Clinical trial NCT01659021
Conditions: Chronic Lymphocytic Leukemia
Keywords: CLL Chronic Lymphocytic Leukemia GS-1101 CAL-101 Ofatumumab
Sponsor: Gilead Sciences
Start date: 2012-12-04; Completion date: 2018-08-15
Enrollment: 261 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to evaluate the effect of the addition of idelalisib to ofatumumab on progression-free survival (PFS) in participants with previously treated chronic lymphocytic leukemia (CLL).

Detailed description:

Arms: arm 1: Randomized Initial Therapy (24 weeks): Idelalisib + ofatumumab for a total of 12 infusions (300 mg on Day 1, followed by 1000 mg weekly for 7 weeks, and then 1000 mg every 4 weeks for 4 doses)

Continuing Therapy/Observation: Idelalisib 150 mg tablets twice daily until the earliest of participant withdrawal from study, definitive progression of CLL, intolerable idelalisib-related toxicity, pregnancy or initiation of breast feeding, substantial noncompliance with study procedures, or study discontinuation.

Long-Term Follow-up: Participants were followed for up to 5 years. Information on medical status, anti-tumor treatments, secondary malignancies, and survival status were collected annually during a routine clinic visit or other contact, such as telephone. arm 2: Randomized Initial Therapy (24 weeks): Ofatumumab for a total of 12 infusions (300 mg on Day 1, followed by 2000 mg weekly for 7 weeks, and then 2000 mg every 4 weeks for 4 doses)

Continuing Therapy/Observation: Observation until the earliest of participant withdrawal from study, definitive progression of CLL, intolerable idelalisib-related toxicity, pregnancy or initiation of breast feeding, substantial noncompliance with study procedures, or study discontinuation.

Long-Term Follow-up: Participants were followed for up to 5 years. Information on medical status, anti-tumor treatments, secondary malignancies, and survival status were collected annually during a routine clinic visit or other contact, such as telephone.
Interventions: intervention 1: Idelalisib intervention 2: Ofatumumab
Intervention descriptions: intervention 1: 150 mg tablets administered orally twice daily intervention 2: Administered intravenously

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 3, Randomized, Controlled Study Evaluating the 
Efficacy and Safety of Idelalisib (GS-1101) in Combination 
with Ofatumumab for Previously Treated 
Chronic Lymphocytic Leukemia
Sponsor:
Gilead Sciences, Inc.
199 East Blaine Street
Seattle, WA 98102
USA
333 Lakeside Drive
Foster City, CA 94404
USA
IND Number:
101254
EudraCT Number:
2012-001236-65
Indication:
Chronic Lymphocytic Leukemia 
Gilead Protocol ID:
GS-US-312-0119
Gilead Sciences
Medical Monitor:
Name:
Office Telephone:
Office Fax:
Mobile Telephone:
E-mail:
Protocol Version/Date:
Version 1.0 (Original):
02 July 2012
Version 2.0:
09 November 2012
Version 3.0:
17 October 2013
Version 4.0:
13 January 2014
Version 5.0:
04 March 2014
Version 6.0:
26 September 2014
Version 7.0:
17 December 2014
Version 8.0:
28 March 2016
Version 9.0:
04 August 2016
Version 10.0:
24 October 2016 
Version 11.0
30 August 2017 
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable 
institutional review board or independent ethics committee. This information is only to be used 
by you in connection with authorized clinical studies of the investigational drug described in the 
protocol. You must not disclose any of the information to others without written authorization 
from Gilead Sciences, Inc., except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered.
PPD
PPD
PPD
PPD
PPD


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................6
LIST OF IN-TEXT FIGURES ......................................................................................................................................6
PROTOCOL SYNOPSIS ..............................................................................................................................................7
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................20
1.
INTRODUCTION ..............................................................................................................................................24
1.1.
Chronic Lymphocytic Leukemia............................................................................................................24
1.2.
Phosphatidylinositol 3-Kinase in Lymphoid Malignancies....................................................................25
1.3.
Idelalisib.................................................................................................................................................26
1.3.1.
General Information .............................................................................................................26
1.3.2.
Safety Pharmacology............................................................................................................27
1.3.3.
Nonclinical Pharmacology and Metabolism.........................................................................27
1.3.4.
Toxicology ...........................................................................................................................28
1.3.5.
Idelalisib Clinical Studies.....................................................................................................29
1.4.
Summary and Justification for the Current Study ..................................................................................33
2.
STUDY DESIGN................................................................................................................................................35
2.1.
Design Overview and Study Schema .....................................................................................................35
2.2.
Design Rationale ....................................................................................................................................36
3.
OBJECTIVES AND ENDPOINTS ....................................................................................................................38
3.1.
Primary Objective ..................................................................................................................................38
3.2.
Secondary Objectives.............................................................................................................................38
3.3.
Primary Endpoint ...................................................................................................................................38
3.4.
Secondary and Exploratory Endpoints...................................................................................................38
3.4.1.
Tumor Control......................................................................................................................39
3.4.2.
Patient Well-Being ...............................................................................................................40
3.4.3.
Pharmacodynamic Markers of Drug Activity and Resistance..............................................40
3.4.4.
Exposure...............................................................................................................................40
3.4.5.
Safety....................................................................................................................................41
3.4.6.
Pharmacoeconomics.............................................................................................................41
3.5.
Endpoint Selection Rationale.................................................................................................................41
3.5.1.
Tumor Control Endpoints.....................................................................................................41
3.5.2.
Measures of Patient Well-Being...........................................................................................43
3.5.3.
Pharmacodynamic Markers of Drug Activity and Resistance..............................................45
3.5.4.
Assessments of Exposure .....................................................................................................46
3.5.5.
Evaluations of Safety............................................................................................................47
3.5.6.
Pharmacoeconomic Measures ..............................................................................................48
4.
SUBJECT POPULATION..................................................................................................................................49
4.1.
Number of Subjects................................................................................................................................49
4.2.
Subject Selection Criteria.......................................................................................................................49
4.2.1.
Inclusion Criteria..................................................................................................................49
4.2.2.
Exclusion Criteria.................................................................................................................52
4.3.
Enrollment Criteria Rationale ................................................................................................................54
5.
TREATMENT OF SUBJECTS ..........................................................................................................................56
5.1.
Randomization .......................................................................................................................................56


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5.1.1.
Interactive Web Response System .......................................................................................56
5.1.2.
Randomization and Stratification.........................................................................................56
5.2.
Study Drugs............................................................................................................................................57
5.2.1.
Idelalisib...............................................................................................................................57
5.2.2.
Ofatumumab.........................................................................................................................59
5.3.
Study Drug Administration ....................................................................................................................61
5.3.1.
Overview of Dosing Regimen..............................................................................................61
5.3.2.
Investigational Study Drug (Idelalisib) ................................................................................64
5.3.3.
Ofatumumab.........................................................................................................................65
5.3.4.
Safety Monitoring and Study Drug Interruption/Dose Modification ...................................67
5.4.
Recommendations for Evaluation, Intervention, and Drug Discontinuation for Specific 
Adverse Events or Conditions................................................................................................................71
5.4.1.
Carcinogenesis and Mutagenesis..........................................................................................71
5.4.2.
Dermatological Events .........................................................................................................71
5.4.3.
Gastrointestinal Events.........................................................................................................72
5.4.4.
Hematological and Immunological Events...........................................................................74
5.4.5.
Hepatic Events......................................................................................................................75
5.4.6.
Immunogenicity ...................................................................................................................76
5.4.7.
Infectious Events..................................................................................................................76
5.4.8.
Progressive Multifocal Leukoencephalopathy .....................................................................77
5.4.9.
Pulmonary Events ................................................................................................................77
5.4.10.
Tumor Lysis Syndrome........................................................................................................78
5.4.11.
Pregnancy, Lactation, and Reproduction..............................................................................78
5.4.12.
PJP Prophylaxis and Pregnancy ...........................................................................................79
5.4.13.
Ultraviolet Exposure ............................................................................................................80
5.5.
Concomitant and Supportive Therapy....................................................................................................80
5.5.1.
Anticancer or Experimental Therapies Other than Investigational 
Treatments............................................................................................................................80
5.5.2.
Antiemetics and Antidiarrheals............................................................................................80
5.5.3.
Contraception .......................................................................................................................81
5.5.4.
Corticosteroids .....................................................................................................................82
5.6.
Diet.........................................................................................................................................................82
5.6.1.
Granulocyte Colony-Stimulating Factors and Erythropoietin..............................................82
5.6.2.
Drugs that Inhibit/Induce CYP3A-Dependent Metabolism..................................................83
5.6.3.
Drugs that Undergo CYP3A-Dependent Metabolism..........................................................83
5.6.4.
Immunization .......................................................................................................................83
5.6.5.
Surgery .................................................................................................................................84
5.7.
Duration of Study Drug..........................................................................................................................84
5.8.
Discontinuation of Study Drug ..............................................................................................................84
5.9.
Discontinuation from Study ...................................................................................................................85
5.10.
Study Treatment Rationale.....................................................................................................................85
6.
STUDY PROCEDURES ....................................................................................................................................88
6.1.
Enrollment and Study Management Procedures ....................................................................................88
6.1.1.
Subject Recruitment .............................................................................................................88
6.1.2.
Subject Compensation for Participation...............................................................................88
6.1.3.
Screening..............................................................................................................................88
6.2.
Explanation of Study Visits....................................................................................................................89
6.2.1.
Visit 1 and Screening Period (Clinic and Radiology Visit)..................................................89
6.2.2.
Visit 2 (Clinic Visit – Randomization and Treatment Start) ................................................91
6.2.3.
Visit 3 (Clinic Visit).............................................................................................................93
6.2.4.
Visit 4 (Clinic Visit).............................................................................................................94
6.2.5.
Visits 5, 7, and 8 (Clinic Visit).............................................................................................96
6.2.6.
Visit 6 (Clinic Visit).............................................................................................................97


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6.2.7.
Visit 9 (Clinic and Radiology Visit).....................................................................................99
6.2.8.
Visit 10 (Clinic Visit).........................................................................................................101
6.2.9.
Visit 11 (Clinic and Radiology Visit).................................................................................103
6.2.10.
Visit 12 (Clinic Visit).........................................................................................................104
6.2.11.
Visit 13 (Clinic and Radiology Visit).................................................................................106
6.2.12.
Visits 14 and 16 (Clinic Visits) ..........................................................................................108
6.2.13.
Visits 15 and 17 (Clinic and Radiology Visits)..................................................................109
6.2.14.
Visit 18 and Subsequent Visits (Every 12 Weeks) 
(Clinic and Radiology Visits).............................................................................................110
6.2.15.
End-of-Study Visit (Clinic Visit) .......................................................................................112
6.2.16.
30 Day and Long-Term Follow-up.....................................................................................113
6.3.
Sample Storage.....................................................................................................................................113
6.4.
Blood Collection ..................................................................................................................................114
6.5.
Study Procedure Rationale...................................................................................................................114
7.
EFFICACY ASSESSMENTS...........................................................................................................................115
7.1.
Tumor Status Assessments...................................................................................................................115
7.2.
Method of Assessment .........................................................................................................................115
7.3.
Timing of Assessments ........................................................................................................................115
7.4.
Identification and Measurement of Tumor Lesions and Organomegaly ..............................................116
7.4.1.
Index Lesions .....................................................................................................................116
7.4.2.
Spleen and Liver.................................................................................................................117
7.4.3.
Non-Index Lesions .............................................................................................................117
7.5.
Definitions of Tumor Response and Progression.................................................................................118
7.5.1.
Complete Response............................................................................................................118
7.5.2.
Partial Response .................................................................................................................119
7.5.3.
Stable Disease ....................................................................................................................119
7.5.4.
Definitive Progressive Disease...........................................................................................120
7.5.5.
Non-Evaluable....................................................................................................................121
7.5.6.
No Disease .........................................................................................................................121
7.6.
Lymphocytosis During Therapy...........................................................................................................122
7.7.
Documentation of Definitive CLL Progression ...................................................................................122
8.
ADVERSE EVENTS AND TOXICITY MANAGEMENT.............................................................................123
8.1.
Definitions of Adverse Events, Adverse Reactions and Serious Adverse Events................................123
8.1.1.
Adverse Event ....................................................................................................................123
8.1.2.
Serious Adverse Events......................................................................................................123
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .......................................................................124
8.2.
Assessment of Adverse Events and Serious Adverse Events...............................................................124
8.2.1.
Assessment of Causality for Study Drugs and Procedures.................................................125
8.2.2.
Assessment of Severity ......................................................................................................125
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead or Designee.................................................................................................126
8.4.
Gilead Reporting Requirements...........................................................................................................127
8.4.1.
Reporting of Adverse Events Relating to the Primary Endpoint and Other 
Anticipated Medical Events in the Study Population.........................................................127
8.5.
Toxicity Management ..........................................................................................................................127
8.5.1.
Warnings & Precautions.....................................................................................................127
8.6.
Special Situations Reports....................................................................................................................130
8.6.1.
Definitions of Special Situations........................................................................................130
8.6.2.
Instructions for Reporting Special Situations.....................................................................131
9.
STATISTICAL CONSIDERATIONS..............................................................................................................133


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9.1.
Analysis Objectives..............................................................................................................................133
9.2.
Analysis Endpoints...............................................................................................................................133
9.2.1.
Primary Endpoint ...............................................................................................................133
9.2.2.
Secondary and Exploratory Endpoints ...............................................................................133
9.3.
Analysis Conventions...........................................................................................................................133
9.3.1.
Analysis Sets ......................................................................................................................133
9.3.2.
Data Handling Conventions ...............................................................................................134
9.4.
Analysis Plan........................................................................................................................................136
9.4.1.
Subject Disposition and Baseline Characteristics...............................................................136
9.4.2.
Exposure and Safety Analyses ...........................................................................................139
9.4.3.
Other Analyses ...................................................................................................................141
9.5.
Sample Size..........................................................................................................................................142
9.6.
Timing of Analyses..............................................................................................................................143
9.6.1.
Interim Analysis .................................................................................................................143
9.6.2.
Final Efficacy Analysis ......................................................................................................143
9.6.3.
Follow-up Analyses............................................................................................................143
10.
RESPONSIBILITIES........................................................................................................................................144
10.1.
Investigator Responsibilities ................................................................................................................144
10.1.1.
Good Clinical Practice........................................................................................................144
10.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval.........................................................................................................144
10.1.3.
Confidentiality....................................................................................................................145
10.1.4.
Study Files and Retention of Records and Biological Samples..........................................145
10.1.5.
Case Report Forms.............................................................................................................147
10.1.6.
Drug Accountability...........................................................................................................147
10.1.7.
Inspections..........................................................................................................................148
10.1.8.
Protocol Compliance..........................................................................................................148
10.2.
Sponsor Responsibilities ......................................................................................................................148
10.2.1.
Protocol Modifications.......................................................................................................148
10.2.2.
Communications with Regulatory Authorities...................................................................148
10.2.3.
Data Management ..............................................................................................................148
10.2.4.
Study Reporting and Publication........................................................................................149
10.3.
Joint Investigator/Sponsor Responsibilities .........................................................................................150
10.3.1.
Access to Information for Monitoring................................................................................150
10.3.2.
Access to Information for Auditing or Inspections ............................................................150
10.3.3.
Public Notification of Study Conduct ................................................................................150
10.3.4.
Study Discontinuation........................................................................................................150
10.4.
Study Committees ................................................................................................................................150
10.4.1.
Data Monitoring Committee ..............................................................................................150
10.4.2.
Independent Review Committee ........................................................................................151
11.
REFERENCES .................................................................................................................................................152
12.
APPENDICES ..................................................................................................................................................164
Appendix 1.
Investigator Signature Page..................................................................................................165
Appendix 2.
Functional Assessment of Cancer Therapy: Leukemia ........................................................166
Appendix 3.
Performance Status Scoring System.....................................................................................169
Appendix 4.
EuroQoL-5 Dimensions (EQ-5D) ........................................................................................170
Appendix 5.
Cockcroft-Gault Method for Estimating Creatinine Clearance ............................................172
Appendix 6.
Cumulative Illness Rating Scale (CIRS) ..............................................................................173
Appendix 7.
Schedule of Study Procedures..............................................................................................179


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LIST OF IN-TEXT TABLES
Table 4-1.
Required Screening Laboratory Values..................................................................................51
Table 5-1.
Planned Dosing Regimen .......................................................................................................63
Table 5-2.
Idelalisib Dose Levels ............................................................................................................64
Table 5-3.
Study Drug (Ofatumumab) Infusion Rates.............................................................................66
Table 5-4.
Recommendations and Required Actions for Idelalisib and Ofatumumab Dose 
Modification Based on Type and Severity of Treatment-Related Adverse Event or 
Laboratory Abnormality.........................................................................................................68
Table 5-5.
Protocol-Recommended Contraceptive Methods ...................................................................81
Table 5-6.
Known Strong Inducers of CYP3A........................................................................................83
Table 6-1.
Procedures and Assessments at Visit 1 (Screening Period)....................................................90
Table 6-2.
Procedures and Assessments at Visit 2 (Treatment Start) ......................................................91
Table 6-3.
Procedures and Assessments at Visit 3...................................................................................93
Table 6-4.
Procedures and Assessments at Visit 4...................................................................................94
Table 6-5.
Procedures and Assessments at Visits 5, 7, and 8 ..................................................................96
Table 6-6.
Procedures and Assessments at Visit 6...................................................................................97
Table 6-7.
Procedures and Assessments at Visit 9...................................................................................99
Table 6-8.
Procedures and Assessments at Visit 10...............................................................................101
Table 6-9.
Procedures and Assessments at Visit 11...............................................................................103
Table 6-10.
Procedures and Assessments at Visit 12...............................................................................104
Table 6-11.
Procedures and Assessments at Visit 13...............................................................................106
Table 6-12.
Procedures and Assessments at Visits 14 and 16 .................................................................108
Table 6-13.
Procedures and Assessments at Visits 15 and 17 .................................................................109
Table 6-14.
Procedures and Assessments at Visit 18 and Subsequent Visits (Every 12 Weeks).............110
Table 6-15.
Procedures and Assessments at End-of-Study Visit.............................................................112
Table 8-1.
Grading of Adverse Event Severity......................................................................................125
LIST OF IN-TEXT FIGURES
Figure 2-1.
Study Design ..........................................................................................................................35
Figure 5-1.
Kaplan-Meier Time to Diarrhea or Colitis .............................................................................73


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
199 East Blaine Street
Seattle, WA 98102, USA
Study Title:
A Phase 3, Randomized, Controlled Study Evaluating the Efficacy and 
Safety of Idelalisib (GS-1101) in Combination with Ofatumumab for 
Previously Treated Chronic Lymphocytic Leukemia
Study Centers 
Planned:
Approximately 115 centers in the United States, Canada, Australia, and 
Europe
IND Number:
101254
EudraCT Number:
2012-001236-65
Primary Objective:

To evaluate the effect of the addition of idelalisib (GS-1101) to 
ofatumumab on progression-free survival (PFS) in subjects with 
previously treated chronic lymphocytic leukemia (CLL)
Secondary
Objectives:

To evaluate the effect of the addition of idelalisib to ofatumumab on 
the onset, magnitude, and duration of tumor control

To evaluate the effect of the addition of idelalisib to ofatumumab on 
the onset, magnitude, and duration of tumor control for subjects with 
17p deletion and/or TP53 mutation

To assess the effect of the addition of idelalisib to ofatumumab on 
measures of subject well-being, including overall survival (OS), 
health-related quality of life (HRQL) and performance status

To assess the effects of the addition of idelalisib to ofatumumab on 
disease-associated biomarkers and to evaluate potential mechanisms 
of resistance to idelalisib

To characterize the effect of ofatumumab on idelalisib exposure 
through evaluation of idelalisib plasma concentrations over time

To describe the safety profile observed with the addition of idelalisib 
to ofatumumab

To estimate health resource utilization associated with the addition of 
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Study Design:
Study GS-US-312-0119 is a Phase 3, multicenter, 2-arm, randomized, 
controlled, parallel-group, clinical trial.
Study Schema
Treatment Groups

Arm A: idelalisib + ofatumumab (1000-mg dosing regimen)

Arm B: Ofatumumab (2000-mg dosing regimen)
Randomization and Stratification

2:1 allocation to Arm A vs Arm B with implementation through an 
interactive web response system (IWRS)

Fixed-block centralized randomization with allocation of subjects 
within the 8 strata as defined by the intersection of 3 binary 
stratification factors:

17p deletion and/or TP53 mutation in CLL cells: either vs neither 
(or indeterminate)

Immunoglobulin heavy chain variable region (IgHV) mutation: 
unmutated (or IgHV3-21) vs mutated (or indeterminate)

Disease status: refractory (CLL progression < 6 months from 
completion of prior therapy) vs relapsed 
(CLL progression 6 months from completion of prior therapy)
Number of 
Subjects 
Planned:
Total of ~255 subjects (~170 subjects in Arm A and ~85 subjects in Arm B)


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Target 
Population:
The target population comprises adults with previously treated CLL who 
have measurable lymphadenopathy, require treatment for CLL, have 
disease that is not refractory to ofatumumab, and might benefit from a 
change in therapy because they have experienced CLL progression 
< 24 months since the completion of the last prior treatment.
Duration of 
Treatment:
Idelalisib will be taken continuously until the earliest of subject 
withdrawal from study, definitive progression of CLL, intolerable study 
drug-related toxicity, pregnancy, substantial noncompliance with study 
procedures, or study discontinuation. Idelalisib administration should be 
continued in subjects with a positive benefit-risk profile assessment as 
per the investigator.
Ofatumumab will be administered until the earliest of a maximum of 
12 infusions, subject withdrawal from study, definitive progression of 
CLL, intolerable ofatumumab-related toxicity, pregnancy, substantial 
noncompliance with study procedures, or study discontinuation.
Subjects in Arm A will continue with idelalisib or ofatumumab, even if 
the other drug must be discontinued due to toxicity.
Diagnosis and 
Main Eligibility 
Criteria:
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible 
for participation in this study:
1)
Male or female 18 years of age.
2)
Diagnosis of B-cell CLL, with diagnosis established according to 
International Workshop on Chronic Lymphocytic Leukemia 
(IWCLL) criteria and documented within medical records.
3)
CLL that warrants treatment (consistent with accepted 
IWCLL criteria for initiation of therapy). Any of the following 
conditions constitute CLL that warrants treatment:
a) Evidence of progressive marrow failure as manifested by the 
onset or worsening of anemia and/or thrombocytopenia, or
b) Massive (ie, lower edge of spleen 6 cm below the 
left costal margin), progressive, or symptomatic splenomegaly, 
or
c) Massive (ie, 10 cm in the longest diameter), progressive, or 
symptomatic lymphadenopathy, or
d) Progressive lymphocytosis in the absence of infection, with an 
increase in blood absolute lymphocyte count (ALC) 50% over 
a 2-month period or lymphocyte doubling time of < 6 months 
(as long as initial ALC was 30,000/L), or


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e) Autoimmune anemia and/or thrombocytopenia that is poorly 
responsive to corticosteroids or other standard therapy, or
f)
Constitutional symptoms, defined as any one or more of the 
following disease-related symptoms or signs occurring in the 
absence of evidence of infection:
i)
Unintentional weight loss of 10% within the previous 
6 months, or
ii) Significant fatigue (Grade 2), or
iii) Fevers > 100.5 °F or 38.0 °C for 2 weeks, or
iv) Night sweats for >1 month
4)
Presence of measurable lymphadenopathy (defined as the presence 
of ≥1 nodal lesion that measures ≥2.0 cm in the longest diameter 
[LD] and 1.0 cm in the longest perpendicular diameter [LPD] as 
assessed by computed tomography [CT] or magnetic resonance 
imaging [MRI]). 
5)
Prior treatment for CLL comprising therapy with either of the 
following types of drugs given alone or in combination:
a) A purine analog (eg, fludarabine, pentostatin, cladribine) 
administered for ≥2 cycles of cytotoxic treatment
b) Bendamustine administered for ≥2 cycles of treatment
Note: Prior drugs may have been administered as single agents or 
as components of combination therapies. Subjects may also have 
received other commercially available therapies 
(eg, rituximab, alemtuzumab, ofatumumab, lenalidomide, 
corticosteroids, or others) or non-excluded investigational 
therapies. Each repeated but separated therapeutic application of 
the same single-agent or combination is considered an independent 
regimen.
6) Documentation of CLL progression < 24 months since the 
completion of the last prior therapy for CLL.
7) Discontinuation of all therapy (including radiotherapy, 
chemotherapy, immunotherapy, or investigational therapy) for the 
treatment of CLL 6 weeks before randomization. 
Note: Subjects may be receiving corticosteroids to manage CLL 
manifestations.
8) All acute toxic effects of any prior antitumor therapy resolved to 
Grade 1 before randomization (with the exception of alopecia 
[Grade 1 or 2 permitted], neurotoxicity [Grade 1 or 2 permitted], or 
bone marrow parameters Grade 1, 2, 3, or 4 permitted]).


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9) Karnofsky performance score of ≥60.
10) Required baseline laboratory data (within 4 weeks prior to 
randomization) as shown in the table below.
Note: Confirmation should be considered for out-of-range values 
to determine if the abnormality is real or artifactual. Values should 
be obtained within the screening period and should generally be 
the most recent measurement obtained. Subjects with any degree of 
neutropenia, thrombocytopenia, or anemia due to CLL or prior 
therapy may enroll.
Required Screening Laboratory Values
Organ System
Parameter
Required Value
Hepatic
Serum total bilirubin
1.5 x ULN (unless elevated due to
Gilbert syndrome or hemolysis)
Serum ALT
2.5 x ULN
Serum AST
Renal
eCCr
a
> 30 ml/min
Pregnancy
-HCGb
Negative
Infection
HIV
Negative HIV antibody
HBV
Negative HBsAg and negative HBc 
antibody or positive HBc and negative 
for HBV DNA by quantitative PCR
HCV
Negative viral RNA
(if HCV antibody is positive)
a
As calculated by the Cockcroft-Gault formula {Cockcroft 1976} (see Appendix 5)
b
For women of child-bearing potential only; serum -HCG must be negative during screening 
and serum -HCG or urine dipstick pregnancy test must be negative at randomization (Visit 2)
Abbreviations: -HCG= beta human chorionic gonadotropin, ALT=alanine aminotransferase, 
AST=aspartate aminotransferase, DNA=deoxyribonucleic acid, 
eCCr=estimated creatinine clearance, HBc antibody=anti-hepatitis B core antibody, 
HBsAg=hepatitis B surface antigen, HBV=hepatitis B virus, HCV=hepatitis C virus, 
HIV=human immunodeficiency virus, Ig=immunoglobulin, PCR=polymerase chain reaction, 
RNA=ribonucleic acid, ULN=upper limit of normal
11) For female subjects of child-bearing potential, willingness to use a 
protocol-recommended method of contraception from the screening 
visit (Visit 1) throughout the study treatment period and to 30 days 
from the last dose of study drug or 12 months from the last dose of 
ofatumumab (whichever is later). Note: A female subject is 
considered to be of child-bearing potential unless she has had a 
hysterectomy, bilateral tubal ligation, or bilateral oophorectomy; has 
medically documented ovarian failure (with serum estradiol and 
follicle-stimulating hormone [FSH] levels within the institutional 
postmenopausal range and a negative serum or urine HCG); or is 
menopausal (age 54 years with amenorrhea for 6 months).


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12) For male subjects of child-bearing potential having intercourse with 
females of child-bearing potential, willingness to use a 
protocol-recommended method of contraception from the 
randomization visit (Visit 2) throughout the study and for 90 days 
following the last dose of study drug and to refrain from sperm 
donation from randomization (Visit 2) throughout the study and for 
90 days following the last dose of study drug. Note: A male subject 
is considered able to father a child unless he has had a bilateral 
vasectomy with documented aspermia or a bilateral orchiectomy, or 
has ongoing testicular suppression with a depot luteinizing hormone-
releasing hormone (LH-RH) agonist (eg, goserelin acetate 
[Zoladex®]), leuprolide acetate [Lupron®]), or triptorelin pamoate 
[Trelstar®]).
13) In the judgment of the investigator, participation in the protocol 
offers an acceptable benefit-to-risk ratio when considering current 
CLL disease status, medical condition, and the potential benefits and 
risks of alternative treatments for CLL.
14) Willingness and ability to comply with scheduled visits, drug 
administration plan, imaging studies, laboratory tests, other study 
procedures, and study restrictions. Note: Psychological, social, 
familial, or geographical factors that might preclude adequate study 
participation should be considered.
15) 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.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be 
enrolled in this study:
1) Known histological transformation from CLL to an aggressive 
lymphoma (ie, Richter transformation). Note: Biopsy documentation 
of the absence or presence of transformation is not required.
2) Known presence of intermediate- or high-grade 
myelodysplastic syndrome (ie, subjects are excluded who have 
5% bone marrow blasts; karotypic abnormalities other than 
normal, Y deletion, 5q deletion, or 20q deletion; or 2 lineages of 
cytopenias due to myelodysplasia).


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3) History of a non-CLL malignancy except for the following: 
adequately treated local basal cell or squamous cell carcinoma of the 
skin, cervical carcinoma in situ, superficial bladder cancer, 
asymptomatic prostate cancer without known metastatic disease and 
with no requirement for therapy or requiring only hormonal therapy 
and with normal prostate-specific antigen for 1 year prior to 
randomization, other adequately treated Stage 1 or 2 cancer currently 
in complete remission, or any other cancer that has been in complete 
remission for ≥2 years.
4) Known hypersensitivity or intolerance to any of the active 
substances or excipients in the formulations for either idelalisib or 
ofatumumab.
5) Evidence of ongoing systemic bacterial, fungal, or viral infection at 
the time of randomization (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; anti-pneumocystis prophylaxis is 
encouraged. 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.
6) Ongoing drug-induced liver injury, chronic active hepatitis C 
(HCV), chronic active hepatitis B (HBV), alcoholic liver disease, 
non-alcoholic steatohepatitis, primary biliary cirrhosis, extrahepatic 
obstruction caused by cholelithiasis, cirrhosis of the liver, or portal 
hypertension.
7) Ongoing drug-induced pneumonitis.
8) Ongoing inflammatory bowel disease.
9) Ongoing alcohol or drug addiction.
10) Pregnancy or breastfeeding. 
11) History of prior allogeneic bone marrow progenitor cell or solid 
organ transplantation.
12) Ongoing immunosuppressive therapy other than corticosteroids. 
Note: Subjects may use topical, enteric, inhaled, or systemic 
corticosteroids as therapy for manifestations of CLL, 
comorbid conditions, or autoimmune anemia and/or 
thrombocytopenia. During study participation, subjects may 
receive systemic or other corticosteroids as pretreatment for 
ofatumumab infusions or as needed for treatment-emergent 
comorbid conditions.


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13) In a subject with a history of prior ofatumumab therapy, the time 
from the last dose of ofatumumab to documented CLL progression is 
< 6 months.
14) History of prior therapy with any inhibitor of AKT, Bruton tyrosine 
kinase (BTK), Janus kinase (JAK), mammalian target of rapamycin 
(mTOR), phosphatidylinositol 3-kinase (PI3K) (including idelalisib), 
or spleen tyrosine kinase (SYK). 
15) Prior participation in an idelalisib clinical trial.
16) Concurrent participation in another therapeutic clinical trial.
17) Prior or ongoing clinically significant illness, medical condition, 
surgical history, physical finding, electrocardiogram (ECG) finding, 
or laboratory abnormality that, in the investigator’s opinion, could 
adversely affect the safety of the subject or impair the assessment of 
study results.
Study 
Procedures/
Frequency:
Subjects will be randomized with a 2:1 ratio into Arm A or Arm B of the 
study. In Arm A, subjects will take idelalisib orally BID continuously 
and will receive 12 infusions of ofatumumab over ~24 weeks. In Arm B, 
subjects will receive 12 infusions of ofatumumab over ~24 weeks.
Clinic/laboratory visits will occur weekly for Weeks 1 through 8, every 
4 weeks at Weeks 12, 16, 20, and 24, and every 6 weeks between 
Weeks 24 and 48. Subjects continuing on study drug(s) past Week 48 
will have clinic visits every 12 weeks. Subjects will be assessed for 
safety at each visit. Subjects in Arm A will require monthly CMV 
testing. Subjects will be assessed for CLL disease status by physical 
and/or laboratory examinations at each visit and by CT or MRI at 
Weeks 8, 16, 24, 36, 48 and every 12 weeks thereafter until the primary 
endpoint is met.
Test Therapy, Dose, 
and Mode of 
Administration:

Arm A: Idelalisib: 150 mg taken orally BID starting on Day 1 and 
administered continuously thereafter
Study Drug, Dose, 
and Mode of 
Administration:

Arm A: Ofatumumab: 300 mg intravenously on Day 1 (Week 1);
thereafter 1,000 mg intravenously on Day 8 (Week 2), 
Day 15 (Week 3), Day 22 (Week 4), Day 29 (Week 5), 
Day 36 (Week 6), Day 43 (Week 7), Day 50 (Week 8), 
Day 78 (Week 12), Day 106 (Week 16), Day 134 (Week 20), 
Day 162 (Week 24) (for a total of 12 infusions)


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
Arm B: Ofatumumab: 300 mg intravenously on Day 1 (Week 1); 
thereafter 2,000 mg intravenously on Day 8 (Week 2), 
Day 15 (Week 3), Day 22 (Week 4), Day 29 (Week 5), 
Day 36 (Week 6), Day 43 (Week 7), Day 50 (Week 8), 
Day 78 (Week 12), Day 106 (Week 16), Day 134 (Week 20), 
Day 162 (Week 24) (for a total of 12 infusions)
Criteria for 
Evaluation:
Primary Endpoint

Progression-free survival (PFS) – defined as the interval from 
randomization to the earlier of the first documentation of definitive 
disease progression or death from any cause; definitive disease 
progression is CLL progression based on standard criteria, other than 
lymphocytosis alone
Secondary and Exploratory Endpoints

Five endpoints are designated as secondary endpoints for which 
sequential testing will be performed to control Type I error rate. 
Secondary endpoints will be ORR, lymph node response rate, OS, 
PFS in the subgroup of 17p deleted and/or TP53 mutated subjects, 
and CR rate. All other endpoints will be considered exploratory.
Tumor Control

Overall response rate (ORR) – defined as the proportion of subjects 
who achieve a complete response (CR) or partial response (PR)
response for at least 8 weeks

Lymph node response rate – 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 
lesions

PFS in the subgroup of subjects with 17p deletion and/or 
TP53 mutation

CR rate – defined as the proportion of subjects who achieve a 
confirmed CR
 
 
 
 
CCI
CCI


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Patient Well-Being

Overall survival (OS) – defined as the interval from randomization 
to death from any cause
 
 
 
CCI
CCI
CCI


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Pharmacodynamic Markers of Drug Activity and Resistance
 
 
Exposure
 
 
Safety
 
 
 
 
Pharmacoeconomics
 
 
 
Statistical Methods:
Analysis Methods
Appropriate data analysis sets will be defined. The intent-to-treat (ITT) 
analysis set will be used in the analyses of the primary efficacy endpoint, 
PFS. The ITT analysis set will include data from all subjects who are 
randomized, with study drug assignment designated according to initial 
randomization, regardless of whether subjects receive any study drug(s) 
or receive a different regimen from that to which they were randomized. 
A safety analysis set will comprise data from subjects who receive 
1 dose of study drug, with treatment assignment designated according 
to the actual study drug(s) received. Other analysis sets [per-protocol 
(PP) and pharmacodynamic/pharmacokinetic analysis sets] will be used 
for certain analyses as well.
CCI
CCI
CCI
CCI


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Subject characteristics and study results will be described and 
summarized by treatment arm and assessment for the relevant analysis 
sets. Descriptive summaries will be prepared to show sample size, mean, 
standard deviation, 95% confidence intervals (CIs) on the mean, median, 
minimum, and maximum for continuous variables and counts,
percentages, and 95% CIs on the percentage for categorical variables.
An independent review committee (IRC) will review radiographic data 
and pertinent clinical data in order to provide expert evaluation of tumor 
status. The findings of the IRC will be considered primary for analyses 
of PFS and other tumor control endpoints.
For the primary efficacy analysis, the difference in PFS between the 
treatment arms will be assessed in the ITT analysis set using 
Kaplan-Meier methods and the stratified log-rank test. Medians, ranges, 
the proportions of subjects who are progression-free at 24 and 48 weeks 
from randomization (based on Kaplan-Meier estimates), hazard ratios, 
and the corresponding 95% CIs (as calculated using a Cox proportional 
hazards regression model) will be presented.
Secondary endpoints will be ORR, lymph node response rate, OS, PFS in 
the subgroup of subjects with 17p deletion and/or TP53 mutation, and 
CR rate. The primary efficacy hypothesis relating to PFS must be 
rejected at the pre-specified significance level before the efficacy 
hypotheses for these secondary efficacy endpoints are tested. These 
5 secondary endpoints will be tested at the 2-sided 0.03 significance level 
in the order listed at an interim or final analysis when the primary 
endpoint is rejected. If a null hypothesis is not rejected, formal sequential 
testing will be stopped and only nominal significance will be cited for the 
remaining secondary endpoints.
For secondary or exploratory endpoints relating to tumor control, patient 
well-being, and biomarkers, analyses will be done based on the ITT, PP, 
or pharmacodynamic data sets, as appropriate. Time-to-event efficacy 
endpoints will be analyzed in a similar manner as PFS. Categorical 
variables will be compared using the Cochran Mantel-Haenszel test 
adjusted for stratification factors. Continuous endpoints will be assessed 
using analysis of covariance (ANCOVA) with baseline values and 
stratification factors as covariates. Changes from baseline in HRQL 
parameters and in performance status will be compared between the 
treatment groups using the Wilcoxon rank-sum test, considering 
subjects’ disease progression status.
Based on the safety analysis set, information regarding study drug 
administration, study drug compliance, safety variables, and post-study 
therapies will be described and summarized. Using data from the 
pharmacokinetic analysis set, idelalisib plasma concentrations will also 
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Sample Size Calculation
Based on data from prior studies, it is reasonable to assume that 
administration of ofatumumab to subjects with previously treated CLL in 
Arm B of this trial will result in a median PFS of ~8 months. An 
improvement in median PFS from 8 months to 14 months resulting from 
the addition of idelalisib to ofatumumab in Arm A of the study would 
correspond to a benefit ratio of 1.75 (hazard ratio 0.57).
It is assumed that PFS times are exponentially distributed in each of the 
2 arms. With a hazard ratio equal to 1 under the null hypothesis of no 
difference between the 2 treatment arms and a hazard ratio of 0.57 under 
the alternative hypothesis of superiority of the idelalisib containing 
combination, 129 events (definitive CLL progressions or deaths) are 
required to achieve a power of > 0.85 based on a log-rank test with a 
2-sided significance level of 0.05. Further assuming a planned accrual 
period of 12 months (with approximately half of the subjects enrolled 
during the initial 60% of the accrual period, and the remaining half of the 
subjects enrolled during the last 40% of the accrual period), a minimum 
follow-up period of 12 months, and an expectation that 10% of subjects 
will be lost to follow-up (5% during the accrual period and 5% during 
the follow-up period), and to ensure the primary analysis on PFS will be 
performed before or at the planned minimum 12-month follow-up period,
170 subjects will be enrolled into Arm A and 85 subjects will be enrolled 
into Arm B in order to achieve the expected number of events by the end 
of the planned minimum 12-month follow-up period.
It is expected that there will be approximately 65 deaths at the time of 
final analysis. This would provide ~ 85% power to detect a 
HR of 0.45 for overall survival based on a log-rank test on a 2-sided 
alpha level of 0.03.
Interim Efficacy Analyses
Two formal interim efficacy analyses for PFS are planned. The first 
interim analysis will be performed when ~50% of the planned 129 events 
occur. The second interim will be performed when ~75% of the expected 
events occur. Type I error rate for testing PFS will be controlled by using 
the O’Brien-Fleming boundaries. Based on the planned number of PFS 
events (50% and 75%) for the 2 interim analyses, the 2-sided alpha for 
the interim and the final analyses are 0.003, 0.018, 0.044. The significant 
levels will be recalculated based on the actual observed number of events 
at the time of the interim and final analyses.
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP), 
including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
-HCG
Beta human chorionic gonadotropin
ABCG2
adenosine triphosphate-binding cassette sub-family G member 2 (see also BCRP)
ADCC
antibody-dependent cellular cytotoxicity
AE
adverse event
AKT
AKT (a serine/threonine protein kinase)
ALC
absolute lymphocyte count
ALL
acute lymphocytic leukemia
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
ATC
Anatomical-Therapeutic-Chemical classification system for drugs 
BCRP
breast cancer resistance protein (see also ABCG2)
BID
twice per day
BTK
Bruton tyrosine kinase
CAL-101
Former name for idelalisib
CCL
chemokine (C-C motif) ligand
CDC
complement-dependent cytotoxicity
CFR
Code of Federal Regulations
CI
confidence interval
CIRS
Cumulative Illness Rating Scale
CLL
chronic lymphocytic leukemia
cGMP
current Good Manufacturing Practice
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
CXCL
chemokine (C-X-C motif) ligand
CYP
cytochrome P450 enzyme
DLBCL
Diffuse large B-cell lymphoma
DLCO
diffusing capacity of the lung for carbon monoxide
DMC
data monitoring committee


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DNA
deoxyribonucleic acid
DOR
duration of response
DSPH
Gilead Sciences Department of Safety and Public Health
ECG
Electrocardiogram
eCCr
estimated creatinine clearance
eCRF
electronic case report form
EDC
electronic data capture
ELISA
enzyme-linked immunosorbent assay
EQ-5D
EuroQoL Five-Dimension utility measure
FACT-Leu
Functional Assessment of Cancer Therapy: Leukemia questionnaire
FCεRI
high-affinity IgE receptor
FDA
United States Food and Drug Administration
FDAMA
Food and Drug Modernization Act
FDG
fluorodeoxyglucose (18F)
FISH
fluorescence in-situ hybridization,
FSH
follicle-stimulating hormone
G-CSF
granulocyte colony-stimulating factor
GGT
gamma-glutamyltransferase
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
GM-CSF
granulocyte-macrophage colony-stimulating factor
HBc antibody
anti-hepatitis B core antibody
HbsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
hERG
human ether-à-go-go-related gene
HL
Hodgkin lymphoma
HIV
human immunodeficiency virus
HRQL
health-related quality of life
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
IEC
independent ethics committee
Ig
immunoglobulin (including subtypes A, E, G, and M)
IgHV
immunoglobulin heavy chain variable region
IND
Investigational New Drug (application)
iNHL
indolent non-Hodgkin lymphoma
INR
international normalized ratio
IRB
institutional review board
IRC
independent review committee


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ITT
intention to treat
IUD
intrauterine device
IWCLL
International Workshop on CLL
IWRS
interactive web response system
JAK
Janus kinase
K2-EDTA
potassium-ethylenediaminetetraacetic acid
LD
longest diameter
LDH
lactate dehydrogenase
LH-RH
luteinizing hormone-releasing hormone
LLN
lower limit of normal
LPD
longest perpendicular diameter
LVD
longest vertical dimension
MTD
maximum tolerated dose
MCL
mantle cell lymphoma
MDR
multi-drug resistance
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
mTOR
mammalian target of rapamycin
ND
no disease
NHL
non-Hodgkin lymphoma
OAT
occluded artery trial
OCT
organic cation transporter
ORR
overall response rate
OS
overall survival
pAKT
phosphorylated AKT
PCR
polymerase chain reaction
PD
progressive disease
PET
positron-emission tomography
Pgp
P-glycoprotein
PI3K
phosphatidylinositol 3-kinase
PI3K
phosphatidylinositol 3-kinase p110isoform
PJP
Pneumocystis jirovecii pneumonia
PFS
progression-free survival
PML
progressive multifocal leukoencephalopathy
PP
per protocol
PPD
product of the perpendicular diameters
PRO
patient-reported outcome
PR
partial response
PT
prothrombin time
PVA
polyvinyl alcohol


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QD
once per day
QT (interval)
measure of time between start of Q wave and end of T wave in electrical cycle of heart
RNA
ribonucleic acid
SAE
serious adverse event
SADR
serious adverse drug reaction
SD
stable disease
SJS 
stevens-johnson syndrome 
SPD
sum of the products of the perpendicular diameters of measured lymph nodes
SUSAR
suspected, unexpected, serious adverse reaction
SYK
spleen tyrosine kinase
t1/2
half-life
Tmax
time of maximum concentration
TEN
toxic epidermal necrolysis 
TTR
time to response
UGT
uridine 5'-diphospho-glucuronosyltransferase
ULN
upper limit of normal
WHODRUG
World Health Organization Drug Dictionary
ZAP=70
zeta-associated protein 70


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1.
INTRODUCTION
1.1.
Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia (CLL) is a neoplasia resulting from the progressive accumulation 
of functionally incompetent monoclonal B lymphocytes in blood, bone marrow, lymph nodes, 
spleen, and liver {Dighiero 2008}. CLL constitutes the most commonly occurring leukemia in 
Europe and the United States {Sant 2010, Surveillance Epidemiology and End Results (SEER) 
Program 2011}. While some patients never require treatment, many will need therapy for 
disfiguring or obstructing lymphadenopathy, debilitating constitutional B symptoms (fevers, 
night sweats, fatigue, weight loss) {Redaelli 2004}, or recurrent cytopenias and infections 
{Keating 2002b, Perkins 2002}. CLL is largely a disease of the elderly; at diagnosis, 70% of 
patients are 65 years of age and the median age is 72 years {Surveillance Epidemiology and 
End Results (SEER) Program 2011}.
In patients with treatment-naïve CLL, chemotherapy or chemoimmunotherapy are commonly 
employed to control disease manifestations {Gribben 2011}. Such therapies typically contain 
some combination of a purine analog, an alkylating agent, and the anti-CD20 monoclonal 
antibody, rituximab, and can be effective in providing durable remissions {Byrd 2005, Hallek 
2010, Knauf 2009, Robak 2010}, particularly when administered in fit patients. However, these 
treatments are not curative; the disease will eventually relapse and further intervention is 
required to obtain and maintain tumor control. If the interval from prior therapy has been long 
(24-36 months), retreatment with the previous regimen is advocated {Eichhorst 2010, Zelenetz 
2011}. However, if the interval from prior therapy has been shorter (<24 months), it is presumed 
that resistance to the previously administered cytotoxic agent is likely and that a change in 
therapy is warranted.
Among alternative treatments considered for such patients is alemtuzumab, a humanized 
IgG1γ monoclonal antibody directed against the CD52 antigen that is expressed on the cell 
surface of both B and T cells. The drug was initially approved as therapy for patients with 
previously treated CLL after failure of fludarabine-based treatment. However, alemtuzumab 
showed only modest activity in the pivotal study; the overall response rate (ORR) was 33% and 
the median progression-free survival (PFS) was 4.7 months {Keating 2002a}. In addition, the 
drug proved highly immunosuppressive, leading to frequent opportunistic infections.
A new alternative is ofatumumab, an IgG1κ, fully humanized CD20 monoclonal antibody that 
targets B cells. Ofatumumab binds to an epitope on CD20 that is distinct from the epitope 
recognized by rituximab and is closer to the cell membrane {Teeling 2006}. Its 
antibody-dependent cellular cytotoxicity (ADCC) has been reported to be similar to that of 
rituximab {Li 2009}, but ofatumumab delivers stronger complement-dependent cytotoxicity 
(CDC) in in vitro models, including malignant B cells lines with low CD20 expression levels and 
fresh CLL cells that are considered relatively resistant to rituximab {Li 2009, Pawluczkowycz 
2009, Teeling 2004}. Ofatumumab also binding exhibits a slower off-rate than rituximab 
{Teeling 2004}.


