 
analysis windowing done based on the assessment date. 
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Final Version 1.0 
3.8.3. 
Selection of Data in the Event of Multiple Records in a Window 
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value per visit. 
Unless otherwise noted throughout the rest of this document, when a single value is needed, 
the following rule(s) will be used: 
• 
If more than 1 assessment occurs during the same nominal visit, select the record closest 
to the nominal day for that visit. 
• 
If there are 2 assessments that are equidistant from the nominal day, the data of the 
assessment after the scheduled study day will be used. 
• 
The last measurement will be used if multiple measurements are taken on the same day. 
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Statistical Analysis Plan 
4. 
SUBJECT DISPOSITION 
4.1. 
Subject Enrollment 
Final Version 1.0 
The number and percentage of subjects treated with IDELA will be summarized. A listing of 
subjects treated will be provided to describe site, subject number, inform consent date, 
screening date, and date of first dose of IDE LA. 
A listing of screen failed subjects will be provided to include date of informed consent and 
the reasons for screen failing. 
4.2. 
Disposition of Subjects 
A summary of subject disposition will be provided. This summary will present number of 
subjects: 
• 
screened 
• 
treated with study drug (ie, ITT analysis set) 
• 
treatment ongoing 
• 
treatment completed due to disease progression or death 
• 
discontinued the study treatment (with summary of reasons for not completing), 
• 
entered the 5-year long-term follow-up 
• 
in the PP, phamacodynamic and pharmacokinetic analysis sets 
The denominator for the percentages of subjects in each category will be the number of 
subjects in the ITT analysis set. 
Subjects who completed and discontinued long-term follow-up through 5 years will be 
summarized separately. The reasons for not completing the 5-year follow-up will be 
summarized as well. 
A data listing of reasons for premature study treatment discontinuation will be provided 
along with subject number, site number, first and last dosing date, duration of treatment, and 
last contact date. The most recent, non-missing primary and key secondary endpoint values 
prior to discontinuation will also be included in this listing. 
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Final Version 1.0 
4.3. 
Extent of Exposure 
4.3.1. 
Duration of Exposure to Study Drug 
Duration of exposure to study drug will be defined as (min(last dose date, data cutoff date)-
first dose date+ 1), regardless of temporary interruptions in study drug administration, and 
will be expressed in months. Duration of exposure to study drug will be summarized for ITT 
analysis set using descriptive statistics and as the number and percentage of subjects exposed 
for at least 1 day, 2, 4, 6, 12 months, and every 6 months thereafter. 
Number and percentage of subjects who had dose modification (dose reduction and dose re-
escalation) will also be summarized. 
IDELA dosing records, drug accountability (dispense and return) records and dose 
modification records will be listed in details. 
4.3.2. 
Adherence (Compliance) with Study Drug 
Adherence(%) with study drug will be calculated as: 
Adherence (%) = {sum of pills dispensed minus pills returned for each dosing period} 
divided by {sum over all dosing period of (total daily pills x dosing duration)}, taking into 
account physician-prescribed reductions, escalations and interruptions. 
Descriptive statistics for adherence along with the number and percentage of subjects 
belonging to adherence categories ( eg, < 80% or 2 80%) will be provided for the ITT 
analysis set. No inferential statistics will be provided. 
4.4. 
Protocol Deviations 
Protocol deviations will be identified by the Gilead clinical team. Major protocol deviations 
will be summarized by type of deviation in the clinical study report (CSR) based on ITT 
analysis set. A listing will be provided for all major protocol deviations. 
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Statistical Analysis Plan 
5. 
BASELINE DATA 
5.1. 
Demographics and Baseline Characteristics 
Final Version 1.0 
Demography including gender, race, ethnicity, age (years), weight (kg), height (em) and 
body mass index (BMI, kglm 2) will be summarized for the ITT analysis set. 
Age will be calculated as the number of years between date of birth and date of first dose. 
Age (years)= (date of first dose- date ofbirth+ 1) I 365.25 (round down to an integer) 
BMI (kg/m2) =weight I (heighti (round to 1 decimal point) 
Number and percentage of subjects <65 and ~65 years will also be summarized. A data 
listing will be presented for date of birth and the above demographic data. ECOG 
performance status collected at the baseline will also be summarized. 
5.2. 
Medical History 
Summary tables will be provided based on the ITT analysis set. 
5.2.1. 
Indolent NHL Disease History/Status 
Number and percent of subjects with different types of disease history (as categorized in the 
CRF) for indolent Non-Hodgkin lymphoma (iNHL) and results for organ assessment will be 
summarized using ITT analysis set. Data listings will be presented separately for iNHL 
history and organ assessments. Time since disease diagnosis (in years) will also be 
summarized using descriptive statistics. 
All disease history with partial diagnosis date will be identified and the partial dates will be 
imputed as follows: 
• 
If day and month are missing but year is available, then the imputed day and month will 
be 01 Jan. 
• 
If day is missing but the month and year are available, then the imputed day will be the 
first day of the month. 
No imputation will be done if the year of diagnosis is missing. 
A similar summary will be provided for the PP analysis set. 
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Statistical Analysis Plan 
5.2.2. 
General Medical History 
Final Version 1.0 
Medical conditions will be coded to system organ class (SOC), high level term (HLT), and 
preferred term (PT) using Medical Dictionary for Regulatory Activities (MedDRA) coding 
dictionary version 15.1. Ongoing medical conditions will be graded per Common 
Terminology Criteria for Adverse Events (CTCAE) Version 3.0 (1 =Mild, 2=Moderate, 
3=Severe, 4=Life-threatening or disabling and 5=Fatal). 
General medical history, history of liver disease and clinically significant elevated 
transaminase (alanine aminotransferase/aspartate aminotransferas) or bilirubin will be 
summarized by SOC, HL T, and PT. The summary will be sorted in descending frequency by 
SOC, HLT, and PT. Data will be listed for the 3 types of histories separately. 
Ongoing general medical history will be summarized separately by SOC, HLT, PT, and 
severity. 
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Final Version 1.0 
6. 
EFFICACY ANALYSES 
Imaging-based tumor assessments will be performed within 28 days prior to the start of 
treatment. On-study tumor assessments will be performed at ~8- to 12-week intervals at 
visits 1, 6, 9, 11, 13, and 15 (corresponding to baseline, Weeks 8, 16, 24, 36, and 48) and 
every 12 weeks thereafter. An end-of-treatment tumor assessment (if the subject withdraws 
from the study for reasons other than tumor progression on a routine imaging/scan) should be 
performed if the last assessment was performed > 4 weeks prior to end-of-treatment visit. 
Imaging-based tumor assessments include site of lesion and bi-dimensional measures for the 
largest diameter and the perpendicular diameter. Tumor response will be evaluated by both 
investigators and IRC. 
Data will be presented for both investigators assessments and IRC assessments. A subject's 
response status at each visit, best overall response (BOR), date of progression and date of 
first response will be determined by IRC and recorded in the IRC database. The findings of 
IRC will be considered primary for analyses of ORR and other tumor control endpoints 
(ie, DOR, TTR,% changes in tumor size and PFS). Consistency of evaluation between IRC 
and investigator assessments will be summarized by the percent agreement for overall 
response. 
6.1. 
Defmition of the Primary Efficacy End point 
A best overall response ofCR, PR, stable disease (SD), PD, not evaluable (NE) and no 
disease (ND) is allowed. For subjects with WM, a minor response (MR) is also allowed. In 
the event that a single PD is followed by an assessment that is SD, PR or CR which is the 
same or better than the prior nadir response and there is substantial interruption of exposure 
to study drug, that PD may not be considered in the BOR evaluation in accordance with the 
Gilead Protocol 101-09 Imaging Charter. 
ORR is defined as the proportion of subjects who achieve a CR or PR (or MR for subjects 
with WM) during the IDELA treatment. The response definitions for each category are based 
on standard criteria and defined in Section 8.1.5 of the protocol. Subjects who do not have 
sufficient baseline or on-study tumor status information to be adequately assessed for 
response status (ie, those with best overall responses ofNE or ND) will be included in the 
denominators in calculations of response rates. 
6.2. 
Statistical Hypothesis for the Primary Efficacy Endpoint 
The study will test the hypothesis that ORR is 2: 39% (i.e. 2: ~40%) against the null 
hypothesis that it is :::; 20%. 
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Statistical Analysis Plan 
6.3. 
Analysis ofthe Primary Efficacy Endpoint 
Final Version 1.0 
The ORR and 95% CI will be presented along with the corresponding p-value from the exact 
binomial test. The number and proportion of subjects who were evaluated as CR, PR, SD, 
PD, NE, and ND will also be tabulated. 