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Ofatumumab has recently received approval in Europe and in the United States for the treatment 
of patients with previously treated CLL {Gravanis 2010, Lemery 2010, Wierda 2010}. In the 
pivotal Phase 2 trial, all patients received 8 weekly infusions of ofatumumab followed by 
4 monthly infusions during a 24-week period; the dose of the initial infusion was 300 mg and the 
dose of the remaining 11 infusions was 2,000 mg. The primary efficacy population comprised 
59 patients with CLL refractory to fludarabine and alemtuzumab. Also accrued was a population 
of 79 patients who had fludarabine-refractory disease and bulky lymphadenopathy 
(ie, 1 nodal mass > 5 cm in diameter). The overall response rates were 58% and 47% and the 
median PFS values were 5.7 months and 5.9 months for the 2 groups. Median neutrophil counts 
were stable during treatment and improvements in thrombocytopenia and anemia were observed. 
The most frequent adverse events were infusion reactions and infections. Infusion reactions were 
common during the first 2 doses, typically subsiding with subsequent drug administrations. The 
rates of infection were consistent with historical data {Perkins 2002, Tam 2007} when 
considering the extent of CLL, the amount of prior therapy, and the level of pre-existing 
immunosuppression among the study participants.
The 2000-mg dose selected for the Phase 2 study was based on data indicating that the mass of 
CLL tumor affected the clearance of the drug, with high elimination rates in patients with bulky 
lymphadenopathy {Coiffier 2008, Coiffier 2010}. The data suggested that the 2000-mg dose 
offered necessary target coverage in patients with high-volume CLL. In patients with lower 
tumor burden, drug concentrations were better maintained. The data supported use of lower 
ofatumumab doses in patients receiving concomitant therapy that could reduce tumor volume. 
Nonclinical data have indicated that exposure values consistent with a 1000-mg clinical dose are 
sufficient to provide saturation of the CD20 target {Bleeker 2008}. Based on these collective 
data, current trials for patients with previously treated CLL use a 1000-mg dose of ofatumumab 
when giving the drug as a component of combination therapy.
Ofatumumab offers an active, non-myelotoxic option for patients with recurrent CLL, 
particularly when the disease requires intervention with a new mechanism of action. However, 
while treatment with single-agent ofatumumab offers benefit, tumor response is not universal 
and the duration of PFS is often limited. Moreover, the large amounts of protein necessary for 
single-agent ofatumumab treatment result in frequent infusion reactions and cumbersome 
infusion schedules. Combining ofatumumab with other therapies may generate better efficacy 
while allowing for reductions in ofatumumab dose that may minimize infusion reactions and 
avoid protracted infusion times. Novel, non-myelosuppressive, well-tolerated, and convenient 
therapies are needed that can be successfully combined with ofatumumab to achieve these goals.
1.2.
Phosphatidylinositol 3-Kinase in Lymphoid Malignancies
Phosphatidylinositol 3-kinases (PI3Ks) are enzymes that regulate several cellular functions 
including motility, proliferation, and survival {Okkenhaug 2003b}. PI3K activation recruits and 
activates numerous intracellular signaling enzymes. The most important of these is the 
serine/threonine kinase, AKT, which mediates a positive pleiotropic effect on cell survival, 
proliferation, growth, and metabolism {Engelman 2006} acting by signaling through mammalian 
target of rapamycin (mTOR) {Hay 2005, Osaki 2004}.


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PI3K signaling is mediated by 4 catalytic isoforms of the p110 subunit of the 
enzyme - , , , and . While potentially important in multiple cell types, PI3K p110(PI3K)
shows an expression pattern that is particularly prominent in 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, the B-lymphocyte population in these animals shows a decrease in maturation, 
diminished receptor-induced proliferation, and increased susceptibility to apoptotic cell death.
Conversely, mice with aberrantly elevated PI3K signaling develop lymphadenopathy and have 
an increased incidence of lymphoma {Donahue 2004}. In CLL, sustained activation of the 
PI3K/AKT pathway has been shown to promote malignant B-cell survival through mechanisms 
that are dependent on the PI3Kisoform {Cuni 2004, Herman 2010, Lannutti 2011}.
Knowledge of the critical importance of PI3Kδ in B-cell biology and neoplasia has encouraged a 
search for inhibitors of this enzyme that could provide new options in the therapy of 
lymphoid malignancies, including CLL.
1.3.
Idelalisib
1.3.1.
General Information
Idelalisib was approved by the US FDA on July 23, 2014 and in the European Union on 
September 18, 2014. Refer to local labeling for the approved indication statements.
Gilead Sciences, Inc. has developed novel drugs that can suppress tumor growth through 
targeting of PI3Kδ activity. High-throughput screening was the basis for the discovery of novel 
agents that selectively inhibit PI3Kfunction but spare other PI3K isoforms and other kinases. 
Chemical optimization, pharmacological characterization, and toxicological evaluation have led 
to identification of idelalisib (also known as GS-1101), a 415-dalton, orally bioavailable, 
new chemical entity with potential clinical utility in the treatment of cancers.
In primary tumor samples and in cell lines derived from patients with CLL, 
indolent non-Hodgkin lymphoma (iNHL), mantle cell lymphoma (MCL), B-cell 
acute lymphocytic leukemia (ALL), or Hodgkin lymphoma (HL), idelalisib induces 
dose-dependent reductions in AKT phosphorylation {Herman 2010, Lannutti 2011, Meadows 
2010}. In addition, idelalisib disrupts the PI3Kactivation and supportive intercellular signaling 
observed when CLL or HL cells are cocultured with stromal cells {Hoellenriegel 2011, 
Meadows 2010}. These effects have therapeutic consequences. In multiple lymphoid primary 
tumors and malignant cell lines, idelalisib enhances apoptosis and concentration-dependent cell 
killing when applied as a single agent and increases the therapeutic efficacy of other 
antineoplastic agents when given in combination {Hoellenriegel 2011, Meadows 2011}. In 
preclinical systems, coadministration of idelalisib with a therapeutic antibody 
eg, rituximab, alemtuzumab) has not impaired antibody-mediated activity {Herman 2010}.


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1.3.2.
Safety Pharmacology
In vitro and in vivo safety pharmacology studies with idelalisib have demonstrated a favorable 
non-clinical safety profile. These studies indicate that the drug may minimally slow bone marrow 
progenitor proliferation and differentiation and that it has expected inhibitory effects on B-cell
response to antigen challenge. However, the data indicate 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.
1.3.3.
Nonclinical Pharmacology and 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 
transporers (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, 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. However, in humans GS-563117 plasma 


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levels significantly 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 not a substrate for the renal transporters OCT2, OAT1, and OAT3 or the hepatic 
uptake transporters OATP1B1 and OATP1B3.  GS-563117 is 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 competitive 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).
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 [messenger RNA (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.
Potential clinical implications of these metabolism studies have been evaluated in a formal 
drug-drug interaction study (GS-US-313-0130) which examined the effect of idelalisib on 
cytochrome P450 3A and the drug transporters P-gp, OATP1B1, and OATP1B3. 
Study GS-US-313-0130 also evaluated the impact of an inducer of metabolizing enzymes and 
transporters (rifampin) on the PK of idelalisib in healthy human subjects. Findings from this 
study are presented in Section 1.3.5.1.
1.3.4.
Toxicology
The toxicological profile of idelalisib was well characterized through the conduct of single dose, 
repeat dose, developmental and reproductive, and genetic toxicology and local tolerance studies. 
The primary target organ toxicities following repeated dosing include the lymphoid, hepatic, 
male reproductive systems in rats and dogs, and gastrointestinal system in dogs. Adverse effects 
in the lymphoid system were primarily the result of on target pharmacology resulting in 
decreased lymphocytes in multiple lymphoid organs, primarily involving B-cell regions. Liver 
effects were transient and reversible with continued dosing and did not result in chronic liver 


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injury. Reduction in sperm numbers in males were reversible and did not impact fertility or 
reproductive performance. Gastrointestinal effects in dogs were minor, superficial, and 
considered secondary to effects on lymphocytes in Peyer’s Patches. Idelalisib was shown to be 
teratogenic and associated with embryo-fetal lethality. Effects on the reproductive system have 
been reported for inhibitors which target other isoforms of PI3K. The dose-dependence and 
potential of idelalisib to selectively inhibit additional PI3K isoforms may be responsible for thie 
off-target toxicity. Additionally, the drug may have the potential to produce phototoxic reactions 
in humans. These findings represent toxicities that can be monitored, are considered clinically 
manageable, or are considered acceptable risks in the intended patient population.
Further details on the toxicology of idelalisib can be found in the idelalisib 
Investigator’s Brochure (IB).
1.3.5.
Idelalisib Clinical Studies
1.3.5.1.
Phase 1 Studies in Healthy Subjects and in Patients with Allergic Rhinitis
Three studies in healthy subjects (Studies 101-01, 101-04, and 101-05) have provided 
information regarding drug safety, pharmacokinetics, food effects, and the potential for drug 
interactions with CYP3A4 inhibitors {Webb 2010}. One of these trials also included a 
preliminary evaluation of absorption, metabolism and excretion in healthy volunteers; in this 
trial, unlabeled idelalisib was co-administered with a trace amount of [14C]idelalisib given either 
orally or intravenously and biological samples were assessed by accelerator mass spectrometry.
Safety results from these studies indicated that idelalisib was well tolerated when administered to 
healthy subjects at single doses through 400 mg (the highest dose level tested) and was also 
generally well tolerated when administered to healthy subjects over 7 days at dose levels through 
200 mg BID (the highest dose level tested). Dosing with 200 mg BID for 7 days resulted in a 
skin rash in 3 out of 6 subjects; histological findings were consistent with a delayed-type 
hypersensitivity maculopapular exanthema. Rashes have sometimes occurred in patients with 
hematological malignancies receivingidelalisib, but have not typically proved dose- or 
treatment-limiting.
Repeated ECG evaluations performed in tandem with pharmacokinetic monitoring showed no 
evidence of drug-, dose-, or exposure-dependent effects on cardiac rhythm or cardiac intervals 
(eg, QT interval).
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 across the dose range were 6.5 to 9.8 hours.
Idelalisib dosing after a high-fat, high-calorie meal delayed median time of maximum 
concentration (Tmax) from 0.75 to 3 hours; mean Cmax was unaffected and mean AUC was 
~40% higher. These changes in idelalisib exposures are considered modest/clinically 
non-relevant; thus, idelalisib may be given with or without food.


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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 daily 
dosing with ketoconazole (a potent inhibitor of CYP3A4), modest/moderate increases in mean 
idelalisib Cmax and AUC values of ~30% and ~80%-higher, 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.
The 14C-labeled idelalisib human mass balance results showed that the drug has 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 competitive 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.
Pharmacodynamic results showed that an idelalisib dose of 200 mg inhibited ex vivo basophil 
activation via the PI3K-specific, high-affinity immunoglobulin (Ig)E receptor (anti-FCR1) in
basophils collected from healthy volunteers.
The findings were confirmed when the drug was assessed over 7 days in a Phase 1b study in 
subjects with allergic rhinitis. In this study, idelalisib at a dose level of 100 mg BID showed 
clinical and pharmacodynamic activity (attenuating adverse responses to allergenic challenge and 
decreasing markers of inflammation) and was well tolerated.
1.3.5.2.
Phase 1 Studies in Patients with Hematological Malignancies
1.3.5.2.1.
Phase 1 Monotherapy Study in Patients with Hematological Malignancies
A Phase 1 dose-ranging study (Study 101-02) of single-agent idelalisib 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 {Brown 2011, Coutre 2011, Kahl 2011}. In this study, idelalisib was 
administered in cohorts of subjects across a range of dose levels from 50 mg BID to 350 mg 
BID. Idelalisib administration was continued as long as individual subjects were safely 
benefitting from therapy. Subjects were evaluated in 4-week cycles; response and progression 
assessments were based on standard criteria {Hallek 2008}.


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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 
idelalisib 150 mg BID in 28 day cycles (21 days on idelalisib/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%); 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, pneumonia and diarrhea were notable. Pneumonia was observed in 
23 (12%) subjects, primarily in subjects with CLL. In most instances, these findings were 
considered 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 (5.8%). Other 
Grade ≥3 events 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 have included neutropenia, n=46 (24%); 
thrombocytopenia, n=27 (14%), anemia, n=14 (7.3%), and lymphopenia, n=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 between 2 to 16 weeks after idelalisib initiation and resolution was usually 
seen 2 to 6 weeks after idelalisib interruption. After resolution of ALT/AST increases, 
14 subjects were rechallenged at the same or a reduced dose of idelalisib and 9 (64%) of these 
subjects were able to resume treatment without recurrence of transaminase elevations. 
Two (1.0%) subjects had ≥ 2 x ULN elevations in bilirubin in the context of Grade ≥3 elevated 
AST/ALT, both of whom had confounding factors (recent history of biliary obstruction or 
concomitant use of potentially hepatotoxic medications) so that a definitive 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 


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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 has not been reached in 
subjects with iNHL; 19 subjects continued to receive idelalisb in a long-term extension study. 
The median [range] DOR was 2.7 months [1 month to 8 months] in subjects with MCL; 
6 MCL subjects continued 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 in 
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 (72%) subjects 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.
1.3.5.2.2.
Phase 1 Combination Study in Patients with Hematological Malignancies
A separate Phase 1 trial (Study 101-07) has evaluated the safety and preliminary activity of 
idelalisib given in combination with ofatumumab to subjects with recurrent CLL {Barrientos 
2012, Furman 2012}.
In this study, idelalisib (150 mg BID) was co-administered with a total of 12 infusions of 
ofatumumab given over 24 weeks (300-mg initial dose followed 1 week later by 1,000 mg 
weekly for 7 doses, followed 4 weeks later by 1,000 mg every 4 weeks for 4 doses). Thereafter, 
subjects continued to receive single-agent idelalisib as long as the subject was safely benefiting 
from therapy. Subjects were evaluated in 4-week cycles; response and progression assessments 
were based on standard criteria {Hallek 2008}.
At the time of the data analysis, accrual of the cohorts was complete with 21 subjects enrolled 
and evaluable. Median [range] age was 66 [43-79] years. The majority (14/21; 67%) of patients 
had bulky adenopathy (1 lymph node 5 cm in diameter). The median [range] number of prior 
therapies was 3 [1-6], including prior exposure to alkylating agents (18/21; 86%), 
rituximab (20/21; 95%), purine analogs (16/21; 76%), alemtuzumab (4/21; 19%), and/or 
ofatumumab (3/21; 14%). The median [range] idelalisib treatment duration was 
36+ [0-48+] week.
No idelalisib-related dose-limiting toxicities were observed within the tested subject cohorts. 
Ofatumumab infusion reactions were manageable. One patient developed corticosteroid-related 
hyperglycemia and sepsis. No clinically significant myelosuppression was observed.


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Almost all subjects (17/21, 84%) experienced marked and rapid reductions in lymphadenopathy 
within the first 2 cycles. The lymphocyte mobilization that is expected with PI3Kinhibition 
was significantly reduced in magnitude and duration and persisted past Cycle 1 in only 1 patient. 
The ORR was 16/21 (76%) with 2/21 (10%) subjects showing evidence of complete response 
(CR), as reported by the investigators. Elevated baseline levels of CCL3, CCL4, CXCL13, and 
TNFwere significantly reduced after 28 days of treatment. At the time of the data analysis, 
overall PFS through 48 weeks was >75% and a median PFS had not yet been observed.
Collectively, the emerging data from this study support further evaluation of idelalisib together 
with ofatumumab in subjects with CLL and indicate that co-administration of idelalisib with 
ofatumumab is tolerable when using idelalisib at full dose, ie, at a starting dose level of 
150 mg BID.
For additional or updated information, please refer to the current version of the IB.
1.4.
Summary and Justification for the Current Study
Gilead Sciences is conducting this Phase 3 study to evaluate the efficacy and safety of adding 
idelalisib to ofatumumab in patients with previously treated, recurrent CLL.
The design and conduct of this study is supported by knowledge of the demographics of patients 
with CLL, the natural history and current therapies for the disease, and the nonclinical and 
clinical information regarding idelalisib and oftamumub. The collective data support the 
following conclusions:

CLL is a serious, disabling, and potentially life-threatening disorder that requires sequential 
treatment with agents that provide alternative mechanisms of tumor control. Single-agent 
ofatumumab can offer disease palliation with good tolerability in some patients with relapsed 
CLL but tumor control is not lasting. Development of a non-cytotoxic combination therapy 
of idelalisib with ofatumumab that can address disease pathogenesis with a new mechanism 
of action and might offer complementary nodal and peripheral blood activity would address 
an unmet medical need.

PI3Kδ over-expression plays an important role in CLL biology. Further evaluation of 
idelalisib as a potential treatment for CLL has sound scientific rationale founded on 
knowledge of the actions of the drug to selectively abrogate PI3Kδ activity and to inhibit 
malignant cell growth and stromal cell signaling in nonclinical models of CLL. These data 
are supported by clinical documentation of idelalisib inhibition of PI3Kδ signaling in patients 
with CLL.

The potential for clinical efficacy of idelalisibplus ofatumumab in patients with relapsed or 
refractory CLL is supported by the observed antitumor activity of idelalisib given alone or in 
combination with ofatumumab or other anti-CD20 antibodies in patients with heavily 
pretreated CLL.


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
The safety of advancing development of the regimen of idelalisib plus ofatumumab in this 
Phase 3 study is well supported by safety pharmacology and toxicology studies and by 
Phase 1 single-agent and combination safety data obtained in healthy volunteers and in 
subjects with lymphoid cancers.

Dose-safety, dose-exposure, and dose-activity relationships identified in Phase 1 studies
support the dosing regimen and dose modification provisions in this study.

Observations relating to patterns of CLL response among subjects receiving idelalisib alone 
or in combination with ofatumumab in Phase 1 trials provide the foundation for efficacy
monitoring in this trial. Of particular note is that idelalisib mobilizes CLL cells from tissues 
into the peripheral blood. This characteristic pharmacological action is prominent early in 
therapy but can persist over time and should not be confused with disease progression in 
patients who have persistent control of other CLL-related signs and symptoms. For this 
reason, in this Phase 3 study, subjects will be continued on therapy until the occurrence of 
definitive disease progression, ie, disease progression that is manifest by worsening 
CLL-related signs or symptoms other than lymphocytosis alone.

Thorough nonclinical and clinical characterization of the type, severity, manifestations, and 
expected timing of adverse events establish the safety monitoring plan in this trial.

The scientific correlative work performed in prior preclinical and clinical studies provides 
strong scientific underpinnings for the companion laboratory studies to be performed as a 
component of this clinical trial.

Given the seriousness of previously treated CLL and the aggregate potential benefits 
considered in the context of potential risks, further development of idelalisib together with 
ofatumumab in this Phase 3 clinical trial is justified.
The rationale for specific design features is provided in relevant sections of the protocol, 
including Section 3.5 (Endpoint Selection Rationale), Section 2.2 (Design Rationale), 
Section 4.3 (Enrollment Criteria Rationale), Section 5.10 (Study Treatment Rationale), and 
Section 6.5 (Study Procedure Rationale).


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2.
STUDY DESIGN
2.1.
Design Overview and Study Schema
This study is being conducted as part of an overall clinical program that is evaluating the efficacy 
and safety of idelalisib in the therapy of patients with previously treated CLL 
Study GS-US-312-0119 is a Phase 3, multicenter, 2-arm, randomized, controlled, parallel-group,
clinical trial (see Figure 2-1) that will be conducted internationally.
Figure 2-1.
Study Design
The target population comprises adults with previously treated CLL who have measurable 
lymphadenopathy, require treatment for CLL, have disease that is not refractory to ofatumumab, 
and might benefit from a change in therapy because they have experienced CLL progression 
< 24 months since the completion of the last prior treatment.
Subjects will be stratified based on 17p deletion and/or a TP53 mutation status 
(either vs neither), immunoglobulin heavy chain variable region (IgHV) mutation status 
(unmutated vs mutated), and disease status (refractory vs relapsed), and randomized in a 2:1 ratio 
to receive either idelalisib/ofatumumab combination therapy or ofatumumab single-agent 
therapy.
Subjects receiving combination therapy in Arm A will take idelalisib orally, BID continuously.
All subjects will also receive 12 ofatumumab infusions. Ofatumumab will be administered 
intravenously in the clinic starting at a dose of 300 mg on Day 1 (Week 1) (Arms A and B) and 
will continue with a dose of either 1,000 mg (Arm A) or 2,000 mg (Arm B) on Day 8 (Week 2), 


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Day 15 (Week 3), Day 22 (Week 4), Day 29 (Week 5), Day 36 (Week 6), Day 43 (Week 7), 
Day 50 (Week 8) followed 4 weeks later by 1,000 mg (Arm A) or 2,000 mg (Arm B) given every 
4 weeks for 4 doses on Day 78 (Week 12), Day 106 (Week 16), Day 134 (Week 20), and 
Day 162 (Week 24).
Subjects in Arm A will continue whichever study drug (idelalisib or ofatumumab) continues to 
be tolerated, even if the other drug has been discontinued due to toxicity.
Following permanent discontinuation of study drug(s), subjects shall remain on study until 
definitive progression of CLL or withdrawal from the study for reasons specified in Section 5.8.
The primary objective of Study GS-US-312-0119 will be to evaluate the effect of the addition of 
idelalisib to ofatumumab on PFS. Secondary objectives will focus on determining the effect of 
the addition of idelalisib to ofatumumab on the onset, magnitude, and duration of tumor control; 
overall survival (OS); health-related quality of life (HRQL); changes in subject performance 
status; disease-associated biomarkers and potential mechanisms of resistance; treatment 
administration; safety; and health resource utilization.
2.2.
Design Rationale
The randomized, add-on design is customary in the comparative evaluation of new therapies for 
cancer. While this design provides idelalisib efficacy and safety information only in the context 
of administration of a companion antineoplastic agent, it is appropriate because it documents the 
incremental benefit and toxicity of the investigational therapy in the context of a controlled 
clinical trial while ensuring that all participants receive potentially active treatment.
Randomization is an accepted means to reduce bias and allows for the highest standard of 
evidence in documenting a treatment effect. A centralized, standard block randomization should 
be sufficient to preclude site personnel from making inferences regarding future treatment 
assignments based on existing treatment assignments. A 2:1 randomization is planned in order to 
generate a larger safety database with the idelalisib combination and to enhance study accrual.
The randomization process will be established and performed through an 
interactive web response system (IWRS); the intent is to maximize the integrity and security of 
the randomization and ensure appropriate access and convenience-of-use by the investigational 
sites.
Stratification will be used to balance allocation by potentially important parameters. The selected 
stratification factors are those that are likely to have a substantial influence on prognosis based 
on historical information regarding the therapy of CLL {Cramer 2011, Gonzalez 2011}, 
considering published data regarding use of ofatumumab in patients with CLL {Wierda 2010}, 
or based on information derived from the Phase 1 experience involving the idelalisib treatment of 
CLL {Coutre 2011}. Available data suggest that each of the selected stratification factors may 
divide the population relatively evenly, with > 30% of the subjects having one or the other levels 
of each of the strata. Further stratification factors could be considered, but it is problematic to 
overstratify a trial of this size given the potential loss of statistical power associated with 
expenditure of further degrees of freedom in the analysis.


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The differences in ofatumumab doses between the arms of the study are considered acceptable 
because less ofatumumab is being administered in the investigational combination arm (Arm A) 
than is being administered in the control single-agent arm (Arm B). If the treatment effect is 
better in Arm A than in Arm B despite this difference, the results will provide particularly 
convincing testament to the merits of the idelalisib/ofatumumab combination.
Because of the difference in ofatumumab doses between the arms, both idelalisib and 
ofatumumab placebos would be required to blind the study. Centralized blinding is not possible 
because an ofatumumab placebo is not available. Attempting to blind the trial at the level of the 
pharmacist or nurse would be procedurally insufficient for maintaining the ofatumumab blind. In 
addition, there would be a high likelihood of breaking the blind due to expected differences in 
infusion times between the arms. In view of these constraints, the investigational site and sponsor 
study teams will have knowledge of the treatment assignments for individual subjects. However, 
several steps will be taken to minimize potential bias:

Investigational sites will not be presented with any summary data or analyses during the 
course of the study.

Efficacy results will be subjected to review by an independent review committee (IRC) that 
will be blinded as to treatment arm (see Section 10.4.2).

An independent data monitoring committee (DMC) will be established to review 
accumulating study results in closed data review sessions and provide recommendations 
regarding study conduct.


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3.
OBJECTIVES AND ENDPOINTS
3.1.
Primary Objective

To evaluate the effect of the addition of idelalisib to ofatumumab on progression-free 
survival (PFS) in subjects with previously treated chronic lymphocytic leukemia (CLL)
3.2.
Secondary Objectives

To evaluate the effect of the addition of idelalisib to ofatumumab on the onset, magnitude, 
and duration of tumor control for subjects with 17p deletion and/or TP53 mutation

To evaluate the effect of the addition of idelalisib to ofatumumab on the onset, magnitude, 
and duration of tumor control for subjects with 17p deletion and/or TP53 mutation

To assess the effect of the addition of idelalisib to ofatumumab on measures of subject 
well-being, including overall survival (OS), health-related quality of life (HRQL) and 
performance status

To assess the effects of the addition of idelalisib to ofatumumab on disease-associated 
biomarkers and to evaluate potential mechanisms of resistance to GS-1101

To characterize the effect of ofatumumab on idelalisib exposure through the evaluation of 
idelalisib plasma concentrations over time

To describe the safety profile observed with the addition of idelalisib to ofatumumab

To estimate health resource utilization associated with the addition of idelalisib to 
ofatumumab
3.3.
Primary Endpoint

Progression-free survival (PFS) – defined as the interval from randomization to the earlier of 
the first documentation of definitive disease progression or death from any cause; 
definitive disease progression is CLL progression based on standard criteria, other than 
lymphocytosis alone
3.4.
Secondary and Exploratory Endpoints
The following secondary and exploratory endpoints will be defined and analyzed in this study.
Five endpoints are designated as secondary endpoints for which sequential testing will be 
performed to control Type I error rate (see Section 9.4.1.6). Secondary endpoints will be ORR, 
lymphadenopathy response rate, OS, PFS in the subgroup of subjects with 17p deletion and/or 
TP53 mutation, and CR rate. All other endpoints will be considered exploratory.


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3.4.1.
Tumor Control

Overall response rate (ORR) – defined as the proportion of subjects who achieve a 
complete response (CR) or partial response (PR) and maintain their response for at least 
8 weeks

Lymph node response rate – defined as the proportion of subjects who achieve a 
50% decrease from baseline in the SPD of index lymph nodes

CR rate – defined as the proportion of subjects who achieve a CR
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3.4.2.
Patient Well-Being

Overall survival (OS) – defined as the interval from randomization to death from any cause
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.4.3.
Pharmacodynamic Markers of Drug Activity and Resistance
 
3.4.4.
Exposure
 
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3.4.5.
Safety
 
 
3.4.6.
Pharmacoeconomics
 
 
 
3.5.
Endpoint Selection Rationale
The proposed endpoints have been chosen based on relevance to the pathophysiology and 
clinical manifestations of CLL, the known pharmacology ofidelalisib, and the goals of the study 
in documenting idelalisib benefit-to-risk ratio. These types of endpoints have been employed in 
prior studies in CLL and can be evaluated with acceptable reliability and accuracy.
3.5.1.
Tumor Control Endpoints
Assessments of the magnitude and duration of changes in tumor size are routinely employed in 
registration-directed oncology clinical studies to determine therapeutic effect. Unlike OS, these 
endpoints directly assess the ability of the drug to control the malignancy. Such assessments are 
also integral to treatment decisions; because subjects are being treated until disease progression, 
repeated tumor assessment must be performed in order to define the proper duration of treatment 
for each study participant. Standard response and progression criteria have been established by 
the International Workshop on CLL (IWCLL) {Hallek 2008}; the assessments of treatment 
effects in this study will be based on these criteria, taking into account the specific pharmacology 
ofidelalisib.
In CLL, disease-related nodal enlargement is a major cause of patient discomfort and can cause 
organ dysfunction {Dighiero 2008}. Extensive lymphadenopathy constitutes a reason to treat 
CLL and controlling the size of pathologically enlarged lymph nodes is an important therapeutic 
goal for improving patient well-being and relieving obstructive symptoms {Hallek 2008}. 
Given that the natural history of recurrent CLL is inexorable nodal growth, enhancing tumor 
shrinkage and prolonging tumor control provides strong evidence of pharmacological activity. 
In assessing PFS as the primary outcome measure, this study builds on a past precedent 
in randomized, pivotal trials supporting the approval of rituximab or bendamustine in CLL 
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{Hallek 2010, Knauf 2009, Robak 2010}. PFS offers a well-established primary outcome 
measure that directly measures treatment effect, conveys important longitudinal information 
regarding tumor control, can be characterized in all subjects using intent-to-treat (ITT) 
principles, and is readily analyzed using statistical methods such as Kaplan-Meier techniques, 
log-rank tests, and Cox regression models.
Other endpoints of overall tumor control as evaluated in this trial are customarily assessed and 
reported in studies of new therapies in patients with cancer. In CLL, ORR provides an integrated 
assessment of the magnitude and extent of changes in lymphadenopathy, organomegaly, 
bone marrow infiltration, and bone marrow function that conveniently categorizes and describes 
treatment effects. TTR and DOR are important in characterizing the rapidity of achieving tumor 
shrinkage and the duration of tumor control.
Beyond providing descriptions on overall response assessment using ORR, this protocol will also 
seek to characterize the individual components of response that are important in assessment of 
CLL {Hallek 2008}. Thus, changes in lymph node area and in the proportion of subjects having 
a lymph node response will be analyzed. In addition, among subjects who enter the study with 
splenomegaly or hepatomegaly, the proportion who achieve substantial (50%) reductions in 
spleen or liver size will be assessed. Similarly, the proportions of subjects who experience 
improvements in ALC, platelets, hemoglobin, and neutrophil counts will be characterized in 
order to provide specific insight into the degree to which therapy alters these individual 
parameters.
Because idelalisib mobilizes CLL cells from tissues into the peripheral blood as part of its 
pharmacological effect, there is a risk of falsely declaring a subject to have experienced disease 
progression if lymphocyte count is considered as the sole basis for potential CLL worsening. To 
account for this potential problem, changes in lymphocyte count will not be considered in 
determining whether a subject has progressive disease, ie, subjects will only be declared to have 
progressive CLL if they meet any of the IWCLL criteria for progressive disease other than 
lymphocytosis alone. Thus, subjects with worsening lymphadenopathy, organomegaly, bone 
marrow involvement, progressive cytopenias, appearance of new disease, or transformation to a 
more aggressive lymphoid malignancy histology (eg, Richter syndrome) will be considered to 
have progressed. Subjects with lymphocytosis without any of these other events will not be 
considered to have progressed. Given that lymphocytosis has no prognostic significance in 
patients with relapsed/refractory disease {Silverman 2002, Tsimberidou 2007} and is not 
generally considered a reason to treat in patients with CLL {Eichhorst 2010, Hallek 2008, 
Zelenetz 2011}, this approach does not jeopardize subject safety or subsequent therapy. 
Furthermore, it will allow complete collection of all response and progression data 
(both considering lymphocytosis and ignoring lymphocytosis) with the intent of providing 
complete information for regulatory authority review.
The current IWCLL guidelines indicate that physical examination is generally sufficient to 
evaluate nodal response and progression in patients with CLL {Hallek 2008} but that 
radiographic assessments may be appropriate in clinical trials. Computed tomography (CT) is 
considered the preferred imaging method unless patients have contraindications that require use 
of magnetic resonance imaging (MRI). Given the low fluorodeoxyglucose (FDG) avidity of 


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CLL, positron emission tomography (PET) does not have a role in evaluation of this disease. The 
incremental benefits of using radiographic imaging is limited in patients undergoing long-term
follow-up following first-line therapy {Blum 2007, Eichhorst 2011}. However, in the patients 
with advanced CLL and bulky adenopathy such as those who will be enrolled to this trial, it is 
known that CT scans commonly detect bulky intra-abdominal lymphadenopathy and 
splenomegaly that would be missed by palpation alone and that the presence of large-volume, 
intra-abdominal disease of the nodes and spleen is associated with a poor prognosis {Norin 
2010}. Thus, while use of CT confers greater radiation exposure, subjects have the chance to 
benefit from radiographic imaging because it will offer more accurate information regarding 
their response to protocol therapy and the appropriate duration of protocol treatment. Having this 
information is particularly important in this trial because PI3Kinhibition precludes use of 
lymphocyte counts as evidence for disease progression. Based on published data {Keating 
2002a, Wierda 2010}, median OS for patients with comparably advanced CLL is < 18 months, 
so the long-term secondary malignancy risk from CT-related radiation exposure is very low. 
Finally, in the context of a registration-directed pivotal trial of a new drug with a new 
mechanism of action, radiographic imaging is critically important to provide reassurance 
regarding subject safety and trial validity. In this regard, CT evaluations of the lung can be used 
retrospectively to compare the treatment arms for radiographic evidence of drug-induced lung
changes {Maroto 2011, White 2010}. Furthermore, CT measurements have greater accuracy and 
reproducibility than palpation, are subject to independent expert review, and can be audited 
against electronic case report form (eCRF) information.
The timing of radiographic tumor assessments has been carefully considered. Among subjects 
receiving idelalisib in Phase 1b/2 studies who experienced a nodal response (≥50% regression in 
tumor area), such responses were observed with the first 16 weeks of therapy {Coutre 2011, 
Sharman 2011}; the planned timing of tumor assessments (at Weeks 8, 16, 24, 36, and 48 and 
every 12 weeks thereafter) in this study fits with this known timing of changes in lymph node 
size during idelalisib therapy. Scans at 8-week intervals during the first 24 weeks allow initial 
documentation of response (at Week 8 or 16) and follow-up confirmation of response 8 weeks 
later (at Week 16 or 24) consistent with current response criteria {Hallek 2008}. During this 
period, early documentation of disease progression allows subjects who are not benefiting from 
Study GS-US-312-0119 therapy to move rapidly to alternative treatments. After 24 weeks on 
study, the reduction in the frequency of CT scans (to 12-week intervals) reduces the overall 
protocol burden for subjects while still allowing detection of the incremental ≥6-month 
improvement in PFS (from a median of 8 months to 14 months) that is targeted in this 
comparative trial. As outlined in Section 7.2, iodine-containing or gadolinium contrast material 
may be omitted in subjects for whom use of a contrast agent would be medically contraindicated.
3.5.2.
Measures of Patient Well-Being
3.5.2.1.
Overall Survival
While OS provides an ultimate measure of patient well-being, it has not routinely been used as 
the primary endpoint in CLL clinical trials. Unlike PFS, it does not specifically measure 
drug-mediated tumor control, and thus provides only an indirect assessment of treatment effect. 
Depending upon the treatment setting, long OS times in patients with CLL can preclude use of 


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this endpoint as an efficient method for understanding drug benefits. In both the front-line and 
recurrent disease settings, post-study treatments can influence OS in unpredictable ways, 
potentially confounding differences between treatment groups.
However, given the life-threatening nature of systemic malignancy, documentation of OS is 
customary in oncology therapeutic clinical trials, including those evaluating subjects with 
recurrent CLL {Keating 2002a, Wierda 2010}. Evaluation of OS in this study has the potential to 
ensure that no unexpected, early adverse effect on the likelihood of death occurs as a 
consequence of the addition of idelalisib to ofatumumab in the Phase 3 trial.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3.5.3.
Pharmacodynamic Markers of Drug Activity and Resistance
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3.5.4.
Assessments of Exposure
 
 
 
 
 
 
 
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3.5.5.
Evaluations of Safety
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3.5.6.
Pharmacoeconomic Measures
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects
The planned sample size is 255 subjects. However, as many as 270 subjects may be enrolled in 
order to permit study participation by eligible subjects who have already signed the informed 
consent document and entered screening at the time that study enrollment is closed.
4.2.
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 monitor prior to enrollment.
4.2.1.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study:
1) Male or female 18 years of age.
2) Diagnosis of B-cell CLL, with diagnosis established according to IWCLL criteria 
{Kessenbrock 2010} and documented within medical records.
3) CLL that warrants treatment (consistent with accepted IWCLL criteria for initiation of 
therapy {Hallek 2008}). Any of the following conditions constitute CLL that warrants 
treatment:
a) Evidence of progressive marrow failure as manifested by the onset or worsening of 
anemia and/or thrombocytopenia, or
b) Massive (ie, lower edge of spleen 6 cm below the left costal margin), progressive, or 
symptomatic splenomegaly, or
c) Massive (ie, 10 cm in the longest diameter), progressive, or symptomatic 
lymphadenopathy, or
d) Progressive lymphocytosis in the absence of infection, with an increase in 
blood ALC ≥50% over a 2-month period or lymphocyte doubling time of < 6 months 
(as long as initial ALC was ≥30,000/L), or


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e) Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids 
or other standard therapy, or
f)
Constitutional symptoms, defined as any one or more of the following disease-related 
symptoms or signs occurring in the absence of evidence of infection:
i)
Unintentional weight loss of ≥10% within the previous 6 months, or
ii) Significant fatigue (Grade 2), or
iii) Fevers >100.5 °F or 38.0 °C for ≥2 weeks, or
iv) Night sweats for >1 month.
4) Presence of radiographically measurable lymphadenopathy (defined as the presence of 
≥1 nodal lesion that measures ≥2.0 cm in the longest diameter [LD] and ≥1.0 cm in the 
longest perpendicular diameter [LPD] as assessed by CT or MRI).
5) Prior treatment for CLL comprising therapy with either of the following given alone or in 
combination:
a) A purine analog (eg, fludarabine, pentostatin, cladribine) administered for ≥2 cycles of 
cytotoxic treatment, or
b) Bendamustine administered for ≥2 cycles of treatment
Note: Prior drugs may have been administered as single agents or as components of 
combination therapies. Subjects may also have received other commercially available 
therapies (eg, rituximab, alemtuzumab, ofatumumab, lenalidomide, corticosteroids, 
or others) or non-excluded investigational therapies. Each repeated but separated 
therapeutic application of the same single-agent or combination is considered an 
independent regimen. 
6) Documentation of CLL progression <24 months since the completion of the last prior therapy 
for CLL.
7) Discontinuation of all therapy (including radiotherapy, chemotherapy, immunotherapy, or 
investigational therapy) for the treatment of CLL ≥6 weeks before randomization.
Note: Subjects may be receiving corticosteroids to manage CLL manifestations.
8) All acute toxic effects of any prior antitumor therapy resolved to Grade ≤1 before 
randomization (with the exception of alopecia [Grade 1 or 2 permitted], neurotoxicity 
[Grade 1 or 2 permitted], or bone marrow parameters [Grades 1, 2, 3, or 4 permitted).
9) Karnofsky performance score of ≥60.


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10) Required baseline laboratory data (within 4 weeks prior to randomization) as shown in the 
table below. Note: Confirmation should be considered for out-of-range values to determine 
if the abnormality is real or artifactual. Values should be obtained within the screening 
period and should generally be the most recent measurement obtained. Subjects with any 
degree of neutropenia, thrombocytopenia, or anemia due to CLL or prior therapy may 
enroll.
Table 4-1.
Required Screening Laboratory Values
Organ System
Parameter
Required Value
Hepatic
Serum total bilirubin
≤1.5 x ULN (unless elevated due to Gilbert syndrome or hemolysis)
Serum ALT
2.5 x ULN
Serum AST
Renal
eCCra
> 30 ml/min
Pregnancy
-HCGb
Negative
Infection
HIV
Negative HIV antibody
HBV
Negative HBsAg and negative HBc antibody or positive HBc and 
negative for HBV DNA by quantitative PCR
HCV
Negative viral RNA (if HCV antibody is positive)
a
As calculated by the Cockcroft-Gault formula {Cockcroft 1976} (see Appendix 5)
b
For women of child-bearing potential only; serum -HCG must be negative during screening and serum -HCG or 
urine dipstick pregnancy test must be negative at randomization (Visit 2)
Abbreviations: -HCG= beta human chorionic gonadotropin, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
DNA=deoxyribonucleic acid, eCCr=estimated creatinine clearance, HBc antibody=anti-hepatitis B core antibody, 
HBsAg=hepatitis B surface antigen, HBV=hepatitis B virus, HCV=hepatitis C virus, HIV=human immunodeficiency virus, 
Ig=immunoglobulin, PCR=polymerase chain reaction, RNA=ribonucleic acid, ULN=upper limit of normal
11) For female subjects of child-bearing potential, willingness to use a protocol-recommended 
method of contraception from the screening visit (Visit 1) throughout the study treatment 
period and to 30 days from the last dose of study drug or 12 months from the last dose of 
ofatumumab (whichever is later). Note: A female subject is considered to be of 
child-bearing potential unless she has had a hysterectomy, bilateral tubal ligation, or 
bilateral oophorectomy, has medically documented ovarian failure (with serum estradiol 
and follicle-stimulating hormone [FSH] levels within the institutional postmenopausal 
range and a negative serum or urine HCG), or is menopausal (age ≥54 years with 
amenorrhea for ≥6 months). See Section 5.5.3 for information regarding 
recommendations for contraception.
12) For male subjects of child-bearing potential and having intercourse with females of 
child-bearing potential, willingness to use a protocol-recommended method contraception 
from the randomization visit (Visit 2) throughout the study treatment period and for 90 days 
following the last dose of study drug and to refrain from sperm donation from randomization 
(Visit 2) throughout the study treatment period and for 90 days following the last dose of 
study drug. Note: A male subject is considered able to father a child unless he has had a 


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bilateral vasectomy with documented aspermia or a bilateral orchiectomy, or has ongoing 
testicular suppression with a depot luteinizing hormone-releasing hormone (LH-RH) 
agonist (eg, goserelin acetate [Zoladex®]), leuprolide acetate [Lupron®]), or 
triptorelin pamoate [Trelstar®]). See Section 5.5.3 for information regarding 
recommendations for contraception.
13) In the judgment of the investigator, participation in the protocol offers an acceptable
benefit-to-risk ratio when considering current CLL disease status, medical condition, and the 
potential benefits and risks of alternative treatments for CLL.
14) Willingness and ability to comply with scheduled visits, drug administration plan, imaging 
studies, laboratory tests, other study procedures, and study restrictions. 
Note: Psychological, social, familial, or geographical factors that might preclude adequate 
study participation should be considered.
15) 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.
4.2.2.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study:
1) Known histological transformation from CLL to an aggressive lymphoma
(ie, Richter transformation). Note: Biopsy documentation of the absence or presence of 
transformation is not required.
2) Known presence of intermediate- or high-grade myelodysplastic syndrome (ie, subjects are 
excluded who have ≥5% bone marrow blasts; karotypic abnormalities other than normal, 
Y deletion, 5q deletion, or 20q deletion; or ≥2 lineages of cytopenias due to myelodysplasia) 
{Greenberg 1997}.
3) History of a non-CLL malignancy except for the following: adequately treated local 
basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial 
bladder cancer, asymptomatic prostate cancer without known metastatic disease and with no 
requirement for therapy or requiring only hormonal therapy and with normal 
prostate-specific antigen for 1 year prior to randomization, other adequately treated 
Stage 1 or 2 cancer currently in complete remission, or any other cancer that has been in 
complete remission for ≥2 years.
4) Known hypersensitivity or intolerance to any of the active substances or excipients in the 
formulations for either idelalisib or ofatumumab.


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5) Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of initiation of 
randomization (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; anti-pneumocystis prophylaxis is encouraged. 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. 
6) Ongoing drug-induced liver injury, chronic active hepatitis C (HCV), chronic active 
hepatitis B (HBV), alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary 
cirrhosis, extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, or portal 
hypertension.
7) Ongoing drug-induced pneumonitis.
8) Ongoing inflammatory bowel disease.
9) Ongoing alcohol or drug addiction.
10) Pregnancy or breastfeeding.
11) History of prior allogeneic bone marrow progenitor cell or solid organ transplantation.
12) Ongoing immunosuppressive therapy other than corticosteroids. Note: Subjects may use 
topical, enteric, inhaled, or systemic corticosteroids as therapy for manifestations of CLL, 
comorbid conditions, or autoimmune anemia and/or thrombocytopenia. During study 
participation, subjects may receive systemic or other corticosteroids as pretreatment for 
ofatumumab infusions or as needed for treatment-emergent comorbid conditions.
13) In a subject with a history of prior ofatumumab therapy, the time from the last dose of 
ofatumumab to documented CLL progression is < 6 months.
14) History of prior therapy with any inhibitor of AKT, Bruton tyrosine kinase (BTK), 
Janus kinase (JAK), mammalian target of rapamycin (mTOR), phosphatidylinositol 3-kinase 
(PI3K) (including idelalisib), or spleen tyrosine kinase (SYK).
15) Prior participation in an idelalisib clinical trial.
16) Concurrent participation in another therapeutic clinical trial.
17) Prior or ongoing clinically significant illness, medical condition, surgical history, physical 
finding, electrocardiogram (ECG) finding, or laboratory abnormality that, in the 
investigator’s opinion, could adversely affect the safety of the subject or impair the 
assessment of study results.


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4.3.
Enrollment Criteria Rationale
In general, the eligibility criteria are designed to limit enrollment to subjects who clearly have 
CLL, are able to tolerate study procedures, and will provide interpretable results.
To maximize the likelihood that therapeutic intervention is appropriately matched to disease risk, 
subjects must have CLL that is sufficiently severe to justify therapy as determined by accepted 
criteria {Hallek 2008}. The requirement of measurable lymphadenopathy ensures that subjects 
have disease that can adequately be assessed for evidence of drug activity. Prior therapy 
provisions are intended to identify subjects who have already received appropriate therapies with 
well-defined activity. Exclusion of patients who have experienced CLL recurrence within 
6 months of prior ofatumumab avoids treating those with disease known to be refractory to such 
therapy. Ensuring participation of only patients who are <24 months from prior therapy limits 
enrollment to subjects who require a change in therapy based on current guidelines {Eichhorst 
2010, Zelenetz 2011}.
This protocol focuses on establishing a noncytotoxic combination therapy alternative for 
previously treated fit or unfit CLL patients. Thus, the trial permits any degree of baseline 
myelosuppression and seeks to enroll a relatively broad population of subjects. However, to 
ensure that subjects are able to perform basic self-care functions and are not so ill from 
life-threatening comorbidities that they require hospitalization and stabilization, subjects with 
Karnofsky performance scores < 60 will not be enrolled. Subjects must not have serious prior or 
concomitant conditions or therapies that would compromise safety, compliance, or evaluation. 
Severe comorbid conditions (eg, myelodysplasia, other cancers {Luciani 2009}, active hepatitis, 
hepatic dysfunction, history of drug-induced pneumonitis) may mask, exacerbate, or confound 
the interpretation of adverse effects or efficacy of idelalisib and therefore subjects with such 
medical disorders are excluded.
Pregnancy testing and restrictions on eligibility relating to reproduction, pregnancy, and nursing
are important because idelalisib is a new chemical entity with teratogenic effects in rats and it is 
unknown if it may have adverse effects on conception, on human fetal development, or on the 
health of a breast-feeding child. Ofatumumab is known to have effects on the immune system in 
the developing fetuses of drug-exposed female animals; whether similar effects could exist for a 
human fetus is uncertain.
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.
While it will not be used to determine eligibility, the general health status of study subjects will 
be characterized at baseline using the Cumulative Illness Rating Scale (CIRS) instrument 
(see Appendix 6). The CIRS has a well-established history as a clinical tool for classifying 
patient comorbidities {Linn 1968}. Its utility is based on its validation as a predictor of clinical 
outcomes in older patient populations {Boulos 2006, Castle 2005, Conwell 1993, de Groot 2003, 
Extermann 2000, Extermann 1998, Miller 1992, Parmelee 1995, Salvi 2008, Zekry 2010}; its 


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value in predicting prognosis, appropriate patient selection, and treatment tolerability in patients 
with cancer {Firat 2006, Monfardini 2005, Ngeow 2010, Wedding 2007a, Wedding 2007b}, and 
its increasing use to categorize treatable fit (“GO-GO”) vs treatable unfit (“SLOW-GO”) patients 
with CLL {Eichhorst 2009}, {Hallek 2010}, {Goede 2012}.


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5.
TREATMENT OF SUBJECTS
5.1.
Randomization
5.1.1.
Interactive Web Response System
An IWRS will be employed to manage the conduct of the trial. The IWRS will be used to 
maintain a central log documenting screening, to implement stratification and randomization, to 
manage dose modifications, to assess current inventories of study drug, to initiate any necessary 
resupply of study drug, and to document discontinuation of study.
5.1.2.
Randomization and Stratification
After a subject has completed the necessary screening assessments and has been confirmed to be 
eligible, the subject can be randomized into the study. In order to obtain a treatment arm 
assignment for a subject, a site representative will access the IWRS and supply the system with 
the required information.
Subjects will be randomized in a 2:1 ratio to either of the following treatment assignments:

Arm A: Idelalisib + ofatumumab (1,000-mg dosing regimen)

Arm B: Ofatumumab (2,000-mg dosing regimen)
In order to balance treatment allocation by potentially important predictive factors, a fixed-block 
centralized randomization will allocate subjects within the 8 strata as defined by the intersection 
of the following 3 binary stratification factors:

17p deletion and/or TP53 mutation in CLL cells: either vs neither (or indeterminate)

Immunoglobulin heavy chain variable region (IgHV) mutation: 
unmutated (or IgHV3-21) vs mutated (or indeterminate)

Disease status: refractory (CLL progression < 6 months from completion of prior therapy) 
vs relapsed (CLL progression 6 months from completion of prior therapy)
The IWRS will assign kit numbers for dispensing of study drug. It is anticipated that subjects 
will usually begin study drug immediately after randomization at Visit 2 of the study. In case of 
administrative delays, every attempt should be made to initiate study drug as soon as possible, 
but no more than 7 days from randomization.


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5.2.
Study Drugs
5.2.1.
Idelalisib
5.2.1.1.
Description
For subjects allocated to Arm A of the study, idelalisib will be provided in tablets intended for 
oral administration. Each tablet contains 150 mg or 100 mg of active idelalisib. The 150-mg 
tablets will be used for initial therapy; the 100-mg tablets are provided for use by those subjects 
who require a dose reduction (see Table 5-2). The 150-mg tablets are pink, film-coated, and 
include the following inactive excipients: microcrystalline cellulose, hydroxypropyl cellulose, 
croscarmellose sodium, sodium starch glycolate, magnesium stearate, red iron oxide, 
polyethylene glycol, talc, polyvinyl alcohol (PVA), and titanium dioxide. The 100-mg tablets are 
orange, film-coated, and include the following inactive excipients: microcrystalline cellulose, 
hydroxypropyl cellulose, croscarmellose sodium, sodium starch glycolate, magnesium stearate, 
yellow iron oxide, polyethylene glycol, talc, PVA, and titanium dioxide.
Details regarding the shape and size of each tablet dosage form will be provided in the pharmacy 
manual for the study.
5.2.1.2.
Source
Idelalisib will be supplied free of charge by Gilead Sciences.
5.2.1.3.
Packaging and Labeling
Idelalisib will be provided in bottles. Each bottle contains 60 tablets (4-week supply plus a 
modest overage) of one of the relevant dose strengths (150 mg or 100 mg) and a polyester coil. 
Bottles are white and are made of high-density polyethylene. Each bottle is closed with a white, 
continuous-thread, child-resistant, polypropylene screw cap fitted with an induction-sealed, 
aluminum-faced liner.
Each bottle will have a label with a unique number. All labels for study drugs to be distributed to 
centers in the United States and other countries will meet all applicable requirements of the 
United States Food and Drug Administration (FDA), Annex 13 of Current Good Manufacturing 
Practice (cGMP) (Manufacture of Investigational Medicinal Products, July 2003), and/or other 
local regulations as applicable.
5.2.1.4.
Storage and Handling
Bottles containing tablets of idelalisib should be stored at controlled room temperature 
(ie, ~25 °C, with a range of 15 to 30 °C). While stability of study drug tablets stored at controlled 
room temperature has been confirmed, brief excursions to temperatures as low as -20 °C or as
high as 40 °C (eg, during shipping) will not adversely affect the drug. Updated stability data will 
be provided to the sites, as appropriate. 


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5.2.1.5.
Dispensing
The clinic staff (eg, pharmacist or other qualified person) will be responsible for dispensing 
idelalisib according to the IWRS directions. It is planned that drug will be dispensed at 12-week 
interval. Sufficient study drug will be provided for each study period at the beginning of the 
period. Multiple bottles may be dispensed at a single visit. Tablets should be dispensed in the 
original bottles provided.
5.2.1.6.
Return
The idelalisib should be retrieved from each subject at the end of each dispensing interval. The 
quantity of study drug and the date returned by the subject should be recorded in the study drug 
accountability records. All study drug returned by the subject should be retained for review by 
the study site monitor prior to return to Gilead Sciences or destruction.
5.2.1.7.
Accountability
The disposition of all idelalisib should be documented from the time of receipt at the site through 
subject dispensing and return.
Study personnel must ensure that all study drug is kept in a secure locked area with access 
limited to authorized personnel. The study drug must not be used outside the context of this 
protocol. Under no circumstances should the investigator or site personnel supply study drug to 
other investigators or clinics, or allow the study drug to be used other than as directed by this 
protocol.
The investigator and/or the responsible site personnel must maintain accurate records of the 
receipt of all study drug shipped by Gilead Sciences or its designee, including, but not limited to, 
the date received, lot number, amount received, and the disposition of all study drug. Upon 
receipt of a drug shipment, the shipment must be logged into the IWRS. 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.
Depending upon the decision of Gilead Sciences, remaining unused study drug supply will be 
returned to Gilead Sciences 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, 
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.
5.2.1.8.
Overdose Precautions
In Phase 1 studies, an MTD for idelalisib was not reached when administering the drug 
continuously at dose levels of 350 mg BID (700 mg per day) {Coutre 2011, Kahl 2011}. 
However, in this protocol, an overdose is defined as administration of more than the prescribed 
daily dose.


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In a subject who experiences an overdose, consideration should be given as to whether 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 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 Gilead Sciences medical monitor should be contacted if a study drug overdose occurs. Cases 
of study drug overdose will result in specific reporting requirements (see Section 8.6).
5.2.1.9.
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 tablets. However, 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.
5.2.2.
Ofatumumab
5.2.2.1.
Description
Ofatumumab (Arzerra®) is a human monoclonal IgG1 kappa antibody directed against the 
CD20 antigen found on pre-B and mature B cells. Ofatumumab is generated with hybridoma 
technology by using HCo7 and KM transgenic mice and is produced in a recombinant 
murine cell line (NS0) {Teeling 2004}. The protein has an approximate molecular weight of 
149 kD.
For pharmaceutical use, the drug is provided as a sterile, colorless, preservative-free liquid 
concentrate containing 20 mg/mL for dilution and intravenous administration. Inactive 
ingredients include: 10 mg/mL arginine, diluted hydrochloric acid, 0.019 mg/mL 
edetate disodium, 0.2 mg/mL polysorbate 80, 6.8 mg/mL sodium acetate, 2.98 mg/mL 
sodium chloride and Water for Injection, USP. The pH of the solution is 5.5.
5.2.2.2.
Packaging
Ofatumumab is supplied in single-use 100-mg/5-ml vials or 1,000-mg/50-mL vials.
5.2.2.3.
Source
Ofatumumab will be supplied free of charge by Gilead Sciences and commercial ofatumumab 
may be supplied through a vendor, as needed.


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5.2.2.4.
Storage and Stability
Ofatumumab vials are stable at 2 °C–8 °C (36 °F–46 °F). Vials should be protected from light 
and should not be frozen or shaken.
Diluted ofatumumab solutions for infusion may be stored at 2 °C–8 °C (36 °F–46 °F). The 
infusion should be started within 12 hours of ofatumumab preparation. Prepared solution should 
be discarded after 24 hours from constitution.
5.2.2.5.
Solution Preparation and Dispensing
The clinic staff (eg, pharmacist or other qualified person) will be responsible for preparing 
ofatumumab. A qualified person (eg, nurse or physician with experience in monitoring the 
administration of chemotherapeutic agents) will be responsible for infusing ofatumumab.
Before use, the ofatumumab vials should be visually inspected for particulate matter and 
discoloration. The solution should be colorless and may contain a small amount of visible 
translucent-to-white, amorphous, ofatumumab particles. The solution should not be used if 
discolored or cloudy, or if foreign particulate matter is present.
For the preparation of each 300-mg dose of ofatumumab, 15 ml should be withdrawn from a 
1,000-mL polyolefin or PVC bag of 0.9% Sodium Chloride Injection, USP and discarded, and
5 mL from each of 3 vials containing 100 mg/5 mL of ofatumumab should be aseptically added 
to the bag.
For the preparation of each 1,000-mg dose of ofatumumab, 50 ml should be withdrawn from a 
1,000-mL polyolefin or PVC bag of 0.9% Sodium Chloride Injection, USP and discarded, and 
50 mL from a vial containing 1000 mg/50mL of ofatumumab should be aseptically added to the 
bag.
For the preparation of each 2,000-mg dose of ofatumumab, 100 ml should be withdrawn from a 
1,000-mL polyolefin or PVC bag of 0.9% Sodium Chloride Injection, USP and discarded, and 
50 mL from each of 2 vials containing 1000 mg/50 mL of ofatumumab should be aseptically 
added to the bag.
The diluted solution should be mixed by gentle inversion. The infusion solution should not be 
mixed or diluted with other drugs.
Using an infusion pump, ofatumumab should be administered via polyvinyl chloride 
administration sets and through an in-line filter. The intravenous line should be flushed with 
0.9% Sodium Chloride Injection, USP before and after each dose. 
5.2.2.6.
Accountability
The disposition of all ofatumumab should be documented from the time of receipt at the site 
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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 Gilead Sciences or its designee, including, but not limited to, 
the date received, lot number, amount received, and the disposition of all study drug. Upon 
receipt of a drug shipment, the shipment must be logged into the IWRS. 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.
Depending upon the decision of Gilead Sciences, remaining unused study drug supply will be 
returned to Gilead Sciences 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, 
standard institutional policy should be followed and be readily available for review by 
Gilead Sciences and/or its designee. Records documenting the date of study drug shipping or 
destruction, relevant lot numbers, and amount shipped or destroyed should be maintained.
5.2.2.7.
Overdose Precautions
Ofatumumab doses as high as 2,000 mg have been administered without inducing excessive 
toxicity {Coiffier 2008, Coiffier 2010, Wierda 2010}. Accordingly, for this protocol, an 
overdose is defined as infusion of >2,000 mg of ofatumumab in a single day. In a subject who 
experiences an overdose, any further ofatumumab infusion on that day should be interrupted. 
Observation for any symptomatic side effects should be instituted, 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, as necessary.
The Gilead Sciences medical monitor should be contacted if an ofatumumab overdose occurs. 
Cases of ofatumumab overdose may result in specific reporting requirements (see Section 8.6).
5.2.2.8.
Exposure and Spill Precautions
Based on available data, ofatumumab does not appear to be irritative, acutely toxic, or genotoxic 
at levels that are likely to result from inadvertent exposure to the drug. No special precautions 
relating to exposure are required.
5.3.
Study Drug Administration
5.3.1.
Overview of Dosing Regimen
Table 5-1 provides information regarding the planned dosing regimen. All subjects will receive 
the recommended premedication ~30 to ~60 minutes (or per institution-specific standard) before 
the ofatumumab infusion. In Arm A, idelalisib will be administered together with the 
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(Arm A and Arm B) the first infusion of ofatumumab will be administered at a dose of 300 mg. 
At each of Visits 3 through 13, subjects on both arms will be given the recommended 
premedications, and ofatumumab will be infused at a dose of 1,000 mg (Arm A) or 
2,000 mg (Arm B).


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Table 5-1.
Planned Dosing Regimen
Period
Screen
Initial Therapy
Continuing
Therapy
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14+
Week
-4
1
2
3
4
5
6
7
8
12
16
20
24
30+
Study Day
-28 Days
1
8
15
22
29
36
43
50
78
106
134
162
204+
Purpose
Screening
Clinic
Visit
Clinic
Visit
Clinic
Visit
Clinic
Visit
Clinic
Visit
Clinic
Visit
Clinic
Visit
Clinic
Visit
Clinic
Visit
Clinic
Visit
Clinic
Visit
Clinic
Visit
Clinic
Visit
Idelalisib (Arm A)
150 mg BID or highest tolerated dose, taken continuously
Pre-medications
(Arms
A and B) 
Antipyretic
X
X
X
X
X
X
X
X
X
X
X
X
Antihistamine
X
X
X
X
X
X
X
X
X
X
X
X
Prednisolone
Xa
Xa
Xb
Xb
Xb
Xb
Xb
Xb
Xa
Xc
Xc
Xc
Ofatumumab, 
mg
Arm A
300
1000
1000
1000
1000
1000
1000
1000
1000
1000
1000
1000
Arm B
300
2000
2000
2000
2000
2000
2000
2000
2000
2000
2000
2000
a
Corticosteroid should be given at full dose (prednisolone 100 mg or equivalent).
b
Corticosteroid may be given at gradually decreasing doses for successive infusions if a Grade 3 reaction did not occur with the preceding ofatumumab infusion.
c
Corticosteroid dose (prednisolone doses of 50 mg to 100 mg or equivalent) may be given if a Grade 3 reaction did not occur with the preceding ofatumumab infusion.
Abbreviation: BID=twice per day


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5.3.2.
Investigational Study Drug (Idelalisib)
5.3.2.1.
Premedication
No specific premedications or supporting medications are required in conjunction with idelalisib 
administration.
In the absence of concomitant cytotoxic administration, tumor lysis syndrome is uncommon with 
either idelalisib or ofatumumab. However, investigators are at liberty to consider additional 
monitoring and prophylaxis for tumor lysis syndrome according to local practices.
5.3.2.2.
Administration Instructions
The prescribed dose of idelalisib should be taken orally. At each dose administration, the tablet 
number corresponding to the appropriate dose of study drug is to be swallowed whole with 
100 to 200 mL (~ 4 to 8 ounces) of water. In case of breakage of the tablets in the oral cavity, 
additional water should be taken as a rinse.
Study drug may be taken with or without food. There are no known dietary restrictions related to 
study drug use.
5.3.2.3.
Dosing Schedule
Idelalisib will be started on a BID schedule beginning ~30 minutes prior to the initial 
ofatumumab infusion. Study drug should be taken 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 outpatient setting, the prescribed 
regimen should be followed as closely as possible, especially in the clinic.
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 6.2, clinic staff should record 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.
5.3.2.4.
Dose Levels
Idelalisibdose levels are shown in Table 5-2 below. The starting dose level will be 150 mg BID. 
The lower dose level (Dose Level -1) is provided in case a subject requires a study drug dose
modification.
Table 5-2.
Idelalisib Dose Levels
Dose Level
Dosing Regimen
Starting
150 mg BID
-1
100 mg BID
Abbreviation: BID=twice per day


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5.3.2.5.
Dose Schedule Interruptions and Vomited Doses
Subjects who have a delay in administration of a dose of idelalisib of < 6 hours should take the 
planned dose as soon as possible after the intended time of administration. For subjects who have 
a delay in administration of study drug of 6 hours, the dose should not be taken. Study drug 
administration may continue but the missed dose should not be made up and the planned timing 
of subsequent study drug dosing should not be altered.
Vomited doses may be retaken, but only if the tablet is visible in the vomitus.
5.3.3.
Ofatumumab
5.3.3.1.
Premedications
Before administration of ofatumumab, subjects must be premedicated to reduce the incidence 
and severity of infusion reactions. Although institution-specific standards may be followed, a
recommended regimen is an oral antipyretic (acetaminophen [paracetamol], 
1,000 mg or equivalent); an oral or intravenous antihistamine (cetirizine, 10 mg or equivalent); 
and an intravenous corticosteroid (prednisolone, 100 mg or equivalent). All premedications 
should be given ~30 to ~60 minutes prior to each ofatumumab administration. Local practices 
may be followed.
For the 1st, 2nd, and 9th ofatumumab infusions, intravenous corticosteroid at full dose
(prednisolone, 100 mg or equivalent) should be administered. For the 3rd through 8th ofatumumab
infusions, the corticosteroid dose may be gradually reduced prior to successive infusions if a 
Grade 3 reaction did not occur with the preceding ofatumumab infusion. For the 
10th through 12th ofatumumab infusions, reduced corticosteroid doses (prednisolone doses of 
50 mg to 100 mg) may be administered if a Grade 3 reaction did not occur with the prior 
infusion.
In the absence of concomitant cytotoxic administration, tumor lysis syndrome is uncommon with 
either idelalisib or ofatumumab. However, investigators are at liberty to consider additional 
monitoring and prophylaxis for tumor lysis syndrome according to local practices.
Institution of antibiotic prophylaxis for Pneumocystis (carinii) jiroveci is required for all 
subjects, and should be continued for up to 12 months following treatment with ofatumumab, 
particularly in patients with multiple risk factors for pneumocystis infection {Green 2007}.
5.3.3.2.
Administration Instructions
The recommended initial infusion rate for the first dose of ofatumumab is 12 mL/hour. 
Subsequent infusions can be initiated at 25 mL/hour. In the absence of infusion toxicity, the 
infusion rate can be increased as described in Table 5-3. Ofatumumab should not be
administered as an intravenous push or bolus. Infusion rates should not exceed the indicated 
values.


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Table 5-3.
Study Drug (Ofatumumab) Infusion Rates
Interval After Start 
of Infusion, min
Arm A
Arm B
Infusion 1
(300 mg),
ml/hr
Infusion 2-12
(1,000 mg),
ml/hr
Infusion 1
(300 mg),
ml/hr
Infusion 2
(2,000 mg),
ml/hr
Infusion 3-12
(2,000 mg),
ml/hr
0-30
12
25
12
12
25
31-60
25
50
25
25
50
61-90
50
100
50
50
100
91-120
100
200
100
100
200
> 120
200
400
200
200
400
5.3.3.3.
Management of Infusion Toxicity
Ofatumumab can cause infusion reactions manifesting as bronchospasm, dyspnea,
laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, 
cardiac ischemia/infarction, back pain, rigors, abdominal pain, pyrexia, rash, urticaria, and 
angioedema {Coiffier 2008, Glaxo Group Limited 2011, Wierda 2010}. Reactions are typically 
more frequent and severe during the first infusion and are generally less frequent and less severe 
with subsequent infusions. In the Phase 2 pivotal trial {Wierda 2010}, infusion reactions 
occurred in 44% of patients on the day of the first infusion (300 mg), in 29% of patients on the 
day of the second infusion (2,000 mg), and less frequently during subsequent infusions. The time 
to onset of infusion toxicity may range from 30 to 120 minutes.
Subjects should be monitored (including vital signs approximately every 15 minutes) for infusion 
toxicity for ~1 hour following the administration of the first and second infusions, or until vital 
signs return to normal or baseline for subjects who experience infusion toxicity during any 
infusion. If a subject has not experienced infusion toxicity during the first 2 infusions, it is 
acceptable to perform a final vital signs check 15 to 30 minutes after the end of subsequent 
infusions.
Patients with pre-existing pulmonary or cardiac conditions, those who experienced prior 
cardiopulmonary adverse reactions to ofatumumab, and those with high numbers of circulating 
malignant cells (25 x 109/L) may be at particular risk. For example, in a study of patients with 
moderate to severe chronic obstructive pulmonary disease, 2 of 5 patients developed Grade 3 
bronchospasm during infusion {Glaxo Group Limited 2011}.
If an infusion reaction Grade ≤2 occurs, the infusion may be temporarily slowed or interrupted 
and then can be restarted when the subject’s condition has stabilized. Upon restarting, the 
infusion rate should be half of the infusion rate at the time the infusion was paused but not less 
than 12 mL/hour. After resuming the infusion, the infusion rate may be increased consistent with 
Table 5-3 based on patient tolerance.


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If an infusion reaction Grade ≥3 occurs, the infusion must be interrupted. Medical management 
(eg, oxygen, epinephrine, bronchodilators, and/or glucocorticoids) should be instituted, as 
needed. After the severity of the reaction has decreased to Grade 2 the investigator may restart 
the infusion at the initial rate for this ofatumumab dose (ie, at 12 mL/hour or 25 mL/hour).
If the severity of the infusion reaction does not rapidly resolve to Grade ≤2 despite adequate 
clinical intervention, or if infusion reactions of Grade 3 occur on 3 occasions during a 
single infusion, the subject may be withdrawn from ofatumumab treatment at the discretion of 
the investigator. If the subject is being treated on Arm A of the study, the subject should continue 
idelalisib if the subject is tolerating idelalisib therapy.
5.3.4.
Safety Monitoring and Study Drug Interruption/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 4.03 for grading the 
severity of adverse events and laboratory abnormalities.
Recommendations and requirements for modifications of the dosing regimens based on the drug
agent as well as the type and severity of adverse events or laboratory abnormalities are provided 
in Table 5-4 below. The dose modification instructions focus on the types of events most 
commonly attributed to each of the study agents. Required dose modifications and actions 
(in bold and italic) provided in Table 5-4 must be followed based on the type and severity of 
adverse event.The recommendations provided in Table 5-4 (not italicized) comprise only 
guidelines; variations from these recommendations may be warranted based on an investigator’s 
individual judgment in considering potential risks, benefits, and therapeutic alternatives available 
to each subject.
Consistent with Table 5-4, if a subject experiences an adverse event that is suspected to be 
related to idelalisib during the course of study, then study drug administration should be held, as 
outlined in Table 5-4, until the adverse event resolves or stabilizes to an acceptable degree 
(requirements vs recommendations defined in Table 5-4). Thereafter, study drug may be 
reinstituted at either the starting dose level (150 mg BID) or at Dose Level-1 (100 mg BID) 
consistent with the instructions in Table 5-4. One further attempt at reinitiation of therapy at 
Dose Level -1 (100 mg BID) may be attempted if the investigator feels that a second rechallenge 
at that dose level is medically appropriate. If the subject cannot tolerate study drug at 100 mg 
BID after 2 rechallenges, then the subject should be discontinued from study drug therapy unless 
continued therapy is permitted by the Gilead Sciences medical monitor.
After a study drug dose reduction, the dose need not be re-escalated, even if there is minimal or 
no toxicity with the reduced dose. However, if the subject tolerates the lower dose level of study 
drug for ≥4 weeks then the dose may be increased to 150 mg BID, 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. The starting dose 
level should not intentionally be exceeded in this study.


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Escalations or reductions in ofatumumab dosing are not planned. As noted in Table 5-4, 
ofatumumab administrations may be delayed to allow subjects to recover from 
ofatumumab-related adverse events or intercurrent illness.
Whenever possible, any dose adjustment of idelalisib should be discussed between the 
investigator and the Gilead Sciences medical monitor prior to implementation. To implement 
either a dose reduction or a dose reescalation, the investigator/study staff member will access the 
IWRS, select the subject number, and inform the IWRS of the need for dose titration. The IWRS 
will provide details regarding the kit numbers to be dispensed to the subject. The appropriate 
clinic staff should instruct the subject/caregiver about the change in dose.
Table 5-4.
Recommendations and Required Actions for Idelalisib and 
Ofatumumab Dose Modification Based on Type and Severity of 
Treatment-Related Adverse Event or Laboratory Abnormality
NCI CTCAE Grade
Recommendations and Required Action (in italics)
Idelalisib
Ofatumumab
HEMATOLOGICAL ADVERSE EVENTS
Neutropenia
Grade 2 neutropenia
Maintain current dose level and schedule.
Maintain current dose level and 
schedule.
Grade ≤3 neutropenia
Maintain current dose level and schedule.
Blood counts must be monitored at least 
weekly until ANC < Grade 2.
Maintain current dose level and 
schedule. Consider G-CSF support.
Grade 4 neutropenia
(or occurrence of 
neutropenic fever 
or infection)
Interrupt idelalisib.
Blood counts must be monitored at least 
weekly until ANC < Grade 2, at which point 
idelalisib dosing may be resumed at lower 
dose level.
Delay ofatumumab until Grade 3 
(ANC ≥0.5 x 109/L) and/or neutropenic 
fever or infection is resolved; thereafter, 
resume at full dose. Consider G-CSF 
support to avoid delays. If delay is 
> 4 weeks, discontinue ofatumumab.
Thrombocytopenia
Grade 3
Maintain current dose level and schedule.
Maintain current dose level and 
schedule.
Grade 4
During combination therapy period, maintain 
current idelalisib dose level. During 
continuing therapy period, withhold 
idelalisib for bruising or bleeding until 
Grade 3. May resume idelalisib at same or
reduced dose level at investigator discretion.
Delay ofatumumab until Grade 3 
(platelets ≥25 x 109/L); thereafter, 
resume at full dose. If delay is 
> 4 weeks, discontinue ofatumumab.
NON-HEMATOLOGICAL ADVERSE EVENTS
Cutaneous
Grade 1
Maintain current dose level and schedule.
Maintain current dose level and 
schedule.
Grade 2
Maintain current dose level and schedule.
Delay ofatumumab until Grade 1; 
thereafter, resume at full dose.


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NCI CTCAE Grade
Recommendations and Required Action (in italics)
Idelalisib
Ofatumumab
Grade 3 or 4
Withhold idelalisib until Grade 1. May
resume at lower dose level or discontinue 
idelalisib at investigator discretion.
Delay ofatumumab until Grade 1; 
thereafter, may resume at full dose or 
discontinue ofatumumab at investigator 
discretion.
Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis
Any Grade
Discontinue idelalisib. Interrupt 
coadministered medications potentially 
associated with SJS or TEN. Institute 
treatment per institutional standards. 
Gastrointestinal Inflammation/Diarrhea
Grade 1
Provide anti-diarrheal agent (eg, loperamide) 
and maintain current idelalisib dose level and 
schedule. Obtain history and perform 
physical exam as outlined in Section 5.4.3.2
Maintain current dose level and 
schedule.
Grade 2
Provide anti-diarrheal (eg, loperamide). 
Consider addition of anti-inflammatory agent 
(eg, sulfasalazine, budesonide). Maintain 
current study drug dose and schedule. Obtain 
stool culture, history, and perform physical 
exam as outlined in Section 5.4.3.2
Maintain current dose level and 
schedule.
Grade 3
Withhold idelalisib.  Rule out infectious 
etiology including CMV. Consider 
anti-diarrheal agent (eg, loperamide) and/or 
addition of anti-inflammatory agent 
(eg, sulfasalazine, budesonide). Obtain stool 
culture, history, and perform physical exam
as outlined in Section 5.4.3.2. 
Perform endoscopy with biopsy as outlined in 
Section 5.4.3.2.
At Grade 1, may resume at lower dose level 
or discontinue study drug at investigator 
discretion.
Delay ofatumumab as necessary to 
ensure subject is sufficiently stable to 
receive further treatment; thereafter 
maintain full dose and schedule.
Grade 4
Withhold idelalisib.  Rule out infectious 
etiology including CMV. Consider 
anti-diarrheal agent (eg, loperamide) and/or 
addition of anti-inflammatory agent 
(eg, sulfasalazine, budesonide). Obtain stool 
culture, history, and perform physical exam
as outlined in Section 5.4.3.2. 
Peform endoscopy with biopsy as outlined in 
Section 5.4.3.2.
At Grade 1, may resume at lower dose level 
or discontinue study drug at investigator 
discretion.
Delay ofatumumab as necessary to 
ensure subject is sufficiently stable to 
receive further treatment; thereafter 
maintain full dose and schedule.


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NCI CTCAE Grade
Recommendations and Required Action (in italics)
Idelalisib
Ofatumumab
Hepatic Adverse Events (elevations in ALT, AST, or bilirubin)
Grade 1
(ALT/AST3xULN)
(Bilirubin1.5xULN)
Maintain current dose level and schedule.
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 until all abnormalities are 
Grade <1.
Maintain current dose level and 
schedule.
Grade 3
(ALT/AST>5-20xUL
N)
(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 idelalisib at lower 
dose level.
Delay ofatumumab as necessary to 
ensure subject is sufficiently stable to 
receive further treatment; thereafter 
maintain full dose and schedule.
Grade 4
(ALT/AST>20xULN)
(Bilirubin>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 < 4, resume idelalisib 
at lower dose level. If bilirubin abnormality 
was Grade 4, discontinue idelalisib.
Delay ofatumumab as necessary to 
ensure subject is sufficiently stable to 
receive further treatment; thereafter 
maintain full dose and schedule.
Pneumonitis (with new onset or worsening of baseline, dyspnea, cough, or hypoxia without obvious infectious 
cause)
Grade 1 
(asymptomatic)
Withhold idelalisib until resolution to 
baseline. May resume at lower dose level or 
discontinue study drug at investigator 
discretion.
Maintain current dose level and 
schedule.
Grade ≥ 2
Discontinue idelalisib permanently in 
subjects with any severity of symptomatic 
pneumonitis and institute therapy  as 
clinically appropriate.
Delay ofatumumab as necessary to 
ensure subject is sufficiently stable to 
receive further treatment; thereafter 
maintain full dose and schedule.
Other Nonhematological Adverse Events
Grade 2
Maintain current dose level and schedule
Maintain current dose level and 
schedule.
Grade 3
Withhold idelalisib until Grade 1. May 
resume idelalisib at initial or lower dose level 
or discontinue idelalisib at investigator 
discretion.
Delay ofatumumab as necessary to 
ensure subject is sufficiently stable to 
receive further treatment; thereafter 
maintain full dose and schedule or 
discontinue ofatumumab at investigator 
discretion.
Pneumocystis jirovecii pneumonia (PJP)
Any Grade
Discontinue idelalisib permanently 


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NCI CTCAE Grade
Recommendations and Required Action (in italics)
Idelalisib
Ofatumumab
Organizing Pneumonia
Any Grade
Discontinue idelalisib permanently 
CMV infection/reactivation
Any Grade
Interrupt idelalisib upon unequivocal clinical or laboratory evidence of CMV infection. 
Provide 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.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST= aspartate aminotransferase, 
ANC=absolute neutrophil count, CTCAE=Common Terminology Criteria for Adverse Events, 
G-CSF=granulocyte colony-stimulating factor, NCI=National Cancer Institute, ULN=upper limit of normal, CMV=Cytomegalovirus
5.4.
Recommendations for Evaluation, Intervention, and Drug Discontinuation
for Specific Adverse Events or Conditions
5.4.1.
Carcinogenesis and Mutagenesis
Idelalisib was not genotoxic in a standard battery of assays. No carcinogenicity or mutagenicity 
studies of ofatumumab have been conducted. In a repeat-dose toxicity study, no tumorigenic or 
unexpected mitogenic responses were noted in cynomolgus monkeys treated for 7 months with 
up to 3.5 times the human dose of ofatumumab. Patients receiving therapies such as idelalisib or 
ofatumumab for CLL or iNHL have developed more aggressive lymphoid malignancies 
(eg, experienced Richter transformation) {Coutre 2011, Kahl 2011, Wierda 2010}. The specific 
association of the therapeutic agents with these types of events has not been determined.
Subjects who develop Richter transformation or acute myeloid leukemia should have study drug 
(idelalisib and ofatumumab) discontinued. For the new diagnosis of other types of disorders 
(eg, myelodysplastic syndrome, myeloproliferative disorders, a solid tumor), study drug 
(idelalisib and/or ofatumumab) may be continued at the investigator’s discretion considering 
benefit:risk relating to therapy, CLL, and the new dysplastic or neoplastic condition.
5.4.2.
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 must be interrupted. Once rash resolves to Grade <1 
idelalisib can be resumed at a lower dose level or discontinued at the investigator’s discretion.
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 


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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 must be discontinued if such events occur.
Severe dermatological reactions can occur in patients receiving ofatumumab, most commonly as 
manifestations of an infusion reaction. Dermatological adverse events have included macular 
rash, vesicular rash, urticaria, and hyperhidrosis {Glaxo Group Limited 2011}.
In the case of the occurrence of mucocutaneous reactions during ofatumumab infusion, the 
recommendations for the management of infusion toxicity (see Section 5.3.3.3) should be 
followed. The safety of readministration of ofatumumab to patients with other types of severe 
mucocutaneous reactions has not been determined; thus, for subjects experiencing a Grade 3 
non-infusion-related ofatumumab mucocutaneous reaction, consideration should be given to 
discontinuation of ofatumumab.
5.4.3.
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.  Study treatment 
(idelalisib) must be discontinued 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. Upon recovery, 
ofatumumab may be resumed. 
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 


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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.
Upon recovery and depending upon the type and severity of the initial gastrointestinal event, 
idelalisib therapy may be continued or resumed and ofatumumab administration may be 
completed if continued drug administration offers the potential for clinical benefit.
5.4.3.1.
Investigation for Idelalisib Late Onset or Severe Diarrhea/Colitis
See CTCAE Version 4.03 for definitions of colitis and diarrhea.
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 5-1
Figure 5-1.
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}.
5.4.3.2.
Evaluation for Gastrointestinal Events/Colitis 
For any grade diarrhea or colitis the following is 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).


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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), testing for
Clostridium difficile toxin, Rotavirus, Cytomegalovirus (CMV), and 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 strongly recommended. All biopsy samples 
should include immunohistochemistry (IHC) and PCR for CMV, Adenovirus.  
 
5.4.3.3.
Differentiation Between Small-bowel and Large-bowel Diarrhea
Differentiation between small-bowel and large-bowel diarrhea: maybe possible on a clinical 
basis.  If unclear, consider upper and lower tract endoscopy with biopsy.

Small bowel diarrhea is characterized by large volume diarrhea (more than one per day), and 
is possibly 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 
volumes with gross blood frequently found in the stool; consider  a colonoscopic evaluation 
and biopsy.
5.4.4.
Hematological and Immunological Events
In the Phase 1 experience with idelalisib in CLL, patients with Grade3 neutropenia, anemia, 
and/or thrombocytopenia were enrolled to clinical trials. Decreased levels of neutrophil counts, 
hemoglobin, or platelet counts during therapy were largely due to minor fluctuations in these 
parameters among patients 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 febrile neutropenia, have 
occurred in subjects treated with idelalisib. All subjects should have their blood counts 
monitored at least every 2 weeks for the first 6 months of idelalisib treatment. For subjects who 
develop ANC 0.5 to < 1.0 Gi/L, blood counts must be monitored weekly. For subjects who 
develop ANC < 0.5 Gi/L, idelalisib must be interrupted and blood counts monitored weekly until 
ANC is ≥ 0.5 Gi/L, at which point, idelalisib dosing may be resumed at 100 mg BID. 
Neutropenia should be managed according to established clinical guidelines.
CCI


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Prolonged (≥1 week) severe neutropenia can occur with ofatumumab. Of 108 patients with 
normal neutrophil counts at baseline in the Phase 2 pivotal clinical trial experience {Wierda 
2010}, 45 (42%) developed Grade ≥3 neutropenia and 19 (18%) developed Grade 4 
neutropenia. Some patients experienced new onset Grade 4 neutropenia of > 2 weeks in duration 
{Glaxo Group Limited 2011}. Suppression of mean serum IgG and IgA levels has not been seen. 
Anemia and thrombocytopenia are not as prominent.
Because idelalisib is not associated with substantial myelotoxicity, alterations in idelalisib 
therapy for such events during combination idelalisib/ofatumumab therapy should be avoided, if 
possible. Dose modifications during combination idelalisib/ofatumumab therapy (Arm A) or 
during single-agent ofatumumab therapy (Arm B) should focus on alterations in ofatumumab 
scheduling; in subjects with persistent neutropenia despite G-CSF administration, ofatumumab 
doses may be delayed for as long as 4 weeks to allow recovery of neutrophil counts to Grade 3 
(see Table 5-4). At the conclusion of combination therapy, subjects with protracted or 
symptomatic neutropenia or thrombocytopenia during continuing single-agent idelalisib therapy 
may warrant a study drug dose modification if myelosuppression is unresponsive to G-CSF 
supportive care or is symptomatic. No modification of either drug for changes in circulating 
CD4+ counts or Ig levels is planned.
5.4.5.
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 with holding 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.
HBV Reactivation: HBV reactivation can occur in patients treated with anti-CD20 antibodies. 
Subjects who are HBc antibody positive/HBV DNA PCR negative at screening will be 
monitored for potential HBV reactivation (manifest as detectable HBV DNA by quantitative 
PCR). Although some subjects who are HBc antibody positive with negative PCR may have had 
passive transfer of antibody from intravenous IgG, it cannot be known for certain that any such 
subject did not have natural HBV infection. Therefore, all subjects will be tested monthly for the 
duration of anti-CD20 therapy and every 3 months for 1 year following the last dose of 
ofatumumab during study participation. Following the completion of study participation, 


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monitoring for HBV reactivation will be conducted per standard of care at the discretion of the 
investigator. If there is evidence of HBV reactivation, immediately discontinue anti-CD20 and 
start appropriate treatment for HBV.  In the event of HBV reactivation, please contact the 
Medical Monitor regarding continuation of idelalisib.
5.4.6.
Immunogenicity
It is unknown whether an idelalisib-specific antibody response can occur following exposure 
toidelalisib. There is a potential for immunogenicity with therapeutic proteins such as 
ofatumumab, and some patients show seroconversion during ofatumumab treatment. Although 
formal studies investigating the potential neutralizing effect of an antibody response against 
ofatumumab have not been conducted, fetuses from treated females exhibiting anti-ofatumumab 
antibody responses showed less perinatal B-cell depletion than antibody-negative littermates.
5.4.7.
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, and until the CD4+ T-cell count is documented to be 
>200 cells/mcL. 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. 
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 outweigh the risks, 
consideration should be given to administering pre-emptive CMV therapy. 
Among 138 CLL patients treated with ofatumumab {Wierda 2010}, 45 patients (29%) 
experienced Grade ≥3 infections, of which 19 (12%) were fatal. Serious bacterial, fungal, and 
new or reactivated viral infections have occurred during and for ~1 year following rituximab-
based therapy {Gea-Banacloche 2010}. New or reactivated viral infections in patients receiving 
rituximab have included CMV, herpes simplex virus, parvovirus B19, varicella zoster virus, 
West Nile virus, HBV (see Section 5.4.5) and HCV.