The primary analysis for ORR will be conducted in the ITT set based on the IRC 
assessments. The investigator assessments will also be summarized. Both investigator and 
IRC assessments for tumor response will be listed in detail including site of lesion, date and 
method of evaluation, bidirectional measures and sum of the products of the perpendicular 
diameters of measurable index lesions (SPD). Summaries will also be provided for response 
at each visit separately when tumor assessment is available. 
Agreement in best overall response between IRC and investigator assessments will be 
summarized. 
6.4. 
Secondary Efficacy End points 
6.4.1. 
Defmition of Secondary Efficacy Endpoints 
• 
DOR - defined as the interval from the first documentation of CR or PR (or MR for WM 
subjects) to the earlier of the first documentation of disease progression or death from any 
cause 
• 
LNR- defined as the proportion of subjects who achieve a ~0 50% decrease from 
baseline in the SPD 
• 
TTR - defined as the interval from the start of study drug to the first documentation of 
CR or PR (or MR for WM subjects) 
• 
PFS -defined as the interval from the start of study drug to the earlier of the first 
documentation of disease progression or death from any cause 
• 
OS- defined as the interval from the date of first IDELA to death from any cause 
• 
Changes in HRQL as reported by subjects using the FACT-Lym 
• 
Changes in performance status as documented using the Kamofsky performance criteria 
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Statistical Analysis Plan 
6.4.2. 
Analysis Methods for Secondary Efficacy End points 
6.4.2.1. 
Duration of Response and Progression-Free Survival 
Final Version 1.0 
The date of definitive progression will be the timepoint at which progression is first 
identified by relevant radiographic or imaging data. Death occurring:::; 30 days following the 
discontinuation of study drug will be considered as an event for the DOR and PFS 
calculation. Data will be censored on the date ofthe last tumor assessment (including 
assessments with a NE outcome) for subjects 
• 
who do not have disease progression or die within 30 days after discontinuation of the 
study drug, or 
• 
who start new anti-tumor therapy prior to documented disease progression, or 
• 
who have 2 or more consecutive missing tumor assessments before disease progression or 
death. 
Subjects without adequate baseline tumor response evaluation will be censored on Study Day 
1. PFS will also be summarized for responding subjects (ie, subjects with a CR or PR) and 
non-responding subjects separately. 
To assess the robustness of the primary DOR and PFS results, the following sensitivity 
analyses will be performed: 
• 
DOR and PFS will be assessed based on IRC assessments using the PP analysis set based 
on the same censoring rules as above. 
• 
DOR and PFS will be assessed based on investigators assessments using the same 
censoring rules as above. 
• 
DOR and PFS will be assessed based on the first PD identified by IRC without 
consideration of any drug interruption or the response status post that PD with all other 
censoring rules staying the same as the primary analysis. 
rPPD 
DOR and PFS will be summarized using KM methods and KM curves for DOR and PFS will 
be provided. All the derived endpoints will be listed. 
6.4.2.2. 
Lymph Node Response Rate 
The LNR will be summarized with 95% CI using the exact method based on the ITT and PP 
analysis sets using both the IRC assessments and investigators assessments. 
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Final Version 1.0 
The SPD and percent change in SPD from baseline to each subsequent assessment will be 
summarized using both the IRC assessments and investigators assessments. The best percent 
change from baseline during the study will also be summarized based on the first reader of 
each reader pair ([Gilead ProtocollOl-09 Imaging Charter]) unless the adjudicator choose 
the second reader. The best percent change from baseline in SPD is defined as the largest 
decrease in tumor size while the subject was on-treatment. The baseline SPD will be the last 
value prior to the start of IDELA therapy. Note that for subjects who only have increases in 
tumor size from baseline, the smallest increase will be considered as the best change from 
baseline in SPD. Analyses will be conducted for the ITT and PP analysis sets. 
A waterfall plot of best on-treatment percent change in SPD based on the IRC and 
investigators assessments will be provided. Individual records for measurable and 
nonmeasurable lesions will be listed in detail. 
6.4.2.3. 
Time to Response 
TTR will be evaluated using both the IRC and investigators data based on ITT and PP 
subjects who achieve a CR or PR (or MR for WM subjects). TTR will be summarized using 
descriptive statistics. 
6.4.2.4. 
Overall survival 
OS will be analyzed using the KM method and KM curves for OS will be provided based on 
the ITT analysis set. An on-study OS analysis will be performed by only including deaths 
that occur while a subject is on study treatment or within 30 days post-last study treatment. 
Furthermore, OS will be analyzed by including the long-term follow-up data and considering 
any death as an event. Data from surviving subjects will be censored at the last time that the 
subject was known to be alive. 
6.4.2.5. 
Health-Related Quality of Life 
The FACT-Lym questionnaire includes sub scales for physical well-being (PWB, 7 items), 
social/ family well-being (SWB, 7 items), emotional well-being (EWB, 6 items), functional 
well-being (FWB, 7 items) and additional concerns (Lymphoma Subscale, LymS, 15 items). 
The FACT-Lym scoring guide identifies those negatively stated items that must be reversed 
before being added to obtain subscale totals. Negatively stated items are reversed by 
subtracting the response from "4". After reversing proper items, all subscale items are 
summed to a total, which is the subscale score. For all FACT-Lym scales and symptom 
indices, the higher score is associated with the better quality of life. The scores in the 
following items need to be reversed: 
• 
Physical well-being: all individual items 
• 
Social/family well-being: none 
• 
Emotional well-being: 5 individual items (except for the second item, "I am satisfied with 
how I am coping with my illness") 
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Statistical Analysis Plan 
• 
Functional well-being: none 
• 
Additional concerns: all individual items 
Final Version 1.0 
The subscale scores will be a summation of each individual item score. If -:::; 50% of item 
scores are missing, the subscale score will be calculated by multiplying the sum of the item 
scores by the number of items in the sub scale, then divided by the number of non-missing 
item scores. This imputes the missing scores by the mean of the non-missing scores within a 
subscale. 
Prorated subscale score = [sum of item scores] x [N of items in subscale] D I [N of items 
answered] 
The following composite scores will be derived from the above subscale total scores: 
• 
FACT Lym Trial Outcome Index (TOI, score range: 0-116) = PWB + FWB + LymS 
• 
FACT_ G Total Score (score range: 0-108) = PWB + SWB + EWB + FWB 
• 
FACT Lym Total Score (score range: 0-168) = PWB + SWB + EWB + FWB + LymS 
The FACT-G and FACT-Lym Total scores will be set to missing if20% or more ofthe 
included items are missing ( eg, only calculated if at least 22 of 27 FACT -G items are 
completed) or any of the component subscales are missing. TOI scores are set to missing if 
any of the component subscales are missing. 
If the baseline value is missing for subscale (ie, PWB, SWB, EWB, FWB and LymS), mean 
values ofthe corresponding subscale scores will be used to impute the baseline value. The 
mean and change from baseline in mean scores to each subsequent assessment will be 
summarized for the subscale and composite scores. The best change from baseline during the 
study, defined as the highest positive value among all post-baseline visits minus the baseline 
value, will also be summarized. 
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Final Version 1.0 
Each subject's lymphoma subscale score and FACT-General subscales (ie, PWB, EWB, 
SWB, and FWB) scores at each assessment will be compared to their baseline scores. The 
minimally important difference (MID) for the FACT-Lym subscale is 3-5 points (Hlubocky 
et al, in press) and the MID for FACT-General subscales is 2-3 points (Yost and Eton 2005). 
As recommended by Yost and Eton (2005), the high end ofthis range will be used for 
interpreting individual subject change. An increase of at least 5 points will be required as a 
definition of symptom improvement for the lymphoma subscale and 3 points will be required 
as a definition of symptom improvement for the FACT -General subscales. A decline of at 
least 5 points will define symptom worsening for the lymphoma subscale and a decline of at 
least 3 points will define symptom worsening for the FACT -General subscales. Time to 
symptom response will be assessed by defining the first occurrence of symptom 
improvement as an event. Subjects who do not experience a symptom improvement 
compared to baseline will be censored at their last available PRO assessment time. 
Time-to-event analyses will be performed using the KM method. The cumulative distribution 
function (CDF) of best (or worst) change from baseline will be also provided. For the MID 
improvement comparison in Lyms, subjects with baseline score >55 will be excluded 
(ie, subjects with no room for improvement). For the MID improvement comparison in 
FACT-General subscales subjects with baseline score >57 will be excluded. 
A data listing for each individual item, the subscale scores and the composite scores will be 
presented for each subject at each visit. 
6.4.2.6. 
Performance Status 
The Kamofsky performance status scores and the change from baseline scores to each 
subsequent assessment will be summarized. The best and worst changes from baseline 
during the study will also be summarized. The best change from baseline is defined as the 
highest change score at post baseline. The worst change from baseline is defined as the 
lowest change score at post baseline. 
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7. 
SAFETY ANALYSES 
7.1. 