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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.
5.4.8.
Progressive Multifocal Leukoencephalopathy
PML due to polyomavirus JC has been observed in a patient with CLL who received 
ofatumumab therapy {Wierda 2010}. PML has been observed in patients who have received 
rituximab therapy for hematologic malignancies {Carson 2009}. The specific causal role of 
ofatumumab or rituximab is unknown because patients have often had other risk factors 
(eg, low CD4+ counts, concomitant chemotherapy or hematopoietic stem cell transplantation). 
For subjects receiving rituximab, most cases of PML were diagnosed within 12 months of the 
last infusion.
The diagnosis of PML should be considered in any subject presenting with new-onset or 
worsening neurologic manifestations {Glaxo Group Limited 2011}, especially weakness or 
paralysis, vision loss, impaired speech, or cognitive deterioration. Evaluation of PML should
include consultation with a neurologist, brain MRI, and lumbar puncture. Subjects diagnosed 
with PML should receive no further ofatumumab. Idelalisib should also be permanently 
discontinued.
5.4.9.
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. 
Ofatumumab-related pulmonary adverse events including pneumonia, interstitial lung disease, 
and other respiratory tract infections have been described {Coiffier 2008, Wierda 2010}.
Given the potential for infectious or drug-related pulmonary adverse events, clinicians should be 
particularly observant for evidence of respiratory events in subjects participating in this trial. 
Subjects 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) should be evaluated. 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 lower dose level or discontinued at 
investigator discretion. For subjects with suspected 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. 
5.4.10.
Tumor Lysis Syndrome
Tumor lysis syndrome has not been observed with idelalisib monotherapy but may be seen with 
ofatumumab treatment. Patients with tumor lysis syndrome may experience hyperkalemia, 
hypocalcemia, hyperuricemia, hyperphosphatemia, cardiac dysrhythmias, and acute renal failure.
Subjects with tumor lysis syndrome should receive rapid reversal of hyperkalemia, 
intravenous hydration, antihyperuricemic agents, and appropriate cardiac and renal support, 
including dialysis as indicated. Upon recovery to baseline functioning, such subjects should 
continue study drug (idelalisib and/or ofatumumab) to maintain tumor control.
5.4.11.
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.
Reproduction studies of ofatumumab in cynomolgus monkeys dosed with up to 3.5 times the 
human dose of ofatumumab weekly during the period of organogenesis (gestation days 20 to 50) 
had no maternal toxicity or teratogenicity {Glaxo Group Limited 2011}. However, fetuses from 
ofatumumab-treated females exhibited depletion of peripheral B cells and decreased spleen and 
placental weights as well as a decrease in the thymus weight. The kinetics of B-lymphocyte 
recovery and the potential long-term effects of perinatal B-cell depletion in offspring from 
ofatumumab-treated females have not been studied in animals. The biological significance of 
decreased placental and thymic weights is unknown.
Given the potential the 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 


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sexual intercourse or use an effective form of contraception (see Section 5.5.3). If a female study 
participant becomes pregnant or decides to breastfeed during the course of the study, all study 
therapy (idelalisib, ofatumumab) must be discontinued.
5.4.12.
PJP Prophylaxis and Pregnancy
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.
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.


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5.4.13.
Ultraviolet Exposure
In vitro studies indicate enhanced cytotoxicity when embryonic murine fibroblasts treated with 
GS-563117 (the major metabolite ofidelalisib) 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.
5.5.
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.
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 eCRFs.
Information regarding use or restrictions on specific concomitant medications, dietary measures, 
or other interventions is provided below.
5.5.1.
Anticancer or Experimental Therapies Other than Investigational 
Treatments
Except for corticosteroids, no other systemic anticancer therapies (including chemotherapy, 
radiation, antibody therapy, immunotherapy, or other experimental therapies) of any kind are 
permitted. Subjects are not allowed to participate concurrently in any other therapeutic clinical 
study.
5.5.2.
Antiemetics and Antidiarrheals
Drug-related nausea and/or vomiting have not been commonly observed with idelalisib in prior 
studies. Mild to moderate nausea was seen in up to 12% of CLL patients receiving ofatumumab 
{Glaxo Group Limited 2011}. Subjects who experience nausea or vomiting while on study 


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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). The neurokinin receptor antagonist, 
aprepitant, may be considered but is a mild inhibitor of CYP3A4 and so may modestly increase 
idelalisib plasma exposures. Other classes of antiemetic medications that may be employed 
include dopamine antagonists or benzodiazepines.
As needed, subjects may be prescribed loperamide (Imodium® or others) or diphenoxylate and 
atropine (Lomotil®) to control diarrheal symptoms.
5.5.3.
Contraception
In the context of this protocol, a female subject is considered to be of child-bearing potential 
unless she has had a hysterectomy, a bilateral tubal ligation, or a bilateral oophorectomy; has 
medically documented ovarian failure (with serum estradiol and FSH levels within the 
institutional postmenopausal range and a negative serum or urine HCG); or is menopausal 
(age 54 years with amenorrhea for 6 months).
Sexually active females of child-bearing potential must accept continuous heterosexual 
abstinence as a lifestyle choice or agree to use a protocol-recommended method of contraception 
during heterosexual intercourse throughout the study treatment period and for 30 days from the 
last dose of study drug or 12 months from the last dose of ofatumumab (whichever is later). The 
investigator should counsel subjects on the most effective methods for avoiding pregnancy 
during the trial. Protocol-recommended contraceptive methods are described in Table 5-5.
Table 5-5.
Protocol-Recommended Contraceptive Methods
Individual Methods
Combination Methods
Hormonal Methods
(One method to be used 
with a barrier method)
Barrier Methods
(Both of these methods to be used
OR one of these methods to be
used with a hormonal method)
IUD

Copper T 380A IUD

LNg 20 IUD
Tubal sterilization
Hysterectomy
Estrogen and progesterone

Oral contraceptives

Transdermal patch

Vaginal ring
Progesterone

Injection

Implant

Diaphragm with spermicide

Male condom (with spermicide)
Abbreviation: IUD=intrauterine device


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In the context of this protocol, a male subject is considered able to father a child unless he has 
had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy, or is receiving
ongoing testicular suppression with a depot luteinizing hormone-releasing hormone (LH-RH) 
agonist (eg, goserelin acetate [Zoladex®]), leuprolide acetate [Lupron®]), or triptorelin pamoate 
[Trelstar®]).
Sexually active male subjects who can father a child must accept continuous heterosexual 
abstinence as a lifestyle choice; limit intercourse to female partners who are surgically sterile, 
post-menopausal, or using effective contraception (as noted in Table 5-5); or agree to use a 
protocol-recommended method of contraception during heterosexual intercourse throughout the 
study treatment period and for 90 days following discontinuation of idelalisib or > 12 months 
following the last dose of ofatumumab (whichever is later) (as noted in Table 5-5).
The Gilead Sciences medical monitor should be consulted regarding any questions relating to 
child-bearing status or contraception.
5.5.4.
Corticosteroids
Subjects may receive topical, inhaled, enteric, or systemic corticosteroids while on study. It 
should be realized that the use of systemic corticosteroids in patients with CLL may confound 
interpretation of antitumor effects mediated by study drug (idelalisib or ofatumumab). However, 
systemic corticosteroids should be used to prevent ofatumumab infusion reactions
(see Section 5.3.3). In addition, subjects who develop conditions that may be alleviated by 
systemic corticosteroid therapy are permitted to receive such drugs and are not required to 
discontinue study participation.
5.6.
Diet
There are no specific dietary restrictions in the study. Idelalisib may be taken with or without 
food.
5.6.1.
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.
G-CSF (eg, filgrastim, PEG-filgrastim, lenograstim) may be administered in response to Grade 4
neutropenia or neutropenic complications; use should be particularly considered if providing 
hematopoietic support might help to maintain study drug treatment (see Table 5-4).
While erythropoietic agents (eg, erythropoietin or darbepoetin) may be administered for
Grade 3 anemia, their use in this study is discouraged given the potential to confound 
assessments of improvements in bone marrow function related to study drug(s).
Reference may be made to the American Society of Clinical Oncology guidelines {Rizzo 2008, 
Smith 2006}.


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5.6.2.
Drugs that Inhibit/Induce CYP3A-Dependent Metabolism
Idelalisib is metabolized primarily via aldehyde oxidase and in part by CYP3A. A clinical 
drug-drug interaction study indicated that administration of a potent CYP3A inhibitor together 
with idelalisib resulted in an ~80% increase in idelalisib plasma exposures (AUC) 
(see Section 1.3.5), which is not considered to be clinically relevant and suggesting that idelalisib 
is a weak CYP3A substrate. Preliminary data indicate when coadministered with rifampin, a 
highly potent inducer of CYP3A, idelalisib exposures are ~75% lower. Coadministration of 
potent inducers of CYP3A with idelalisib should be avoided; a list of strong inducers is provided 
in Table 5-6:
Table 5-6.
Known Strong Inducers of CYP3A
Effect on CYP3A
Drug Class
Medications
Strong CYP3A Inducers
Antimycobacterial
Rifampin
Anticonvulsants
carbamazepine, phenytoin
Foods/herbs
St. John’s wort
Abbreviation: CYP=cytochrome P450 enzyme
5.6.3.
Drugs that Undergo CYP3A-Dependent Metabolism
The major metabolite of idelalisib, 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, and warfarin). Avoid coadministration of drugs that are narrow therapeutic index 
CYP3A substrates (eg, alfentanil, cyclosporine, sirolimus, tacrolimus, cisapride, pimozide, 
fentanyl, quinidine, ergotamine, dihydroergotamine, astemizole, terfenadine) with idelalisib.
5.6.4.
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. In randomized clinical trials, 
rituximab has been shown to reduce the antibody response to pneumococcal vaccination 
(a T-cell-independent antigen) or to anti-keyhole limpet hemocyanin antibodies 
(a novel protein antigen) {Genentech Inc 2011}. Response to tetanus toxoid vaccine 
(a T-cell-dependent antigen with existing immunity) or maintenance of a positive Candida skin 
test (as a measure of T-cell-mediated delayed-type hypersensitivity) was not altered. The ability 
to generate an immune response to any vaccine following administration of ofatumumab has not 
been studied {Glaxo Group Limited 2011}
The specific clinical relevance of these findings are unknown. However, for subjects who are at 
substantial risk of an infection (eg, influenza) that might be prevented by immunization, 
consideration should be given to providing the vaccine prior to initiation of study therapy.


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Of note, the safety of immunization with live viral vaccines following idelalisib or ofatumumab
therapy has not been studied and vaccination with live virus vaccines during study treatment is 
not recommended.
5.6.5.
Surgery
There are no known effects of idelalisib or ofatumumab on coagulation or wound healing. 
Pending receipt of additional information and considering the subject’s current platelet counts, 
idelalisib may be continued in the peri-procedural period in subjects who require surgery or 
invasive procedures.
5.7.
Duration of Study Drug
Subjects may continue receiving idelalisib until the occurrence of any events requiring study 
drug discontinuation as defined in Section 5.8.
Subjects may continue to receive ofatumumab until the earliest of a maximum of 12 infusions or 
the occurrence of any events requiring study drug discontinuation as defined in Section 5.8.
Note: Subjects in Arm A will continue receiving idelalisib or ofatumumab, even if the other 
drug must be discontinued due to toxicity.
5.8.
Discontinuation of Study Drug
All study participants may receive idelalisib indefinitely and may receive ofatumumab through 
12 infusions. However:

Any subject has the right to discontinue study drug at any time.

Any subject who has objective evidence of definitive CLL progression (confirmed by IRC)
will discontinue study drug.

Any subject unable to tolerate a second rechallenge with protocol-described, dose-modified 
idelalisib at Dose Level –1 (100 mg BID) (see Section 5.3.4) should discontinue idelalisib.

Any subject who becomes pregnant or begins breastfeeding should discontinue study drug.

Any subject who becomes significantly noncompliant with study drug administration, study 
procedures, or study requirements should discontinue study drug.

The investigator may discontinue study drug, if it is not in the subject’s best interest to 
continue.

Any subject who is diagnosed with any grade of SJS, TEN, PJP, or organizing pneumonia, or 
any subject diagnosed with Grade ≥2 pneumonitis should discontinue study drug.

Any subject whose benefit-risk profile is not deemed positive by the investigator should 
discontinue study drug.


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If allowed by local regulations, Gilead Sciences may transition subjects from study drug to 
commercial drug supply when idelalisib becomes commercially available in the country where 
the subject is living.
5.9.
Discontinuation from Study
Subject study participation may be ended due to any of the following reasons:

Disease progression (confirmed by the IRC)

Withdrawal of consent

Initiation of other anticancer therapy

Physician’s decision to remove the subject from the study

Pregnancy

The subject is lost to follow-up

Death

Discontinuation of study by the Sponsor, a Regulatory Agency, or an IRB or EC
Subjects who permanently discontinue study drug(s) for a reason other than disease progression 
(as determined by the IRC) shall continue with assessments per the schedule of procedures until 
disease progression or until study participation is ended.
5.10.
Study Treatment Rationale
Selection of the idelalisib treatment regimen (including starting dose level, dose-modifications 
and supportive care, schedule, duration, and conditions of administration) for this study has been 
based primarily on safety, exposure, and activity profiles from previous Phase 1 clinical studies 
involving healthy volunteers, patients with allergic rhinitis, and patients with refractory/relapsed 
lymphoid malignancies {Coutre 2011, Kahl 2011, Webb 2010}. The following information was 
considered in selecting the study drug dosing regimen for this study:

Idelalisib was symptomatically well tolerated in patients with lymphoid malignancies 
receiving dose levels of 50 mg BID through 350 mg BID (the highest dose level tested). 
No specific MTD was apparent over the dose range tested. However, monitorable, reversible 
transaminase elevations were observed in some patients and may have been more frequent at 
higher dose levels (~10% rate among patients with CLL receiving starting doses 
of 150 mg). Thus, while doses through 350 mg BID appear tolerable, the starting dose of 
150 mg BID appears to appropriately balance safety with efficacy in idelalisib-naïve 
subjects.


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
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 3 study.

A positive correlation was noted between idelalisib dose and measures of tumor control and 
chemokine normalization in patients with B-cell malignancies. The majority of patients 
appear to have tumor responses and protracted PFS when receiving starting doses of 
100 mg BID. Thus, treatment with a idelalisib at a starting dose of 150 mg BID appears to 
offer most patients the potential to benefit from therapy.

Based on evaluations of idelalisib steady-state plasma Cmax, AUC, and Ctrough values over a 
range of doses, administration of starting doses of idelalisib of 150 mg BID appears 
appropriate to ensure adequate exposure in the majority of patients. Flattening of the 
exposure curves at starting dose levels of > 150 mg BID suggest that higher doses may 
achieve smaller incremental gains in exposure.

In Phase 1 studies, the mean plasma t1/2 of idelalisib was ~6.5 to 9.8 hours across all dose 
levels and there was no substantive plasma accumulation over 7 or 28 days. The collective 
data support a study drug administration schedule of BID administration to maintain 
idelalisib plasma Ctrough values without inducing excessively high plasma Cmax values.

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.

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 planned for this protocol. Thus, use of the lower dose level to accommodate 
individual subject tolerability in this protocol is justified because subjects receiving such an
idelalisib dose level still have the potential for benefit.

Study treatment will be continued for each subject until the occurrence of disease 
progression. Such a strategy is considered appropriate under the assumption that persistent 
interference with PI3Ksignaling in Arm A is likely to extend treatment effect.


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Use of ofatumumab in this study is based on product labeling, precedence established with 
ofatumumab and other monoclonal antibodies in patients with CLL, and clinical observations 
relating to coadministration of ofatumumab or other anti-CD20 antibodies with idelalisib:

The ofatumumab dosing regimen (including the ofatumumab dose of 2000-mg/infusion) 
selected for the control arm (Arm B) of this study is the approved dose in product labeling 
{Glaxo Group Limited 2011}. Phase 1 pharmacodynamic data have suggested that this dose 
is appropriate to achieve CD20 target coverage when using ofatumumab as a single agent in 
patients with advanced, bulky lymphadenopathy {Coiffier 2010}.

The ofatumumab dose of 1000 mg/infusion to be used in combination with idelalisib in the 
investigation arm (Arm A) of this study is supported by nonclinical and clinical data. 
Nonclinical data have indicated that exposure values consistent with a 1000-mg clinical dose 
are sufficient to provide saturation of the CD20 target {Bleeker 2008}. The findings of the 
Phase 1 pharmacodynamic study of ofatumumab suggest that this dose is appropriate in 
patients receiving concomitant therapy that could reduce tumor volume {Coiffier 2010}. 
Based on these collective results, current trials for patients with previously treated CLL use a 
1000-mg dose of ofatumumab when giving the drug as a component of combination therapy.
It is further conjectured that mobilization of CLL cells from sanctuary sites into the 
peripheral blood may enhance ofatumumab-mediated CLL cell killing. Additional benefits 
resulting from the lower ofatumumab dose may include reductions in the frequency and 
severity of ofatumumab-dependent infusion reactions and in the duration of ofatumumab 
administration.

Administration of ofatumumab therapy for 24 weeks is consistent with recommendations in 
the ofatumumab package insert {Glaxo Group Limited 2011} and matches the total planned 
durations of drug administration typically employed with other antibodies (eg, alemtuzumab 
{Keating 2002a} or rituximab {Robak 2010} used in the therapy of previously treated CLL.

In a Phase 1/2, single-arm, dose-ranging study, concomitant administration of idelalisib at a 
dose of 150 mg BID together with ofatumumab at a dose of 1,000 mg has been shown to be 
safe and active {Barrientos 2012, Furman 2012}.

Consistent with the current product package insert for ofatumumab, subjects who are 
HBc antibody positive at screening will be monitored for HBV reactivation 
(manifest as detectable HBV DNA by quantitative PCR). Subjects will be tested monthly for 
the duration of ofatumumab therapy and every 3 months thereafter for 1 year from the end of 
therapy.

Recommendations for managing ofatumumab infusion reactions, and interrupting or 
discontinuing ofatumumab therapy for specific adverse events are consistent with experience 
described in product labeling {Glaxo Group Limited 2011}.


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6.
STUDY PROCEDURES
6.1.
Enrollment and Study Management Procedures
6.1.1.
Subject Recruitment
Study candidates comprise subjects with CLL who are being followed at the specified study sites 
or are referred to the study sites. Subjects will be enrolled from investigational sites in the 
United States and other countries. 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. The study sponsor will post a description of the study on the 
ClinicalTrials.gov website.
Promotional information generated by the sponsor or investigational sites will be submitted for 
IRB/IEC review, as required.
6.1.2.
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.
6.1.3.
Screening
The investigator must inform each prospective subject of the nature of the study, explain the 
potential risks, and obtain written informed consent from the subject and/or a legal guardian 
prior to performing any study-related screening procedures. At the time the study candidate signs 
the informed consent, a site representative should access the IWRS to indicate that a study 
candidate is being screened. The user will need to supply the IWRS with required information 
identifying the site and subject. The IWRS will use this information to assign a subject number 
and maintain a central screening log that track screening, screen failures, and randomization.
Any consented subject who is excluded from the study before randomization will be considered a 
screen failure. All screen failures must be documented along with an adequate description of the 
reason the subject was considered a screen failure. If available, information should be provided 
as to why the subject did not meet eligibility criteria, withdrew consent, experienced an 
intercurrent illness, or had other events that precluded randomization. Of note, subjects may be 
rescreened only once for study eligibility.


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Study GS-US-312-0119 shares many screening requirements with Study GS-US-312-0115 and 
GS-US-312-0116. In some instances, a subject may initiate screening for one trial but may prove 
ineligible for that study and may subsequently be judged to be eligible for another idelalisib 
study. To reduce the burden to study candidates and to avoid redundancy of assessments that do 
not affect the safety of trial subjects, the following screening assessments performed for any of 
Study GS-US-312-0115, GS-US-312-0116, or GS-US-312-0119 can be used in screening for 
another of these trials. These tests do not need to be repeated if they fall into the screening 
windows defined below and there has been no intervening therapy for CLL between the time of 
the test and randomization to the study:

CLL peripheral blood or bone marrow evaluations (ie, FISH, DNA mutational analysis, 
flow cytometry, and cytology) used for determining stratification and CLL prognosis if 
obtained within 12 weeks prior to randomization

Baseline CT/MRI scan – if obtained within 6 weeks prior to randomization
6.2.
Explanation of Study Visits
The specific study procedures to be conducted for each subject enrolled in the study are 
presented in tabular form in Appendix 7 and are described in the sections that follow. Additional 
information on the study procedures is provided in the study manual.
For visits at which HRQL and healthy utility data are obtained, it is important that the subject be 
administered the FACT-Leu and the EQ-5D before any other procedures are performed and 
before any study-related information is communicated to the subject; this is necessary to avoid 
biasing the PRO responses provided by the subject. Once the subject has completed the 
FACT-Leu and the EQ-5D 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.
In addition to clinical assessments of tumor status, CT or MRI imaging of the neck, chest, 
abdomen, and pelvis will be performed as a component of tumor assessments during the study 
based on the rationale provided in Section 3.5.1.
6.2.1.
Visit 1 and Screening Period (Clinic and Radiology 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. The presence of radiographically measurable 
lymphadenopathy will be confirmed by the IRC during the screening period. 


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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 randomization. Of note, the screening period may be 
extended to 6 weeks for subjects with a delay in the analysis of stratification variables 
(TP53 mutation/17p deletion status or IgHV mutation status) or with a delay in the acquisition of 
adequate baseline radiographic imaging data.
The tests and evaluations outline in Table 6-1 will be performed at Visit 1 or during the 
screening period prior to randomization and initiation of study treatment.
Table 6-1.
Procedures and Assessments at Visit 1 (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)
IWRS access
Access IWRS to document that subject is in screening and obtain a screening number
Medical history
Including relevant information regarding CLL history, stage of disease 
(Rai and Binet staging system) reasons for treatment, prior therapies for CLL, 
documentation of relapsed or refractory CLL, and past history of other medically 
significant medical conditions
CIRS assessment
Recording of comorbid conditions using the CIRS scoring instrument 
(see Appendix 6)
Concomitant medications
Recording of ongoing concomitant medication use
Performance status
Using Karnofsky performance status criteria (Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including assessment of height, weight, lymph nodes, spleen, and liver
Serum virology
Including HBsAg, HBc antibody, HCV antibody, HIV antibody, CMV serology; 
if HBc or HCV antibody is positive, subjects must be evaluated for the presence of 
HBV DNA or HCV RNA, respectively
Serum β-HCG
Women of child-bearing potential only
CLL peripheral blood 
evaluation
Including FISH for chromosome 11q deletion, 13q deletion, 17p deletion and 
12 trisomy; DNA mutational analysis for TP53, IgHV (including IgHV3-21), and 
other genes of interest in CLL (eg, Notch); flow cytometry for CD5, CD10, CD11c, 
CD19, CD20, CD23, CD38, CD45, kappa and lambda light chains, and ZAP-70; 
bone marrow aspirate may be used if peripheral blood lymphocyte count is too low
CLL serology
Serum 2 microglobulin
Coagulation
aPTT, PT, INR
Urinalysis
Including pH, protein, glucose, ketones, bilirubin, urobilinogen, blood, nitrite, 
leukocyte esterase
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


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Assessment or Procedure
Explanation
12-lead ECG
To be obtained while subject is resting in the supine position
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis, to be scheduled within 
6 weeks prior to randomization; the same method of assessment (CT, 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
To be performed at investigator discretion in subjects for whom assessment of extent 
of CLL involvement and bone marrow cellularity is important in determining 
eligibility
Abbreviations: -HCG=beta human chorionic gonadotropin, ALP=alkaline phosphatase, ALT=alanine aminotransferase, 
aPTT=activated partial thromboplastin time, AST=aspartate aminotransferase, CIRS=cumulative illness rating scale, 
CLL=chronic lymphocytic leukemia, CMV=cytomegalovirus, CT=computed tomography, DNA=deoxyribonucleic acid, 
ECG=electrocardiogram, FISH= fluorescence in-situ hybridization, GGT=gamma--glutamyltransferase, 
HBc antibody=anti-hepatitis B core antibody, HBsAg=hepatitis B surface antigen, HBV=hepatitis B virus, 
HCV=hepatitis C virus, HIV=human immunodeficiency virus, INR=international normalized ratio, 
IgHV=immunoglobulin heavy chain variable region, IWRS=interactive web response system, LDH=lactate dehydrogenase, 
MRI=magnetic resonance imaging, PT=partial thromboplastin time, RNA=ribonucleic acid, ZAP-70=zeta-associated protein 70
6.2.2.
Visit 2 (Clinic Visit – Randomization and Treatment Start)
The procedures outlined in Table 6-2 will be performed at Visit 2.
Table 6-2.
Procedures and Assessments at Visit 2 (Treatment Start)
Assessment or Procedure
Explanation
Pre-Treatment Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
other procedures are performed and before study-related information is 
communicated to the subject
Adverse events
Recording of adverse events occurring since the initiation of the screening period
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
Perform physical examination including assessment for fever, dizziness, abdominal 
pain/cramping, and weakness (ie, evaluate for sepsis, bowel obstruction, dehydration)
Concomitant medications
Recording of concomitant medication use since the initiation of the screening period
Performance status
Using Karnofsky performance status criteria (Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including assessment of weight, lymph nodes, spleen, and liver
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count


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Assessment or Procedure
Explanation
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 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines 
and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Idelalisib pharmacokinetics
(Arm A)
Pre-dose collection of plasma sample for idelalisib pharmacokinetics
(with recording of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to stratify and randomize subject, and to obtain kit number(s)
Study Treatment Administration
Study drug administration
(Arm A)
First dose of idelalisib to be administered to the subject in clinic
(with recording of the date and actual clock time of the study drug administration)
Pretreatment
Oral antipyretic, oral or IV antihistamine, and IV corticosteroid to be administered to 
the subject at the same time as idelalisib (Arm A) and ~30 to ~60 minutes prior to 
ofatumumab infusion
Ofatumumab infusion
Ofatumumab, 300 mg, to be administered by intravenous infusion 
~30 to ~60 minutes after pretreatment
Ofatumumab infusion 
severity and duration 
assessment
Worst severity of ofatumumab infusion reaction to be graded and total duration of 
ofatumumab infusion to be recorded. Following the ofatumumab infusion, monitor 
the subject for infusion toxicity, including vital signs, ~every 15 minutes for ~1 hour
Post-Treatment Procedures and Assessments
Idelalisib pharmacokinetics
(Arm A)
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours 
after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensing
(Arm A)
Dispensing of 12-week supply of idelalisib to the subject with instructions for 
self-administration at home
Abbreviations: -HCG=beta human chorionic gonadotropin, AKT=AKT (a serine/threonine protein kinase), 
ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, DNA=deoxyribonucleic acid, 
EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, 
GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
IWRS=interactive web response system, LDH=lactate dehydrogenase, mTOR=mammalian target of rapamycin, 
PI3K=phosphatidylinositol 3-kinase, RNA=ribonucleic acid
CCI


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6.2.3.
Visit 3 (Clinic Visit)
The procedures outlined in Table 6-3 will be performed at Visit 3.
Table 6-3.
Procedures and Assessments at Visit 3
Assessment or Procedure
Explanation
Pre-Treatment Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
other procedures are performed and before study-related information is 
communicated to the subject
Adverse events
Recording of adverse events occurring since the last clinic visit
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
Perform physical examination including assessment for fever, dizziness, abdominal 
pain/cramping, and weakness (ie, evaluate for sepsis, bowel obstruction, dehydration)
Concomitant medications
Recording of concomitant medication use since the last clinic visit
Performance status
Using Karnofsky performance status criteria (Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
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
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
IWRS access
Access of IWRS to document subject visit and to obtain kit number(s)
Study Treatment Administration
Pretreatment
Oral antipyretic, oral or IV antihistamine, and IV corticosteroid to be administered to 
the subject at the same time as idelalisib (Arm A) and ~30 to ~60 minutes prior to 
ofatumumab infusion
Ofatumumab infusion
Ofatumumab, 1000 mg (Arm A) or 2000 mg (Arm B) to be administered by 
intravenous infusion ~30 to ~60 minutes after pretreatment
Ofatumumab infusion 
severity and duration 
assessment
Worst severity of ofatumumab infusion reaction to be graded and total duration of 
ofatumumab infusion to be recorded. Following the ofatumumab infusion, monitor 
the subject for infusion toxicity, including vital signs, ~every 15 minutes for ~1 hour


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Assessment or Procedure
Explanation
Post-Treatment Procedures and Assessments
Instruction regarding 
in-clinic study drug dosing 
(Arm A)
Instruction to the subject that the morning dose of idelalisib should not be taken on 
the day of the next treatment clinic visit.
Abbreviations: AKT=AKT (a serine/threonine protein kinase), ALP=alkaline phosphatase, ALT=alanine aminotransferase, 
AST=aspartate aminotransferase, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, HRQL=health-related quality of life, GGT=gamma-glutamyltransferase, Ig=immunoglobulin, 
IWRS=interactive web response system, LDH=lactate dehydrogenase, mTOR=mammalian target of rapamycin, 
PI3K=phosphatidylinositol 3-kinase
6.2.4.
Visit 4 (Clinic Visit)
The procedures outlined in Table 6-4 will be performed at Visit 4.
Table 6-4.
Procedures and Assessments at Visit 4
Assessment or Procedure
Explanation
Pre-Treatment Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
other procedures are performed and before study-related information is 
communicated to the subject
Adverse events
Recording of adverse events occurring since the last clinic visit
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
Perform physical examination including assessment for fever, dizziness, abdominal 
pain/cramping, and weakness (ie, evaluate for sepsis, bowel obstruction, dehydration)
Concomitant medications
Recording of concomitant medication use since the last clinic visit
Performance status
Using Karnofsky performance status criteria (Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
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
Circulating cells
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM


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Assessment or Procedure
Explanation
Idelalisib pharmacokinetics
(Arm A)
Recording of the date and actual clock time of the last prior subject 
self-administration of study drug (should be the prior evening dose); 
pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording 
of the date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to document subject visit and to obtain kit number(s)
Study Treatment Administration
Study drug administration
(Arm A)
Morning dose of idelalisib to be administered to the subject in clinic
(with recording of the date and actual clock time of the study drug administration)
Pretreatment
Oral antipyretic, oral or IV antihistamine, and IV corticosteroid to be administered to 
the subject at the same time as idelalisib (Arm A) and ~30 to ~60 minutes prior to 
ofatumumab infusion
Ofatumumab infusion
Ofatumumab, 1000 mg (Arm A) or 2000 mg (Arm B) to be administered by 
intravenous infusion ~30 to ~60 minutes after pretreatment
Ofatumumab infusion 
severity and duration 
assessment
Worst severity of ofatumumab infusion reaction to be graded and total duration of 
ofatumumab infusion to be recorded. Perform final check of vital signs 
~15 to 30 minutes following the end of the infusion
Post-Treatment Procedures and Assessments
Idelalisib pharmacokinetics
(Arm A)
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours 
after study drug administration
(with recording of the date and actual clock time of blood collection)
Abbreviations: AKT=AKT (a serine/threonine protein kinase), ALP=alkaline phosphatase, ALT=alanine aminotransferase, 
AST=aspartate aminotransferase, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, HRQL=health-related quality of life, GGT=gamma-glutamyltransferase, Ig=immunoglobulin, 
IWRS=interactive web response system, LDH=lactate dehydrogenase, mTOR=mammalian target of rapamycin, 
PI3K=phosphatidylinositol 3-kinase


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6.2.5.
Visits 5, 7, and 8 (Clinic Visit)
The procedures outlined in Table 6-5 will be performed at Visits 5, 7, and 8.
Table 6-5.
Procedures and Assessments at Visits 5, 7, and 8
Assessment or Procedure
Explanation
Pre-Treatment Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
other procedures are performed and before study-related information is 
communicated to the subject
Adverse events
Recording of adverse events occurring since the last clinic visit
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
Perform physical examination including assessment for fever, dizziness, abdominal 
pain/cramping, and weakness (ie, evaluate for sepsis, bowel obstruction, dehydration)
Concomitant medications
Recording of concomitant medication use since the last clinic visit
Performance status
Using Karnofsky performance status criteria (Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
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
IWRS access
Access of IWRS to document subject visit and to obtain kit number(s)
Study Treatment Administration
Pretreatment
Oral antipyretic, oral or IV antihistamine, and IV corticosteroid to be administered to 
the subject at the same time as idelalisib (Arm A) and ~30 to ~60 minutes prior to 
ofatumumab infusion
Ofatumumab infusion
Ofatumumab, 1000 mg (Arm A) or 2000 mg (Arm B) to be administered by 
intravenous infusion ~30 to ~60 minutes after pretreatment
Ofatumumab infusion 
severity and duration 
assessment
Worst severity of ofatumumab infusion reaction to be graded and total duration of 
ofatumumab infusion to be recorded. Perform final check of vital signs 
~15 to 30 minutes following the end of the infusion
Post-Treatment Procedures and Assessments
Instruction regarding 
in-clinic study drug dosing 
(Arm A)
Instruction to the subject that the morning dose of idelalisib should not be taken on 
the day of the next treatment clinic visit; instruction to .be given at Visits 5 and 8 
(in anticipation of pharmacokinetic blood sample collection at 
Visits 6 and 9, respectively)
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase,
EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, 
HRQL=health-related quality of life, GGT=gamma-glutamyltransferase, IWRS=interactive web response system, 
LDH=lactate dehydrogenase


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6.2.6.
Visit 6 (Clinic Visit)
The procedures outlined in Table 6-6 will be performed at Visit 6.
Table 6-6.
Procedures and Assessments at Visit 6
Assessment or Procedure
Explanation
Pre-Treatment Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
other procedures are performed and before study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since the last clinic visit
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
Perform physical examination including assessment for fever, dizziness, abdominal 
pain/cramping, and weakness (ie, evaluate for sepsis, bowel obstruction, dehydration)
Concomitant medications
Recording of concomitant medication use since the last clinic visit
Performance status
Using Karnofsky performance status criteria (Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including assessment of weight, lymph nodes, spleen, and liver
Urine β-HCG dipstick
For women of child-bearing potential only
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
HBV DNA by PCR
Only subjects who are HBc antibody positive and HBV DNA negative at screening, 
per Section 5.4.5.
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines 
and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
CMV Surveillance
Arm A only: Surveillance for active disease must be conducted approximately every 
4 weeks.
Idelalisib pharmacokinetics
(Arm A)
Recording of the date and actual clock time of the last prior subject 
self-administration of study drug (should be the prior evening dose); 
pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording 
of the date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to document subject visit and obtain kit number(s)


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Assessment or Procedure
Explanation
Study Treatment Administration
Study drug administration
(Arm A)
Morning dose of idelalisib to be administered to the subject in clinic
(with recording of the date and actual clock time of the study drug administration)
Pretreatment
Oral antipyretic, oral or IV antihistamine, and IV corticosteroid to be administered to 
the subject at the same time as idelalisib (Arm A) and ~30 to ~60 minutes prior to 
ofatumumab infusion
Ofatumumab infusion
Ofatumumab, 1000 mg (Arm A) or 2000 mg (Arm B) to be administered by 
intravenous infusion ~30 to ~60 minutes after pretreatment
Ofatumumab infusion 
severity and duration 
assessment
Worst severity of ofatumumab infusion reaction to be graded and total duration of 
ofatumumab infusion to be recorded. Perform final check of vital signs 
~15 to 30 minutes following the end of the infusion
Post-Treatment Procedures and Assessments
Idelalisib pharmacokinetics
(Arm A)
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours 
after study drug administration
(with recording of the date and actual clock time of blood collection)
Abbreviations: -HCG= beta human chorionic gonadotropin, AKT=AKT (a serine/threonine protein kinase),
ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase,
EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, 
HRQL=health-related quality of life, GGT=gamma-glutamyltransferase, Ig=immunoglobulin, 
IWRS=interactive web response system, LDH=lactate dehydrogenase, mTOR=mammalian target of rapamycin, 
PI3K=phosphatidylinositol 3-kinase, CMV Surveillance=Arm A only: Surveillance for active disease must be conducted 
approximately every 4 weeks.


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6.2.7.
Visit 9 (Clinic and Radiology Visit)
The procedures outlined in Table 6-7 will be performed at Visit 9.
Table 6-7.
Procedures and Assessments at Visit 9
Assessment or Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week of the visit; 
the same method of assessment (CT or MRI) should be used as was used at baseline.
Pre-Treatment Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
other procedures are performed and before study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since the last clinic visit
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
Perform physical examination including assessment for fever, dizziness, abdominal 
pain/cramping, and weakness (ie, evaluate for sepsis, bowel obstruction, dehydration)
Concomitant medications
Recording of concomitant medication use since the last clinic visit
Performance status
Using Karnofsky performance status criteria (Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including assessment of weight, lymph nodes, spleen, and liver
Urine β-HCG dipstick
For women of child-bearing potential only
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
HBV DNA by PCR
Only subjects who are HBc antibody positive and HBV DNA negative at screening, 
per Section 5.4.5.
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
CMV Surveillance
Arm A only: Surveillance for active disease must be conducted approximately every 
4 weeks.


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Assessment or Procedure
Explanation
Bone marrow biopsy 
and/or aspirate
To be performed post-baseline to confirm CR or PD. If the subject does not otherwise 
meet criteria for CR or if the nature of PD does not require bone marrow 
confirmation, it is not necessary to obtain a follow-up bone marrow biopsy/aspirate
Idelalisib pharmacokinetics 
(Arm A)
Recording of the date and actual clock time of the last prior subject 
self-administration of study drug (should be the prior evening dose); pre-dose 
collection of plasma sample for idelalisib pharmacokinetics (with recording of the 
date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to document subject visit and to obtain kit number(s)
Study Treatment Administration
Study drug administration 
(Arm A)
Morning dose of idelalisib to be administered to the subject in clinic
(with recording of the date and actual clock time of the study drug administration)
Pretreatment
Oral antipyretic, oral or IV antihistamine, and IV corticosteroid to be administered to 
the subject at the same time as idelalisib (Arm A) and ~30 to ~60 minutes prior to 
ofatumumab infusion
Ofatumumab infusion
Ofatumumab, 1000 mg (Arm A) or 2000 mg (Arm B) to be administered by 
intravenous infusion ~30 to ~60 minutes after pretreatment
Ofatumumab infusion 
severity and duration 
assessment
Worst severity of ofatumumab infusion reaction to be graded and total duration of 
ofatumumab infusion to be recorded. Perform final check of vital signs 
~15 to 30 minutes following the end of the infusion
Post-Treatment Procedures and Assessments
Idelalisib pharmacokinetics 
(Arm A)
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours 
after study drug administration
(with recording of the date and actual clock time of blood collection)
Instruction regarding 
in-clinic study drug dosing
(Arm A)
Instruction to the subject that the morning dose of idelalisib should not be taken on 
the day of the next treatment clinic visit.
Abbreviations: -HCG= beta human chorionic gonadotropin, AKT=AKT (a serine/threonine protein kinase),
ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, CT=computed tomography, 
EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, 
HRQL=health-related quality of life, GGT=gamma-glutamyltransferase, Ig=immunoglobulin, 
IWRS=interactive web response system, LDH=lactate dehydrogenase, MRI=magnetic resonance imaging, 
mTOR=mammalian target of rapamycin, PI3K=phosphatidylinositol 3-kinase, CMV Surveillance=Arm A only: Surveillance for 
active disease must be conducted approximately every 4 weeks.


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6.2.8.
Visit 10 (Clinic Visit)
The procedures outlined in Table 6-8 will be performed at Visit 10.
Table 6-8.
Procedures and Assessments at Visit 10
Assessment or Procedure
Explanation
Pre-Treatment Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
other procedures are performed and before study-related information is 
communicated to the subject
Adverse events
Recording of adverse events occurring since the last clinic visit
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
Perform physical examination including assessment for fever, dizziness, abdominal 
pain/cramping, and weakness (ie, evaluate for sepsis, bowel obstruction, dehydration)
Concomitant medications
Recording of concomitant medication use since the last clinic visit
Study drug 
return/accounting
Counting returned idelalisib
Performance status
Using Karnofsky performance status criteria (Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including assessment of weight, lymph nodes, spleen, and liver
Urine β-HCG dipstick
For women of child-bearing potential only
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
HBV DNA by PCR
Only subjects who are HBc antibody positive and HBV DNA negative at screening, 
per Section 5.4.5.
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines 
and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
CMV Surveillance
Arm A only: Surveillance for active disease must be conducted approximately every 
4 weeks.


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Version 11.0
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Assessment or Procedure
Explanation
Idelalisib pharmacokinetics 
(Arm A)
Recording of the date and actual clock time of the last prior subject 
self-administration of study drug (should be the prior evening dose); 
pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording 
of the date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to document subject visit and to obtain kit number(s)
Study Treatment Administration
Study drug administration 
(Arm A)
Morning dose of idelalisib to be administered to the subject in clinic
(with recording of the date and actual clock time of the study drug administration)
Pretreatment
Oral antipyretic, oral or IV antihistamine, and IV corticosteroid to be administered to 
the subject at the same time as idelalisib (Arm A) and ~30 to ~60 minutes prior to 
ofatumumab infusion
Ofatumumab infusion
Ofatumumab, 1000 mg (Arm A) or 2000 mg (Arm B) to be administered by 
intravenous infusion ~30 to ~60 minutes after pretreatment
Ofatumumab infusion 
severity and duration 
assessment
Worst severity of ofatumumab infusion reaction to be graded and total duration of 
ofatumumab infusion to be recorded. Perform final check of vital signs 
~15 to 30 mins following the end of the infusion
Post-Treatment Procedures and Assessments
Idelalisib pharmacokinetics 
(Arm A)
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours 
after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensing 
(Arm A)
Dispensing of 12-week supply of idelalisib to the subject with instructions for 
self-administration at home
Abbreviations: -HCG= beta human chorionic gonadotropin, AKT=AKT (a serine/threonine protein kinase),
ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, 
HRQL=health-related quality of life, GGT=gamma-glutamyltransferase, Ig=immunoglobulin, 
IWRS=interactive web response system, LDH=lactate dehydrogenase, mTOR=mammalian target of rapamycin, 
PI3K=phosphatidylinositol 3-kinase, CMV Surveillance=Arm A only: Surveillance for active disease must be conducted 
approximately every 4 weeks.


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Version 11.0
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6.2.9.
Visit 11 (Clinic and Radiology Visit)
The procedures outlined in Table 6-9 will be performed at Visit 11.
Table 6-9.
Procedures and Assessments at Visit 11
Assessment or Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week of the visit; 
the same method of assessment (CT or MRI) should be used as was used at baseline.
Pre-Treatment Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
other procedures are performed and before study-related information is communicated 
to the subject
Adverse events
Recording of adverse events occurring since the last clinic visit
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
Perform physical examination including assessment for fever, dizziness, abdominal 
pain/cramping, and weakness (ie, evaluate for sepsis, bowel obstruction, dehydration)
Concomitant medications
Recording of concomitant medication use since the last clinic visit
Performance status
Using Karnofsky performance status criteria (Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including assessment of weight, lymph nodes, spleen, and liver
Urine β-HCG dipstick
For women of child-bearing potential only
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
HBV DNA by PCR
Only subjects who are HBc antibody positive and HBV DNA negative at screening, 
per Section 5.4.5.
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
CMV Surveillance
Arm A only: Surveillance for active disease must be conducted approximately every 
4 weeks.


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Final
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Version 11.0
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Assessment or Procedure
Explanation
Bone marrow biopsy 
and/or aspirate
To be performed post-baseline to confirm CR or PD. If the subject does not otherwise 
meet criteria for CR or if the nature of PD does not require bone marrow confirmation, 
it is not necessary to obtain a follow-up bone marrow biopsy/aspirate
IWRS access
Access of IWRS to document subject visit and to obtain kit number(s)
Study Treatment Administration
Pretreatment
Oral antipyretic, oral or IV antihistamine, and IV corticosteroid to be administered to 
the subject at the same time as idelalisib (Arm A) and ~30 to ~60 minutes prior to 
ofatumumab infusion
Ofatumumab infusion
Ofatumumab, 1000 mg (Arm A) or 2000 mg (Arm B) to be administered by 
intravenous infusion ~30 to ~60 minutes after pretreatment
Ofatumumab infusion 
severity and duration 
assessment
Worst severity of ofatumumab infusion reaction to be graded and total duration of 
ofatumumab infusion to be recorded. Perform final check of vital signs 
~15 to 30 minutes following the end of the infusion
Abbreviations: -HCG= beta human chorionic gonadotropin, AKT=AKT (a serine/threonine protein kinase),
ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, CT=computed tomography, 
EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, 
HRQL=health-related quality of life, GGT=gamma-glutamyltransferase, Ig=immunoglobulin, 
IWRS=interactive web response system, LDH=lactate dehydrogenase, MRI=magnetic resonance imaging, 
mTOR=mammalian target of rapamycin, PI3K=phosphatidylinositol 3-kinase, CMV Surveillance= Arm A only: Surveillance for 
active disease must be conducted approximately every 4 weeks.
6.2.10.
Visit 12 (Clinic Visit)
The procedures outlined in Table 6-10 will be performed at Visit 12.
Table 6-10.
Procedures and Assessments at Visit 12
Assessment or Procedure
Explanation
Pre-Treatment Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
other procedures are performed and before study-related information is 
communicated to the subject
Adverse events
Recording of adverse events occurring since the last clinic visit
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
Perform physical examination including assessment for fever, dizziness, abdominal 
pain/cramping, and weakness (ie, evaluate for sepsis, bowel obstruction, dehydration)
Concomitant medications
Recording of concomitant medication use since the last clinic visit
Performance status
Using Karnofsky performance status criteria (Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air


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Version 11.0
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Assessment or Procedure
Explanation
Physical examination
Including assessment of weight, lymph nodes, spleen, and liver
Urine β-HCG dipstick
For women of child-bearing potential only
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
HBV DNA by PCR
Only subjects who are HBc antibody positive and HBV DNA negative at screening, 
per Section 5.4.5.
Circulating cells
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
CMV Surveillance
Arm A only: Surveillance for active disease must be conducted approximately every 
4 weeks.
IWRS access
Access of IWRS to document subject visit and to obtain kit number(s)
Study Treatment Administration
Pretreatment
Oral antipyretic, oral or IV antihistamine, and IV corticosteroid to be administered to 
the subject at the same time as idelalisib (Arm A) and ~30 to ~60 minutes prior to 
ofatumumab infusion
Ofatumumab infusion
Ofatumumab, 1000 mg (Arm A) or 2000 mg (Arm B) to be administered by 
intravenous infusion ~30 to ~60 minutes after pretreatment
Ofatumumab infusion 
severity and duration 
assessment
Worst severity of ofatumumab infusion reaction to be graded and total duration of 
ofatumumab infusion to be recorded. Perform final check of vital signs 
~15 to 30 minutes following the end of the infusion
Post-Treatment Procedures and Assessments
Instruction regarding 
in-clinic study drug dosing 
(Arm A)
Instruction to the subject that the morning dose of idelalisib should not be taken on 
the day of the next treatment clinic visit.
Abbreviations: -HCG= beta human chorionic gonadotropin, AKT=AKT (a serine/threonine protein kinase),
ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, 
HRQL=health-related quality of life, GGT=gamma-glutamyltransferase, Ig=immunoglobulin, 
IWRS=interactive web response system, LDH=lactate dehydrogenase, ,mTOR=mammalian target of rapamycin, 
PI3K=phosphatidylinositol 3-kinase, CMV Surveillance= Arm A only: Surveillance for active disease must be conducted 
approximately every 4 weeks.


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Version 11.0
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6.2.11.
Visit 13 (Clinic and Radiology Visit)
The procedures outlined in Table 6-11 will be performed at Visit 13.
Table 6-11.
Procedures and Assessments at Visit 13
Assessment or Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week of the visit; the 
same method of assessment (CT or MRI) should be used as was used at baseline.
Pre-Treatment Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
other procedures are performed and before study-related information is communicated 
to the subject
Adverse events
Recording of adverse events occurring since the last clinic visit
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
Perform physical examination including assessment for fever, dizziness, abdominal 
pain/cramping, and weakness (ie, evaluate for sepsis, bowel obstruction, dehydration)
Concomitant medications
Recording of concomitant medication use since the last clinic visit
Study drug 
return/accounting
Counting returned idelalisib
Performance status
Using Karnofsky performance status criteria (Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including assessment of weight, lymph nodes, spleen, and liver
Urine β-HCG dipstick
For women of child-bearing potential only
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
HBV DNA by PCR
Only subjects who are HBc antibody positive and HBV DNA negative at screening, 
per Section 5.4.5.
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines 
and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM


Idelalisib
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Final
Gilead Sciences, Inc.
Version 11.0
CONFIDENTIAL
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Assessment or Procedure
Explanation
CMV Surveillance
Arm A only: Surveillance for active disease must be conducted approximately every 
4 weeks.
Bone marrow biopsy 
and/or aspirate
To be performed post-baseline to confirm CR or PD. If the subject does not otherwise 
meet criteria for CR or if the nature of PD does not require bone marrow confirmation, 
it is not necessary to obtain a follow-up bone marrow biopsy/aspirate
Idelalisib 
pharmacokinetics (Arm A)
Recording of the date and actual clock time of the last prior subject self-administration 
of study drug (should be the prior evening dose); pre-dose collection of plasma sample 
for idelalisib pharmacokinetics (with recording of the date and actual clock time of the 
date and actual clock time of blood collection)
IWRS access
Access of IWRS to document subject visit and to obtain kit number(s)
Study Treatment Administration
Study drug administration 
(Arm A)
Morning dose of idelalisib to be administered to the subject in clinic
(with recording of the date and actual clock time of the study drug administration)
Pretreatment
Oral antipyretic, oral or IV antihistamine, and IV corticosteroid to be administered to 
the subject at the same time as idelalisib (Arm A) and ~30 to ~60 minutes prior to 
ofatumumab infusion
Ofatumumab infusion 
Ofatumumab, 1000 mg (Arm A) or 2000 mg (Arm B) to be administered by 
intravenous infusion ~30 to ~60 minutes after pretreatment
Ofatumumab infusion 
severity and duration 
assessment
Worst severity of ofatumumab infusion reaction to be graded and total duration of 
ofatumumab infusion to be recorded. Perform final check of vital signs 
~15 to 30 minutes following the end of the infusion
Post-Treatment Procedures and Assessments
Idelalisib 
pharmacokinetics
(Arm A)
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours 
after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensing 
(Arm A)
Dispensing of 12-week supply of idelalisib to the subject with instructions for 
self-administration at home
Abbreviations: -HCG= beta human chorionic gonadotropin, AKT=AKT (a serine/threonine protein kinase),
ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, CT=computed tomography, 
EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, 
HRQL=health-related quality of life, GGT=gamma-glutamyltransferase, Ig=immunoglobulin, 
IWRS=interactive web response system, LDH=lactate dehydrogenase, MRI=magnetic resonance imaging, 
mTOR=mammalian target of rapamycin, PI3K=phosphatidylinositol 3-kinase, CMV Surveillance= Arm A only: Surveillance for 
active disease must be conducted approximately every 4 weeks.


Idelalisib
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Final
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Version 11.0
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6.2.12.
Visits 14 and 16 (Clinic Visits)
The procedures outlined in Table 6-12 will be performed at Visits 14 and 16.
Table 6-12.
Procedures and Assessments at Visits 14 and 16
Assessment or Procedure
Explanation
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
other procedures are performed and before study-related information is 
communicated to the subject
Adverse events
Recording of adverse events occurring since the last clinic visit
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
Perform physical examination including assessment for fever, dizziness, abdominal 
pain/cramping, and weakness (ie, evaluate for sepsis, bowel obstruction, dehydration)
Concomitant medications
Recording of concomitant medication use since the last clinic visit
Performance status
Using Karnofsky performance status criteria (Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including assessment of weight, lymph nodes, spleen, and liver
Urine β-HCG dipstick
For women of child-bearing potential only
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
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
CMV Surveillance
Arm A only: Surveillance for active disease must be conducted approximately every 
4 weeks.
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
IWRS access
Access of IWRS to document subject visit and to obtain kit numbers (if applicable)
Abbreviations: -HCG= beta human chorionic gonadotropin, AKT=AKT (a serine/threonine protein kinase),
ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, 
HRQL=health-related quality of life, GGT=gamma-glutamyltransferase, Ig=immunoglobulin, 
IWRS=interactive web response system, LDH=lactate dehydrogenase, ,mTOR=mammalian target of rapamycin, 
PI3K=phosphatidylinositol 3-kinase, CMV Surveillance= Arm A only: Surveillance for active disease must be conducted 
approximately every 4 weeks.


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Protocol GS-US-312-0119
Final
Gilead Sciences, Inc.
Version 11.0
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6.2.13.
Visits 15 and 17 (Clinic and Radiology Visits)
The procedures outlined in Table 6-13 will be performed at Visits 15 and 17.
Table 6-13.
Procedures and Assessments at Visits 15 and 17
Assessment or Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week of the visit; 
the same method of assessment (CT or MRI) should be used as was used at baseline.
Visit Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
other procedures are performed and before study-related information is 
communicated to the subject
Adverse events
Recording of adverse events occurring since the last clinic visit
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
Perform physical examination including assessment for fever, dizziness, abdominal 
pain/cramping, and weakness (ie, evaluate for sepsis, bowel obstruction, dehydration)
Concomitant medications
Recording of concomitant medication use since the last clinic visit
Study drug 
return/accounting
Counting returned idelalisib
Performance status
Using Karnofsky performance status criteria (Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including assessment of weight, lymph nodes, spleen, and liver
Urine β-HCG dipstick
For women of child-bearing potential only; also performed 6 weeks (5 days) 
following Visit 17
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
HBV DNA by PCR
Only subjects who are HBc antibody positive and HBV DNA negative at screening, 
per Section 5.4.5.
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM


Idelalisib
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Assessment or Procedure
Explanation
CMV Surveillance
Arm A only: Surveillance for active disease must be conducted approximately every 4 
weeks.
Bone marrow biopsy 
and/or aspirate
To be performed post-baseline to confirm CR or PD. If the subject does not otherwise 
meet criteria for CR or if the nature of PD does not require bone marrow 
confirmation, it is not necessary to obtain a follow-up bone marrow biopsy/aspirate
IWRS access
Access of IWRS to document subject visit and to obtain kit numbers (if applicable)
Study drug dispensing 
(Arm A)
Dispensing of 12-week supply of idelalisib to the subject with instructions for 
self-administration at home
Abbreviations: -HCG= beta human chorionic gonadotropin, AKT=AKT (a serine/threonine protein kinase),
ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, CT=computed tomography, 
EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, 
HRQL=health-related quality of life, GGT=gamma-glutamyltransferase, Ig=immunoglobulin,
IWRS=interactive web response system, LDH=lactate dehydrogenase, MRI=magnetic resonance imaging, 
mTOR=mammalian target of rapamycin, PI3K=phosphatidylinositol 3-kinase
6.2.14.
Visit 18 and Subsequent Visits (Every 12 Weeks)
(Clinic and Radiology Visits)
The procedures outlined in Table 6-14 will be performed at Visit 18 and subsequent visits 
(every 12 weeks).
Table 6-14.
Procedures and Assessments at Visit 18 and Subsequent Visits
(Every 12 Weeks)
Assessment or Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week of the visit; 
the same method of assessment (CT or MRI) should be used as was used at baseline.
Visit Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
other procedures are performed and before study-related information is communicated 
to the subject
Adverse events
Recording of adverse events occurring since the last clinic visit
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
Perform physical examination including assessment for fever, dizziness, abdominal 
pain/cramping, and weakness (ie, evaluate for sepsis, bowel obstruction, dehydration)
Concomitant medications
Recording of concomitant medication use since the last clinic visit
Study drug 
return/accounting
Counting returned idelalisib


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Assessment or Procedure
Explanation
Performance status
Using Karnofsky performance status criteria (Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including assessment of weight, lymph nodes, spleen, and liver
Urine β-HCG dipstick
For women of child-bearing potential only; also performed 6 weeks (5 days) 
following Visit 18 and subsequent visits
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
HBV DNA by PCR
Only subjects who are HBc antibody positive and HBV DNA negative at screening, 
per Section 5.4.5.
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
CMV Surveillance
Arm A only: Surveillance for active disease must be conducted approximately every 
4 weeks.
PJP prophylaxis
Subjects must receive trimethoprim-sulfamethoxazole or other established prophylaxis 
for PJP throughout the course of idelalisib treatment and for 2 to 6 months after the 
last dose of idelalisib and until the CD4+ T-cell count is documented to be >200 
cells/mcL.
Serum complement
CH50
Bone marrow biopsy 
and/or aspirate
To be performed post-baseline to confirm CR or PD. If the subject does not otherwise 
meet criteria for CR or if the nature of PD does not require bone marrow confirmation, 
it is not necessary to obtain a follow-up bone marrow biopsy/aspirate
IWRS access
Access of IWRS to document subject visit and to obtain kit numbers (if applicable)
Study drug dispensing 
(Arm A)
Dispensing of 12-week supply of idelalisib to the subject with instructions for 
self-administration at home
Abbreviations: -HCG= beta human chorionic gonadotropin, AKT=AKT (a serine/threonine protein kinase), 
ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, CT=computed tomography, 
EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, 
HRQL=health-related quality of life, GGT=gamma-glutamyltransferase, Ig=immunoglobulin,
IWRS=interactive web response system, LDH=lactate dehydrogenase, MRI=magnetic resonance imaging, 
mTOR=mammalian target of rapamycin, PI3K=phosphatidylinositol 3-kinase, CMV Surveillance= Arm A only: Surveillance for 
active disease must be conducted approximately every 4 weeks.


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6.2.15.
End-of-Study Visit (Clinic Visit)
At the time of discontinuation from the study, the subject should have the procedures and 
assessments performed as documented in Table 6-15. An end-of-study CT/MRI tumor 
assessment should be performed unless the subject already has radiographic confirmation of 
definitive disease progression or a CT/MRI has been performed within 4 weeks prior to the 
end-of-study visit.
Table 6-15.
Procedures and Assessments at End-of-Study 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
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed
Adverse events 
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
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
Perform physical examination including assessment for fever, dizziness, abdominal 
pain/cramping, and weakness (ie, evaluate for sepsis, bowel obstruction, dehydration)
Concomitant medications
Recording of concomitant medication used since prior visit
Study drug 
return/accounting
Counting returned idelalisib
Performance status
Using Karnofsky performance status criteria (Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including assessment of weight, lymph nodes, spleen, and liver
Serum β-HCG
Women of child-bearing potential only
CLL peripheral blood 
evaluation
Including FISH for chromosome 11q deletion, 13q deletion, 17p deletion and 
12 trisomy; DNA mutational analysis for TP53, IgHV (including IgHV3-21), and 
other genes of interest in CLL (eg, Notch); flow cytometry for CD5, CD10, CD11c, 
CD19, CD20, CD23, CD38, CD45, kappa and lambda light chains, and ZAP-70; 
cytology for karyotyping; bone marrow aspirate may be used if peripheral blood 
lymphocyte count is too low
CLL serology
Serum 2 microglobulin
Urine β-HCG dipstick
For women of child-bearing potential only
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Assessment or Procedure
Explanation
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
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Serum complement
CH50
PJP prophylaxis
Subjects must receive trimethoprim-sulfamethoxazole or other established 
prophylaxis for PJP throughout the course of idelalisib treatment and for 2 to 6 
months after the last dose of idelalisib and until the CD4+ T-cell count is documented 
to be >200 cells/mcL.
IWRS
Access IWRS to document that subject has permanently discontinued study therapy
a
An end-of-study CT/MRI tumor assessment should be performed unless the subject already has radiographic confirmation 
of definitive disease progression or a CT/MRI has been performed within 4 weeks prior to end-of-study.
Abbreviations: -HCG=beta human chorionic gonadotropin, AKT=AKT (a serine/threonine protein kinase), 
ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase,
CLL=chronic lymphocytic leukemia, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, 
FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, FISH= fluorescence in-situ hybridization, 
GGT=gamma-glutamyltransferase, Ig=immunoglobulin, IgHV=immunoglobulin heavy-chain variable-region, 
IWRS=interactive web response system, LDH=lactate dehydrogenase, MRI=magnetic resonance imaging, 
mTOR=mammalian target of rapamycin, PI3K=phosphatidylinositol 3-kinase, RNA=ribonucleic acid, 
ZAP-70=zeta-associated protein 70, CMV Surveillance= Arm A only: Surveillance for active disease must be conducted 
approximately every 4 weeks.
6.2.16.
30 Day and Long-Term Follow-up
A 30 Day follow-up visit will be performed 30 days (5 days) following the end-of-study visit; 
however, it may be waived for subjects who have permanently discontinued study drug and have 
had a study visit > 30 days after the last dose of study drug.
Long-term follow-up will be conducted at annual intervals (± 4 weeks) for 5 years, starting at 
the EOS visit. Information may be gathered during a routine clinic visit or other contact with the 
subject, or via telephone. Information gathered will include medical status, anti-tumor 
treatments, secondary malignancies, and survival status.
6.3.
Sample Storage
 
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6.4.
Blood Collection
The maximum amount of blood to be drawn at a visit is ~114 mL and the total amount of blood 
to be drawn over the initial 52-week study period (including the 4-week screening period, 
through Week 48 of the study, and with a possible end-of-study visit) is ~587 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 ~2.9 mL/kg and a total blood volume per body weight 
per average 6-week period of ~1.7 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 a 
6-week period.
Specific details regarding blood sample collection and processing requirements will be provided 
separately in the laboratory manual.
 
 
6.5.
Study Procedure Rationale
The planned study assessments and timing have been selected as appropriate for screening of 
subjects, for determination of drug- 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 clinical and radiological procedures. For discussion of the rationale for endpoint 
selection, see Section 3.5.
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7.
EFFICACY ASSESSMENTS
7.1.
Tumor Status Assessments
The determination of CLL response and progression will be based on standardized 
IWCLL criteria {Hallek 2008}, as specifically modified for this study to reflect current 
recommendations which consider the mechanism of action of idelalisib and similar drugs 
{Cheson 2012}. During the course of the study, investigators will assess the status of each 
subject’s CLL according to schedule. If CLL progression is suspected, the IRC will be notified 
and will review radiographic and pertinent clinical data in order to provide expert interpretation
(see Section 10.4.2). The findings of the IRC will be considered primary for analyses of PFS and 
other tumor control endpoints.
7.2.
Method of Assessment
Imaging-based evaluation will be used in this study in all subjects enrolled. CT scan is the 
preferred method for radiographic tumor assessment. MRI scanning may be used at the 
investigator’s discretion in subjects for whom this may be a preferred alternative to CT scanning; 
however, if MRI is performed, a non-contrast CT of the chest should be performed
Contrast-enhanced scanning is preferred, but iodine-containing or gadolinium contrast material 
may be omitted in subjects for whom use of a contrast agent would be medically contraindicated. 
Chest x-ray, ultrasound, endoscopy, laparoscopy, PET, radionuclide scans, or tumor markers will 
not be considered for response assessment.
For radiographic evaluations, 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. 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 10.4.2).
7.3.
Timing of Assessments
During screening, clinical and imaging-based tumor assessments should be performed within the 
specified screening period. Clinical tumor assessments should be performed at each designated 
clinical visit (see Appendix 7). On-study CT/MRI tumor assessments should be performed as 
indicated in Appendix 7, until ~129 events have been observed in the study population. An 
end-of-study CT/MRI tumor assessment should be performed unless the subject already has 
radiographic confirmation of disease progression 4 weeks prior. If a subject permanently 
discontinues study drug prior to objective documentation of CLL progression, investigators 
should continue further follow-up according to the protocol specified schedule until CLL 
progression is documented by the central IRC.


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7.4.
Identification and Measurement of Tumor Lesions and Organomegaly
7.4.1.
Index Lesions
At baseline, up to 6 lymph nodes 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. Only peripheral nodes need be selected as index lesions. 
However, it is optimal if mediastinal and retroperitoneal areas of disease are assessed whenever 
these sites are involved.
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 LD × the LPD will be recorded (in cm) for each index lesion. The product of the 
perpendicular diameters (PPD) for each index lesion and the SPD for all index lesions will be 
calculated and recorded. The baseline SPD will be used as references by which objective tumor 
response will be characterized during treatment. The nadir LD of individual lesions and the nadir 
SPD will be used as references by which CLL progression will be characterized. All LD and 
LPD diameters will be reported in centimenters and all PPDs and SPDs will be reported in 
centimeters squared.
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 1.5 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.
Index lesions measuring > 1.5 cm in the LD and > 1.0 cm in the LPD, will be prioritized during 
baseline index lesion selection.
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, 
(ie, if all lymph nodes measure < 1.0 cm2).
A new node that measures > 1.5 cm in the LD and > 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 sub-components Lesion sub-components will have the true 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.


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7.4.2.
Spleen and Liver
Both the spleen and liver should be assessed by physical examination and by CT/MRI scan at 
baseline and at the stipulated intervals during treatment. The baseline and nadir values for the 
longest vertical dimension (LVD) of each organ will be used as reference to further characterize 
the objective tumor response of the measurable dimensions of the CLL during treatment. All 
spleen and liver LVD measurements should be recorded in centimeters.
By imaging, the spleen will be considered enlarged if it is >12 cm in LVD {Bezerra 2005}, 
{Asghar 2011}, with the LVD being obtained by multiplying the number of sections on which 
the spleen is visualized by the thickness of the sections (eg, if the spleen is seen in 14 contiguous 
cross-sectional images with 0.5-cm thickness, the LVD is recorded as 7 cm).
For subjects with splenomegaly at baseline or at the splenic LVD nadir, respective response and 
progression evaluations of the spleen will consider only changes relative to the enlargement of 
the spleen at baseline or nadir, not changes relative to the total splenic LVD.
A 50% decrease (minimum 2 cm) from baseline in the enlargement of the spleen in its LVD or 
decrease to 12 cm in the s LVD is required for declaration of a splenomegaly response. 
Conversely, an increase in splenic enlargement by ≥50% (minimum increase of 2 cm) from 
nadir is required for declaration of splenic progression.
By imaging, the liver will be considered enlarged if it is > 18 cm in LVD {Erturk 2006}.
A 50% decrease (minimum 2 cm) from baseline in the enlargement of the liver in its LVD or to 
18 cm in the LVD is required for declaration of a hepatomegaly response. Conversely, an 
increase in liver enlargement by 50% (minimum increase of 2 cm) from nadir is required for 
declaration of hepatic progression.
7.4.3.
Non-Index Lesions
Any other measurable and abnormal nodal lesions not selected for quantitation as index lesions 
may be considered non-index lesions. In addition, non-measurable evidence of CLL such as 
nodal lesions with both diameters < 1.0 cm, extra-nodal lesions, 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, 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 
regression or progression of CLL during assessments of the objective tumor response during 
treatment. Measurements are not required and these lesions should be followed as 
“present” or “absent”.


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7.5.
Definitions of Tumor Response and Progression
Responses will be categorized by the IRC as CR, PR, SD, or 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 absence of tumor both at baseline and 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). BOR of CR or PR needs to be 
maintained at least 8 weeks to confirm a response. Subjects who initially responded but did not 
have an evaluable follow-up visit or did not maintain a response (i.e. progressed) for at least
8 weeks will not be counted as a confirmed responder. Subjects with a best overall response of 
NE or ND will be counted in the denominators in calculations of tumor response rates. Where 
imaging data are available, these data will supersede physical examination data in determining 
tumor status.
7.5.1.
Complete Response
To satisfy criteria for a CR, all of the following criteria must be met:

No evidence of new disease

ALC in peripheral blood of < 4 x 109/L

Regression of all index lesions to normal size ≤1.5 cm in the LD 

Normal spleen and liver size

Regression to normal of all nodal non-index disease and disappearance of all detectable 
non-nodal, non-index disease

Morphologically negative bone marrow defined as < 30% of nucleated cells being lymphoid 
cells and no lymphoid nodules in a bone marrow sample that is normocellular for age

Peripheral blood counts meeting all of the following criteria:
ANC > 1.5 x 109/L without need for exogenous growth factors (eg, G-CSF)
Platelet count ≥100 x 109/L without need for exogenous growth factors
Hemoglobin ≥110 g/L (11.0 g/dL) without red blood cell transfusions or need for 
exogenous growth factors (eg, erythropoietin)
Note: Subjects who fulfill all the criteria for a CR (including bone marrow criteria) but who 
have a persistent anemia, thrombocytopenia, or neutropenia or a hypocellular bone marrow 
that is related to prior or ongoing drug toxicity (and not to CLL) will be considered as a CR 
with incomplete marrow recovery (CRi).


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7.5.2.
Partial Response
To satisfy criteria for a PR, all of the following criteria must be met:

No evidence of new disease

A change in disease status meeting 2 of the following criteria, with 2 exceptions in which 
only 1 criterion is needed: (1) Only lymphadenopathy is present at baseline; 
(2) Only lymphadenopathy and lymphocytosis are present at baseline. In these 2 cases, only 
lymphadenopathy must improve to the extent specified below:
In a subject with baseline lymphocytosis (ALC ≥4 x 109/L), a decrease in peripheral 
blood ALC by 50% from baseline or a decrease to < 4 x 109/L
A decrease by ≥50% from the baseline in the SPD of the index nodal lesions
In a subject with enlargement of the spleen at baseline, a splenomegaly response as 
defined in Section 7.4.2
In a subject with enlargement of the liver at baseline, a hepatomegaly response as defined 
in Section 7.4.2
A decrease by ≥50% from baseline in the CLL marrow infiltrate or in B-lymphoid 
nodules
No index, splenic, liver, or non-index disease with worsening that meets the criteria for 
definitive PD

Peripheral blood counts meeting ≥1 of the following criteria:
ANC ≥1.5 x 109/L or ≥50% increase over baseline without need for exogenous growth 
factors (eg, G-CSF)
Platelet count ≥100 x 109/L or ≥50% increase over baseline without need for exogenous 
growth factors
Hemoglobin ≥110 g/L (11.0 g/dL) or ≥50% increase over baseline without 
red blood cell transfusions or need for exogenous growth factors (eg, erythropoietin)
7.5.3.
Stable Disease
To satisfy criteria for SD, the following criteria must be met:

No evidence of new disease

There is neither sufficient evidence of tumor shrinkage to qualify for PR nor sufficient 
evidence of tumor growth to qualify for definitive PD


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7.5.4.
Definitive Progressive Disease
The occurrence of any of the following events indicates definitive PD: 

Evidence of any new disease:
A new node that measures > 1.5 cm in the LD and >1.0 cm in the LPD
New or recurrent splenomegaly, with a minimum LVD of 14 cm
New or recurrent hepatomegaly, with a minimum LVD of 20 cm
Unequivocal reappearance of an extra-nodal lesion that had resolved
A new unequivocal extra-nodal lesion of any size
New non-index disease (eg, effusions, ascites, or other organ abnormalities 
related to CLL)
Note: Isolated new effusions, ascites, or other organ abnormalities are not sufficient 
evidence alone of PD unless histologically confirmed. Thus, a declaration of PD should 
not be made if this is the only manifestation of apparently new disease.

Evidence of worsening of index lesions, spleen or liver, or non-index disease:
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
Splenic progression, defined as an increase in splenic enlargement by 50% from nadir 
(with a minimum 2 cm increase and a minimum LVD of 14 cm)
Hepatic progression, defined as an increase in splenic enlargement by 50% from nadir 
(with a minimum 2 cm increase and minimum LVD of 20 cm)
Unequivocal increase in the size of non-index disease (eg, effusions, ascites, or other 
organ abnormalities related to CLL) 
Transformation to a more aggressive histology (eg, Richter syndrome) as established by 
lymph node or other tissue biopsy, or fluid cytology (with the biopsy or fluid cytology
date being considered the date of CLL progression if the subject has no earlier objective 
documentation of CLL progression). 


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
Decrease in platelet count or hemoglobin that is attributable to CLL, is not attributable to an 
autoimmune phenomenon, and is confirmed by bone marrow biopsy showing an infiltrate of 
clonal CLL cells
The current platelet count is < 100 x 109/L and there has been a decrease by > 50% from 
the highest on-study platelet count
The current hemoglobin is < 110 g/L (11.0 g/dL) and there has been a decrease by 
> 20 g/L (2 g/dL) from the highest on-study hemoglobin
Note: If there is uncertainty regarding whether there is true progression, the subject should 
continue study treatment and remain under close observation (eg, evaluated at 
4-week intervals) pending confirmation of progression status by the IRC. In particular, 
worsening of constitutional symptoms in the absence of objective evidence of worsening CLL 
will not be considered definitive disease progression; in such subjects, both CLL-related and 
non-CLL-related causes for the constitutional symptoms should be considered. Worsening of 
disease during temporary interruption of study treatment (eg, for intercurrent illness) is not 
necessarily indicative of resistance to study treatment. In these instances, CT/MRI or other 
relevant evaluations should be considered in order to document whether definitive disease 
progression has occurred. If subsequent evaluations suggest that the subject has experienced 
persistent definitive CLL progression, then the date of progression should be the timepoint at 
which progression was first objectively documented.
7.5.5.
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

Images of the liver and/or spleen are missing at that time point (with the exception that 
absence of splenic images will not result in an NE designation in a subject known to have
undergone splenectomy).
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.
7.5.6.
No Disease
Subjects have a status of ND if all of the following conditions occur

Index disease absent at both baseline and on-treatment

Non-index disease absent at both baseline and on-treatment


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
Enlargement of the liver and spleen absent at both baseline and on-treatment

Abnormalities of peripheral blood counts (elevated ALC and abnormally low 
ANC, platelet count, and hemoglobin) and evidence of CLL in bone marrow (if available) 
absent at both baseline and on treatment
7.6.
Lymphocytosis During Therapy
Idelalisib can mobilize CLL cells from tissues into the peripheral blood. This characteristic 
pharmacological action can be prominent early in therapy but can persist over time and should 
not be confused with disease progression in subjects who have persistent control of other 
CLL-related signs and symptoms. In the absence of other objective evidence of disease 
progression and on both arms of the study, the occurrence of lymphocytosis will not preclude 
subjects from meeting the criteria for a PR if other criteria for PR are met and will not be 
considered evidence of CLL progression if occurring in isolation. Subjects with lymphocytosis 
should be continued on study drug until the occurrence of definitive disease progression 
(ie, disease progression that is manifest by worsening CLL-related signs other than 
lymphocytosis alone), or the occurrence of another reason to discontinue study drug as described 
in Section 5.8.
7.7.
Documentation of Definitive CLL Progression
Of importance, CLL response and progression data will be subjected to IRC review 
(see Section 10.4.2). The subject should continue study drug pending confirmation of 
progression status. CT/MRI should be attempted in order to document definitive disease 
progression, and thus allow objective confirmation by the IRC.


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8.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
8.1.
Definitions of Adverse Events, Adverse Reactions and Serious Adverse 
Events
8.1.1.
Adverse Event
An adverse event (AE) is any untoward medical occurrence in a clinical study subject which
does not necessarily have a causal relationship with the treatment. An AE can therefore be any 
unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. AEs may also 
include pre- or post-treatment complications that occur as a result of protocol specified 
procedures. Preexisting events that increase in severity or change in nature during or as a 
consequence of participation in the clinical study will also be considered AEs.
An AE does not include the following:

Lymphocytosis

Laboratory abnormalities not requiring clinical intervention or further investigation. Such 
abnormalities will be captured as part of overall laboratory monitoring

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion. 
The condition that led to the procedure may be an adverse event and must be reported

Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (eg, hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not at 
AE. It is considered to be pre-existing and should be documented on the medical history 
eCRF
8.1.2.
Serious Adverse Events
A serious adverse event (SAE) is defined as an event that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.)


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
In-patient hospitalization or prolongation of existing hospitalization

Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. Infections resulting from contaminated medicinal product will be considered a 
medically important event and subject to expedited reporting requirements.
8.1.2.1.
Protocol-Specific Serious Adverse Event Instructions
Hospital admissions for administration of the study drug, procedures required by the study 
protocol, or tumor-related diagnostic procedures are not considered SAEs.
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to IMP interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Sections 8.1.1 and 8.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (eg, anemia), not the 
laboratory result (ie, decreased hemoglobin).
8.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified sub-investigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.


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8.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified sub-investigator is responsible for assessing the relationship to IMP 
therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the IMP. For SAEs, an 
alternative causality must be provided (eg, pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting.
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures (eg, venipuncture)
8.2.2.
Assessment of Severity
The severity of adverse events will be graded using the CTCAE, Version 4.03. 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 8-1.
Table 8-1.
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.


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The distinction between the seriousness and the severity of an adverse event should be noted. 
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 8.1.2.
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead or Designee
All SAEs, regardless of cause or relationship, that occur after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
eCRF database and Gilead Drug Safety and Public Health (DSPH) or designee as instructed. 
This also includes any SAEs resulting from protocol-associated procedures performed from 
screening onwards.
All AEs, regardless of cause or relationship, that occur from initiation of study medication until 
30 days after last administration of study IMP must be reported to the eCRF database as 
instructed.
Any SAEs and deaths that occur after the post treatment follow-up visit but within 30 days of the 
last dose of study IMP, regardless of causality, should also be reported.
All AEs should be followed up until resolution if possible. If by the last day on study 
(including the off-study medication follow-up period) the AE has not resolved, then the AE will 
be followed up until the investigator and/or Gilead Sciences determine that the subject's 
condition is stable. However, Gilead Sciences may request that certain AEs be followed until 
resolution.
Investigators are not obligated to actively seek SAEs after the 30 day period. However, if the 
investigator learns of any SAEs that occur after study participation has concluded and the event 
is deemed relevant to the use of IMP, he/she should promptly document and report the event to 
Gilead DSPH or designee as instructed.
All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guidelines.
SAEs will be reported using a paper SAE reporting form. During the course of the study, there 
may be a transition to an electronic SAE (eSAE) system. Gilead will notify sites in writing and 
provide training and account information prior to implementing an eSAE system.
All SAEs will be recorded on the SAE report form and submitted by faxing the report form 
within 24 hours of the investigator’s knowledge of the event to the attention of Gilead DSPH or 
to the designated CRO.


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8.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable 
US FDA Code of Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and 
relevant updates, and other country-specific legislation or regulations, Gilead may be required to 
expedite to worldwide regulatory agencies reports of SAEs, serious adverse drug reactions 
(SADRs), or suspected unexpected serious adverse reactions (SUSARs). In accordance with the 
EU Clinical Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide 
regulatory agencies and the relevant IEC in concerned Member States of applicable SUSARs as 
outlined in current regulations.
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.
All investigators will receive a safety letter notifying them of relevant SUSAR reports. The 
investigator should notify the IRB/IEC of SUSAR reports as soon as is practical, where this is 
required by local regulatory agencies, and in accordance with the local institutional policy.
8.4.1.
Reporting of Adverse Events Relating to the Primary Endpoint and Other 
Anticipated Medical Events in the Study Population
Given the endpoints of the study and in order to maintain the integrity of the study, the following 
events that are assessed as unrelated to IMP will not be considered SAEs:

Progression of CLL

Death related to progression of CLL
Disease progression and death from disease progression should be reported as SAEs by the 
investigator only if it is assessed that the study drugs caused or contributed to the disease 
progression (ie, by a means other than lack of effect). Unrelated disease progression should be 
captured on the eCRF.
These will be reported, as appropriate, in the final clinical study report and in any relevant 
aggregate safety reports.  The safety information from this study will also be reviewed by an 
independent DMC on an ongoing basis.
8.5.
Toxicity Management
Please refer to the current Idelalisib IB and local ofatumumab prescribing information for 
information related to toxicity management. See Section 5.3.4 for more information related to 
recommended dose modifications associated with toxicities.
8.5.1.
Warnings & Precautions
Refer to the current Idelalisib IB for updated information. At the time of protocol approval, the 
following Warnings and Precautions were relevant.


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8.5.1.1.
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 repeated 
throughout the program and transaminase elevations are now well characterized as follows: they 
occur within the first 3 months of treatment; are generally asymptomatic and transient in nature; 
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 lower dose levels 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 early during therapy is therefore important to permit 
appropriate study drug (idelalisib) interruption and reinstitution so that subjects who appear to be 
benefiting can continue with study drug treatment.
8.5.1.2.
Severe Diarrhea
Cases of ≥ Grade 3 diarrhea have been reported in subjects with hematologic malignancies 
treated with idelalisib for which the more common etiologies anticipated for the study population 
could not be readily identified. In the majority of such cases, subjects presented after several 
months of idelalisib administration with several weeks of watery diarrhea unresponsive to 
antidiarrheals or to empiric treatment with antimicrobials. Resolution has been documented in 
almost all cases, and treatment regimens have included budesonide, mesalamine, systemic 
steroids, and supportive care, with some subjects receiving more than 1 treatment approach 
concomitantly. Resolution of the diarrhea occurred within approximately 1 month from the 
discontinuation of idelalisib (regardless of treatment approach.) In subjects with ≥Grade 3 
diarrhea who were rechallenged with idelalisib, recurrence of diarrhea has occurred in some but 
not all subjects.
For subjects who develop severe persistent diarrhea for which an underlying etiology cannot be 
identified (eg, infection), study drug (idelalisib) should be interrupted. Resumption of study drug 
should be considered once diarrhea resolves if the subject is experiencing evidence of clinical 
benefit from therapy. Refer to Gastrointestinal Inflammation/Diarrhea section in Table 5-4 for 
specific instruction related to Grade. 
8.5.1.3.
Maculopapular Rash
Rash in association with idelalisib was first reported in Study 101-01, a Phase 1, 
placebo-controlled, sequential dose escalation study in healthy male volunteers. 
Three of 6 subjects at the 200 mg dose experienced mild (2 subjects) and moderate (1 subject) 
rashes on Day 7 of idelalisib exposure. One subject was rechallenged with 100 mg BID idelalisib 
for 7 days with no recurrence. A second subject was rechallenged with 200 mg BID idelalisib 


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and on Day 5 had a recurrence of rash on the thorax. Skin biopsies of the rash following 
rechallenge showed a histological pattern consistent with a maculopapular exanthema due to 
delayed type hypersensitivity reaction. In the Phase 1 study 101-02, rash was among the most 
frequently reported AEs, although the frequency of ≥ Grade 3 and serious dermatological AEs 
have remained low. Subjects 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 steroids. 
The occurrence of ≥Grade 3 rash has been more frequent when idelalisib was administered in 
combination with immunochemotherapy agents. Rechallenge with idelalisib has resulted in 
recurrence of rash in some but not all subjects. 
For subjects who develop a severe maculopapular rash for which an underlying etiology cannot 
be identified (eg, infection, co-suspect drug), study drug (idelalisib) should be interrupted. 
Resumption of study drug should be considered once rash resolves if the subject is experiencing 
evidence of clinical benefit from therapy.
8.5.1.4.
Pneumonitis and Organizing Pneumonia
Some subjects receiving idelalisib alone or in combination have developed evidence of 
pneumonitis or organizing pneumonia with infection having been ruled out on bronchoscopy. 
Some of these events have required mechanical ventilation or have been fatal. Nonclinical 
evaluations of pulmonary function and pathology do not indicate a direct toxic effect of idelalisib 
on the lungs, and disease-related factors or toxicity from prior or concomitant therapies may 
have contributed to these clinical events.
For subjects with suspected Grade 1 pneumonitis, withhold idelalisib until resolution to baseline. 
Upon resolution to baseline, idelalisib may be resumed at lower dose level or discontinued at 
investigator discretion. For subjects with suspected 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.
Idelalisib has induced embryo lethality and teratogenicity when administered to pregnant female 
rats at maternally toxic doses. The specific effects of idelalisib on human embryogenesis, fetal 
development, or post-natal development are unknown.
All female subjects of reproductive potential are required to have a negative pregnancy test prior 
to initial study drug (idelalisib) administration. Idelalisib must not be administered to female 
study participants of childbearing potential unwilling to use protocol-specified highly effective 
contraception with heterosexual intercourse. Administration to female study participants who are 
breastfeeding is prohibited. Female study subjects who become pregnant must be removed from 
study drug (idelalisib) therapy as soon as pregnancy is diagnosed. If an in utero study drug 
exposure in a female subject occurs or a male subject receiving study drug conceives a child, 
Gilead must be notified immediately and follow up reporting actions must be taken as specified 
in study protocols.


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8.5.1.5.
Drug-Drug Interactions
Consistent with nonclinical data indicating that GS-563117, the dominant idelalisib metabolite,
is a reversible and time-dependent inhibitor of CYP3A, coadministration with idelalisib resulted 
in higher midazolam systemic exposures (AUC: approximately 5-fold increase; 
Cmax: approximately 2.3-fold increase), indicating that idelalisib is a strong inhibitor of CYP3A. 
Accordingly, 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, and warfarin). 
Avoid coadministration of idelalisib with 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, and terfenadine).
Preliminary data indicate when coadministered with rifampin, a highly potent inducer of 
CYP3A, idelalisib exposures are approximately 75% lower. Coadministration of potent inducers 
of CYP3A (rifampin, carbamazepine, phenytoin, and St. John’s wort) with Idelalisib should be 
avoided.
8.6.
Special Situations Reports
8.6.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, lack of 
effect reports and pregnancy reports regardless of an associated AE. They also include reports of 
adverse reactions in infants following exposure from breastfeeding, and reports of 
adverse reactions associated with product complaints and reports arising from occupational 
exposure.

A pregnancy report is used to report any pregnancy in female subjects on study or female 
partners of male subjects on study.

Medication error is any unintentional error in the prescribing, dispensing, or administration 
of a medicinal product while in the control of the health care provider, subject, or consumer.

Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by 
a subject.

Misuse is defined as any intentional or inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.

An overdose is defined as an accidental or intentional administration of a quantity of a 
medicinal product given per administration or cumulatively which is above the maximum 
recommended dose as per protocol or in the product labelling (as it applies to the daily dose 
of the subject in question). In cases of a discrepancy in drug accountability, overdose will be 
established only when it is clear that the subject has taken the excess dose(s). Overdose 
cannot be established when the subject cannot account for the discrepancy except in cases in 
which the investigator has reason to suspect that the subject has taken the additional dose(s).


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
Lack of effect is defined as a situation where there is apparent failure of the medicinal 
product or medical technology to bring about the intended beneficial effect on the individual 
in a defined population with a given medical problem, under ideal conditions of use.

Product complaint is defined as complaints arising from potential deviations in the 
manufacture, packaging, or distribution of the medicinal product.
8.6.2.
Instructions for Reporting Special Situations
8.6.2.1.
Instructions for Reporting Pregnancies
The investigator should report all pregnancies that are identified after the subject first consents to 
participate in the study (ie, signs the informed consent) and throughout the study, including the 
post study drug follow-up period, to Gilead DSPH or designee using the pregnancy report form 
within 24 hours of becoming aware of the pregnancy. Refer to the eCRF completion guidelines 
for full instructions on the mechanism of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE, and therefore should be reported as 
such. Furthermore, any SAE occurring as an adverse pregnancy outcome post study must be 
reported to Gilead DSPH or designee.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead DSPH or designee using the pregnancy 
outcome report form. If the end of the pregnancy occurs after the study has been completed, the 
outcome should be reported directly to Gilead DSPH. 
Pregnancies of female partners of male study subjects exposed to Gilead or other drugs required 
on study (ofatumumab) must also be reported and relevant information should be submitted to 
Gilead DSPH or designee using the pregnancy and pregnancy outcome forms within 24 hours. 
Monitoring of the subject should continue until 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 DSPH.
Gilead DSPH contact information is as follows: Email:
 and 
Fax:
Refer to Section 5.5.3 for Pregnancy Precautions, Definitions for Female of Childbearing 
Potential, and Contraceptive Recommendations.
PPD
PPD


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8.6.2.2.
Reporting Other Special Situations
All other special situations (excluding pregnancy) must be reported on the special situations 
report form and forwarded to Gilead DSPH or designee within 24 hours of the investigator 
becoming aware of the situation. These reports must consist of situations that involve study IMP, 
but do not apply to concomitant medications. Any inappropriate use of medications prohibited by 
this protocol should not be reported as “misuse,” but may be more appropriately documented as a 
protocol deviation.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and 
signs, clinical management, and outcome will be reported, when available.