Adverse Events and Deaths 
Final Version 1.0 
The start of the AE reporting for a study subject will coincide with signing of the informed 
consent. The end of the adverse-event-reporting period occurs 30 days after discontinuation 
from study or when any ongoing drug-related AEs and/or serious adverse events (SAEs) 
have resolved or become stable. 
The focus of AE summarization will be on treatment-emergent AEs using the ITT analysis 
set. All AEs will be listed. 
7.1.1. 
Adverse Event Dictionary 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
version 15.1. System organ class (SOC), high level group term (HLGT), high level term 
(HL T), preferred term (PT), and lower level term (LL T) will be attached to the clinical 
database. 
7.1.2. 
Adverse Event Severity 
The severity of AEs will be graded by the investigator according to the CTCAE, Version 3.0, 
whenever possible. If a CTCAE criterion does not exist, the grade corresponding to the 
appropriate adjective will be used by the investigator to describe the maximum intensity of 
the AE. The severity grade will be categorized as: 
• Grade 1 (mild) 
• Grade 2 (moderate) 
• Grade 3 (severe) 
• Grade 4 (life threatening), or 
• Grade 5 (fatal) 
A missing severity grade will be considered as missing. 
7.1.3. 
Relationship of Adverse Events to Study Drug 
The investigator-described relationship of the adverse event to the study drug will be 
categorized as: 
• 
Definite 
• 
Probable 
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Statistical Analysis Plan 
• 
Possible 
• 
Unlikely, or 
• 
Unrelated 
Final Version 1.0 
AE will be considered as treatment-related ifthe causal relationship with study drug is 
recorded as definite, probable or possible. Events for which the investigator did not record 
relationship to study drug will be considered related and data listings will show relationship 
as mtssmg. 
7.1.4. 
Serious Adverse Events 
SAEs are those identified as serious in the clinical database. The clinical database will be 
reconciled with the SAE database from the Drug Safety and Public Health (DSPH) 
department before database finalization. 
7.1.5. 
Treatment-Emergent Adverse Events 
7.1.5.1. 
Definition of Treatment-Emergent 
Treatment-emergent AEs are events in a given study period that meet one of the following 
criteria: 
• 
Events with onset dates on or after the start of treatment and up to 30 days after the 
permanent discontinuation of the study medication. 
• 
The continuing AEs diagnosed prior to the start of treatment and worsening in severity 
grade, or non-serious AEs at baseline which become serious, or AEs resulting in 
treatment discontinuation after the start of treatment. 
7.1.5.2. 
Incomplete Dates 
All AEs with partial onset or stop dates will be identified and the partial dates will be 
imputed as follows: 
• 
For AE onset date: If day and month are missing but year is available, then the imputed 
day and month will be OlJan or the first dosing date ifthey have the same year, 
whichever is later. If day is missing but the month and year are available, then the 
imputed day will be the first day of the month or the first dosing date if they have the 
same month and year, whichever is later. 
• 
For AE stop date: If day and month are missing but year is available, then the imputed 
day and month will be 31Dec or 30 days after the last dose of IDELA if they have the 
same year, whichever is earlier. If day is missing but the month and year are available, 
then the imputed day will be the last day of the month or 30 days after the last dose of 
IDELA if they have the same month and year, whichever is earlier. 
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Statistical Analysis Plan 
7.1.6. 
Summaries of Adverse Events and Deaths 
Final Version 1.0 
A brief summary of treatment-emergent AEs will show the number and percentage of 
subjects who (1) had any AE, (2) had any Grade 2:3 AE, (3) had any treatment-related AE, 
( 4) had any Grade 2:3 treatment-related AE, (5) had any SAE, (6) had any treatment-related 
SAE, (7) discontinued from study drug due to an AE, (8) dose reduction due to an AE, 
(9) death due to AEs (1 0) death during study drug treatment up to 30 days post last dose and 
(11) all deaths including long-term follow up . 
Summaries (number and percentage of subjects) of treatment-emergent AEs (by SOC, HLT 
and PT) will be provided as follows: 
• All AEs 
• All AEs by severity 
• Grade 2:3 AE 
• All AEs occurring in at least 10% of subjects 
• All treatment-related AEs 
• All treatment-related AEs by severity 
• Grade 2:3 treatment-related AEs 
• All SAEs 
• All treatment-related SAEs 
• 
All AEs that caused discontinuation from study drug 
• 
AEs leading to deaths 
Multiple events will be counted once only per subject in each summary. For data 
presentation, SOC, HL T and PT will be sorted by decreasing frequency. For summaries by 
severity grade, the most severe event will be selected. In addition to the presentation by SOC 
and HL T, each summary listed above will also be presented by preferred term in decreasing 
frequency. 
Summary of all treatment-emergent AEs will also be summarized by SOC, HLT and PT, and 
by PT only in the following subgroups: sex (Male or Female), age group (<65 or >=65 years) 
and race (White or Non-White). 
In addition to the by-treatment summaries, data listings will be provided for the following: 
• 
All AEs (with a variable indicating whether the event is treatment-emergent) 
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Statistical Analysis Plan 
• 
SAEs (with a variable indicating whether the event is treatment-emergent) 
• 
AEs leading to deaths 
• 
AEs leading to discontinuation of study drug 
Final Version 1.0 
Relative day from first dose date will be provided for each AE in the listings. If the AE onset 
date is after the first dose date, the relative day will be calculated as (AE onset date- first 
dose date + 1 ), however, if the AE onset date is prior to the first dose date, the relative day 
will be calculated as (AE onset date- first dose date). 
7.2. 
Laboratory Evaluations 
All laboratory data will be listed. Summaries of laboratory data will be based on observed 
data and will be reported using SI units. The focus of laboratory data summarization will be 
on treatment-emergent laboratory abnormalities using the ITT analysis set. 
7.2.1. 
Summaries of Numeric Laboratory Results 
Descriptive statistics (sample size, mean, standard deviation, median, Ql, Q3, minimum and 
maximum) will be provided for each laboratory test specified in the study protocol as 
follows: 
• 
Baseline values 
• 
Values at each post-baseline analysis window 
• 
Change from baseline at each post-baseline analysis window 
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3. In addition, the mean change from baseline for lab parameters will 
be plotted over time. 
7.2.2. 
Summaries of Categorical Laboratory Results 
Laboratory data that are categorical will be summarized using number and percentage of 
subjects in the study with the given response at baseline and each scheduled post-dose 
assessment. 
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7.2.3. 
Graded Laboratory Values 
Final Version 1.0 
Applicable hematological and serum biochemistry laboratory data will be programmatically 
graded according to CTCAE, Version 4.03 severity grade [grade laboratory results as 
Grade 0, mild (Grade 1), moderate (Grade 2), severe (Grade 3), or life threatening (Grade 4)]. 
Grade 0 includes all values that do not meet criteria for an abnormality of at least Grade 1. 
Some laboratory tests have criteria for both increased and decreased levels; analyses for each 
direction (ie, increased, decreased) will be presented separately. 
7.2.3.1. 
Treatment-Emergent Laboratory Abnormalities 
A treatment-emergent laboratory abnormality is defined as an abnormality that, compared to 
baseline, worsens by ?:1 grade in the period from the first dose ofiDELA to 30 days after the 
last dose of study treatment. If baseline data are missing, then any graded abnormality 
(ie, an abnormality that is Grade ?: 1 in severity) will be considered treatment-emergent. 
7.2.3.2. 
Summaries of Laboratory Abnormalities 
The following summaries (number and percentage of subjects) oftreatment-emergent 
laboratory abnormalities will be provided (subjects will be categorized according to most 
severe abnormality grade): 
• 
Baseline and worst post-baseline laboratory abnormalities 
• 
Grade ?: 3 laboratory abnormalities 
For all summaries of laboratory abnormalities, the denominator is the number of subjects in 
the ITT analysis set. A listing of treatment-emergent Grade ?: 3 laboratory abnormalities will 
be provided. 
7.2.4. 
Shift in CTCAE Grade Relative to Baseline 
Shift tables will be presented by showing change in CTCAE severity grade from baseline to 
the worst grade post baseline. 
7.2.5. 
Transaminase elevations 
Analysis of transaminase elevations will be based on laboratory values. Number and 
percentage of subjects will be summarized for subjects 
• 
with Grade 3 or 4 ALT/AST elevation 
• 
with Grade 3 or 4 ALT/AST elevation resolved to both ALT/AST of Grade 1 or less 
• 
re-challenged after dose interruption due to Grade 3 or 4 ALT/AST elevation 
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Statistical Analysis Plan 
• 
with recurrence of grade 3 or 4 ALT/ASTelevation 
Final Version 1.0 
• 
with recurrent Grade 3 or 4 ALT/ AST elevation resolved to both ALT/ AST of Grade 1 or 
less 
Kaplan-Meier curves and estimates will be provided for time to onset of first Grade 3 or 4 
treatment-emergent ALT/ AST elevations. Time to onset of first event is defined as time from 
start of study treatment to the start date of first Grade 3 or 4 treatment-emergent AL T I AS T 
elevation, ie, time in days is calculated as (start date of first occurrence) - (date of first dose 
of study drug) + 1. In the absence of an event, the censoring date applied will be the earliest 
from the following dates: last dose date (if treatment discontinued)+ 30 days, analysis data 
cut-off date and death. 