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9.
STATISTICAL CONSIDERATIONS
9.1.
Analysis Objectives
As noted in Section 3.1, the primary objective of this clinical trial will be to evaluate the effect of 
the addition of idelalisib to ofatumumab on PFS.
As described in Section 3.2, the secondary objectives of this clinical trial will focus on 
determining the effect of the addition of idelalisib to ofatumumab on the onset, magnitude, and 
duration of tumor control; measures of patient well-being (including OS, HRQL; and changes in 
subject performance status); disease-associated biomarkers and potential mechanisms of 
resistance; treatment administration; safety; and health resource utilization.
9.2.
Analysis Endpoints
9.2.1.
Primary Endpoint
The primary endpoint of the study is PFS, as defined in Section 3.3.
9.2.2.
Secondary and Exploratory Endpoints
The secondary and exploratory endpoints of the study are defined in Section 3.4, grouped in 
categories relating to tumor control, patient well-being, pharmacodynamic markers of drug 
activity and resistance, exposure, safety, and pharmacoeconomics.
Of these endpoints, 5 endpoints are designated as secondary endpoints for which sequential 
testing will be performed to control Type I error rate (see Section 9.4.1.6). These secondary 
endpoints will be ORR, lymphadenopathy node response rate, OS, PFS in the subgroup of 
subjects with 17p deletion and/or TP53 mutatation, and CR rate. Other endpoints will be 
considered exploratory.
9.3.
Analysis Conventions
9.3.1.
Analysis Sets
9.3.1.1.
Intent-to-Treat Analysis Set
The ITT analysis set includes data from all subjects who are randomized regardless of whether 
subjects receive any study drug(s), or receive a different regimen from that to which they were 
randomized. Study drug assignment will be designated according to randomization.
This analysis set will be used in the analyses of subject characteristics, PFS, ORR, OS, CR rate
and health outcome variables. The analysis of PFS based on the ITT analysis set will be 
considered the primary analysis of the study. Subjects in the ITT analysis set 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 of NE or ND) will be included in the denominators in 
calculations of response rates.


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9.3.1.2.
Per-Protocol Analysis Set
The PP analysis set includes data from subjects in the ITT analysis set who meet the general 
criteria defining the target population for this study, are adherent to the protocol, are compliant 
with study drug treatment, and are evaluable for relevant efficacy endpoints. Study drug 
assignment will be designated according to the actual treatment received. The specific 
classification of subjects to be included in the PP analysis set will be included in the statistical 
analysis plan which will be finalized prior to database lock.
The PP analysis set will be used in sensitivity analyses of the primary and the following 
secondary efficacy variables: PFS, ORR, lymphadenopathy node response rate, and PFS in the 
subgroup of subjects with 17p deletion and/or TP53 mutation.
9.3.1.3.
Safety Analysis Set
A safety analysis set will include data from subjects who receive 1 dose of study treatment, 
with treatment assignments designated according to the actual treatment received.
This analysis set will be used in the analyses of safety variables as well as study treatment 
administration (for idelalisib and ofatumumab), and post-study therapy.
9.3.1.4.
Pharmacodynamic/Pharmacokinetic Analysis Sets
The pharmacodynamic/pharmacokinetic analysis sets include data from subjects in the safety 
analysis set who have the necessary baseline and on-study measurements to provide interpretable 
results for the specific parameters of interest.
These analysis sets will be used in the analyses of AKT phosphorylation, chemokines/cytokines, 
and idelalisib plasma concentrations.
9.3.2.
Data Handling Conventions
9.3.2.1.
General Methods
By-subject listings will be created for important variables from each eCRF module. 
Summary tables for continuous variables will contain the following statistics: 
N (number in analysis set), n (number with data), mean, and standard deviation, 
95% confidence intervals (CIs) on the mean, median, minimum, and maximum. Summary tables 
for categorical variables will include: N, n, percentage, and 95% CIs on the percentage. Unless 
otherwise indicated, 95% CIs for binary variables will be calculated using the 
binomial distribution (exact method) and will be 2-sided. Data will be described and summarized 
by relevant treatment arm, analysis set, and timepoint. As appropriate, changes from baseline to 
each subsequent timepoint will be described and summarized by treatment arm. Similarly, as 
appropriate, the best change from baseline during the study will also be described and 
summarized by treatment arm. Graphical techniques (eg, waterfall plots, Kaplan-Meier curves, 
line plots) may be used when such methods are appropriate and informative.


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The baseline value used in each analysis will be the last (most recent) pre-treatment value. 
Subjects with discrepancies between the stratification factor values at randomization and the 
actual values as documented on data review will be categorized in the analyses according to the 
actual values. In the situation that there is insufficient information in a stratum (ie, if there are 
< 6 subjects or there is no informative event in a stratum), that stratum will be pooled with the 
smallest adjacent stratum for stratified analyses; the smallest stratum is defined as that stratum 
having the fewest number of subjects or the fewest number of events in case the former is a tie 
and the adjacent stratum is defined as a stratum having 2 factors of the 3 at the same level. 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.
9.3.2.2.
Calculation of Tumor Control and Patient Well-being Variables
Tumor control assessments will be based on standardized IWCLL criteria {Hallek 2008}, as 
specifically modified for this study considering the pharmacology of idelalisib and ofatumumab.
The individual and composite endpoints of response and progression (considering changes in 
lymph node area, liver and spleen size, bone marrow, platelet counts, hemoglobin, neutrophil 
counts, and peripheral blood lymphocyte counts) will be determined. Tumor control will be 
documented at each assessment by response category (eg, CR, PR, SD, definitive PD, NE, ND) 
as defined for each response parameter, SPD value, percentage change in SPD values from 
baseline or nadir, date that response is first documented, date that response is confirmed, and 
date of definitive CLL progression.
The date of definitive CLL progression will be the timepoint at which progression is first 
identified by relevant objective radiographic or laboratory data. Where imaging data are 
available, these data will supersede physical examination data in determining tumor status. For 
purposes of analysis, subjects who have only physical examination evidence of definitive disease 
progression that is not confirmed by CT/MRI will be considered to have progressed at the time 
of the physical examination finding. Because of the characteristic redistribution lymphocytosis 
that expected with PI3Kinhibition, lymphocyte count will be ignored in the evaluations of 
progression.
Changes in tumor status as provided by the investigator and changes in tumor status as 
adjudicated by the IRC (see Section 10.4.2) will be described. The findings of the IRC will be 
considered primary for analyses of PFS and other tumor control endpoints.
The following censoring conventions will be applied:

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 definitive CLL progression was objectively documented. Data from subjects who 
have CLL progression or die after 2 consecutive missing tumor assessments will be
censored at the last time prior to the missing assessments that lack of definitive CLL 
progression was objectively documented.


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
DOR: 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 definitive CLL progression was objectively documented.

OS: Data from surviving subjects will be censored at the last time that the subject was known 
to be alive.
9.4.
Analysis Plan
9.4.1.
Subject Disposition and Baseline Characteristics
A listing of all ITT analysis set subjects will be generated to describe site, subject number, 
first screening date, first treatment date, subject stratification, randomized treatment arm 
assignment (Arm A or Arm B), actual treatment arm allocation (Arm A or Arm B), the longest 
duration of study drug and ofatumumab treatment, and the reason for discontinuing study 
treatment. Available information on subjects who were screened or registered but not 
randomized or not treated will be listed separately. A table will be created summarizing these 
categories in terms of number and percent for the ITT analysis set.
Subject baseline characteristics will be listed and summarized by treatment arm and stratification 
factor for the ITT and responding analysis sets. Baseline data (eg, from the CIRS or FACT-Leu) 
will not be reconciled with other medical information (eg, adverse event data or 
past medical history data). Efficacy Analyses
9.4.1.1.
Primary and Supportive Analyses of the Primary Endpoint
For the primary efficacy analysis, the difference in PFS between the treatment arms will be 
assessed in the ITT analysis set using Kaplan-Meier methods and the stratified log-rank test, 
adjusted for the stratification factors. Medians, ranges, the proportion of subjects who are 
progression-free at 24 and 48 weeks from randomization (based on Kaplan-Meier estimates), 
hazard ratios and corresponding 95% CIs (as calculated using a Cox proportional hazards 
regression model) will be presented.
The following exploratory sensitivity analyses will be performed:

PFS will be compared between the treatment arms in the ITT analysis set using 
Kaplan-Meier methods and an unstratified log-rank test.

PFS will also be compared between treatment arms in the PP analysis set using 
Kaplan-Meier methods and a stratified log-rank test.

PFS will be further analyzed by censoring data from surviving, non-progressing subjects only 
at the last time that lack of definitive CLL progression was objectively documented. An 
additional worst-case sensitivity analysis will be performed in which surviving, 
nonprogressing subjects who are lost to follow-up are categorized as having an event at the 
time of the last known CLL tumor status assessment if they were in Arm A and are 
categorized as censored at the time of the last known CLL tumor status assessment if they 
were in Arm B. These analyses will be performed in the ITT analysis set using 
Kaplan-Meier methods and the stratified log-rank test.


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The Cox regression approach will be used to explore the influences of the stratification factors, 
other baseline characteristics, and treatment on PFS. Beyond the stratification variables, 
additional baseline subject characteristics may be included as covariates, focusing on those with 
expected prognostic significance, particularly if these show imbalance between treatment groups. 
For the Cox regression modeling, a stepwise selection process will be applied to these variables 
to identify the final subset of relevant factors. Each prognostic factor will be preliminarily 
evaluated in the Cox regression model. Only the variables significant at the 0.20 level will be 
considered to build the multivariate model. A forward selection process will be applied to these 
variables to identify the final subset of relevant factors. Once a model has been established, 
treatment will be added to the final subset of factors to study its effect on the model. 
Treatment-by-factor interactions will be explored for the subset of factors included in the final 
model.
9.4.1.2.
Other Time-to-Event Tumor Control and Survival Endpoints
Differences between the treatment arms in TTR, DOR, and OS will be assessed in the appropriate 
analysis set using Kaplan-Meier methods and stratified log-rank tests. Medians, ranges, 
hazard ratios and corresponding 95% CIs will be presented.
A supportive Cox regression analysis of OS in the ITT analysis set will be performed using the 
same methods as in the analysis of PFS if a sufficient number of events occur.
Sensitivity analysis for ORR, CR rate, DOR, and TTR will be performed based on responses 
without the need for confirmation.
9.4.1.3.
Categorical Endpoints
Differences between Arms A and B for ORR, CR and PR rates, nodal response rate, 
splenomegaly response rate, hepatomegaly response rate, ALC response rate, platelet response 
rate, hemoglobin response rate, and neutrophil response rate will be compared using 
Cochran-Mantel-Haenszel Chi-square tests for association between treatment and response, after 
adjusting for stratification factors. In the analyses of ORR, subjects who do not have sufficient 
baseline or on-study tumor assessment to characterize response will be counted as failures. For 
all analyses, odds ratios and the corresponding 95% CIs will be presented.
The potential influence of subject baseline characteristics and of treatment on response rates will 
be explored with logistic regression modeling.
9.4.1.4.
Continuous Endpoints
Differences between treatment arms for percentage changes in lymph node area and for changes 
in performance status, PI3K/AKT/mTOR pathway activation, and plasma chemokines/cytokines 
will be assessed using analysis of covariance (ANCOVA) with baseline values and stratification 
factors as covariates; in these analyses, both changes from baseline to each subsequent timepoint 
and best overall on-study changes will be compared. Least-squares means and 95% CI will be 
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9.4.1.5.
Health-Related Quality of Life and Performance Status
The FACT-Leu questionnaire data will be scored, processed, and standardized 
(ranging from 0-100) according to the user manual. Missing items in a subscale will be imputed 
consistently with the user manual instructions. Data collected from the FACT-Leu instrument 
will not be reconciled with adverse event or laboratory data or with EQ-D5 findings.
The mean and change from baseline in mean scores to each subsequent assessment will be
summarized for the FACT-Leu 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. Mixed-effects models will be used to assess the 
treatment effect on change from baseline over time.
The EQ-5D questionnaire data will be scored, processed, and standardized according to the user 
manual. U.S. preference-weighted index score computed using EQ-5D data {Shaw 2005} will be 
calculated. Change from baseline in EQ-5D visual analogue scale and EQ-5D index will be 
summarized and analyzed using mixed-effects models.
9.4.1.6.
Control of Type I Error Rate in Efficacy Analyses
In the efficacy analyses, the following procedures will be implemented to preserve the overall 
type I error rate across the primary and secondary endpoints of the study at a 2-sided 
significance level of 0.05.
The primary endpoint analysis will serve as the gatekeeper for the secondary endpoint analyses, 
ie, the primary efficacy hypothesis must be made before the efficacy hypotheses for the 
secondary efficacy endpoints can be tested. The secondary endpoints will be the following:

ORR

Lymphadenopathy node response rate

CR rate

OS

PFS in the subgroup of subjects with 17p deletion and/or TP53 mutation 
If the primary hypothesis is rejected, the 5 secondary endpoints will be sequentially tested at the 
2-sided 0.03 significance level in the order listed above. If a null hypothesis is not rejected, 
formal sequential testing will be stopped and only nominal significance will be cited for the
remaining secondary endpoints. Analyses and p-values will be reported for all the efficacy 
endpoints, including the primary endpoint, the secondary endpoints, and all of the exploratory 
endpoints.


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9.4.2.
Exposure and Safety Analyses
9.4.2.1.
Study Drug Administration and Study Drug Compliance
Descriptive information will be provided by treatment arm regarding the number of doses of 
idelalisib and ofatumumab prescribed, the total number of doses taken, the percent of expected 
doses taken, the number of days (or infusions) of treatment, and the number and timing of 
prescribed dose reductions and interruptions.
Idelalisib compliance will be described by treatment arm 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).
9.4.2.2.
Idelalisib Plasma Concentrations
The idelalisib plasma concentrations immediately pre-dose and at 1.5 hours after administration 
of the dose of study drug at each relevant clinic visit among subjects treated on Arm A of the 
study will be summarized and visit using descriptive statistics.
9.4.2.3.
Prior and Concomitant Medication Use
Prior and concomitant medications will be coded by means of the World Health Organization 
Drug Dictionary (WHODRUG) dictionary into Anatomical-Therapeutic-Chemical classification 
(ATC) codes.
Descriptions of prior medication use will be focused on drugs and regimens used as treatments 
for CLL. To the extent available, information on the sequencing, type, dose, schedule, timing, 
duration of use, and efficacy of prior regimens will be provided.
The type and timing of use of concomitant medications will be listed and summarized by type 
and treatment arm. Information regarding the type and use of specific supportive medications 
(eg, pneumocystis prophylaxis, hematopoietic growth factors, and corticosteroids) during study 
treatment, and within 30 days post-study treatment, will be described.
9.4.2.4.
Adverse Events
All adverse events will be listed. The focus of adverse event 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 from the first dose of study treatment 
(idelalisib or ofatumumab) to 30 days after the last dose of study drug.
Adverse events will be classified using MedDRA (http://www.meddra.org) with descriptions by 
System Organ Class, High-Level Group Term, High-Level Term, Preferred Term, and Lower-
Level Term. The severity of adverse events will be graded by the investigator according to the 
CTCAE, Version 4.03 (http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf), whenever possible. If a CTCAE criterion does not exist for a 
specific type of adverse event, the grade corresponding to the appropriate adjective will be used 


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by the investigator to describe the maximum intensity of the adverse event: Grade 1 (mild), 
Grade 2 (moderate), Grade 3 (severe), Grade 4 (life threatening), or Grade 5 (fatal). The 
relationship of the adverse event to the study drug will be categorized as related or unrelated.
Separate listings and summaries will be prepared for the following types of treatment-emergent 
adverse events:

Study-treatment-related (idelalisib or ofatumumab) adverse events

Adverse events that are Grade 3 in severity

Adverse events leading to study treatment (idelalisib or ofatumumab) interruption and/or 
dose modification

Adverse events leading to study drug (idelalisib or ofatumumab) discontinuation

Serious adverse events (with categorization of the primary reason that the adverse event is 
considered serious, eg, death, hospitalization, etc)
The severity of ofatumumab-related infusion reactions and of the total durations of ofatumumab 
infusions will be compared between treatment arms to determine whether idelalisib pretreatment 
modifies the magnitude of such events or alters the length of the ofatumumab infusion due to 
such events; the focus of this analysis will be on the first 2 ofatumumab infusions 
(ie, those on Study Day 1 and on Day 8). However, assessment of infusion reaction severity and 
duration will be performed for all 12 planned infusions of ofatumumab. Comparisons will be 
done using the Chi-square test for severity grade and the Wilcoxon rank-sum test for infusion 
duration.
Separate listings and summaries will be prepared for long-term follow-up safety data.
9.4.2.5.
Laboratory Evaluations
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
(idelalisib or ofatumumab) 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 central laboratory will be used to determine programmatically if 
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Hematological and serum biochemistry and their changes from baseline will be summarized by 
treatment arm, by visit, and by combination therapy vs monotherapy periods 
(during ofatumumab treatment vs following ofatumumab treatment). 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 by showing change in 
CTCAE severity grade from baseline to the worst grade post baseline. 
Separate listings and summaries will be prepared for laboratory abnormalities that are Grade 3 
in severity.
9.4.2.6.
Oxygen Saturation Values
All oxygen saturation data will be listed. Summaries of oxygen saturation data will be based on 
observed data and will be reported as % saturation. Data and changes from baseline will be 
summarized by treatment arm, by visit, and by combination therapy vs monotherapy periods 
(during ofatumumab treatment vs following ofatumumab treatment). Summary tables will be 
presented for values below 92% and for declines from baseline of 5% to show the number of 
subjects with corresponding percentages. Subjects will be characterized only once for each of 
these categorizations, based on their lowest value observed during a period of interest 
(eg, during the study or from baseline to a particular visit).
9.4.3.
Other Analyses
9.4.3.1.
Health Care Resource Utilization
The EQ-D5 questionnaire data will be scored, processed, and standardized according to the user 
manual. As for the FACT-Leu, data will be analyzed using appropriate methods specified in the 
user manual to account for incomplete completion of questionnaires. Data collected from the 
EQ-D5 will not be reconciled with adverse event or laboratory data or with FACT-Leu findings.
Health care resource utilization data collection will be based on information provided in the 
eCRFs and will be focused on the most relevant direct medical resource utilization such as 
physician visits, laboratory tests, medications (including dose and route), medical procedures, 
interventions (eg, transfusions), and hospitalizations.
The basic approach to the health economic analysis will be to combine the resource utilization 
data from the trial with data on unit prices (collected separately) to estimate total costs in 
preparation for a full-cost analysis.


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The perspective of this analysis will be that of the third-party payer(s) and the hospital over a 
lifetime horizon in the base case. One possibility is that the addition of idelalisib to ofatumumab 
will reduce costs directly and, if so, perhaps no further analysis will be required. A second 
possibility is that the addition of idelalisib to ofatumumab will increase costs overall. In this 
latter case the increase in costs due to adding idelalisib to treatment will be compared relative to 
the health care gains as measured by duration of tumor control, the symptom-free survival 
period, life-years saved (gained), utility gains or other measure of appropriate clinical benefits. In
order to facilitate the calculation of utilities for use in the cost effectiveness analyses, the health 
status of subjects will be evaluated using PFS, Karnofsky performance status, FACT-Leu, and 
EQ-5D. One-way, 2-way, and probabilistic sensitivity analyses will be conducted to assess the 
robustness of the results.
9.4.3.2.
Data Explorations
Changes in biomarkers during acquisition of resistance will be evaluated descriptively. Data 
explorations may be performed to evaluate potential associations between subject characteristics 
and outcome measures. Similarly, explorations may be performed to assess the potential 
associations between different outcomes measures (eg, relationships between HRQL changes 
and clinical/radiographic endpoints of tumor control).
9.5.
Sample Size
Based on data from the Phase 2 pivotal study ofatumumab {Wierda 2010} and considering the 
population of subjects to be enrolled to this study, it is reasonable to assume that administration 
of ofatumumab to subjects with previously treated CLL in Arm B of this trial will result in a 
median PFS of ~8 months. An improvement in median PFS from 8 months to 14 months due to 
the addition of idelalisib to ofatumumab in Arm A of the study would correspond to a 
benefit ratio of 1.75 (hazard ratio 0.57).
It is assumed that PFS times are exponentially distributed in each of the 2 arms. With a 
hazard ratio equal to 1 under the null hypothesis of no difference between the 2 treatment arms 
and a hazard ratio of 0.57 under the alternative hypothesis of superiority of the 
idelalisib-containing combination, 129 events (definitive CLL progressions or deaths) are 
required to achieve a power of >0.85 based on a log-rank test with a 2-sided significance level 
of 0.05. Further assuming a planned accrual period of 12 months (with approximately 
half of the subjects enrolled during the initial 60% of the accrual period, and the remaining 
half of the subjects enrolled during the last 40% of the accrual period), a minimum follow-up 
period of 12 months, and an expectation that 10% of subjects will be lost to follow-up 
(5% during the accrual period and 5% during the follow-up period), and to ensure the primary 
analysis on PFS will be performed before or at the planned minimum 12-month follow-up 
period, 170 subjects will be enrolled into Arm A and 85 subjects will be enrolled into Arm B in 
order to achieve the expected number of events by the end of the planned minimum 12-month 
follow-up period. If the planned subject enrollment does not appear adequate to accrue the 
expected number of events within the proposed follow-up period, the sample size may be 
adjusted upward.


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It is expected that there will be approximately 65 deaths at the time of final analysis. This would 
provide ~85% power to detect a HR of 0.45 for overall survival based on a log-rank test at 
2-sided alpha level of 0.03.
The resulting safety data set provided by the idelalisib-treated subjects (N=170) compares 
favorably with the safety data set derived from the initial pivotal registration trials for 
ofatumumab (N=138) {Wierda 2010}, oral fludarabine (N=78) {Boogaerts 2001}, or 
alemtuzumab (N=93) {Keating 2002a}.
9.6.
Timing of Analyses
9.6.1.
Interim Analysis
The DMC will have access to serious adverse events requiring expedited reporting and will be 
provided with accumulating safety data on a regular basis. An interim safety review will be 
conducted by the DMC at ~6 months after the first subject is enrolled. Thereafter, interim safety 
reviews will be performed by the DMC at intervals of ~6 months; the specific frequency of these 
reviews will depend upon the rate at which the trial is enrolled, the nature of any emerging safety 
signals, and monitoring recommendations from the DMC. At each review, all available safety 
data will be summarized and evaluated.
Two formal interim efficacy analyses for PFS are planned. The first interim analysis will be 
performed when ~50% of the expected 129 events occur. The second interim will be performed 
when ~75% of the expected events occur. Type I error rate for testing PFS will be controlled by 
using the O’Brien-Fleming boundaries. Based on the planned number of PFS events for the 
2 interim analyses, the 2-sided alpha for the interim and the final analyses are 
(0.003, 0.018, 0.044). The significant levels will be recalculated based on the actual observed 
number of events at the time of the interim and final analyses.
9.6.2.
Final Efficacy Analysis
The efficacy analysis will be conducted after approximately 129 events (definitive CLL
progression or death) are accrued. It is expected that this number of events will occur after a 
minimum of approximately 12 months of follow-up. Once outstanding data queries have been 
resolved, the database will be locked and the efficacy analysis of the study will be performed.
9.6.3.
Follow-up Analyses
After the final analysis, additional supplemental analyses of efficacy and safety may be 
performed to satisfy regulatory requirements and to perform long-term efficacy, safety, and 
OS follow-up.


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10.
RESPONSIBILITIES
10.1.
Investigator Responsibilities
10.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
“Declaration of Helsinki” (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), International Conference on Harmonsation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study subject. These standards are consistent with the European Union 
Clinical Trials Directive 2001/20/EC and Good Clinical Practive Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of GCP as outlined in the 
United States (US) Federal Regulations 21 CFR 312, subpart D, “Responsibilities of Sponsors 
and Investigators,” 21 CFR, part 50, 1998, and 21 CFR, part 56, 1998.
The investigator an all applicable subinvestigators will comply with US Federal Regulation 
21 CFR, Part 54, 1998 providing documentation of their financial interest or arrangements with 
Gilead Sciences, or proprietary interests in the drug being studied. This documentation must be 
provided prior to the investigator’s (and any subinvestigator’s) participation in the study. The 
investigator or subinvestigator agrees to notify Gilead Sciences of any change in reportable 
financial interests during the study and for 1 year following completion of the study. Study 
completion is defined as the date that the last subject has completed the protocol-defined 
activities.
10.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval
This investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) to an IRB/IEC. The investigator will not begin any study subject activities 
until approval from the IRB/IEC has been documented and provided as a letter to the 
investigator. Before implementation, the investigator will submit to and receive documented 
approval from the IRB/IEC for any modifications made to the protocol or any accompanying 
material to be provided to the subject after initial approval, with the exception of those necessary 
to reduce immediate risk to study subjects Informed Consent.
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 
investigator must use the most current IRB/ or IEC-approved consent form for documenting 
written informed consent. Each informed consent (or assent as applicable) will be appropriately
signed and dated by the subject or the subject’s legally authorized representative and the person 


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conducting the consent discussion, and also by an impartial witness if required by IRB or IEC or 
local requirements. The consent form will inform subjects about pharmacogenomics analysis 
results.
10.1.3.
Confidentiality
The investigator must assure that each subject’s anonymity will be strictly maintained and that 
each subject’s identity is protected from unauthorized parties. Only subject initials, date of birth, 
and an identification code (but no subject names) should be recorded on any form or biological 
sample submitted to the Gilead Sciences or designees (eg, laboratories), or to the IRB/IEC.
However, sufficient information must be retained at the site to permit sample data and data in the 
database to be connected with the unique subject number assigned to each study participant.
The investigator agrees that all information received from Gilead Sciences, including but not 
limited to the idelalisib investigator brochure, this protocol, eCRFs, the investigational new drug, 
and any other study information, remain the sole and exclusive property of Gilead Sciences
during the conduct of the study and thereafter. This information is not to be disclosed to any 
third party (except employees or agents directly involved in the conduct of the study or as 
required by law) without prior written consent from Gilead Sciences. The investigator further 
agrees to take all reasonable precautions to prevent the disclosure by any employee or agent of 
the study site to any third party or otherwise into the public domain.
10.1.4.
Study Files and Retention of Records and Biological Samples
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following 2 categories: (1) investigator’s study file, and 
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, eCRF and query forms, the 
IRB/IEC and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.
The required source data referenced in the monitoring plan for the study, and should include 
sequential notes containing at least the following information for each subject:

Subject identification (name, date of birth, gender)

Documentation that subject meets eligibility criteria, eg, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria)

Documentation of the reason(s) a consented subject is not enrolled

Participation in trial (including trial number)

Trial discussed and date of informed consent


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
Dates of all visits

Documentation that protocol-specific procedures were performed

Results of efficacy parameters, as required by the protocol

Start and end date (including dose regimen) of trial medication (including relevant drug 
dispensing and return information)

Record of all adverse events and other safety parameters (including start and end date, 
causality and intensity)

Concomitant medication (including start and end date and dose if relevant dose changes 
occur)

Date of trial completion and reason for discontinuation, if applicable
All clinical study documents must be retained by the investigator until at least 2 years after the 
last approval of a marketing application in an ICH region (ie, the United States, Europe, 
or Japan) and until there are no pending or contemplated marketing applications in an ICH 
region; or, if no application is filed or if the application is not approved for such indication, until 
2 years after the investigation is discontinued and regulatory authorities have been notified. 
Investigators may be required to retain documents longer if required by applicable regulatory 
requirements, by local regulations, or by an agreement with Gilead Sciences. The investigator 
must notify Gilead Sciences before destroying any clinical study records. The investigator will 
promptly notify Gilead Sciences in the event of accidental loss or destruction of any study 
records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead Sciences must be notified in advance.
If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead Sciences
to store these in sealed containers outside of the site so that they can be returned sealed to the 
investigator in case of a regulatory audit. When source documents are required for the continued 
care of the subject, appropriate copies should be made for storage outside of the site.
Biological samples retained by the investigator will be stored and maintained by the investigator 
until notification is received from Gilead Sciences that the retained samples and records no 
longer need to be retained. 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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10.1.5.
Case Report Forms
An 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). As 
required by the protocol, eCRFs should also be completed for those subjects who fail to complete 
the study (even during a prerandomization screening period). If a subject withdraws from the 
study, the reason must be noted on the eCRF. If a subject is withdrawn from the study because of 
a treatment-limiting adverse event, thorough efforts should be made to clearly document the 
outcome.
The eCRFs for this study will exist within a Web-based electronic data capture (EDC) system. 
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 eCRF must be completed and signed by the principal investigator or subinvestigator 
(as appropriate) within a reasonable time period after data collection. This signature serves to 
attest that the information contained in the eCRF is true.
10.1.6.
Drug Accountability
As described in the relevant sections for (see Section 5.2.1.7 for idelalisib and 
Section 5.2.2.6 for ofatumumab), the investigator is responsible for ensuring adequate 
accountability of all used and unused investigational medicinal product and comparators. This 
responsibility includes acknowledgment of receipt of each shipment of study product 
(quantity and condition), subject dispensing records, and returned or destroyed study product. 
Dispensing records will document quantities received from Gilead Sciences and quantities 
dispensed to subjects, including lot number, date dispensed, subject identifier number, subject 
initials, and the initials of the person dispensing the medication.
At study initiation, the monitor will evaluate the site’s standard operating procedure for 
investigational medicinal product disposal/destruction in order to ensure that it complies with 
Gilead Sciences requirements. Drug may be returned or destroyed on an ongoing basis during the 
study if appropriate. At the end of the study, following final drug inventory reconciliation by the 
monitor, the study site will dispose of and/or destroy all unused investigational medicinal 
product supplies, including empty containers, according to these procedures. If the site cannot 
meet Gilead Sciences’ requirements for disposal, arrangements will be made between the site 
and Gilead Sciences or its representative for destruction or return of unused investigational 
medicinal product supplies.
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study.


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10.1.7.
Inspections
The investigator should understand that source documents for this trial should be made available 
to appropriately qualified personnel from Gilead Sciences or its representatives, to IRB/IECs, 
and to regulatory authority or health authority inspectors. It is important that the investigator and 
relevant institutional personnel are available during monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process.
10.1.8.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
10.2.
Sponsor Responsibilities
10.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, will be 
made only by Gilead Sciences. All protocol modifications must be submitted to the IRB/IEC in 
accordance with local requirements. Except as noted in Section 10.1.2, IRB/IEC approval must 
be obtained before changes can be implemented.
10.2.2.
Communications with Regulatory Authorities
Gilead Sciences, working either directly or through designees, will assume responsibility for 
regulatory interactions with relevant regulatory authorities. Gilead Sciences 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, Gilead Sciences (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. Gilead Sciences (or a designee) will also 
assume responsibility for adverse event reporting to regulatory authorities as described in 
Section 8.4.
10.2.3.
Data Management
Electronic data capture will be used to enter study data eCRFs and to transfer the 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. As appropriate, eCRFs, listings, tables, 
and SAS datasets will be provided to the investigational sites for review.
Quality assurance and quality control systems will be implemented and maintained according to 
written standard operating procedures to ensure that the data are generated, recorded, and 
reported in compliance with the protocol, GCP, and applicable regulatory requirements. 


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Data collection and storage systems will provide audit trail, security mechanisms, and electronic 
signature capabilities that meet the requirements of FDA Title 21 of 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 and at 
Gilead Sciences or its designee. 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 when not under review.
10.2.4.
Study Reporting and Publication
Gilead Sciences may make information obtained during this study available in order to further 
the scientific or business needs of the company or as required by law or regulation. In this 
regard, Gilead Sciences 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).
Gilead Sciences will prepare a clinical study report for submission to relevant regulatory 
agencies. Gilead Sciences will ensure that the report meets the standards set out in the 
ICH Guideline for Structure and Content of Clinical Study Reports (ICH E3). An abbreviated 
report may be prepared in certain cases, as appropriate.
Gilead Sciences intends that the data from this study will be presented and published. 
Gilead Sciences will work in collaboration with the principal investigators in preparing 
presentations and writing manuscripts for publication.
Investigators may publish or present the results of the study generated by their individual site
either with the advance written consent of Gilead or > 2 years after the completion of the study at 
all participating institutions.
No such communication, presentation, or publication will include Gilead Sciences’ 
confidential information (see Section 10.1.3).
The investigator will submit to Gilead Sciences any proposed publication or presentation along 
with the respective scientific journal or presentation forum prior to submission of the publication 
(at least 30 days prior for manuscripts and 15 days prior for abstracts and oral presentations). The 
investigator will comply with Gilead Sciences’ request to delete references to its confidential 
information (other than the study results) in any paper or presentation. If deemed necessary by 
Gilead Sciences, the investigator also agrees to withhold publication or presentation for an 
additional 60 days in order to obtain patent protection.


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10.3.
Joint Investigator/Sponsor Responsibilities
10.3.1.
Access to Information for Monitoring
In accordance with ICH Good Clinical Practice (ICH GCP) guidelines, the study monitor must 
have direct access to the investigator’s source documentation in order to verify the data recorded 
in the eCRFs for consistency.
The monitor is responsible for routine review of the eCRFs at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the eCRFs. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected in the course of these monitoring visits are resolved.
10.3.2.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead Sciences may conduct inspections or audits 
of the clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead Sciences medical monitor immediately. The investigator 
agrees to provide to representatives of a regulatory agency or Gilead Sciences access to records, 
facilities, and personnel for the effective conduct of any inspection or audit.
10.3.3.
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, Gilead Sciences will be responsible 
for ensuring that this protocol is listed at the ClinicalTrials.gov website (or equivalent) 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 
Gilead Sciences with appropriate contact information for study site personnel.
10.3.4.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authorities and IRB/IECs. In terminating the study, Gilead Sciences and the 
investigator will assure that adequate consideration is given to the protection of the subjects’ 
interests. 
10.4.
Study Committees
10.4.1.
Data Monitoring Committee
A DMC, operating autonomously from Gilead Sciences, and the clinical investigators, will be 
responsible for providing independent recommendations to Gilead Sciences about evolving 
risk-benefit observed in the course of the study and any modifications required during the course 


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of the study. The DMC will consist of a biostatistician and 2 physicians experienced in treating 
patients with lymphoid malignancies. The DMC will be chaired by one of these individuals.
DMC members must not be actively involved in study design, conduct, or subject accrual and 
must not have financial, proprietary, professional, or other interests that may affect impartial, 
independent decision-making. Specialists may be invited to participate as non-voting members at 
any time if additional expertise is desired. The DMC will operate under a charter developed as a 
collaborative document between Gilead Sciences and the DMC.
The primary responsibility of the DMC is to protect the safety and welfare of subjects 
participating in this clinical trial and to ensure the integrity of the clinical trial. In general, the 
DMC will be responsible for:

Examining accumulated safety, efficacy, and other relevant data during the course of the 
study in order to make recommendations concerning continuation, termination, or 
modification of the study

Reviewing the general progress of the study as regards subject accrual, study conduct, and 
protocol violations

Reviewing major study design modifications proposed by Gilead Sciences prior to 
implementation of those modifications

Providing expert advice to the Gilead Science medical monitor on an ad hoc basis regarding 
matters such as safety concerns or diagnostic evaluations in individual subjects
Based on the results of its deliberations during the course of the study, the DMC can recommend
appropriate actions (eg, continuation of the study with modifications in design or 
monitoring plan, interruption of study accrual, study termination).
10.4.2.
Independent Review Committee
An IRC will be established to provide a blinded review of radiographic data and pertinent 
clinical data in order to provide expert interpretation of changes in tumor status. The IRC will 
include 1 independent board-certified radiologist and 1 independent board-certified 
hematologist or oncologist, and will be managed by a CRO selected by Gilead Sciences. The 
review of radiographic and clinical data by the IRC will be performed on an ongoing basis. The 
specifics of the IRC’s processes and reading methods will be described in an independent review 
charter developed by the contracted imaging facility in conjunction with Gilead Sciences. The 
findings of the IRC will be considered primary for analyses of PFS and other tumor control 
endpoints.


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11.
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12.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Functional Assessment of Cancer Therapy: Leukemia
Appendix 3.
Performance Status Scoring System
Appendix 4.
EuroQoL-5 Dimensions (EQ-5D)
Appendix 5.
Cockcroft-Gault Method for Estimating Creatinine Clearance
Appendix 6.
Cumulative Illness Rating Scale (CIRS)
Appendix 7.
Schedule of Study Procedures


PPD
PPD
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Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
199 EAST BLAINE STREET 
SEATTLE, WA 98102 
STUDY ACKNOWLEDGEMENT 
A Phase 3, Randomized, Controlled Study Evaluating the Efficacy and Safety ofldelalisib 
(GS-1101) in Combination with Ofatumumab for Previously Treated 
Chronic Lymphocytic Leukemia 
GS-US-312-0119, Version 11.0, 30 August 2017 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
Gilead Sciences Medical Monitor 
Date 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator 
Printed Name 
Date 
CONFIDENTIAL 
Page 165 
Signature 
Site Number 
30 August 2017 


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Appendix 2.
Functional Assessment of Cancer Therapy: Leukemia
FACT-Leu (Version 4) 
Below is a list of statements that other people with your illness have said are important. Please circle 
or mark one number per line to indicate your response as it applies to the past 7 days. 
GPI 
GP2 
GPl 
GP4 
GP> 
GPO 
GP7 
PHYSICAL WELL-BEl G 
ot 
at all 
I have a lack of energy ....................................................... 
0 
I have nausea ...................................................................... 
0 
Because of my phy ical condition, I have trouble 
meeting the needs of my family ......................................... 
0 
I have pain .......................................................................... 
0 
I am bothered by side effects of treatment ...... ................... 
0 
I feel ill ............................................................................... 
0 
I am forced to spend time in bed ........................................ 
0 
A little 
Some-
bit 
what 
2 
2 
2 
2 
2 
2 
2 
Quite 
a bit 
3 
3 
3 
3 
3 
3 
3 
SOCIALIFAMIL Y WELL-BEING 
ot 
A little 
Some-
Quite 
at all 
bit 
what 
a bit 
GSI 
I feel close to my friend .................................................... 
0 
GSl 
I get emotional support from my family ............................ 
0 
GSl 
I get support from my friends............................................. 
0 
My family has accepted my illne 
.................................... 
0 
GS> 
I am atisfied with family communication about my 
illness.................................................................................. 
0 
GS6 
I feel clo e to my partner (or the per on who i my main 
upport) .................................................... .......................... 
0 
Ql 
Regardless o,(your curre/11 level ofsexual acJivily. please 
answer I he following queslion. lfyou prefer no/Jo answer il. 
please mark I his box 0 and go 10 I he nexl sec/ion. 
GS7 
I am ati tied with my sex life ............................................ 
0 
I) 
1987, 199'"' 
2 
3 
2 
3 
2 
3 
2 
3 
2 
3 
2 
3 
2 
3 
Very 
much 
4 
4 
4 
4 
4 
4 
4 
Very 
much 
4 
4 
4 
4 
4 
4 
4 


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F 
·-L u ( 
Plea e circl 
r mark one numb r 1> r lin t indicat y ur r pon 
a it applic t th Jl!!.Ul 
d:w . 
I feet 
d ..... 
I m 
ti lied' 'th h w I am coping with m illnc 
I am to ing hope in the fight again tm illn 
I feet nervou 
................................................................. 
lw rry boutd ing .... 
.......................... 
......................... 
FU 
I m abl t w rk (in tude' rk t hom ) ... 
M w 
· includ w rk t h me i fulfilling . 
I am able to njo lifi .... 
I have a 
pled m illn 
I am lecping' II ........ 
I m enj 
ing th thin 
I usually d for fun 
I am ontent with thequalit ofm lifi right no\ 
ot 
t\ littl 
m 
Quit 
V ry 
:11 all 
bit 
wh I 
11 bit 
much 
0 
2 
4 
0 
2 
4 
0 
2 
4 
0 
2 
4 
0 
2 
4 
0 
2 
4 
ot 
t\ Iiiii 
m 
Quit 
I')' 
at all 
it 
wh 1 
11 bit 
much 
0 
0 
0 
0 
0 
0 
0 
2 
2 
2 
2 
2 
2 
4 
4 
4 
4 
4 
4 
,. 