For subjects with at least 1 episode of Grade 3 or 4 ALT/AST elevation, time to resolution of 
first episode oftreatment-emergent Grade 3 or 4 ALT/AST elevation to Grade 1 or less will 
be summarized using Kaplan-Meier estimates. The same censoring rule described above for 
time to onset will be used. In addition, the same analysis will be performed for subjects who 
are rechallenged due to Grade 3 or 4 treatment-emergent ALT/ AST elevations. 
7.3. 
Vital Signs 
Vital sign data (body temperature, sitting systolic and diastolic blood pressures, and sitting 
pulse rate) will be summarized in the following tables: 
• 
Actual values and the changes from baseline by visit for each measure 
• 
Number and percent of subjects by systolic (SBP) and diastolic blood pressure (DBP) 
category (high, normal, low) at each visit categorizing SBP ?: 140 mmHg as high and 
< 90 mmHg as low; DBP ?: 90 mmHg as high and < 60 mmHg as low. 
Data for body weight and height will be listed with the vital signs as collected in the CRF. 
High or low values for vital signs will be flagged. 
7.4. 
Prior Therapy and Prior Radiation 
Number of prior regimens and time since the completion of last regimen will be summarized 
using descriptive statistics (sample size, mean, standard deviation, median, Q1, Q3, 
minimum and maximum). A partial completion date will be imputed using the following 
algorithm for the last regimen: 
• 
If day and month are missing but year is available, then the imputed day and month will 
be OlJan or the starting date ofthe last regimen, whichever is later; 
• 
If day is missing but the month and year are available, then the imputed day will be the 
first day of the month, or the starting date of the last regimen, whichever is later; 
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• 
If year is missing, no imputation will be done and the completion date will be treated as 
mtssmg. 
Number(%) of subjects who received 1, 2, 3, ... prior regimens will also be provided. In 
addition, number(%) of subjects refractory to rituximab, refractory to alkylating-agent, 
refractory to bendamustine, and refractory to last therapy will also be summarized. 
Descriptive statistics will be provided for number of subjects who received certain regimens 
(eg, BR, CHOP, R-CHOP). Descriptive statistics will also be provided for the last regimen 
subjects received prior to study entry. The best response (n, %) to last therapy, and duration 
of response to the last therapy will be summarized. 
Number of subjects received prior radiation will be summarized and will be listed. 
7.5. 
Concomitant Medications 
Concomitant medications will be coded by means ofthe World Health Organization Drug 
Dictionary (WHO DRUG) dictionary, June 2010 into Anatomical-Therapeutic-Chemical 
classification (ATC) codes. 
Concomitant medications are defined as any medications meeting the following criteria: 
• 
Starting on or after the first dose of IDE LA treatment up to 30 days post the last dose 
• 
Starting before and continuing after the first dose of IDELA treatment up to 30 days post 
the last dose 
The incomplete dates handling method used for AE summaries will be used for concomitant 
medication summaries (section 7.1.5.2). 
Prior medications are defined as any medications stopped before the first dose of study drug. 
Summaries of the number and percentage of subjects who used prior and concomitant 
medications will be presented in tabular form by preferred drug name based on ITT analysis 
set. The summary tables will be sorted by descending frequency of preferred term in the 
total column. Subjects will only be counted once for multiple drug use (by preferred drug 
name) per subject. 
Concomitant medications started on/ -after the start of study medication or ongoing 
medications will be flagged on the prior and concomitant medication data listing. 
The summaries and listings will be based on the ITT analysis set. 
7.6. 
Electrocardiogram Results 
The following analyses of electrocardiogram (ECG) results are intended to identify gross 
changes in QT intervals. The 12-lead ECG measurements will be collected at screening, 
Visit 9 (Week 16), and end oftreatment visit. 
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7.6.1. 
Corrected QT Intervals 
Final Version 1.0 
Corrected QT (QTc) intervals will be derived by using Bazett and Fridericia methods: 
Bazett: QTc-B = QT I (RR)112, and 
Fridericia: QTc-F = QT I (RR)113, 
Where, RR is calculated as [60 I Heart Rate (beats/min)]. 
The QTc data (msec) obtained by using the Bazett and Fridericia corrections will be 
categorized separately into the following classifications and summarized by visit: 
• 
~ 450 
• 
451~480 
• 
481~500 
• 
> 500 
The change in QTc values (msec) obtained by using the Bazet's and Fridericia's correction 
will also be categorized separately as follows: 
• 
~ 30 
• 
31-60 
• 
> 60 
QTcB, QTcF, and uncorrected QT values at each visit and change from baseline at each visit 
will be summarized for the ITT analysis set using descriptive statistics (sample size, mean, 
standard deviation, median, Q1, Q3, minimum, and maximum). 
7.6.2. 
Investigator Assessment of ECG Readings 
The number and percentage of subjects in the ITT analysis set with an investigator's ECG 
assessment of normal, abnormal and clinically significant, or abnormal but not clinically 
significant will be summarized for baseline and for each visit. 
7. 7. 
Physical Examination 
Physical examination results will be summarized by body system and visit. All results will 
be listed. 
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7 .8. 
Post Treatment Assessments 
Final Version 1.0 
Information for post IDELA therapy for iNHL, new non-iNHL-related health problems and 
follow-up contact records will be listed as reported in the CRF. 
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Statistical Analysis Plan 
8. 
PHARMACOKINETIC ANALYSES 
Final Version 1.0 
Limited plasma samples will be collected for concentrations of IDELA and its metabolite, 
GS-563117 (formerly CAL-244), prior to;;;;~~6-~
an~d~
1.~5~h~o~u~
rs::..__\:::....:::....~~~..e:::.:.::....:~~~ 
1, 29, 57, and 113 for all 
8.1. 
Estimation of Pharmacokinetic Parameters 
rPPD 
8.2. 
Statistical Analysis Methods 
rPPD 
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[pPD 
I 
I 
I 
I 
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Statistical Analysis Plan 
9. 
PHARMACODYNAMIC ANALYSES 
Final Version 1.0 
If data are available, pharmacodynamic measures may be summarized. For example, the 
concentrations of relevant chemokines and cytokines with a particular focus on CCL 7, 
CCL17, CCL22, CXCL12, CXCL13, interleukin-6, tumor necrosis factor-a, and C-reactive 
protein, serum iron metabolism ( eg, hepcidin, iron, ferritin, transferrin) will be summarized. 
IDELA drug concentration and pharmacodynamic measures will be listed. 
For each pharmacodynamic variable, the concentration at each assessment will be described. 
The change from baseline to each assessment will be summarized. The best change from 
baseline during the study will also be summarized. 
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10. 
REFERENCES 
Final Version 1.0 
International Conference on Harmonisation of Teclmical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Statistical 
Principles for Clinical Trials (E9), 5 February 1998. 
International Conference on Harmonisation of Teclmical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Structure 
and Content of Clinical Study Reports (E3), 30 November 1995. 
International Conference on Harmonisation of Teclmical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Good 
Clinical Practice (E6), April1996. 
The Functional Assessment of Chronic Illness Therapy (F ACIT) Measurement System: 
properties, applications, and interpretation, Kimberly Webster, David Cella* and 
Kathleen Yost, 16 December 2003. http://www.hqlo.com/contentllll/79 
Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989 
Mar; 10(1): 1-10. 
BioClinica Bio-READ® Imaging Charter for Gilead Sciences, Inc. Protocol101-09. 
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Statistical Analysis Plan 
11. 
SOFTWARE 
SAS® Software Version 9.1 or higher, SAS Institute Inc. , Cary, NC, USA. 
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Statistical Analysis Plan 
12. 
SAP REVISION 
Revision Date 
(dd month, yyyy) 
Section 
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Reason for Revision 
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Statistical Analysis Plan 
13. 
APPENDICES 
Table Number 
Title 
1.1.1 
Demographics 
1.1.2 
Baseline Characteristics 
1.2.1 
Subject Disposition 
1.2.2 
Subject Disposition at Long-term Follow-up 
1.3 
Major Protocol Deviations 
1.4.1 
Disease History 
1.4.2 
Disease History 
1.4.3 
Baseline Disease Status 
1.4.4 
Baseline Disease Status 
1.5.1 
Medical History - General 
1.5.2 
Medical History- Liver Disease 
Medical History - Clinically Significant Elevated 
1.5.3 
Transaminase (AL T/AST) or Bilirubin Levels 
1.6.1 
Prior Therapy 
1.6.1.1 
Prior Therapy by Regimen Type 
1.6.1.2 
Prior Therapy Subjects Refractory To by Regimen Type 
1.6.1.3 
Prior Therapy by Preferred Terms 
1.6.2 
Most Recent Regimen Prior to Receiving Study Drug 
Most Recent Regimen Prior to Receiving Study Drug by 
1.6.2.1 
Regimen Type 
1.6.3 
Prior Radiation 
1.7 
Concomitant Medications by Preferred Terms 
1.8 
Study Drug Exposure 
2.1.1 
Overall Response Rate (ORR) 
2.1.1.1 
Overall Response Rate (ORR) by Gender 
2.1.1.2 
Overall Response Rate (ORR) by Age 
2.1.1.3 
Overall Response Rate (ORR) by Race 
2.1.1.4 
Overall Response Rate (ORR) by Disease 
2.1.1.5 
Overall Response Rate (ORR) byNum ber of Prior Therapies 
Overall Response Rate (ORR) by Refractory to Last Prior 
2.1.1.6 
Therapy 
Overall Response Rate (ORR) by Longest Diameter of 
2.1.1.7 
Baseline Lesion 
2.1.1.8 
Overall Response Rate (ORR) by Prior Use of Bendamustine 
Overall Response Rate (ORR) by Refractory to 
2.1.1.9 
Bendamustine 
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Idelalisib Study 101-09 
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Table Number 
Title 
Overall Response Rate (ORR) by Number of Times 
2.1.1.10 
Refractory to an Alkylating Agent 
Overall Response Rate (ORR) by Number of Times 
2.1.1.11 
Refractory to Rituximab 
Overall Response Rate (ORR) by Suitability for 
2.1.1.12 
Radioimm uno therapy 
2.1.1.13 
Overall Response Rate (ORR) by Region 
2.1.2 
Overall Response Rate (ORR) 
Lymph Node Response- Independent Review Committee 
2.2.1 
(IRC) 
2.2.2 
Lymph Node Response- Investigator Assessments 
Tumor Response by Visit- Independent Review Committee 
2.3.1 
(IRC) Assessments 
2.3.2 
Tumor Response by Visit- Investigator Assessments 
Tumor Response by Visit- Agreement between Independent 
2.3.3 
Review Committee (IRC) and Investigator Assessments 
Duration of Response- Independent Review Committee 
2.4.1 
(IRC) Assessments 
Duration of Response- Independent Review Committee 
2.4.1.1 
(IRC) Assessments- by Gender 
Duration of Response- Independent Review Committee 
2.4.1.2 
(IRC) Assessments- by Age 
Duration of Response- Independent Review Committee 
2.4.1.3 
(IRC) Assessments- by Race 
Duration of Response- Independent Review Committee 
2.4.1.4 
(IRC) Assessments- by Disease 
Duration of Response- Independent Review Committee 
2.4.1.5 
(IRC) Assessments- by Number of Prior Therapies 
Duration of Response- Independent Review Committee 
2.4.1.6 
(IRC) Assessments- by Refractory to Last Prior Therapy 
Duration of Response- Independent Review Committee 
2.4.1.7 
(IRC) Assessments - by Longest Diameter of Baseline Lesion 
Duration of Response- Independent Review Committee 
2.4.1.8 
(IRC) Assessments- by Prior Use ofBendamustine 
Duration of Response- Independent Review Committee 
2.4.1.9 
(IRC) Assessments- by Refractory to Bendamustine 
Duration of Response- Independent Review Committee 
(IRC) Assessments- by Number of Times Refractory to an 
2.4.1.10 
Alkylating Agent 
Duration of Response- Independent Review Committee 
(IRC) Assessments- by Number of Times Refractory to 
2.4.1.11 
Rituximab 
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Table Number 
Title 
Duration of Response- Independent Review Committee 
2.4.1.12 
(IRC) Assessments -by Suitability for Radioimmunotherapy 
Duration of Response - Independent Review Committee 
2.4.1.13 
(IRC) Assessments -by Region 
2.4.2 
Duration of Response- Investigator Assessments 
2.4.2.1 
Duration of Response- Investigator Assessments- by Gender 
2.4.2.2 
Duration of Response- Investigator Assessments- by Age 
2.4.2.3 
Duration of Response -Investigator Assessments -by Race 
Duration of Response -Investigator Assessments- by 
2.4.2.4 
Disease 
Duration of Response -Investigator Assessments- by 
2.4.2.5 
Number of Prior Therapies 
Duration of Response -Investigator Assessments- by 
2.4.2.6 
Refractory to Last Prior Therapy 
Duration of Response- Investigator Assessments- by 
2.4.2.7 
Longest Diameter of Baseline Lesion 
Duration of Response -Investigator Assessments -by Prior 
2.4.2.8 
Use of Bendamustine 
Duration of Response- Investigator Assessments- by 
2.4.2.9 
Refractory to Bendamustine 
Duration of Response- Investigator Assessments- by 
2.4.2.10 
Number of Times Refractory to an Alkylating Agent 
Duration of Response- Investigator Assessments- by 
2.4.2.11 
Number of Times Refractory to Rituximab 
Duration of Response- Investigator Assessments- by 
2.4.2.12 
Suitability for Radioimmunotherapy 
Duration of Response- Investigator Assessments- by 
2.4.2.13 
Region 
Duration of Response- Independent Review Committee 
2.4.3 
(IRC) Assessments 
2.4.4 
Duration of Response- Investigator Assessments 
Duration of Response- Investigator Assessments (Sensitivity 
2.4.5 
Analysis) 
Progression Free Survival- Independent Review Committee 
2.5.1 
(IRC) Assessments 
Progression Free Survival -Independent Review Committee 
2.5.1.1 
(IRC) Assessments- by Gender 
Progression Free Survival -Independent Review Committee 
2.5.1.2 
(IRC) Assessments- by Age 
Progression Free Survival -Independent Review Committee 
2.5.1.3 
(IRC) Assessments- by Race 
Progression Free Survival -Independent Review Committee 
2.5.1.4 
(IRC) Assessments- by Disease 
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Idelalisib Study 101-09 
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Table Number 
Title 
Progression Free Survival -Independent Review Committee 
2.5.1.5 
(IRC) Assessments- by Number of Prior Therapies 
Progression Free Survival -Independent Review Committee 
2.5.1.6 
(IRC) Assessments- by Refractory to Last Prior Therapy 
Progression Free Survival -Independent Review Committee 
2.5.1.7 
(IRC) Assessments - by Longest Diameter of Baseline Lesion 
Progression Free Survival -Independent Review Committee 
2.5.1.8 
(IRC) Assessments- by Prior Use ofBendamustine 
Progression Free Survival -Independent Review Committee 
2.5.1.9 
(IRC) Assessments- by Refractory to Bendamustine 
Progression Free Survival -Independent Review Committee 
(IRC) Assessments- by Number of Times Refractory to an 
2.5.1.10 
Alkylating Agent 
Progression Free Survival -Independent Review Committee 
(IRC) Assessments- by Number of Times Refractory to 
2.5.1.11 
Ritux.imab 
Progression Free Survival- Independent Review Committee 
2.5.1.12 
(IRC) Assessments -by Suitability for Radioimmunotherapy 
Progression Free Survival- Independent Review Committee 
2.5.1.13 
(IRC) Assessments -by Region 
2.5.2 
Progression Free Survival- Investigator Assessments 
Progression Free Survival- Investigator Assessments -by 
2.5.2.1 
Gender 
Progression Free Survival - Investigator Assessments - by 
2.5.2.2 
Age 
Progression Free Survival- Investigator Assessments -by 
2.5.2.3 
Race 
Progression Free Survival - Investigator Assessments - by 
2.5.2.4 
Disease 
Progression Free Survival - Investigator Assessments - by 
2.5.2.5 
Number of Prior Therapies 
Progression Free Survival - Investigator Assessments - by 
2.5.2.6 
Refractory to Last Prior Therapy 
Progression Free Survival - Investigator Assessments - by 