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F 
·-L u ( 
PI a c cir I or mark on numb r p r lin t indi at your r pon 
a it appli 
to th ru!&1 
dtl\' . . 
Ull 
nu 
uu 
UUt 
I am bother db • fe er epi od 
of high bod 
tempe tur) 
'ot 
tall 
0 
I have 
nain pan ofm bod where I 
perien 
pain .. 
0 
I am both red b • th chill 
I have night weat ..... . 
f 
I bleed e il 
I brui 
I feel weak all o 
r ......................................................... . 
I g I tired ea il 
0 
0 
0 
0 
0 
0 
0 
I m I . ng w ight. ... ....................................................... 
0 
I have a good ppetite 
I am able to do m u ual acti itie .. 
I ' ony bout getting infeeti n ... 
I feel un en in about m future health 
I' orry that I might g 1 ne' 
mpt m ofm illn 
I ha e emotional up and down ..... 
I r. eli lated fr m othe beeau 
ofm illn 
or 
tr tment 
0 
0 
0 
0 
0 
0 
0 
Iiiii 
rn 
uit 
ry 
bit 
what 
11 bit 
much 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
,. 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 


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Appendix 3.
Performance Status Scoring System
Karnofsky Performance Status
General Description
Score
Specific Description
Able to carry on 
normal activity and to 
work; no special care 
needed
100
Normal; no complaints; no evidence of disease.
90
Able to carry on normal activity; minor signs or symptoms of disease.
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.
60
Requires occasional assistance, but is able to care for most of personal needs.
50
Requires considerable assistance and frequent medical 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.
20
Very sick; hospital admission necessary;
active supportive treatment necessary.
10
Moribund; fatal processes progressing rapidly.
0
Dead


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Appendix 4.
EuroQoL-5 Dimensions (EQ-5D)
Sample


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To help people sa ho ' eood or bad a health state · , 
e ave dra\vn a !>eale rather like a thennometer) on 
\ llic the best state ou can imagine is marked 100 
and 
e orst state you can imagine is marked 0. 
\Xi e would like you to indicate on this scale how good 
or bad your own heal h is oda 
in ot r op1mon. 
Please do thi c; b drawing a line from the box below 
to \ 'ruche er point on e scale 
how good or 
bad ·our health state is oda ·_ 
Yow· own 
health state 
today 
Bes-1 
imagjnable 
heath sla e 
100 
0 
ors 
imaginab.e 
al 
.>tate 


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Appendix 5.
Cockcroft-Gault Method for Estimating Creatinine Clearance
Formulas for calculating the estimated creatinine clearance (eCcr) are provided in the table below
{Cockcroft 1976}. The formula appropriate to the units in which serum creatinine was measured 
and the subject’s gender should be used.
Serum
Creatinine Units
Gender
Formula
mg/dL
Males
eCcr [mL/min]
=
(140-subject age [years]) subject weight [kilograms] 1
72 subject serum creatinine [mg/dl]
Females
eCcr [mL/min]
=
(140-subject age [years]) subject weight [kilograms] 0.85
72 subject serum creatinine [mg/dl]
M/dL
Males
eCcr [mL/min]
=
(140-subject age [years]) subject weight [kilograms] 1.23
Subject serum creatinine [mg/dl]
Females
eCcr [mL/min]
=
(140-subject age [years]) subject weight [kilograms] 1.04
Subject serum creatinine [mg/dl]
Abbreviation: eCcr=estimated creatinine clearance


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Appendix 6.
Cumulative Illness Rating Scale (CIRS)
The CIRS used in this protocol is designed to provide an assessment of recurrent or ongoing 
chronic comorbid conditions, classified by 14 organ systems. Using the lists of organ-specific 
diagnoses, please select any conditions present in the study subject. If the subject has recurrent or 
ongoing chronic conditions that are not described in the list for a given organ system, please 
indicate the name of the conditions under “other chronic condition” for that organ system. Please 
take into account that CLL-induced discomfort, symptoms, or disability should not be 
considered. If additional explanation would be helpful, text comments may be inserted.
Organ System
Diagnosis
Comment
Cardiac
Chronic heart failure
Angina pectoris
Medically relevant arrhythmia
Valve dysfunction
Congenital heart disease
Cardiomyopathy
Myocarditis
Chronic pericarditis
Endocarditis
Other chronic cardiac condition:
Other chronic cardiac condition:
Vascular
Hypertension
Thrombosis
Peripheral diabetic microvascular disease
Peripheral artery disease
Aortic aneurysm
Aortitis
Raynaud disease
Vasculitis
Other chronic vascular condition:
Other chronic vascular condition:
Hematological/
Immunological
Sickle cell anemia
Hemoglobinopathy
Polycythemia
Thrombocythemia
Hemophilia
Paroxysmal nocturnal hemoglobinuria


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Organ System
Diagnosis
Comment
Thrombotic thrombocytopenic purpura
Dysfibrinogenemia
HIV
Other chronic hematological or 
immunological condition:
Other chronic hematological or 
immunological condition:
Respiratory
Asthma
Chronic obstructive pulmonary disease
Cystic fibrosis
Emphysema
Chronic bronchitis
Chronic pleural effusions
Pulmonary fibrosis
Sarcoidosis
Pulmonary embolism
Pulmonary arterial hypertension
Lung cancer
Other chronic respiratory condition:
Other chronic respiratory condition
Ophthalmological/
otolaryngological
Loss of vision
Glaucoma
Cataract
Macular degeneration
Diabetic retinopathy
Loss of hearing
Otitis/chronic otitis
Vestibular impairment
Vertigo
Temporomandibular disorder
Sialolithiasis
Chronic sinusitis
Laryngeal/pharyngeal disorders
Other chronic ophthalmological or 
otolaryngological condition:


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Organ System
Diagnosis
Comment
Upper
Gastrointestinal
Chronic esophagitis
Dysphagia
Achalasia
Gastroduodenal ulceration
Celiac disease
Irritable bowel syndrome
Short bowel syndrome
Malnutrition
Malabsorption
Small bowel obstruction
Hernia
Pseudomyxoma peritonei
Upper gastrointestinal cancer
Other chronic upper gastrointestinal condition:
Other chronic upper gastrointestinal condition:
Lower
Gastrointestinal
Diverticulitis
Inflammatory bowel disease
Volvulus
Colon cancer
Other chronic lower gastrointestinal condition:
Other chronic lower gastrointestinal condition:
Hepatic/
Pancreatic
Chronic hepatitis or hepatic cirrhosis
Biliary obstructive disorders
Pancreatitis
Hepatic, biliary, or pancreatic cancer
Other chronic hepatic or pancreatic condition:
Other chronic hepatic or pancreatic condition:
Renal 
Chronic kidney disease
Diabetic nephropathy
Pyelonephritis
Renal cancer
Other chronic renal condition:
Other chronic renal condition


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Organ System
Diagnosis
Comment
Gynecological/
Urological
Recurrent/chronic urinary tract infection
Nephrolithiasis
Bladder dysfunction
Vaginal/vulvar disease
Uterine/ovarian disease
Prostatitis
Bladder, uterine, ovarian, prostate, or other cancer
Prostate hypertrophy
Other chronic gynecological or urological condition:
Other chronic gynecological or urological condition:
Dermatologic/
musculoskeletal
Dermatitis
Dermatomyositis
Myopathy
Gout
Psoriasis
Keratosis
Urticaria
Scleroderma
Basal cell carcinoma
Squamous cell carcinoma
Melanoma
Osteomyelitis
Osteoarthritis
Rheumatoid arthritis
Spondyloarthritis
Temporal arteritis/polymyalgia rheumatica
Polychondritis
Fibromyalgia
Osteoporosis
Systemic lupus erythematosus
Dermatomyositis
Sjögren syndrome
Other chronic dermatological or 
musculoskeletal condition:
Other chronic dermatological or 
musculoskeletal condition:


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Organ System
Diagnosis
Comment
Neurological
Cerebrovascular disease 
(transient ischemic attack/stroke/hemorrhage)
Dementia
Parkinson disease
Non-Parkinsonian movement disorder 
(eg, ataxia/chorea)
Leukodystrophic disorders
Amyotrophic lateral sclerosis
Multiple sclerosis
Demyelinating disease
Guillain-Barré syndrome
Paralysis (eg, paraplegia/quadriplegia/hemiplegia)
Myelopathy
Cranial nerve disorder
Degenerative disk disease with nerve root 
compression
Migraine headaches
Seizure disorder
Secondary neuropathy 
(eg, diabetic/alcoholic/autoimmune)
Neurofibromatosis/tuberous sclerosis
Benign or malignant central nervous system tumor
Other chronic neurological condition:
Other chronic neurological condition:
Endocrine/
Metabolic
Diabetes
Adrenal disorder
Thyroid disorder
Parathyroid disorder
Pheochromocytoma
Pituitary disorder
Hemochromatosis
Porphyria
Paget's disease
Endocrine or neuroendocrine tumor
Other chronic endocrine or metabolic condition:
Other chronic endocrine or metabolic condition:


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Organ System
Diagnosis
Comment
Psychiatric
Depression
Anxiety
Bipolar disorder
Paranoia
Schizophrenia
Neurosis
Personality disorder
Substance addiction/abuse
Posttraumatic stress disorder
Chronic fatigue syndrome
Other chronic psychiatric condition:
Other chronic psychiatric condition:
Abbreviation: CIRS=Cumulative Illness Rating Scale
For each condition selected from the CIRS List of Comorbid Conditions, please rate the severity 
of that condition. For the severity rating, please use the scoring guidelines shown in the table 
below, considering the magnitude of symptoms, how manageable the condition is, and the extent 
of intervention required:
Score
Severity
Findings
1
Mild
Mild discomfort, symptoms or disability
Easy to control
Requiring either no therapy/medication or only as needed
2
Moderate
Moderate discomfort, symptoms or disability
Manageable
Requiring daily treatment or first-line therapy
3
Severe
Severe discomfort, symptoms or disability
Hard to control
Requiring second-line therapy or multiple medications
4
Extremely severe
Life threatening, permanently disabling disability, causing organ failure
Poorly manageable
Requiring urgent intervention or resistant to therapy
Abbreviation: CIRS=Cumulative Illness Rating Scale


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Appendix 7.
Schedule of Study Procedures
Period
Screen
Treatment
Follow-up
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18+
End
of
Study
30 day
Long-
term
Week
-4
1
2
3
4
5
6
7
8
12
16
20
24
30
36
42
48
Q12
Weeks
Study Day
Within
-28
Days
1
8
15
22
29
36
43
50
78
106
134
162
204
246
288
330
Within
+30
days
To
+5
years
Visit Window
±2
±2
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±7
Informed consent
X
Medical history
X
CIRS assessment
X
Serum virology
X
CMV 
Surveillancee
X
X
X
X
X
X
X
X
X
X
X
PJP prophylaxis
Xg
Xg
β-HCG
(women of 
child-bearing
potential)
X
X
X
X
X
X
X
X
X
X
X
Xa
Xa
X
CLL peripheral 
blood evaluation
X
X
CLL serology
X
X
Coagulation
X
Urinalysis
X
12-lead ECG
X
CCI


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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
17
18+
End
of
Study
30 day
Long-
term
Week
-4
1
2
3
4
5
6
7
8
12
16
20
24
30
36
42
48
Q12
Weeks
Study Day
Within
-28
Days
1
8
15
22
29
36
43
50
78
106
134
162
204
246
288
330
Within
+30
days
To
+5
years
Visit Window
±2
±2
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±7
IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HRQL/
healthy utility –
FACT-Leu/
EQ-5D
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse eventsf
X
X
X
X
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
X
X
X
X
X
X
Performance 
status
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Oxygen saturation 
(by pulse 
oximetry)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical exam 
(includes nodes, 
liver, spleen)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology/
serum chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Circulating 
cells/biomarkers/
serum Igs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum  CH50
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
17
18+
End
of
Study
30 day
Long-
term
Week
-4
1
2
3
4
5
6
7
8
12
16
20
24
30
36
42
48
Q12
Weeks
Study Day
Within
-28
Days
1
8
15
22
29
36
43
50
78
106
134
162
204
246
288
330
Within
+30
days
To
+5
years
Visit Window
±2
±2
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±7
Idelalisib
administration in 
clinic
(Arm A only)
X
X
X
X
X
X
Premedication 
and ofatumumab 
administration
X
X
X
X
X
X
X
X
X
X
X
X
Infusion reaction 
severity/duration 
assessment
X
X
X
X
X
X
X
X
X
X
X
X
Idelalisib
pharmacokinetics 
(Arm A only)
X
X
X
X
X
X
Idelalisib
dispensing/
accounting
(Arm A only)
X
X
X
X
X
X
X
Radiology
assessment 
(CT/MRI)b
X
X
X
X
X
X
X
X
Bone marrow 
biopsy/aspiratec
X
X
X
X
X
X
X
HBV DNA by 
PCRd
X
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
17
18+
End
of
Study
30 day
Long-
term
Week
-4
1
2
3
4
5
6
7
8
12
16
20
24
30
36
42
48
Q12
Weeks
Study Day
Within
-28
Days
1
8
15
22
29
36
43
50
78
106
134
162
204
246
288
330
Within
+30
days
To
+5
years
Visit Window
±2
±2
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±7
Post-study CLL 
therapy
X
Long-term 
follow-up
X
a
After Visit 17 and 18, urine β-HCG to be performed every 6 weeks 5 d (women of child-bearing potential only)
b
At screening, CT/ MRI may be performed within 6 weeks prior to start of randomization; CT or MRI imaging of neck, chest, abdomen, and pelvis can be performed within 
1 week of the visit. CT/MRI assessments will continue until ~129 events have been observed in the study population
c
At baseline, to be performed at investigator discretion to determine extent of CLL involvement and bone marrow cellularity. Post-baseline, to confirm CR or PD; if the subject 
does not otherwise meet criteria for CR or if the nature of PD does not require bone marrow confirmation, it is not necessary to obtain a follow-up bone marrow 
biopsy/aspirate. 
d
Only subjects who are HBc antibody positive and HBV DNA negative at screening. Subjects will be tested monthly for the duration of ofatumumab therapy and every 
3 months thereafter for 1 year from the last dose of ofatumumab per Section 5.4.5.
e
After screening, CMV surveillance for active disease must be conducted approximately every 4 weeks for subjects in Arm A.
f
If reported, 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).
g
PJP prophylaxis:  subjects must receive trimethoprim-sulfamethoxazole or other established prophylaxis for PJP throughout the course of idelalisib treatment and for 2 to 
6 months after the last dose of idelalisib and until the CD4+ T-cell count is documented to be >200 cells/mcL. 
Abbreviations: -HCG=beta human chorionic gonadotropin, CIRS=chronic illness rating scale, CLL=chronic lymphocytic leukemia, CR=complete response, 
CT=computed tomography, ECG=electrocardiogram, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, 
HRQL= health-related quality of life, Ig=immunoglobulin, IWRS=interactive web response system, MRI= magnetic resonance imaging, CMV= cytomegalovirus

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 3, Randomized, Controlled Study Evaluating the 
Efficacy and Safety of Idelalisib (GS-1101) in Combination with 
Ofatumumab for Previously Treated Chronic Lymphocytic 
Leukemia
Name of Test Drug:
Idelalisib (IDELA; GS-1101)
Study Number:
GS-US-312-0119
Protocol Version:
Amendment 6
Protocol Date:
26 September 2014
Analysis Type:
Interim and Final
Analysis Plan Version:
2.0
Analysis Plan Date:
29 September 2014
Analysis Plan Author:
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................3
LIST OF ABBREVIATIONS........................................................................................................................................4
1.
INTRODUCTION ................................................................................................................................................6
1.1.
Study Objectives ......................................................................................................................................6
1.2.
Study Design............................................................................................................................................6
1.3.
Sample Size and Power..........................................................................................................................13
2.
TYPE OF PLANNED ANALYSIS ....................................................................................................................15
2.1.
Interim Analysis.....................................................................................................................................15
2.2.
Final Analysis ........................................................................................................................................16
2.3.
Follow-up Analyses ...............................................................................................................................16
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES............................................................................17
3.1.
Analysis Sets..........................................................................................................................................17
3.1.1.
Intent-to-Treat Analysis Set .................................................................................................17
3.1.2.
Per-Protocol Analysis Set.....................................................................................................17
3.2.
Safety Analysis Set ................................................................................................................................18
3.2.1.
Pharmacokinetic/ Pharmacodynamic Analysis Sets.............................................................18
3.3.
Strata and Covariates..............................................................................................................................18
3.4.
Examination of Subject Subsets.............................................................................................................19
3.5.
Multiple Comparisons............................................................................................................................20
3.6.
Missing Data and Outliers......................................................................................................................20
3.7.
Data Handling Conventions and Transformations .................................................................................21
3.7.1.
Data Handling for Efficacy Endpoints .................................................................................22
3.7.2.
Data Handling for Laboratory data.......................................................................................22
3.8.
Visit Windows........................................................................................................................................22
3.8.1.
Analysis Windows................................................................................................................22
3.8.2.
Selection of Data in the Event of Multiple Records in a Window .......................................23
4.
SUBJECT DISPOSITION ..................................................................................................................................24
4.1.
Subject Enrollment.................................................................................................................................24
4.2.
Disposition of Subjects ..........................................................................................................................24
4.3.
Extent of Exposure.................................................................................................................................25
4.3.1.
Duration of Exposure to Study Drug....................................................................................25
4.3.2.
Modification with IDELA....................................................................................................26
4.3.3.
Adherence with IDELA........................................................................................................26
4.4.
Protocol Deviations................................................................................................................................27
5.
BASELINE DATA .............................................................................................................................................28
5.1.
Demographics and Baseline Characteristics ..........................................................................................28
5.2.
Medical History......................................................................................................................................28
5.3.
Disease History ......................................................................................................................................28
6.
EFFICACY ANALYSES ...................................................................................................................................30
6.1.
Definition of the Primary Efficacy Endpoint .........................................................................................30
6.2.
Statistical Hypothesis for the Primary Efficacy Endpoint......................................................................30
6.3.
Analysis of the Primary Efficacy Endpoint............................................................................................30
6.4.
Additional Analysis of the Primary Efficacy Endpoint..........................................................................32
6.5.
Secondary Efficacy Endpoints ...............................................................................................................33


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6.5.1.
Definition of Secondary Efficacy Endpoints........................................................................33
6.5.2.
Analysis Methods for Secondary Efficacy Endpoints..........................................................33
6.6.
Exploratory Efficacy Endpoints.............................................................................................................35
6.6.1.
Definition of Exploratory Efficacy Endpoints......................................................................35
6.6.2.
Analysis Methods for Exploratory Efficacy Endpoints........................................................36
6.7.
Changes From Protocol-Specified Efficacy Analyses............................................................................39
7.
SAFETY ANALYSES........................................................................................................................................40
7.1.
Adverse Events and Deaths....................................................................................................................40
7.1.1.
Adverse Event Dictionary ....................................................................................................40
7.1.2.
Adverse Event Severity........................................................................................................40
7.1.3.
Relationship of Adverse Events to Study Drug....................................................................40
7.1.4.
Serious Adverse Events........................................................................................................41
7.1.5.
Treatment-Emergent Adverse Events...................................................................................41
7.1.6.
Summaries of Adverse Events and Deaths...........................................................................41
7.1.7.
Exposure-adjusted TEAE Rate.............................................................................................43
7.1.8.
Treatment-Emergent Adverse Events (TEAEs) of Interest ..................................................44
7.2.
Laboratory Evaluations ..........................................................................................................................45
7.2.1.
Summaries of Numeric Laboratory Results .........................................................................45
7.2.2.
Summaries of Categorical Laboratory Results.....................................................................45
7.2.3.
Graded Laboratory Values ...................................................................................................46
7.2.4.
Shift in CTCAE Grade Relative to Baseline ........................................................................46
7.2.5.
Transaminase elevations.......................................................................................................47
7.2.6.
Liver-Related Laboratory Tests............................................................................................47
7.3.
Prior Therapy (Including Radiation) ......................................................................................................48
7.4.
Concomitant Medications ......................................................................................................................49
7.5.
Body Weight and Vital Signs.................................................................................................................49
7.6.
Electrocardiogram Results .....................................................................................................................49
7.6.1.
Corrected QT Intervals.........................................................................................................49
7.6.2.
Investigator Assessment of ECG Readings..........................................................................50
7.6.3.
Oxygen Saturation Levels ....................................................................................................50
7.7.
Other Safety Measures ...........................................................................................................................50
7.8.
Changes From Protocol-Specified Safety Analyses...............................................................................50
8.
PHARMACOKINETIC ANALYSES ................................................................................................................51
9.
PHARMACODYNAMIC ANALYSES .............................................................................................................52
10.
REFERENCES ...................................................................................................................................................53
11.
SOFTWARE.......................................................................................................................................................54
12.
SAP REVISION..................................................................................................................................................55
13.
APPENDICES ....................................................................................................................................................56
Appendix 1.
Schedule of Assessments........................................................................................................57
Appendix 2.
Testing Strategy for secondary endpoints...............................................................................61
Appendix 3.
Table of Contents for Statistical Tables, Figures, and Listings ..............................................64
LIST OF IN-TEXT TABLES
Table 2-1.
The Expected Number of Events at Interim and Final Analyses and Significance 
Levels to Reject H0.................................................................................................................15


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LIST OF ABBREVIATIONS
AE
adverse event
ALC
absolute lymphocyte count
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ATC
Anatomical-Therapeutic-Chemical classification system for drugs 
BID
twice per day
BMI
body mass index
BOR
best overall response
CI
confidence interval
CIRS
Cumulative Illness Rating Scale
CLL
chronic lymphocytic leukemia
CR
complete response
CT
computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
DMC
data monitoring committee
DOR
duration of response
DSPH
Gilead Sciences Department of Safety and Public Health
eCRF
electronic case report form
ECG
electrocardiogram
EQ-5D
EuroQoL Five-Dimension utility measure
EWB
Emotional Well-Being
FACT-Leu
Functional Assessment of Cancer Therapy: Leukemia questionnaire
FWB
Functional Well-Being 
HLGT
high-level group term
HLT
high-level term
HRQL
health-related quality of life
Ig
immunoglobulin (including subtypes A, E, G, and M)
IgHV
immunoglobulin heavy chain variable region
IRB
institutional review board
IRC
independent review committee
ITT
intent to treat
IWCLL
International Workshop on CLL
IWRS
interactive web response system
JAK
Janus kinase
LD
longest diameter
LLN
lower limit of normal
LLT
low level term
LVD
Longest Vertical Dimension


Idelalisib (IDELA)
GS-US-312-0119
Final
Statistical Analysis Plan
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LISTOF ABBREVIATIONS (CONTINUED)
MST
Medical Search Term
MRI
magnetic resonance imaging
ND
no disease
NE
non evaluable
ORR
overall response rate
OS
overall survival
PD
progressive disease
PK
pharmacokinetic
PI3K
phosphatidylinositol 3-kinase
PI3K
phosphatidylinositol 3-kinase p110isoform
PFS
progression-free survival
PPD
product of the perpendicular diameters
PP
per protocol
PRO
patient-reported outcome
PR
partial response
PT
preferred time
PWB
Physical Well-Being
QTc
QT interval corrected
QTc-B
QT interval corrected for heart rate using Bazett’s formula
QTc-F
QT interval corrected for heart rate using Fridericia’s formula
SAE
serious adverse event
SAP
Statistical analysis plan
SD
stable disease
SPD
sum of the products of the perpendicular diameters of measured lymph nodes
SSC
study steering committee
StD
standard deviation
SUSAR
suspected, unexpected, serious adverse reaction
SWB
Social/family Well-Being
Syk
spleen tyrosine kinase
TEAE
treatment-emergent adverse event
TOI
Trial Outcome Index
TTR
time to response
ULN
upper limit of normal
WHODRUG
World Health Organization Drug Dictionary


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1.
INTRODUCTION
This document details the planned interim and final analyses for Study GS-US-312-0119, 
a Phase 3, randomized, controlled study evaluating the efficacy and safety of IDELA in 
combination with ofatumumab for previously treated chronic lymphocytic leukemia (CLL).
Related documents are the study protocol and electronic case report form (eCRF).
1.1.
Study Objectives
Primary 
Study Objectives

To evaluate the effect of the addition of IDELA to ofatumumab on 
PFS in subjects with previously treated CLL
Secondary 
Study Objectives

To evaluate the effect of the addition of IDELA to ofatumumab on 
the onset, magnitude, and duration of tumor control

To evaluate the effect of the addition of IDELA to ofatumumab on 
the onset, magnitude, and duration of tumor control for subjects 
with 17p deletion and/or p53 mutation

To assess the effect of the addition of IDELA to ofatumumab on 
measures of subject well-being, including OS, HRQL, and 
performance status

To assess the effects of the addition of IDELA to ofatumumab on 
disease-associated biomarkers and to evaluate potential 
mechanisms of resistance to IDELA

To characterize the effect of ofatumumab on IDELA exposure 
through evaluations of IDELA plasma concentrations over time

To describe the safety profile observed with the addition of 
IDELA to ofatumumab

To estimate health resource utilization associated with the addition 
of IDELA to ofatumumab
1.2.
Study Design
Design Configuration 
and 
Subject Population
This study is being conducted as part of an overall clinical program 
that is evaluating the efficacy and safety of IDELA in the therapy of 
patients with previously treated CLL. Study GS-US-312-0119 is a 
Phase 3, multicenter, 2-arm, randomized, controlled, parallel-group
study that is conducted at centers in North America, Europe and 
Australia.


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Target Population: Adult subjects with previously treated recurrent 
CLL who have measurable lymphadenopathy, require therapy for 
CLL, have disease that is not refractory to ofatumumab, and might 
benefit from a change in therapy because they have experienced CLL 
progression <24 months since the completion of the last prior 
treatment.
Treatment Groups

Arm A: IDELA + Ofatumumab (1000 mg)

Arm B: Ofatumumab (2000 mg)
Key Eligibility 
Criteria
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible 
for participation in this study:
1) Male or female 18 years of age.
2) Diagnosis of B-cell CLL, with diagnosis established according to 
International Workshop on Chronic Lymphocytic Leukemia 
(IWCLL) criteria and documented within medical records.
3) CLL that warrants treatment (consistent with accepted IWCLL 
criteria for initiation of therapy). Any of the following conditions 
constitute CLL that warrants treatment:
a) Evidence of progressive marrow failure as manifested by the 
onset or worsening of anemia and/or thrombocytopenia, or
b) Massive (ie, lower edge of spleen 6 cm below the 
left costal margin), progressive, or symptomatic splenomegaly, 
or
c) Massive (ie, 10 cm in the longest diameter), progressive, or 
symptomatic lymphadenopathy, or


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d) Progressive lymphocytosis in the absence of infection, with an 
increase in blood absolute lymphocyte count (ALC) 50% over 
a 2-month period or lymphocyte doubling time of <6 months 
(as long as initial ALC was 30,000/L), or
e) Autoimmune anemia and/or thrombocytopenia that is poorly 
responsive to corticosteroids or other standard therapy, or
f)
Constitutional symptoms, defined as any one or more of the 
following disease-related symptoms or signs occurring in the 
absence of evidence of infection:
i)
Unintentional weight loss of 10% within the previous 
6 months, or
ii) Significant fatigue (Grade 2), or
iii) Fevers >100.5°F or 38.0°C for 2 weeks, or
iv) Night sweats for >1 month.
4) Presence of measurable lymphadenopathy (defined as the presence 
of ≥1 nodal lesion that measures ≥2.0 cm in the longest diameter
[LD] and 1.0 cm in the longest perpendicular diameter [LPD] as 
assessed by computed tomography [CT] or 
magnetic resonance imaging [MRI]). 
5) Prior treatment for CLL comprising therapy with either of the 
following types of drugs given alone or in combination:
a) A purine analog (eg, fludarabine, pentostatin, cladribine) 
administered for ≥2 cycles of treatment
b) Bendamustine administered for ≥2 cycles of treatment
Note: Prior drugs may have been administered as single agents 
or as components of combination therapies. Subjects may also 
have received other commercially available therapies 
(eg, rituximab, alemtuzumab, ofatumumab, lenalidomide, 
corticosteroids, or others) or non-excluded investigational 
therapies. Each repeated but separated therapeutic application of 
the same single-agent or combination is considered an 
independent regimen.
6) Documentation of CLL progression <24 months since the 
completion of the last prior therapy for CLL.
7) Discontinuation of all therapy (including radiotherapy, 
chemotherapy, immunotherapy, or investigational therapy) for the 
treatment of CLL 6 weeks before randomization.
Note: Subjects may be receiving corticosteroids to manage 
CLL manifestations.


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8) All acute toxic effects of any prior antitumor therapy resolved to 
Grade 1 before randomization (with the exception of alopecia 
[Grade 1 or 2 permitted], neurotoxicity [Grade 1 or 2 permitted], 
or bone marrow parameters [any of Grade 1, 2, 3, or 4 permitted]).
9) Karnofsky performance score of ≥60.
10) Required baseline laboratory data (within 4 weeks prior 
to randomization) as shown in the table below.
Note: Confirmation should be considered for out-of-range values 
to determine if the abnormality is real or artifactual. Values 
should be obtained within the screening period and should 
generally be the most recent measurement obtained. Subjects 
with any degree of neutropenia, thrombocytopenia, or anemia 
due to CLL or prior therapy may enroll.
Required Screening Laboratory Values
Organ System
Parameter
Required Value
Hepatic
Serum total bilirubin
1.5 x ULN
(unless elevated due to 
Gilbert syndrome or hemolysis)
Serum ALT
2.5 x ULN
Serum AST
Renal
eCCr
a
>30 ml/min
Pregnancy
-HCGb
Negative 
Infection
HIV
Negative HIV antibody
HBV
Negative HBsAg and negative HBc 
antibody or positive HBc and negative 
for HBV DNA by quantitative PCR
HCV
Negative viral RNA
(if HCV antibody is positive)
a
As calculated by the Cockcroft-Gault formula {2202}
b
For women of child-bearing potential only; serum -HCG must be negative during 
screening and serum -HCG or urine dipstick pregnancy test must be negative at 
randomization (Visit 2)
Abbreviations: -HCG= beta human chorionic gonadotropin, ALT=alanine aminotransferase, 
AST=aspartate aminotransferase, DNA=deoxyribonucleic acid, 
eCCr=estimated creatinine clearance, HBc antibody=anti-hepatitis B core antibody, 
HBsAg=hepatitis B surface antigen, HBV=hepatitis B virus, HCV=hepatitis C virus, 
HIV=human immunodeficiency virus, Ig=immunoglobulin, PCR=polymerase chain reaction, 
RNA=ribonucleic acid, ULN=upper limit of normal


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11) For female subjects of child-bearing potential, willingness to use a 
protocol-recommended method of contraception from the 
screening visit (Visit 1) throughout the study, and for 30 days from 
the last dose of study drug or 12 months from the last dose of 
ofatumumab (whichever is later). Note: A female subject is 
considered to be of child-bearing potential unless she has had a 
hysterectomy, bilateral tubal ligation, or bilateral oophorectomy; 
has medically documented ovarian failure (with serum estradiol 
and follicle-stimulating hormone [FSH] levels within the 
institutional postmenopausal range and a negative serum or 
urine HCG); or is menopausal (age 55 years with amenorrhea 
for 6 months).
12) For male subjects of child-bearing potential having intercourse 
with females of child-bearing potential, willingness to use a 
protocol-recommended method of contraception from the 
randomization visit (Visit 2) throughout the study and for 90 days 
following the last dose of study drug and to refrain from sperm 
donation from randomization (Visit 2) throughout the study and 
for 90 days following the last dose of study drug. Note: A male 
subject is considered able to father a child unless he has had a 
bilateral vasectomy with documented aspermia or a bilateral 
orchiectomy, or has ongoing testicular suppression with a 
depot luteinizing hormone-releasing hormone (LH-RH) agonist 
(eg, goserelin acetate [Zoladex®]), leuprolide acetate 
[Lupron®]), or triptorelin pamoate [Trelstar®]).
13) In the judgment of the investigator, participation in the protocol 
offers an acceptable benefit-to-risk ratio when considering current 
CLL disease status, medical condition, and the potential benefits 
and risks of alternative treatments for CLL.
14) Willingness and ability to comply with scheduled visits, drug 
administration plan, imaging studies, laboratory tests, other study 
procedures, and study restrictions. Note: Psychological, social, 
familial, or geographical factors that might preclude adequate 
study participation should be considered.
15) 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.


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Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be 
enrolled in this study:
1) Known histological transformation from CLL to an aggressive 
lymphoma (ie, Richter transformation). 
Note: Biopsy documentation of the absence or presence of 
transformation is not required.
2) Known presence of intermediate- or high-grade myelodysplastic 
syndrome (ie, subjects are excluded who have 5% bone marrow 
blasts; karotypic abnormalities other than normal, Y deletion, 
5q deletion, or 20q deletion; or 2 lineages of cytopenias due 
to myelodysplasia).
3) History of a non-CLL malignancy except for the following: 
adequately treated local basal cell or squamous cell carcinoma of 
the skin, cervical carcinoma in situ, superficial bladder cancer, 
asymptomatic prostate cancer without known metastatic disease 
and with no requirement for therapy or requiring only hormonal 
therapy and with normal prostate-specific antigen for 1 year prior 
to randomization, other adequately treated Stage 1 or 2 cancer 
currently in complete remission, or any other cancer that has been 
in complete remission for ≥2 years. 
4) Known hypersensitivity or intolerance to any of the active 
substances or excipients in the formulations for either IDELA or 
ofatumumab.
5) Evidence of ongoing systemic bacterial, fungal, or viral infection 
at the time of randomization (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; anti-pneumocystis 
prophylaxis is encouraged. 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. 
6) Ongoing drug-induced liver injury, chronic active hepatitis C 
(HCV), chronic active hepatitis B (HBV), alcoholic liver disease, 
non-alcoholic steatohepatitis, primary biliary cirrhosis, 
extrahepatic obstruction caused by cholelithiasis, cirrhosis of the 
liver, or portal hypertension.
7) Ongoing drug-induced pneumonitis.
8) Ongoing inflammatory bowel disease.


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9) Ongoing alcohol or drug addiction.
10) Pregnancy or breastfeeding. 
11) History of prior allogeneic bone marrow progenitor cell or 
solid organ transplantation.
12) Ongoing immunosuppressive therapy other than corticosteroids. 
Note: Subjects may use topical, enteric, inhaled, or systemic 
corticosteroids as therapy for manifestations of CLL, 
comorbid conditions, or autoimmune anemia and/or 
thrombocytopenia. During study participation, subjects may 
receive systemic or other corticosteroids as pretreatment for 
ofatumumab infusions or as needed for treatment-emergent 
comorbid conditions.
13) In a subject with a history of prior ofatumumab therapy, the time 
from the last dose of ofatumumab to documented CLL progression 
is <6 months.
14) History of prior therapy with any inhibitor of AKT, 
Bruton tyrosine kinase (BTK), Janus kinase (JAK), 
mammalian target of rapamycin (mTOR), 
phosphatidylinositol 3-kinase (PI3K) (including IDELA), or 
spleen tyrosine kinase (SYK). 
15) Prior participation in an IDELA clinical trial.
16) Concurrent participation in another therapeutic clinical trial.
17) Prior or ongoing clinically significant illness, medical condition, 
surgical history, physical finding, electrocardiogram (ECG) 
finding, or laboratory abnormality that, in the investigator’s 
opinion, could adversely affect the safety of the subject or impair 
the assessment of study results.
Study Periods/ Phases
Subjects will be randomized with a 2:1 ratio into Arm A or Arm B of 
the study. In Arm A, subjects will take IDELA orally BID 
continuously and will receive 12 infusions of ofatumumab over 
~24 weeks.
IDELA will be taken continuously until the earliest of subject 
withdrawal from study, definitive progression of CLL, intolerable 
study drug-related toxicity, pregnancy, substantial noncompliance with 
study procedures, or study discontinuation.
Ofatumumab will be administered until the earliest of a maximum of 
12 infusions, subject withdrawal from study, definitive progression of 
CLL, intolerable ofatumumab-related toxicity, pregnancy, substantial 
noncompliance with study procedures, or study discontinuation.
Subjects in Arm A will continue with IDELA or ofatumumab, even if 
the other drug must be discontinued due to toxicity.


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Schedule of Assessments
The schedule of assessments is located in Appendix 1 of this SAP.
Randomization and 
Stratification

2:1 allocation to Arm A vs Arm B with implementation through an 
interactive web response system (IWRS)

Fixed-block centralized randomization with allocation of subjects 
within the 8 strata as defined by the intersection of 3 binary 
stratification factors:
17p deletion and/or p53 mutation in CLL cells: 
either vs neither (or indeterminate)
Immunoglobulin heavy chain variable region (IgHV) mutation: 
unmutated (or IgHV3-21) vs mutated (or indeterminate)
Disease status: refractory (CLL progression < 6 months from 
completion of prior therapy) vs relapsed (CLL progression 
6 months from completion of prior therapy)
There is no pre-specified limit to the number of subjects enrolled at a 
given site or within a stratum.
Site and/or Stratum 
Enrollment Limits
Approximately 115 centers in the United States, Canada, Australia, 
and Europe.
Study Duration
The study will continue until approximately the 129th PFS event
occurs. It is expected that the study accrual period is approximately 
12 months and the 129th event will occur after a minimum of 
12 months of follow-up. 
1.3.
Sample Size and Power
Planned Sample Size
The planned sample size is 255 subjects (170 subjects in Arm A and 
85 subjects in Arm B).
Power Statement
Based on data from prior studies, it is reasonable to assume that 
administration of ofatumumab to subjects with previously treated 
CLL in Arm B of this trial will result in a median PFS of ~8 months. 
An improvement in median PFS from 8 months to 14 months 
resulting from the addition of IDELA to ofatumumab in Arm A of the 
study would correspond to a benefit ratio of 1.75 (hazard ratio 0.57).


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It is assumed that PFS times are exponentially distributed in each of 
the 2 arms. With a hazard ratio (HR) equal to 1 under the null 
hypothesis of no difference between the 2 treatment arms and a HR of 
0.57 under the alternative hypothesis of superiority of the IDELA 
containing combination, 129 events (definitive CLL progressions or 
deaths) are required to achieve a power of ~0.85 based on a log-rank
test with a 2-sided significance level of 0.05. Further assuming a 
planned accrual period of 12 months (with approximately half of the 
subjects enrolled during the initial 60% of the accrual period, and the 
remaining half of the subjects enrolled during the last 40% of the 
accrual period), a minimum follow-up period of 12 months, and an 
expectation that 10% of subjects will be lost to follow-up 
(5% during the accrual period and 5% during the follow-up period)
and to ensure the primary analysis on PFS will be performed before 
or at the planned minimum 12-month follow-up period,
approximately 170 subjects will be enrolled into Arm A and 
approximately 85 subjects will be enrolled into Arm B. Using these 
assumptions, the expected number of events would be achieved by 
the end of the planned minimum 12-month follow-up period.
It is expected that there will be approximately 65 deaths at the time of 
final analysis. This would provide ~ 85% power to detect a HR of 
0.45 for overall survival based on a log-rank test at a 2-sided 
alpha level of 0.03.
Actual Enrollment and 
Impact on Power
The study is fully enrolled as it was originally planned and there is no 
impact on the power of the planned analyses. 


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2.
TYPE OF PLANNED ANALYSIS
2.1.
Interim Analysis
The data monitoring committee (DMC) will have access to serious adverse events (SAEs) 
requiring expedited reporting and will be provided with cumulative safety data on a regular 
basis. An interim safety review will be conducted by the DMC at ~6 months after the 
first subject is enrolled. Thereafter, interim safety reviews will be performed by the DMC at 
intervals of ~6 months; the specific frequency of these reviews will depend upon the rate at 
which the trial is enrolled, the nature of any emerging safety signals, and monitoring 
recommendations from the DMC. At each review, all available safety data will be summarized 
and evaluated.
Two formal interim efficacy analyses are planned after approximately the 
50% and 75% progression free survival (PFS) event has occurred. Although the study is 
open-label, the Gilead Sciences 312-0119 Study Team will remain blinded to any integrated 
summary by treatment groups throughout the trial until either the decision is made to stop the 
study early or all planned subjects have completed the study and the database has been locked 
and unblinded. The DMC will review unblinded integrated interim efficacy results and make 
recommendations per pre-specified efficacy boundaries to Gilead Executive Management as 
outlined in the DMC Charter. These analyses offer the opportunity to assess for evidence of 
substantial clinical benefit. For these analyses, all available PFS data will be evaluated.
Stopping the study for substantial evidence of IDELA benefit will be considered if the PFS is 
significantly better in Arm A (IDELA + ofatumumab) compared to Arm B (ofatumumab). The 
significance level for the first interim analysis will be 0.003 and for the second interim analysis 
will be 0.018, using the O’Brien Fleming (OF) alpha spending function. Based on the 
assumptions of the study and the timing of the planned analysis, boundary-crossing probabilities 
for the trial are provided in Table 2-1. If a decision is made to stop the trial based on an interim 
analysis, the database will be cleaned and locked for the subsequent final analysis the date of 
which will be determined in discussions with regulatory authorities, for which all the remaining 
alpha will be spent.
Table 2-1.
The Expected Number of Events at Interim and Final Analyses and 
Significance Levels to Reject H0
Analyses
Expected Number of Eventsa
n (%)
Significant Level to reject H0
Interim #1
65
(50%)
<0.003
Interim #2
97
(75%)
<0.018
Final
129
(100%)
<0.044
a
Definitive CLL progressions or deaths


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2.2.
Final Analysis
The final efficacy analysis will be conducted after approximately 129 events
(definitive CLL progression or death) or ~15 months after last subjected enrolled, whichever 
occurs first, unless a decision is made to stop the trial early based on an interim analysis. It is 
expected that this number of events will occur after a minimum of 12 months of follow-up. 
Once outstanding data queries have been resolved, the database will be locked, and the efficacy
analysis of the study will be performed. The significance level planned for the final analysis is at 
0.044 but will be adjusted based on the actual number of events observed at the time of 
final analysis.
2.3.
Follow-up Analyses
After the final analysis, additional supplemental analyses of efficacy and safety may be 
performed to satisfy regulatory requirements and to perform long-term efficacy, safety, and 
overall survival (OS) follow-up.


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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 includes all subjects who are randomized regardless of 
whether subjects receive any study drug(s), or receive a different regimen from the regimen they 
were randomized to. Treatment assignment will be designated according to randomization.
This analysis set will be used in the analyses of subject characteristics, PFS, overall response rate 
(ORR), OS, lymph node response (LNR) rate, complete response (CR) rate, and health outcome 
variables. The analysis of PFS based on the ITT analysis set will be considered primary. Subjects 
in the ITT analysis set who do not have sufficient baseline or on-study tumor status information 
to be adequately assessed for response status will be included in the denominators in the 
calculation of ORR and CR rate.
3.1.2.
Per-Protocol Analysis Set
The per-protocol (PP) analysis set includes data from subjects in the ITT analysis set who meet 
the general criteria defining the target population for this study, are adherent to the protocol, are 
compliant with study drug treatment, and are evaluable for relevant efficacy endpoints. Study 
drug assignment will be designated according to the actual treatment received. Subjects who 
meet any of the following criteria may be excluded from this analysis set:

Do not have documented diagnosis of CLL within medical records during the time course of 
disease 

Do not have measurable lymphadenopathy (defined as the presence of ≥1 nodal lesion that 
measures ≥2.0 cm in the longest diameter [LD] and 1.0 cm in the longest perpendicular 
diameter [LPD] as assessed by computed tomography [CT] or magnetic resonance imaging 
[MRI]) at baseline as determined by the independent review committee (IRC)

No documentation of CLL progression in <  24 months since the completion of the last prior 
treatment for CLL

Known histological transformation from CLL to an aggressive lymphoma 
(ie, Richter transformation)

Prior treatment for CLL not comprising any of the following:
A) A purine analog (eg, fludarabine, pentostatin, cladribine) administered for ≥2 cycles of 
treatment
B) Bendamustine administered for ≥2 cycles of treatment


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
Prior therapy with any inhibitor of AKT, Bruton tyrosine kinase (BTK), Janus kinase (JAK), 
mammalian target of rapamycin (mTOR), phosphatidylinositol 3 kinase (PI3K) 
(including IDELA), or spleen tyrosine kinase (SYK).

Karnofsky performance score of <60 at screening

In a subject with a history of prior ofatumumab therapy, the time from the last dose of 
ofatumumab to documented CLL progression is < 6 months.

Do not receive study treatment

Adherence with study drug of <75% for subjects in arm A.

Non-evaluable (ie, do not have a PFS event [definitive disease progression or death], and 
no baseline or on-study disease evaluations)
The specific classification of subjects to be excluded in the PP analysis set will be finalized prior 
to database lock.
The PP analysis set will be used in sensitivity analyses of the primary and following efficacy 
endpoints: PFS, ORR, LNR rate, duration of response (DOR), Time to Response (TTR),
and CR rate.
3.2.
Safety Analysis Set
A safety analysis set will include data from subjects who receive ≥1 dose of study treatment, 
with treatment assignments designated according to the actual treatment received.
This analysis set will be used in the analyses of safety variables as well as study treatment 
administration (for IDELA and ofatumumab).
3.2.1.
Pharmacokinetic/ Pharmacodynamic Analysis Sets
The pharmacokinetic/pharmacodynamic (PK/PD) analysis sets include data from subjects in the 
safety analysis set who have the necessary baseline and on-study measurements to provide 
interpretable results for the specific parameters of interest.
These analysis sets will be used in the analyses of AKT phosphorylation, chemokines/cytokines, 
and IDELA plasma concentrations.
3.3.
Strata and Covariates
Subjects will be stratified to receive study treatment via IWRS based on the following 
stratification factors:


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
17p deletion and/or p53 mutation in CLL cells: either vs neither (or indeterminate)

Immunoglobulin heavy chain variable region (IgHV) mutation: unmutated (or IgHV3-21) 
vs mutated (or indeterminate)

Disease status : refractory (CLL progression < 6 months from completion of prior therapy) 
vs relapsed (CLL progression ≥ 6 months from completion of prior therapy)
For subjects with discrepancies between the stratification factor values at randomization 
(ie, according to IWRS) and the actual values as documented in the eCRF, the actual strata 
information will be used in the analyses.
Analyses will be adjusted for the randomization strata. In the situation that there is insufficient 
information in a stratum (ie, if there are <6 subjects or there is no informative event in a stratum), 
that stratum will be pooled with the smallest adjacent stratum for stratified analyses; the smallest 
stratum is defined as that stratum having the fewest number of subjects or the fewest number of 
events in case the former is a tie and the adjacent stratum is defined as a stratum having 
2 factors of the 3 at the same level.
3.4.
Examination of Subject Subsets
Primary, secondary,
 endpoints 
 
will be 
examined in the following subgroups:

Stratification factors:
17p deletion and/or p53 mutation in CLL cells: either vs neither (or indeterminate)
Immunoglobulin heavy chain variable region (IgHV) mutation: unmutated (or IgHV3-21) 
vs mutated (or indeterminate)
Disease status: refractory vs relapsed

17p deletion (Yes or No [including indeterminate])

Gender (Male or Female)

Age group (<65 or ≥65) 

Race (White or Non-White)
All subgroup efficacy analyses will be performed using IRC assessments if there is sufficient 
sample size in the subgroup.
CCI
CCI


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AEs and lab abnormalities will be examined in the following subgroups:

Gender (Male or Female)

Age group (<65 or ≥65) 

Race (White or Non-White)
3.5.
Multiple Comparisons
In the efficacy analyses, the following procedures will be implemented to preserve the overall 
type I error rate across the primary and secondary endpoints of the study at a 2-sided 
significance level of 0.05.
The primary endpoint analysis will serve as the gatekeeper for the secondary endpoint analyses, 
ie, the primary efficacy hypothesis must be rejected at the pre-specified significance level before 
the efficacy hypotheses for the secondary efficacy endpoints can be evaluated. The secondary 
endpoints will be the following:

ORR

LNR rate

OS

PFS in the subgroup of 17p deletion and/or p53 mutated subjects

CR rate (if there are subjects who will respond with a CR)
If the primary hypothesis is rejected either at an interim or final analysis, the 
5 secondary endpoints will be sequentially tested at the 2-sided significance level of 0.03 in the 
order listed above. The significant level is chosen such that the overall type I error rate of testing 
primary and secondary endpoints is preserved at the 2-sided 0.05 significance level. The detail is 
described in Appendix 2. If a null hypothesis is not rejected, formal sequential testing will be 
stopped and only nominal significance will be cited for the remaining secondary endpoints. 
Analyses and p-values will be reported for all the efficacy endpoints, including the 
primary endpoint, the secondary endpoints, 
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:

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
CCI


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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: Leukemia (FACT Leu) will be 
handled according to the administration and scoring guidelines.
Outliers
No data will be excluded from the analyses, including any outliers.
3.7.
Data Handling Conventions and Transformations

By-subject listings will be created for important variables in each eCRF module, and 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), median, 
Q1, 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 and 2 more decimal places than in 
the raw data will be presented when reporting StD.  