2.5.2.7 
Longest Diameter of Baseline Lesion 
Progression Free Survival- Investigator Assessments -by 
2.5.2.8 
Prior Use of Bendamustine 
Progression Free Survival - Investigator Assessments - by 
2.5.2.9 
Refractory to Bendamustine 
Progression Free Survival- Investigator Assessments -by 
2.5.2.10 
Number of Times Refractory to an Alkylating Agent 
Progression Free Survival- Investigator Assessments -by 
2.5.2.11 
Number of Times Refractory to Rituximab 
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Table Number 
Title 
Progression Free Survival- Investigator Assessments- by 
2.5.2.12 
Suitability for Radioimmunotherapy 
Progression Free Survival- Investigator Assessments - by 
2.5.2.13 
Region 
Progression Free Survival -Independent Review Committee 
2.5.3 
(IRC) Assessments 
2.5.4 
Progression Free Survival- Investigator Assessments 
Progression Free Survival- Investigator Assessments 
2.5.5 
(Sensitivity Analysis) 
Time to Response- Independent Review Committee (IRC) 
2.6.1 
Assessments 
Time to Response -Independent Review Committee (IRC) 
2.6.1.1 
Assessments - by Gender 
Time to Response- Independent Review Committee (IRC) 
2.6.1.2 
Assessments - by Age 
Time to Response- Independent Review Committee (IRC) 
2.6.1.3 
Assessments - by Race 
Time to Response- Independent Review Committee (IRC) 
2.6.1.4 
Assessments- by Disease 
Time to Response -Independent Review Committee (IRC) 
2.6.1.5 
Assessments- by Number of Prior Therapies 
Time to Response- Independent Review Committee (IRC) 
2.6.1.6 
Assessments- by Refractory to Last Prior Therapy 
Time to Response -Independent Review Committee (IRC) 
2.6.1.7 
Assessments -by Longest Diameter of Baseline Lesion 
Time to Response- Independent Review Committee (IRC) 
2.6.1.8 
Assessments- by Prior Use ofBendamustine 
Time to Response -Independent Review Committee (IRC) 
2.6.1.9 
Assessments- by Refractory to Bendamustine 
Time to Response -Independent Review Committee (IRC) 
Assessments- byNum ber of Times Refractory to an 
2.6.1.10 
Alkylating Agent 
Time to Response- Independent Review Committee (IRC) 
2.6.1.11 
Assessments- by Number of Times Refractory to Rituximab 
Time to Response- Independent Review Committee (IRC) 
2.6.1.12 
Assessments- by Suitability for Radioimmunotherapy 
Time to Response- Independent Review Committee (IRC) 
2.6.1.13 
Assessments- by Region 
2.6.2 
Time to Response- Investigator Assessments 
2.6.2.1 
Time to Response- Investigator Assessments- by Gender 
2.6.2.2 
Time to Response- Investigator Assessments- by Age 
2.6.2.3 
Time to Response- Investigator Assessments- by Race 
2.6.2.4 
Time to Response- Investigator Assessments- by Disease 
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Table Number 
Title 
Time to Response- Investigator Assessments- by Number of 
2.6.2.5 
Prior Therapies 
Time to Response- Investigator Assessments- by Refractory 
2.6.2.6 
to Last Prior Therapy 
Time to Response- Investigator Assessments- by Longest 
2.6.2.7 
Diameter of Baseline Lesion 
Time to Response- Investigator Assessments- by Prior Use 
2.6.2.8 
of Bendamustine 
Time to Response- Investigator Assessments- by Refractory 
2.6.2.9 
to Bendamustine 
Time to Response- Investigator Assessments- by Number of 
2.6.2.10 
Times Refractory to an Alkylating Agent 
Time to Response- Investigator Assessments- by Number of 
2.6.2.11 
Times Refractory to Rituximab 
Time to Response- Investigator Assessments - by Suitability 
2.6.2.12 
for Radioimmunotherapy 
2.6.2.13 
Time to Response- Investigator Assessments - by Region 
Time to Response- Independent Review Committee (IRC) 
2.6.3 
Assessments 
2.6.4 
Time to Response- Investigator Assessments 
Percent Change in SPD- Independent Review Committee 
2.7.1 
(IRC) Assessments 
2.7.2 
Percent Change in SPD- Investigator Assessments 
Percent Change in SPD- Independent Review Committee 
2.7.3 
(IRC) Assessments 
2.8.1 
Overall Survival during Study Treatment 
2.8.2 
Overall Survival including Data from Long-Term Follow-Up 
Health Related Quality of Life (HRQL) - Summary of 
2.9.1 
Change inFACT-Lym Subscale Scores 
Health Related Quality of Life (HRQL)- Summary of 
Symptom Improvement/Worsening [a] in FACT -Lym 
2.9.2 
Subscale Scores 
Health Related Quality of Life (HRQL)- Relation Between 
Symptom Improvement/Worsening and Best Overall 
Response -Independent Review Committee (IRC) 
2.9.3.1 
Assessments 
Health Related Quality of Life (HRQL)- Relation Between 
Symptom Improvement/Worsening and Best Overall 
2.9.3.2 
Response- Investigator Assessments 
2.10 
Change in Kamofsky Performance Status 
3.1.1 
Overall Summary of Treatment-Emergent Adverse Events 
Overall Summary of Treatment-Emergent Adverse Events-
3.1.1.1 
by Age 
CONFIDENTIAL 
Page 50 
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131-fuy 2013 


Idelalisib Study 101-09 
Statistical Analysis Plan 
Table Number 
Title 
Overall Summary of Treatment-Emergent Adverse Events-
3.1.1.2 
by Race 
Overall Summary of Treatment-Emergent Adverse Events-
3.1.1.3 
by Gender 
Overall Summary of Treatment-Emergent Adverse Events-
3.1.1.4 
by Region 
Treatment-Emergent Adverse Events by System Organ Class, 
3.1.2.1 
High Level Term and Preferred Term 
Treatment-Emergent Adverse Events by System Organ Class, 
3.1.2.1.1 
High Level Term and Preferred Term -by Age 
Treatment-Emergent Adverse Events by System Organ Class, 
3.1.2.1.2 
High Level Term and Preferred Term -by Race 
Treatment-Emergent Adverse Events by System Organ Class, 
3.1.2.1.3 
High Level Term and Preferred Term -by Gender 
Treatment-Emergent Adverse Events by System Organ Class, 
3.1.2.1.4 
High Level Term and Preferred Term -by Region 
Grade 3 or Higher Treatment-Emergent Adverse Events- by 
3.1.2.2 
System Organ Class, High Level Term and Preferred Term 
Grade 3 or Higher Treatment-Emergent Adverse Events by 
System Organ Class, High Level Term and Preferred Term -
3.1.2.2.1 
by Age 
Grade 3 or Higher Treatment-Emergent Adverse Events by 
System Organ Class, High Level Term and Preferred Term -
3.1.2.2.2 
by Race 
Grade 3 or Higher Treatment-Emergent Adverse Events by 
System Organ Class, High Level Term and Preferred Term -
3.1.2.2.3 
by Gender 
Grade 3 or Higher Treatment-Emergent Adverse Events by 
System Organ Class, High Level Term and Preferred Term-
3.1.2.2.4 
by Region 
Treatment-Emergent Adverse Events Related to Study Drug 
by System Organ Class, High Level Term and Preferred 
3.1.2.3 
Term 
Treatment-Emergent Adverse Events Related to Study Drug 
by System Organ Class, High Level Term and Preferred 
3.1.2.3.1 
Term- by Age 
Treatment-Emergent Adverse Events Related to Study Drug 
by System Organ Class, High Level Term and Preferred 
3.1.2.3.2 
Term - by Race 
Treatment-Emergent Adverse Events Related to Study Drug 
by System Organ Class, High Level Term and Preferred 
3.1.2.3.3 
Term - by Gender 
Treatment-Emergent Adverse Events Related to Study Drug 
by System Organ Class, High Level Term and Preferred 
3.1.2.3.4 
Term - by Region 
CONFIDENTIAL 
Page 51 
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131-fuy 2013 


Idelalisib Study 101-09 
Statistical Analysis Plan 
Table Number 
Title 
Grade 3 or Higher Treatment-Emergent Adverse Events 
Related to Study Drug by System Organ Class, High Level 
3.1.2.4 
Term and Preferred Term 
Grade 3 or Higher Treatment-Emergent Adverse Events 
Related to Study Drug by System Organ Class, High Level 
3.1.2.4.1 
Term and Preferred Term- by Age 
Grade 3 or Higher Treatment-Emergent Adverse Events 
Related to Study Drug by System Organ Class, High Level 
3.1.2.4.2 
Term and Preferred Term- by Race 
Grade 3 or Higher Treatment-Emergent Adverse Events 
Related to Study Drug by System Organ Class, High Level 
3.1.2.4.3 
Term and Preferred Term - by Gender 
Grade 3 or Higher Treatment-Emergent Adverse Events 
Related to Study Drug by System Organ Class, High Level 
3.1.2.4.4 
Term and Preferred Term- by Region 
Serious Adverse Events by System Organ Class, High Level 
3.1.2.5 
Term and Preferred Term 
Serious Adverse Events by System Organ Class, High Level 
3.1.2.5.1 
Term and Preferred Term- by Age 
Serious Adverse Events by System Organ Class, High Level 
3.1.2.5.2 
Term and Preferred Term - by Race 
Serious Adverse Events by System Organ Class, High Level 
3.1.2.5.3 
Term and Preferred Term - by Gender 
Serious Adverse Events by System Organ Class, High Level 
3.1.2.5.4 
Term and Preferred Term -by Region 
Treatment-Emergent Serious Adverse Events Related to 
Study Drug by System Organ Class, High Level Term and 
3.1.2.6 
Preferred Term 
Treatment-Emergent Serious Adverse Events Related to 
Study Drug by System Organ Class, High Level Term and 
3.1.2.6.1 
Preferred Term -by Age 
Treatment-Emergent Serious Adverse Events Related to 
Study Drug by System Organ Class, High Level Term and 
3.1.2.6.2 
Preferred Term - by Race 
Treatment-Emergent Serious Adverse Events Related to 
Study Drug by System Organ Class, High Level Term and 
3.1.2.6.3 
Preferred Term - by Gender 
Treatment-Emergent Serious Adverse Events Related to 
Study Drug by System Organ Class, High Level Term and 
3.1.2.6.4 
Preferred Term- by Region 
Treatment-Emergent Adverse Events Leading to Study Drug 
Discontinuation by System Organ Class, High Level Term 
3.1.2.7 
and Preferred Term 
Treatment-Emergent Adverse Events Leading to Study Drug 
Discontinuation by System Organ Class, High Level Term 
3.1.2.7.1 
and Preferred Term - by Age 
CONFIDENTIAL 
Page 52 
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131-fuy 2013 


Idelalisib Study 101-09 
Statistical Analysis Plan 
Table Number 
Title 
Treatment-Emergent Adverse Events Leading to Study Drug 
Discontinuation by System Organ Class, High Level Term 
3.1.2.7.2 
and Preferred Term - by Race 
Treatment-Emergent Adverse Events Leading to Study Drug 
Discontinuation by System Organ Class, High Level Term 
3.1.2.7.3 
and Preferred Term - by Gender 
Treatment-Emergent Adverse Events Leading to Study Drug 
Discontinuation by System Organ Class, High Level Term 
3.1.2.7.4 
and Preferred Term - by Region 
Treatment-Emergent Adverse Events Leading to Death by 
3.1.2.8 
System Organ Class, High Level Term and Preferred Term 
Treatment-Emergent Adverse Events Leading to Death by 
System Organ Class, High Level Term and Preferred Term -
3.1.2.8.1 
by Age 
Treatment-Emergent Adverse Events Leading to Death by 
System Organ Class, High Level Term and Preferred Term-
3.1.2.8.2 
by Race 
Treatment-Emergent Adverse Events Leading to Death by 
System Organ Class, High Level Term and Preferred Term-
3.1.2.8.3 
by Gender 
Treatment-Emergent Adverse Events Leading to Death by 
System Organ Class, High Level Term and Preferred Term-
3.1.2.8.4 
by Region 
Treatment-Emergent Adverse Events by System Organ Class, 
3.1.3.1 
High Level Term, Preferred Term, and Severity 
Treatment-Emergent Adverse Events by System Organ Class, 
3.1.3.1.1 
High Level Term, Preferred Term, and Severity- by Age 
Treatment-Emergent Adverse Events by System Organ Class, 
3.1.3.1.2 
High Level Term, Preferred Term, and Severity- by Race 
Treatment-Emergent Adverse Events by System Organ Class, 
3.1.3.1.3 
High Level Term, Preferred Term, and Severity- by Gender 
Treatment-Emergent Adverse Events Related to Study Drug 
by System Organ Class, High Level Term, Preferred Term, 
3.1.3.1.4 
and Severity- by Region 
Treatment-Emergent Adverse Events Related to Study Drug 
by System Organ Class, High Level Term, Preferred Term, 
3.1.3.2 
and Severity 
Treatment-Emergent Adverse Events Related to Study Drug 
by System Organ Class, High Level Term, Preferred Term, 
3.1.3.2.1 
and Severity - by Age 
Treatment-Emergent Adverse Events Related to Study Drug 
by System Organ Class, High Level Term, Preferred Term 
3.1.3.2.2 
and Severity by Race 
Treatment-Emergent Adverse Events Related to Study Drug 
by System Organ Class, High Level Term, Preferred Term 
3.1.3.2.3 
and Severity - by Gender 
CONFIDENTIAL 
Page 53 
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131-fuy 2013 


Idelalisib Study 101-09 
Statistical Analysis Plan 
Table Number 
Title 
Treatment-Emergent Adverse Events Related to Study Drug 
by System Organ Class, High Level Term, Preferred Term, 
3.1.3.2.4 
and Severity- by Region 
Grade 3 or Higher Treatment-Emergent Adverse Events by 
System Organ Class, High Level Term, Preferred Term, and 
3.1.4.1 
Severity 
Grade 3 or Higher Treatment-Emergent Adverse Events by 
System Organ Class, High Level Term, Preferred Term, and 
3.1.4.1.1 
Severity - by Age 
Grade 3 or Higher Treatment-Emergent Adverse Events by 
System Organ Class, High Level Term, Preferred Term, and 
3.1.4.1.2 
Severity - by Race 
Grade 3 or Higher Treatment-Emergent Adverse Events by 
System Organ Class, High Level Term, Preferred Term, and 
3.1.4.1.3 
Severity- by Gender 
Grade 3 or Higher Treatment-Emergent Adverse Events by 
System Organ Class, High Level Term, Preferred Term, and 
3.1.4.1.4 
Severity- by Region 
Grade 3 or Higher Treatment-Emergent Adverse Events 
Related to Study Drug by System Organ Class, High Level 
3.1.4.2 
Term, Preferred Term, and Severity 
Grade 3 or Higher Treatment-Emergent Adverse Events 
Related to Study Drug by System Organ Class, High Level 
3.1.4.2.1 
Term, Preferred Term ,and Severity- by Age 
Grade 3 or Higher Treatment-Emergent Adverse Events 
Related to Study Drug by System Organ Class, High Level 
3.1.4.2.2 
Term, Preferred Term, and Severity- by Race 
Grade 3 or Higher Treatment-Emergent Adverse Events 
Related to Study Drug by System Organ Class, High Level 
3.1.4.2.3 
Term, Preferred Term, and Severity- by Gender 
Grade 3 or Higher Treatment-Emergent Adverse Events 
Related to Study Drug by System Organ Class, High Level 
3.1.4.2.4 
Term, Preferred Term, and Severity- by Region 
3.1.5.1 
Treatment-Emergent Adverse Events by Preferred Term 
Treatment-Emergent Adverse Events by Preferred Term -by 
3.1.5.1.1 
Age 
Treatment-Emergent Adverse Events by Preferred Term -by 
3.1.5.1.2 
Race 
Treatment-Emergent Adverse Events by Preferred Term -by 
3.1.5.1.3 
Gender 
Treatment-Emergent Adverse Events by Preferred Term -by 
3.1.5.1.4 
Region 
Grade 3 or Higher Treatment-Emergent Adverse Events by 
3.1.5.2 
Preferred Term 
CONFIDENTIAL 
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131-fuy 2013 


Idelalisib Study 101-09 
Statistical Analysis Plan 
Table Number 
Title 
Grade 3 or Higher Treatment-Emergent Adverse Events by 
3.1.5.2.1 
Preferred Term -by Age 
Grade 3 or Higher Treatment-Emergent Adverse Events by 
3.1.5.2.2 
Preferred Term - by Race 
Grade 3 or Higher Treatment-Emergent Adverse Events by 
3.1.5.2.3 
Preferred Term - by Gender 
Grade 3 or Higher Treatment-Emergent Adverse Events by 
3.1.5.2.4 
Preferred Term- by Region 
Treatment-Emergent Adverse Events Related to Study Drug 
3.1.5.3 
by Preferred Term 
Treatment-Emergent Adverse Events Related to Study Drug 
3.1.5.3.1 
by Preferred Term - by Age 
Treatment-Emergent Adverse Events Related to Study Drug 
3.1.5.3.2 
by Preferred Term -by Race 
Treatment-Emergent Adverse Events Related to Study Drug 
3.1.5.3.3 
by Preferred Term - by Gender 
Treatment-Emergent Adverse Event Related to Study Drug 
3.1.5.3.4 
by Preferred Term - by Region 
Grade 3 or Higher Treatment-Emergent Adverse Events 
3.1.5.4 
Related to Study Drug by Preferred Term 
Grade 3 or Higher Treatment-Emergent Adverse Events 
3.1.5.4.1 
Related to Study Drug by Preferred Term- by Age 
Grade 3 or Higher Treatment-Emergent Adverse Events 
3.1.5.4.2 
Related to Study Drug by Preferred Term - by Race 
Grade 3 or Higher Treatment-Emergent Adverse Events 
3.1.5.4.3 
Related to Study Drug by Preferred Term -by Gender 
Grade 3 or Higher Treatment-Emergent Adverse Events 
3.1.5.4.4 
Related to Study Drug by Preferred Term - by Region 
3.1.5.5 
Serious Adverse Events by Preferred Term 
3.1.5.5.1 
Serious Adverse Events by Preferred Term -by Age 
3.1.5.5.2 
Serious Adverse Events by Preferred Term- by Race 
3.1.5.5.3 
Serious Adverse Events by Preferred Term -by Gender 
3.1.5.5.4 
Serious Adverse Events by Preferred Term- by Region 
Treatment-Emergent Serious Adverse Events Related to 
3.1.5.6 
Study Drug by Preferred Term 
Treatment-Emergent Serious Adverse Events Related to 
3.1.5.6.1 
Study Drug by Preferred Term- by Age 
Treatment-Emergent Serious Adverse Events Related to 
3.1.5.6.2 
Study Drug by Preferred Term - by Race 
Treatment-Emergent Serious Adverse Events Related to 
3.1.5.6.3 
Study Drug by Preferred Term -by Gender 
Treatment-Emergent Serious Adverse Events Related to 
3.1.5.6.4 
Study Drug by Preferred Term- by Region 
CONFIDENTIAL 
Page 55 
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131-fuy 2013 


Idelalisib Study 101-09 
Statistical Analysis Plan 
Table Number 
Title 
Treatment-Emergent Adverse Events Leading to Study Drug 
3.1.5. 7 
Discontinuation by Preferred Term 
Treatment-Emergent Adverse Events Leading to Study Drug 
3.1.5. 7.1 
Discontinuation by Preferred Term- by Age 
Treatment-Emergent Adverse Events Leading to Study Drug 
3.1.5.7.2 
Discontinuation by Preferred Term -by Race 
Treatment-Emergent Adverse Events Leading to Study Drug 
3.1.5.7.3 
Discontinuation by Preferred Term -by Gender 
Treatment-Emergent Adverse Events Leading to Study Drug 
3.1.5. 7.4 
Discontinuation by Preferred Term- by Region 
Treatment-Emergent Adverse Events Leading to Death by 
3.1.5.8 
Preferred Term 
Treatment-Emergent Adverse Events Leading to Death by 
3.1.5.8.1 
Preferred Term -by Age 
Treatment-Emergent Adverse Events Leading to Death by 
3.1.5.8.2 
Preferred Term - by Race 
Treatment-Emergent Adverse Events Leading to Death by 
3.1.5.8.3 
Preferred Term - by Gender 
Treatment-Emergent Adverse Events Leading to Death by 
3.1.5.8.4 
Preferred Term - by Region 
Treatment-Emergent Adverse Events Occurring in At Least 
3.1.5.9 
10% of Subjects by Preferred Term 
Treatment-Emergent Adverse Events Occurring in At Least 
3.1.5.9.1 
10% of Subjects by Preferred Term -by Age 
Treatment-Emergent Adverse Events Occurring in At Least 
3.1.5.9.2 
10% of Subjects by Preferred Term- by Race 
Treatment-Emergent Adverse Events Occurring in At Least 
3.1.5.9.3 
10% of Subjects by Preferred Term -by Gender 
Treatment-Emergent Adverse Events Occurring in At Least 
3.1.5.9.4 
10% of Subjects by Preferred Term- by Region 
Treatment-Emergent Adverse Events by Preferred Term and 
3.1.6.1 
Severity 
Treatment-Emergent Adverse Events by Preferred Term and 
3.1.6.1.1 
Severity- by Age 
Treatment-Emergent Adverse Events by Preferred Term and 
3.1.6.1.2 
Severity - by Race 
Treatment-Emergent Adverse Events by Preferred Term and 
3.1.6.1.3 
Severity- by Gender 
Treatment-Emergent Adverse Events by Preferred Term and 
3.1.6.1.4 
Severity - by Region 
Treatment-Emergent Adverse Events Related to Study Drug 
3.1.6.2 
by Preferred Term and Severity 
Treatment-Emergent Adverse Events Related to Study Drug 
3.1.6.2.1 
by Preferred Term and Severity- by Age 
CONFIDENTIAL 
Page 56 
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131-fuy 2013 


Idelalisib Study 101-09 
Statistical Analysis Plan 
Table Number 
Title 
Treatment-Emergent Adverse Events Related to Study Drug 
3.1.6.2.2 
by Preferred Term and Severity- by Race 
Treatment-Emergent Adverse Events Related to Study Drug 
3.1.6.2.3 
by Preferred Term and Severity- by Gender 
Treatment-Emergent Adverse Events Related to Study Drug y 
3.1.6.2.4 
Preferred Term and Severity- by Region 
Grade 3 or Higher Treatment-Emergent Adverse Events by 
3.1.7.1 
Preferred Term and Severity 
Grade 3 or Higher Treatment-Emergent Adverse Events by 
3.1.7.1.1 
Preferred Term and Severity- by Age 
Grade 3 or Higher Treatment-Emergent Adverse Events by 
3.1. 7.1.2 
Preferred Term and Severity- by Race 
Grade 3 or Higher Treatment-Emergent Adverse Events by 
3.1. 7.1.3 
Preferred Term and Severity- by Gender 
Grade 3 or Higher Treatment-Emergent Adverse Events by 
3.1.7.1.4 
Preferred Term and Severity- by Region 
Grade 3 or Higher Treatment-Emergent Adverse Events 
3.1.7.2 
Related to Study Drug by Preferred Term and Severity 
Grade 3 or Higher Treatment-Emergent Adverse Events 
Related to Study Drug by Preferred Term and Severity- by 
3.1. 7.2.1 
Age 
Grade 3 or Higher Treatment-Emergent Adverse Events 
Related to Study Drug by Preferred Term and Severity- by 
3.1.7.2.2 
Race 
Grade 3 or Higher Treatment-Emergent Adverse Events 
Related to Study Drug by Preferred Term and Severity- by 
3.1.7.2.3 
Gender 
Grade 3 or Higher Treatment-Emergent Adverse Events 
Related to Study Drug by Preferred Term and Severity- by 
3.1. 7.2.4 
Region 
Treatment-Emergent Adverse Events Leading to Study Drug 
3.1.8.1 
Reduction by Preferred Term 
Treatment-Emergent Adverse Events Leading to Study Drug 
3.1.8.1.1 
Reduction by Preferred Term- by Age 
Treatment-Emergent Adverse Events Leading to Study Drug 
3.1. 8.1.2 
Reduction by Preferred Term- by Race 
Treatment-Emergent Adverse Events Leading to Study Drug 
3.1.8.1.3 
Reduction by Preferred Term - by Gender 
Treatment-Emergent Adverse Events Leading to Study Drug 
3.1.8.1.4 
Reduction by Preferred Term- by Region 
Hematology: Summary of Actual Values and Change from 
3.2.1.1 
Baseline 
Hematology: Summary by Treatment-Emergent CTCAE 
3.2.1.2 
Severity Grade 
CONFIDENTIAL 
Page 57 
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131-fuy 2013 


Idelalisib Study 101-09 
Statistical Analysis Plan 
Table Number 
Title 
3.2.1.3 
Hematology: Shift from Baseline by CTCAE Severity Grade 
Serum Chemistry: Summary of Actual Values and Change 
3.2.2.1 
from Baseline 
Serum Chemistry: Summary by Treatment-Emergent CTCAE 
3.2.2.2 
Severity Grade 
Serum Chemistry: Shift from Baseline by CTCAE Severity 
3.2.2.3 
Grade 
3.2.2.4 
Summary of Transaminase Elevations 
Time to Onset and Time to Resolution of Transaminase 
3.2.2.5 
Elevations 
3.2.3 
Urinalysis: Summary of Actual Values at Baseline 
Immunophenotyping Immunoglobulin and Serum protein 
3.2.4 
electrophoresis (SPEP): Actual and Change from Baseline 
3.2.5 
Physical Examination 
3.2.6 
Palpable Lymphoma 
3.2.7 
Vital Signs: Actual and Change from Baseline 
3.2.8 
Vital Signs: Blood Pressure by Abnormal Status 
12-Lead Electrocardiograms: Actual and Change from 
3.2.9.1 
Baseline 
12-Lead Electrocardiograms: Overall Results Shift From 
3.2.9.2 
Baseline 
12-Lead Electrocardiograms: QTc Interval and QTc Interval 
3.2.9.3 
Change from Baseline 
12-Lead Electrocardiograms: QTc Interval Shift from 
3.2.9.4 
Baseline 
3.3.1 
IDELA Plasma Pharmacokinetic Concentration 
3.3.2 
GS-563117 Plasma Pharmacokinetic Concentration 
3.3.3 PPD 
3.3.4 
3.3.5 
3.3.6 
CONFIDENTIAL 
Page 58 
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131-fuy 2013