Summary tables for categorical variables for baseline and safety data will include: N, n, 
and percentage. The tables for efficacy endpoints will include standard error, and 
95% confidence intervals (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 ITT analysis set at 
the same stratum or total as appropriate, unless otherwise specified. Missing data will be 
included as a row in tables where it is appropriate. All percentages will be presented as 
1-decimal point, unless otherwise specified. Percentages equal to 100 will be presented as 
100% and percentages will not be presented for zero frequencies.

Tables and figures will be displayed by visit (as appropriate) for each treatment group and 
total (as appropriate).

The actual stratification factor values at randomization from electronic case report form 
eCRF (not the ones from IWRS) will be used in all analyses.

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.


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
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.

For Kaplan-Meier estimates, the 95% CIs will be calculated using the Greenwood’s formula 
with (complementary) log-log transformation.
3.7.1.
Data Handling for Efficacy Endpoints
If there is a significant degree of non-normality for a continuous endpoint, analyses 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” (x is 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” (x is 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 “≥ x” (x is considered as the limit of quantitation).
3.8.
Visit Windows
3.8.1.
Analysis Windows
For parameters that will be summarized by visit, the nominal visit as recorded on the eCRF 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. 
Unscheduled visits prior to randomization will be included for the calculation of baseline values. 
Unscheduled scans will be used for determination of the time-to-event and tumor response
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3.8.2.
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, 
whereas a time-to-event analysis would not require 1 value per analysis window but rather 
1 value for the study. 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 all taken on the same day.

For the EuroQol Five-Dimension (EQ-5D), if 2 values are selected for a single dimension, 
the value of this dimension should be treated as missing.
The following algorithm will be applied for the Functional Assessment of Cancer Therapy: 
Leukemia FACT-Leu:

If 2 adjacent responses are checked, 1 of them will be picked randomly.

All others (ie, more than 2 responses are checked or 2 non-adjacent responses are checked) 
are counted as missing.


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment
A summary of subject enrollment will be provided by treatment group. The denominator for this 
calculation will be the number of randomized subjects. Similarly, the number and percentage of 
subjects randomized in each randomization stratum will be summarized. A listing of all 
randomized subjects will be generated to describe site, subject number, randomization date, 
first treatment date, subject stratification, randomized treatment arm assignment, 
actual treatment arm allocation, exposure of IDELA and ofatumumab, and the reason for 
discontinuing study treatment. If there were discrepancies in the value used for stratification 
assignment between IWRS and eCRF, the value collected on the CRF will be used for this 
summary. A listing of subjects with randomization strata that differ from stratification factor data 
entered in the CRF at the time of data finalization will be provided. A by-subject listing for 
screening failures will be provided by screening identification (ID) in an ascending order with 
reasons for not being eligible for enrollment to the study.
4.2.
Disposition of Subjects
Study treatment disposition and study disposition summaries will be provided by treatment 
group.
Study treatment disposition for IDELA and ofatumumab combination arm will present the 
number of subjects who:

were randomized 

were randomized but were not treated

were treated with study drug 

have treatment ongoing

met the primary study endpoint at the time of study drug completion according to the 
investigator

discontinued the study drug (with summary of reason for discontinuation of study drug and 
with summary of subjects who stay on the study after discontinuation of drug)
Study disposition will present the number of subjects who:

were randomized 

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
were treated with study drug 

are ongoing on the study

discontinued the study (with summary of reason for not completing)

met the primary study endpoint at the time of study completion according to the investigator
Study disposition will be also presented with 12 weeks intervals.
Long-term follow-up disposition will present the number of subjects who:

entered long-term follow-up

completed long-term follow-up (with the completion of 5-year follow-up or Death)

are on-going with long-term follow-up 

discontinued the long-term follow-up (with summary of reasons for not completing)
A separate table will also be provided to summarize the number of subjects in the 
PP and PK/PD 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 screen failed with the reason for screen failure and subjects 
who were excluded for each analysis set with reasons for exclusion will be listed.
Time to discontinuation from study will be summarized and plotted. Kaplan-Meier estimates 
of the median, Q1, Q3, and the number of discontinued subjects and censored subjects will be 
provided. Subjects who discontinued without PFS events will be categorized as having an event 
at the time of discontinuation. Subjects who have a PFS event or are on-going will be censored at 
the time of the PFS event or data cut-off, respectively.
4.3.
Extent of Exposure
4.3.1.
Duration of Exposure to Study Drug
Duration of exposure to IDELA will be defined as (min (last IDELA dosing date [as captured on 
study drug completion CRF page], data cutoff date) – first IDELA dosing date + 1), regardless of 
temporary interruptions in study drug administration, and will be expressed in months. Duration 
of exposure to IDELA will be summarized for the safety analysis set who received at least 
one dose of IDELA during the study using descriptive statistics and as the number and 
percentage of subjects exposed for at least 1 day, 2, 4, 6, and 12 months, and every 6 months 
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The number of ofatumumab infusions subjects received will be summarized for the safety 
analysis set using descriptive statistics and the number and percentage of subjects who received 
at least 1, 2, 4, 6, 8, 10, and 12 ofatumumab infusions.
For on-going subjects who have not completed the IDELA dosing CRF page at the time of 
interim analysis, the last IDELA dosing date will be imputed with the date of data cut-off. 
The last available ofatumumab infusion date will be used as the last ofatumumab infusion date.
For subjects who have completed IDELA, but the day of last dose is missing, the following 
imputation rule will be applied:

If day is missing but the month and year are available, then the imputed day will be the 
first day of the month.
4.3.2.
Modification with IDELA
For subjects who have IDELA modification for subjects in Arm A, the following will be 
summarized and the details will be listed:

Number and percent of subjects with dose modification

Number and percent of subjects with dose interruption with reasons for interruption

Number and percent of subjects who are re-challenged at the starting dose (150 mg BID) and 
at the reduced dose (100 mg BID).

Number and percent of subjects who were re-escalated for subjects who are re-challenged at 
the reduced dose.
Continuous records of IDELA dosing from the day of first dosing day of IDELA to the last dose 
of IDELA including modification (interruption and reduction) will be listed. Drug accountability 
(dose dispense and return) records will be listed in a separate listing.
4.3.3.
Adherence with IDELA
Adherence (%) with IDELA will be calculated for the subjects in Arm A:
Adherence (%) = (sum of pills dispensed minus pills returned) divided by (sum over all dosing 
period of [total daily pills x dosing duration]), taking into account investigator-prescribed 
interruption, reductions, and escalations.
Descriptive statistics for adherence along with the number and percentage of subjects belonging 
to adherence categories (eg, < 75% or ≥75%) will be provided.


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4.4.
Protocol Deviations
Protocol deviations will be categorized before database finalization by Gilead. The important 
(major) protocol deviations will be summarized by type of deviation in the clinical study report 
(CSR) based on the ITT analysis set.  A listing will be provided for all important protocol 
deviations.


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5.
BASELINE DATA
5.1.
Demographics and Baseline Characteristics
Demographics including gender, race, ethnicity, age (years), weight (kg), height (cm), and 
body mass index (BMI, kg/m2) will be summarized for the ITT analysis set. Gender, race,
ethnicity, and Karnofsky performance status will be summarized by using summary statistics for 
categorical variables. Age (years), weight (kg), and height (cm) will be summarized using 
summary statistics for continuous variables. Age will be calculated as the number of years 
between date of birth and date of randomization.
Age (years) = (date of randomization – date of birth+1) / 365. 25 (round down to an integer)
BMI (kg/m2) = weight / (height)2 (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 the above demographic data.

For date of birth, only year (not day and month) may be collected due to regulation in some 
countries. If day and month are missing but year is available, then the day and month will be 
imputed as 01 Jan.
5.2.
Medical History
Total CIRS scores assessed at screening and CIRS score by organ systems will be summarized 
using descriptive statistics and presented by treatment group based on the ITT analysis set.
Other baseline comorbidities will also be summarized using descriptive statistics. No inferential 
statistics will be generated.
A by-subject listing of medical history will be provided.
5.3.
Disease History
Time since diagnosis (year) will be calculated by 
(Date of Randomization - Date of Diagnosis)/365.25. Time since diagnosis will be summarized 
by using summary statistics for a continuous variable. Disease stage at diagnosis and current 
disease stage will be summarized using summary statistics for a categorical variable.
The number and percent of subjects who meet the following inclusion criteria that warrants 
treatment for CLL at the entry of study will be summarized. The details of each category are 
summarized Section 1.2.

Subjects with progressive marrow failure – Evidence of progressive marrow failure as 
manifested by the onset or worsening of anemia and/or thrombocytopenia

Subjects with massive, progressive, or symptomatic splenomegaly


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
Subjects with massive, progressive, or symptomatic lymphadenopathy

Subjects with progressive lymphocytosis

Subjects with autoimmune anemia and/or thrombocytopenia that is poorly responsive to 
corticosteroids or other standard therapy

Subjects with constitutional symptoms
Subjects who meet the radiographic eligibility criteria and who have bulky lymphadenopathy
criteria determined by the IRC will be summarized.
Bulky lymphadenopathy is defined in 2 ways:

The presence of 1 nodal lesion that measures 5.0 cm in the LD.

The presence of 1 nodal lesion that measures 10.0 cm in the LD.
5.3.1.1.
Incomplete Dates
All partial dates of diagnosis and dates of last regimen 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.


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6.
EFFICACY ANALYSES
An IRC was established for this study and includes primary board-certified radiologists, a 
board-certified adjudicating radiologist, and an independent board-certified hematologist or 
oncologist to perform an independent review of response and disease progression for each 
subject. The review comprises of an assessment of radiographic images and prospectively 
defined clinical data acquired during the study according to the Gilead Protocol 
GS-US-312-0119 Imaging Charter. The determination of CLL response and progression will be 
based on standardized criteria promulgated by the International Workshop on CLL {12154}, as 
specifically modified for this study to reflect current recommendations which consider the 
mechanism of action of IDELA and similar drugs {22541}. The findings of the IRC will be 
considered primary for analyses of PFS and other tumor control endpoints. 
6.1.
Definition of the Primary Efficacy Endpoint
The primary endpoint for this study is PFS, defined as the interval from randomization to the 
earlier of the first documentation of definitive disease progression or death from any cause; 
definitive disease progression is CLL progression based on standard criteria ({12154}, {22541}) 
other than lymphocytosis alone.
6.2.
Statistical Hypothesis for the Primary Efficacy Endpoint
H0: HR equals to 1 between Arm A (IDELA + ofatumumab) and Arm B (ofatumumab)
H1: HR is less than 1 (Arm A is superior to Arm B in terms of PFS)
6.3.
Analysis of the Primary Efficacy Endpoint
For the primary efficacy analysis, the PFS between the 2 treatment arms will be compared based 
on the ITT analysis set using a stratified log-rank test, adjusted for the stratification factors used 
for randomization. The analysis strategy for the situation where there is insufficient information 
in a stratum is detailed in Section 3.3. Medians, Q1, Q3, the proportion of subjects who are 
progression-free at 6 months and 12 months from randomization (based on 
Kaplan-Meier estimates), HRs, and corresponding 95% CIs (as calculated using a 
Cox proportional hazards regression model) will be presented. The Kaplan-Meier curve will also 
be plotted.
The date of definitive CLL progression will be the time point at which progression is identified 
by relevant objective radiographic or clinical data per the IRC.
Data will be censored on the date of the last tumor assessment (including assessments with a 
not evaluable [NE] outcome) for subjects

who do not have disease progression, or

who do not die prior to the end of study.


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Data will be censored on the date of the last tumor assessment prior to the initiation of new 
anti-tumor therapy (including assessments with a not evaluable [NE] outcome) for subjects who 
start new anti-tumor therapy prior to documented disease progression.
Data will be censored on the date of the last tumor assessment prior to 2 consecutive missing 
tumor assessments (including assessments with a not evaluable [NE] outcome) for subjects who 
have 2 consecutive missing tumor assessments before disease progression or death.
Subjects without adequate baseline tumor response evaluation will be censored on the 
randomization date. 
To assess the robustness of the primary PFS results, the following exploratory sensitivity 
analyses will be performed:

PFS will be compared between the treatment arms in the ITT analysis set using the 
unstratified log-rank test.

PFS will also be compared between treatment arms in the PP analysis set using the 
Kaplan-Meier method and the stratified log-rank test.

PFS will be further analyzed by censoring data from surviving, non-progressing subjects only 
at the last time when lack of definitive CLL progression was objectively documented.

Worst-case sensitivity analysis will be performed in which surviving, non-progressing 
subjects who are lost to follow-up are categorized as having an event at the time of the last 
known CLL tumor status assessment if they were in Arm A and are categorized as censored 
at the time of the last known CLL tumor status assessment if they were in Arm B. These 
analyses will be performed based on the ITT analysis set using the Kaplan-Meier method and 
the stratified log-rank test.
The Cox regression approach will be used to explore the influences of the stratification factors, 
other baseline characteristics, and treatment on PFS. Beyond the stratification variables, 
additional baseline subject characteristics (ie, gender, age, race, number of prior therapies, 
disease staging, etc.) may be included as covariates, focusing on those with expected prognostic 
significance, particularly if these show imbalance between treatment groups. For the 
Cox regression modeling, a stepwise selection process will be applied to these variables to 
identify the final subset of relevant factors. Each prognostic factor will be preliminarily 
evaluated in the Cox regression model. Only the variables significant at the 0.20 level will be 
considered to build the multivariate model. A forward selection process with significance level 
of 0.10 will be applied to these variables to identify the final subset of relevant factors. Once a 
model has been established, treatment will be added to the final subset of factors to study its 
effect on the model. Treatment-by-factor interactions will be explored for the subset of factors 
included in the final model.
To explore the potential impact for any imbalance due to different rates of drop-out between 
treatment groups, inverse probability of censoring weights (IPCW) {30871} with various 
covariates including stratification factors, and time varying covariates will be used to investigate
the robustness of the primary PFS analysis.


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6.4.
Additional Analysis of the Primary Efficacy Endpoint
For subjects with disease progression, the reasons for PD (which criteria were met) will be 
summarized. Subjects who were assessed by the IRC as having PD on the basis of 1, 2, or 3 
criteria will be listed and summarized by treatment arm.
The following disease progression criteria will be included:

Progression based on index lesion
Increase from the nadir by ≥50% in the SPD of index lesions
A new node that measures >1.5 cm in the LD and >1.0 cm in the LPD
Increase from the nadir by ≥50% in the LD of an individual node

Progression based on non-index lesion
Unequivocal increase in the size of non-index disease

Progression based on hepatomegaly
New hepatomegaly
Recurrent splenomegaly, with a minimum longest vertical dimension (LVD) of 140 mm 
and a minimum increase from the nadir (if there is splenomegaly at nadir) of ≥50% in 
the size of the enlargement

Progression based on splenomegaly
New splenomegaly
Recurrent splenomegaly, with a minimum LVD of 140 mm and a minimum increase 
from the nadir (if there is splenomegaly at nadir) of ≥50% in the size of the 
enlargement

Progression based on hematological parameters confirmed by bone marrow
The current platelet count is <100 x 109/L and there has been a decrease by >50% from 
the highest on-study platelet count with confirmation from a bone marrow result
The current hemoglobin is <110 g/L (11.0 g/dL) and there has been a decrease by 
>20 g/L (2 g/dL) from the highest on-study hemoglobin with confirmation from a
bone marrow result

Transformation to a more aggressive histology


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6.5.
Secondary Efficacy Endpoints
6.5.1.
Definition of Secondary Efficacy Endpoints
Secondary efficacy endpoints include:

ORR – defined as the proportion of subjects who achieve a CR or PR and maintain their 
response for at least 8 weeks (with a 1-week window)

LNR rate – defined as the proportion of subjects who achieve a ≥50% decrease from baseline 
in the SPD of index lesions per IRC assessments

OS – defined as the interval from randomization to death from any cause during the study

PFS in the subgroup of subjects with 17p deletion and/or p53 mutation - defined as the 
interval from randomization to the earlier of the first documentation of definitive disease 
progression or death from any cause 

CR rate  – defined as the proportion of subjects who achieve a CR and maintain their
response for at least 8 weeks (with a 1-week window)
To preserve the overall type I error rate across the primary and secondary endpoints of the study 
at a 2-sided significance level of 0.05, the primary efficacy hypothesis must be rejected at the 
pre-specified significance level before the efficacy hypotheses for the secondary efficacy 
endpoints can be tested. The 5 secondary endpoints will be sequentially tested at the 2-sided 
0.03 significance level in the order listed above. The significant level is chosen in such a way 
that the overall type I error rate of testing primary and secondary endpoints are preserved at the 
2-sided 0.05 significance level in this group-sequential designed study. The detail is described in 
Appendix 2. If a null hypothesis is not rejected, formal sequential testing will be stopped and 
only nominal p-value will be cited for the remaining secondary endpoints.
6.5.2.
Analysis Methods for Secondary Efficacy Endpoints
Responses will be categorized as CR, PR, stable disease (SD), or PD. For subjects who initially 
responded but did not have an evaluable follow up visit or did not maintain a response 
(ie, progressed) for at least 8 weeks (with a 1-week window) will be categorized as having a SD.
In addition, a response category of 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.
6.5.2.1.
Overall response rate
ORR is defined as the proportion of subjects who achieve a CR or PR during the study and 
maintain the response for at least 8 weeks (with a 1-week window). Differences in number and 
percentage of subjects between the treatment arms in ORR will be compared using 
CMH Chi-square tests after adjusting for stratification factors. Odds ratios and the corresponding 
95% CIs will be presented as well.


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The potential influence of subject baseline characteristics (gender, age, race, number of prior
therapies, disease staging, etc.), and of treatment on response rates will be explored with logistic 
regression modeling. For the regression modeling, a stepwise selection process will be applied to 
these variables to identify the final subset of relevant factors. Each prognostic factor will be 
preliminarily evaluated in the logistic regression model separately. Only the variables significant 
at the 0.20 level will be considered to build the multivariate model. A forward selection process 
with significance level of 0.10 will be applied to these variables to identify the final subset of 
relevant factors. Once a model has been established, treatment will be added to the final subset of 
factors to study its effect on the model. Treatment-by-factor interactions will be explored for the 
subset of factors included in the final model.
The primary ORR analysis will be evaluated using the IRC assessments based on the 
ITT analysis set. Sensitivity analyses will be performed using the IRC assessments based on the
PP analysis set, and defining ORR as the proportion of subjects who achieve a CR or PR during 
the study.
Investigators assessments with 8 weeks (with a 1-week window) confirmation will also be used 
for ORR analysis. Consistency of evaluation between IRC and investigator assessments in each 
treatment arm will be summarized by the percent agreement for overall response
6.5.2.2.
Lymph node response rate
Differences in LNR between the 2 treatment arms will be compared using CMH Chi-square tests 
after adjusting for stratification factors. Only subjects that have both baseline and ≥1 evaluable 
post-baseline SPD will be included for this analysis. Logistic regression for lymph node response 
rate will be performed in a similar fashion that is described in Section 6.5.2.1.
6.5.2.3.
Overall Survival
The OS analysis will be performed using the ITT analysis set (according to the 
original randomization) which includes all available survival information during the study with 
long-term follow-up to the data cut-off date. Data from surviving subjects will be censored at the 
last time that the subject was known to be alive on study (including all the in-person visit dates 
captured in the datasets, ie, BM biopsy, central lab collection, CT scan, physical exam, drug 
administration in clinic, concomitant medication and therapy start date, ECG, PRO collection, 
long term follow up, hospitalization, transfusion, pregnancy testing). Differences between 
treatment arms in OS will be assessed in the ITT analysis set using a stratified log rank test, 
adjusted for the stratification factors. Plots of time to event by treatment arm will be done using 
the Kaplan-Meier method. Medians, Q1, Q3, ranges, HRs, and corresponding 95% CIs will be 
presented by treatment arm.
A supportive Cox regression analysis of OS in the ITT analysis set will be performed using the 
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6.5.2.4.
PFS in the subgroup of 17p deletion and/or p53 mutated subjects
Details of PFS analysis is described in Section 6.3. PFS between the 2 treatment arms will be 
compared based on the ITT set with the subgroup of subjects with 17p deletion and/or 
p53 mutation using unstratified log-rank test.
6.5.2.5.
Complete Response Rate
The same analyses as specified for ORR in Section 6.5.2.1 will be performed for the CR rate. 
A sensitivity analysis of CR rate will be performed by assigning subjects without a confirmed 
response of CR to the initial response of CR.
6.6.
Exploratory Efficacy Endpoints 
6.6.1.
Definition of Exploratory Efficacy Endpoints
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6.6.2.
Analysis Methods for Exploratory Efficacy Endpoints
 
 
 
 
 
 
 
 
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6.7.
Changes From Protocol-Specified Efficacy Analyses
By the time of the data cut specified for the first interim analysis (50% PFS events), the actual 
number of PFS events was close to the number of PFS events targeted for the second interim
(75% PFS events). Therefore, per the OF alpha spending function, the alpha level 0.018 will be 
used for this first interim analysis and there will be no second interim analysis. 
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7.
SAFETY ANALYSES
7.1.
Adverse Events and Deaths
The focus of AE summarization will be on treatment-emergent AEs (TEAEs). All AEs and
deaths occurring on study will be summarized by treatment arm and listed in detail based on the 
safety analysis set.
7.1.1.
Adverse Event Dictionary
AEs will be coded using the current Medical Dictionary for Regulatory Activities (MedDRA) by
system organ class (SOC), high level group term (HLGT), high level term (HLT), preferred term 
(PT), and lower level term (LLT).
7.1.2.
Adverse Event Severity
The severity of AEs will be graded by the investigator according to the CTCAE, Version 4.03, 
whenever possible. If a CTCAE criterion does not exist, the grade corresponding to the 
appropriate adjective 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 relationship of an AE to the component of study drug (IDELA) and ofatumumab and to the 
infusion of ofatumumab should be assessed by the investigator using clinical judgment, 
describing the event as either unrelated or related. Events for which the investigator did not 
record relationship to study drug and ofatumumab will be considered related to study drug and 
ofatumumab. Data listings will show relationship as missing.


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7.1.4.
Serious Adverse Events
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 Department before database finalization.
7.1.5.
Treatment-Emergent Adverse Events
7.1.5.1.
Definition of Treatment-Emergent
TEAEs 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 treatment.

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 01Jan or the first dosing date if they 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 study treatment 
(ie, ofatumumab or 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 study treatment if they have the same month and year, 
whichever is earlier.
7.1.6.
Summaries of Adverse Events and Deaths
A brief summary of TEAEs by treatment arms (or for the relevant treatment arm) will show the 
number and percentage of subjects who (1) had any AE, (2) had any Grade ≥3 AE, 
(3) had any IDELA-related AE, (4) had any ofatumumab -related AE, (5) had any Grade ≥3 
IDELA-related AE, (6) had any Grade ≥3 ofatumumab -related AE, (7) had any SAE, 
(8) had any IDELA-related SAE, (9) had any ofatumumab -related SAE (10) discontinued from 
study drug due to an AE, (11) dose interruption or modification due to an AE, 
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Summaries (number and percentage of subjects) of TEAEs (by SOC, HLT, and PT) will be 
provided by treatment arms (or for the relevant treatment arm) using the safety analysis set as 
follows:

AEs

AEs by CTCAE Grade

Grade ≥3 AE

IDELA related AEs 

Ofatumumab related AEs

Infusion related AEs based on PT and based on Gilead medical search terms (MST) list

SAEs

IDELA and ofatumumab related SAEs 

AEs leading to IDELA reduction and/or interruption

AEs leading to IDELA interruption

AEs leading to IDELA reduction

AEs leading to ofatumumab delay

AEs leading to discontinuation from IDELA 

AEs leading to discontinuation from ofatumumab 

AEs leading to death

All non-serious AEs occurring in at least 5% of subjects in any treatment group

AE occurring more frequently in either treatment group by PT ( Relative Risk and P-value)

AE by Time interval (12 weeks intervals)

AE incidence rate adjusted for Total exposure
Multiple events will be counted once only per subject in each summary. For data presentation, 
SOC, HLT, 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 HLT, each 
summary will also be presented by preferred term only, ordered by decreasing frequency. 


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In addition, TEAE difference 22% ( all grades) or 22% in Grade 23 between the 2 treatment arms 
will be summarized by PT and volcano plot for relative risk of TEAEs between the 
treatment arms and their p-values will be plotted. 
In addition to the by-treatment summaries, data listings will be provided for the following: 
• 
All TEAEs 
• 
All AEs recorded between screening and first dose of study treatment (ie, non-TEAEs) 
• 
SAEs (with a variable indicating whether the event is treatment-emergent) 
• 
AEs leading to discontinuation of ID ELA 
• 
Deaths 
• 
TEAE difference 22% (all grades) or 22% in Grade 23 between the 2 treatment arms 
Relative day from first dose date will be provided for each AE in the listings. The relative day 
will be calculated as (AE onset date - first dose date + 1). 
Incidence ofTEAEs will also be summarized by time interval, 0 to <12 weeks, 12 to <24 weeks, 
24 to <36 weeks, 36 to <48 weeks, and >= 48 weeks. Incidence of TEAE within the first 
6 months from the first dose will be summarized. Incidence of TEAEs in an interval is defined as 
the proportions of subjects with TEAEs within the interval in the safety analysis set. 
7.1.7. 
Exposure-adjusted TEAE Rate 
The exposure-adjusted TEAE rate is defined as the number of subjects with a specific event 
divided by the total exposure-time among the subjects in the treatment group and at risk of an 
initial occurrence of the event. Specifically, 
Exposure-Adjusted TEAE Rate = !:. = / 
T 
L... ti 
Where n is the number of subjects with events, ti is the lh subject exposure time in weeks and 
Tis the total exposure time in weeks of all subjects. If a subject has multiple events, 
the ti is the time of the first event. For a subject with no event, the ti will be censored at the time 
of data cut-off date if the subject is still on study drug; and the ti will be censored at the time of 
last does date plus 30 days or data cutoff date whichever is shorter if the subject discontinues 
study drug. 
The exposure-adjusted TEAE rate will be summarized for certain AEs of interest by treatment 
arm based on the safety analysis set. 
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7.1.8.
Treatment-Emergent Adverse Events (TEAEs) of Interest
Additional analyses on AEs of interest will be performed.
The following AEs of interest will be summarized similarly to TEAE by treatment arms. AEs of 
interest leading to interruption and/or reduction, and leading to treatment discontinuation will be 
also summarized.

Grade ≥ 3 Rash based on Gilead medical search list including multiple MedDRA preferred 
terms dermatitis exfoliative, drug eruption, rash, rash erythematous, rash generalised, 
rash macular, rash maculo-papular, rash papular, rash prutitic, rash morbiliform, and 
exfoliative rash 

Grade ≥ 3 Diarrhea/Colitis including diarrhea and colitis

Any Grade Pneumonitis

Grade ≥ 3 Pneumonia including pneumonia, lung infection, lung infiltration, 
pneumocystis jiroveci pneumonia, pneumonia legionella, lung infection pseudomonal, 
pneumonia fungal, lower respiratory tract infection, and lower respiratory tract infection 
bacterial.
Number and percentage of subjects with AEs of interest will be summarized by treatment arms 
for subjects:

with any grade (or Grade 3 or 4) AEs of interest

re-challenged after dose interruption due to AEs of interest

re-challenged successfully after interruption with resumption of IDELA at a starting dose

re-challenged successfully after interruption with resumption of IDELA at a reduced dose

with recurrence of AEs of interest among re-challenged
Incidence of AEs of interest (of any grade and Grade 3 or higher) over time in 12-week 
intervals will be summarized and plotted.  Incidence of TEAEs in an interval is defined as the 
proportion of subjects with onset of the TEAE in the interval among those at risk at the 
beginning of the interval. The incidence over time describes the risk (constant or changing) of 
developing a new or recurrent event over time. The subjects at risk include those on treatment or 
within 30 days post last dose date for subjects who didn’t die at the beginning of the interval.
Prevalence of AEs of interest (of any grade and Grade 3 or higher) over time in 12-week 
intervals will be summarized and plotted. Prevalence of TEAEs is defined as the proportion of 
subjects experiencing a TEAE in the interval among those at risk at the beginning of the interval. 
The prevalence over time describes the risk (constant or changing) of having an event over time. 
The subjects at risk include those on treatment or within 30 days post last dose date for subjects 
who didn’t die at the beginning of the interval.


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The following analyses of time to onset and time to resolution will be done for pneumonitis and 
diarrhea/colitis.
Time to first onset of AE of interest (of any grade and Grade 3 or higher) and 
time to resolution will be summarized and plotted. Kaplan-Meier estimates of the median, 
Q1, Q3, and the number of subjects with event and censored subjects will be provided.
Time to onset of first event is defined as time from start of study treatment to the date of 
first incident treatment-emergent AEs of interest, ie, time in weeks is calculated as 
(start date of first occurrence – date of first dose of study drug +1)/7. In the absence of an event,
the censoring date applied will be the earliest from the following dates: last dose date 
(if treatment discontinued or 12 doses of ofatumumab is completed for Arm B subjects)
+ 30 days, analysis data cut-off date and death date. Time to resolution of AE of interest is 
calculated as (AE resolution date - start date of first occurrence of AE +1)/7.
7.2.
Laboratory Evaluations
Summaries of laboratory data (including hematology, serum chemistry, and selected 
immunoglobulin parameters) will be provided for the safety analysis set. 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 safety analysis set.
7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics (sample size, mean, StD, median, Q1, 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 visit

Change from baseline at each post-baseline visit
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.2. In addition, the raw values (StD), mean change from baseline
(standard error) and median raw values (Q1/Q3) for all lab parameters will be plotted over 
time by treatment arms.
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 by 
treatment arms.


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7.2.3.
Graded Laboratory Values
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. Local labs will be graded based 
on central lab normal ranges with in-house macro. Local labs of ANC, lymphocytes, Platelet, 
Hemoglobin, Aspartate aminotransferase, Alanine aminotransferase, Total bilirubin, and 
Alkaline Phosphatase are included in the table summaries when central labs are not available.
All central and local labs will be listed.
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 of study drug 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
Summary (number and percentage of subjects) of baseline and worst post-baseline 
treatment-emergent laboratory abnormalities for treatment-emergent lab abnormalities and 
treatment-emergent Grade 3 or 4 lab abnormalities will be provided by treatment arms. Subjects 
will be categorized according to most severe abnormality grade.
For all summaries of laboratory abnormalities, the denominator is the number of subjects in the 
safety analysis set. A listing of treatment-emergent Grade ≥ 3 laboratory abnormalities will be 
provided. Lab abnormalities incidence difference ≥ 5% (all grades) or ≥ 2% in Grade ≥3 
between 2 arms will be summarized and volcano plot for relative risk of lab abnormalities 
between the treatment arms and their p-values will be plotted.
7.2.3.3.
Exposure-adjusted Treatment-Emergent Laboratory Abnormalities Rate
The exposure-adjusted treatment-emergent lab abnormalities will be analyzed similarly to the 
exposure-adjusted TEAE rates (outlined in Section 7.1.7).
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.


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7.2.5.
Transaminase elevations
Analyses of transaminase elevations will be based on laboratory values using the safety analysis 
set. Number and percentage of subjects will be summarized by treatment arms 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

with recurrence of Grade 3 or 4 ALT/AST elevation among re-challenged 

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 ALT/AST 
elevation, ie, time in weeks is calculated as (start date of first occurrence – date of first dose of 
study drug +1)/7. In the absence of an event, the censoring date applied will be the earliest from 
the following dates: last ALT/AST collection date, last dose date (if treatment discontinued or 
12 doses of ofatumumab is completed) + 30 days, analysis data cut-off date, and death date.
For subjects with at least 1 episode of Grade 3 or 4 ALT/AST elevation, time to resolution of 
first episode of treatment-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 
re-challenged due to Grade 3 or 4 treatment-emergent ALT/AST elevations.
7.2.6.
Liver-Related Laboratory Tests
The number and percentage of subjects will be summarized for the following liver-related 
laboratory tests and categories:

Aspartate aminotransferase (AST): (a) 3 to <5 x ULN, (b) 5 to <10 x ULN, 
(c) 10 to <20 x ULN, (d) ≥ 20 x ULN

Alanine aminotransferase (ALT): (a) 3 to <5 x ULN, (b) 5 to <10 x ULN, 
(c) 10 to <20 x ULN, (d) ≥ 20 x ULN

AST or ALT: (a) 3 to <5 x ULN, (b) 5 to <10 x ULN, (c) 10 to <20 x ULN, (d) ≥20 x ULN

Total bilirubin: (a) > ULN, (b) > 1.5 x ULN, (c) > 2 x ULN 

AST or ALT > 3 x ULN and total bilirubin > 1.5 x ULN


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
AST or ALT > 3 x ULN and total bilirubin > 2 x ULN

Alkaline Phosphatase >1.5 x ULN
For individual laboratory tests, subjects will be counted once based on the most severe 
post-baseline values.
Among the subjects with elevated AST or ALT (> 3 x ULN), the following 2 approaches will be 
used for counting subjects with total bilirubin elevation/normal alkaline phosphatase 
(≤1.5 x ULN):

Subjects will be counted once when total bilirubin elevation/normal alkaline phosphatase 
occurred at any post-baseline visit.

Subjects will be counted once when total bilirubin elevation/normal alkaline phosphatase 
occurred concurrently at the same post-baseline visit with AST or ALT elevation.
In addition, a listing of subjects meeting each category will be provided 
7.3.
Prior Therapy (Including Radiation)
Number of prior regimens and time since the completion of last regimen will be summarized by 
treatment arms using descriptive statistics (sample size, mean, standard deviation, median, 
Q1, Q3, minimum and maximum) based on the safety analysis set. 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 
01 Jan or the starting date of the 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;

If year is missing, no imputation will be done and the completion date will be treated as 
missing.
Number (%) of subjects who received 1, 2, 3, ... prior regimens will also be provided. The 
regimens and prior therapies (n, %) that the subjects received will be summarized. The last 
regimen subjects received prior to study entry and the best response (n, %) to last therapy will be 
summarized.
Number of subjects who received prior radiation will be summarized and will be listed.


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7.4.
Concomitant Medications
Concomitant medications will be coded by means of the World Health Organization Drug 
(WHODRUG) dictionary, Q1 2011 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 study drug up to 30 days post the last dose

Starting before and continuing after the first dose of study drug 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 the safety 
analysis set. The summary tables will be sorted by descending frequency of preferred terms. 
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 safety analysis set.
7.5.
Body Weight and Vital Signs
Body weight at each visit, and change from baseline in body weight will be summarized for the 
safety analysis set using descriptive statistics by treatment group for each post baseline visit. In 
the case of multiple values in an analysis window, data will be selected for analysis as described 
in Section 3.8.2. No inferential statistics will be generated.
7.6.
Electrocardiogram Results
The following analyses of electrocardiogram (ECG) results are intended to identify gross
changes in QT intervals. ECG data will be categorized at the investigational sites as normal, 
abnormal but not clinically significant, or abnormal and clinically significant.
7.6.1.
Corrected QT Intervals
Corrected QT (QTc) intervals will be derived by using Fridericia method:
Fridericia: QTc-F = QT / (RR)1/3, 
where, RR is calculated as [60 / Heart Rate (beats/min)].


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The QTc data (msec) obtained by using the Fridericia correction will be categorized separately 
into the following classifications and summarized for screening:

450

451–480

481–500

> 500
The change in QTc values (msec) obtained by using the Fridericia’s correction will also be 
categorized separately as follows:

30

31-60

> 60
7.6.2.
Investigator Assessment of ECG Readings
The number and percentage of subjects in the safety analysis set with an investigator’s ECG 
assessment of normal, abnormal but not clinically significant, or abnormal and clinically 
significant will be summarized by treatment group for screening.
7.6.3.
Oxygen Saturation Levels
Oxygen percent saturation and its change from baseline will be summarized for the safety 
analysis set using descriptive statistics by treatment group. Summaries of oxygen saturation data 
will be based on observed data and will be reported as % saturation. The number and percentage 
of subjects who achieve the lowest value below 92% and ≥5% decrease from baseline in 
oxygen percent saturation will be summarized by treatment group.
7.7.
Other Safety Measures
Physical examination results will be summarized by body system and visit. All results will be 
listed.
A data listing will be provided for subjects experiencing pregnancy during the study.
7.8.
Changes From Protocol-Specified Safety Analyses
Not applicable.


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8.
PHARMACOKINETIC ANALYSES
Bioanalytical analyses will performed independently so that the study team and investigators will 
not have knowledge of data from individual subjects. For Arm A, the IDELA plasma 
concentrations immediately pre-dose and at 1.5 hours after administration of the dose of study 
drug at each relevant clinic visit will be summarized by treatment and visit using descriptive 
statistics.


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9.
PHARMACODYNAMIC ANALYSES
A separate biomarker analysis plan will be prepared to detail pharmacodynamics and biomarker 
analyses.


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10.
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Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum 
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a report from the International Workshop on Chronic Lymphocytic Leukemia 
(IWCLL) updating the National Cancer Institute-Working Group (NCI-WG) 1996 
guidelines. Blood 2008;111 (12):5446-56.
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Cheson BD, Byrd JC, Rai KR, Kay NE, O'Brien SM, Flinn IW, et al. Novel 
targeted agents and the need to refine clinical end points in chronic lymphocytic 
leukemia. J Clin Oncol 2012;30 (23):2820-2.
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Hung HM, Wang SJ, O'Neill R. Statistical considerations for testing multiple 
endpoints in group sequential or adaptive clinical trials. J Biopharm Stat 2007;17 
(6):1201-10.
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Shaw JW, Johnson JA, Coons SJ. US valuation of the EQ-5D health states: 
development and testing of the D1 valuation model. Medical care 2005;43 
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Robins JM, Finkelstein DM. Correcting for noncompliance and dependent 
censoring in an AIDS Clinical Trial with inverse probability of censoring 
weighted (IPCW) log-rank tests. Biometrics 2000;56 (3):779-88.
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Trask PC, Cella D, Besson N, Kelly V, Masszi T, Kim DW. Health-related 
quality of life of bosutinib (SKI-606) in imatinib-resistant or imatinib-intolerant 
chronic phase chronic myeloid leukemia. Leuk Res 2012;36 (4):438-42.
30874
Tamhane AC, Mehta CR, Liu L. Testing a primary and a secondary endpoint in a 
group sequential design. Biometrics 2010;66 (4):1174-84.


Idelalisib (IDELA)
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11.
SOFTWARE
SAS® Software Version 9.2. SAS Institute Inc., Cary, NC, USA.


Idelalisib (IDELA)
GS-US-312-0119
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12.
SAP REVISION
Revision Date
(dd month, yyyy)
Section
Summary of Revision
Reason for Revision
25Sep2014
6.7
Change in alpha level for the interim 
analysis
See section 6.7


Idelalisib (IDELA)
GS-US-312-0119
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29 September 2014
13.
APPENDICES
Appendix 1.
Schedule of Assessments
Appendix 2.
Testing Strategy for secondary endpoints
Appendix 3.
Table of Contents for Statistical Tables, Figures, and Listings


Idelalisib (IDELA)
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09 September 2014
Appendix 1.
Schedule of Assessments
Period
Screen
Treatment
Follow-up
Visit
1
2
3
4
5
6
7
8
9 10 11
12 13 14 15 16 17
18+
End of Study
30 day
Long-term
Week
-4
1
2
3
4
5
6
7
8 12 16
20 24 30 36 42 48
Q12 Weeks
Study Day
Within -28 Days
1
8 15 22 29 36 43 50 78 106 134 162 204 246 288 330
Within 
+30 days To +5 years
Visit Window
±2 ±2 ±2 ±2 ±2 ±2 ±2 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3
±7
Informed consent
X
Medical history
X
CIRS assessment
X
Serum virology
X
β-HCG
(women of child-bearing 
potential)
X
X
X
X X
X
X
X
X
X
X
Xa
Xa
X
CLL peripheral blood 
evaluation
X
X
CLL serology
X
X
Coagulation
X
Urinalysis
X
12-lead ECG
X
Genotyping and 
expression analysis
X
X
IWRS
X
X
X X X X X X X X
X
X
X
X
X
X
X
X
X


Idelalisib (IDELA)
GS-US-312-0119
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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 17
18+
End of Study
30 day
Long-term
Week
-4
1
2
3
4
5
6
7
8 12 16
20 24 30 36 42 48
Q12 Weeks
Study Day
Within -28 Days
1
8 15 22 29 36 43 50 78 106 134 162 204 246 288 330
Within 
+30 days To +5 years
Visit Window
±2 ±2 ±2 ±2 ±2 ±2 ±2 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3
±7
HRQL/healthy utility –
FACT-Leu/EQ-5D
X
X X X X X X X X
X
X
X
X
X
X
X
X
X
Adverse events
X
X X X 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
X
X
X
X
X
X
Performance status
X
X
X X X X X X X X
X
X
X
X
X
X
X
X
X
Oxygen saturation (by 
pulse oximetry)
X
X
X X X X X X X X
X
X
X
X
X
X
X
X
X
Physical exam 
(includes nodes, liver, 
spleen)
X
X
X
X X
X
X
X
X
X
X
X
X
X
Hematology/
serum chemistry
X
X
X X X X X X X X
X
X
X
X
X
X
X
X
X
Circulating 
cells/biomarkers/serum 
Igs
X
X X
X
X X
X
X
X
X
X
X
X
X
X
Idelalisib administration 
in clinic (Arm A only)
X
X
X
X X
X


Idelalisib (IDELA)
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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 17
18+
End of Study
30 day
Long-term
Week
-4
1
2
3
4
5
6
7
8 12 16
20 24 30 36 42 48
Q12 Weeks
Study Day
Within -28 Days
1
8 15 22 29 36 43 50 78 106 134 162 204 246 288 330
Within 
+30 days To +5 years
Visit Window
±2 ±2 ±2 ±2 ±2 ±2 ±2 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3
±7
Premedication and 
ofatumumab 
administration
X
X X X X X X X X
X
X
X
Infusion reaction 
severity/
duration assessment
X
X X X X X X X X
X
X
X
Idelalisib
pharmacokinetics 
(Arm A only)
X
X
X
X X
X
Idelalisib
dispensing/accounting 
(Arm A only)
X
X
X
X
X
X
X
Radiology assessment 
(CT/MRI) b
X
X
X
X
X
X
X
X
Bone marrow biopsy/
aspiratec
X
X
X
X
X
X
X
HBV DNA by PCRd
X
X X
X
X
X
X
X
X
Post-study CLL therapy
X
Long-term follow-up
X
a
After Visit 17 and 18, urine β-HCG to be performed every 6 weeks 5 d (women of child-bearing potential only)
b
At screening, CT/ MRI may be performed within 6 weeks prior to start of randomization); CT or MRI imaging of neck, chest, abdomen, and pelvis can be performed within 
1 week of the visit. CT/MRI assessments will continue until ~129 events have been observed in the study population


Idelalisib (IDELA)
GS-US-312-0119
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09 September 2014
c
At baseline, to be performed at investigator discretion to determine extent of CLL involvement and bone marrow cellularity. Post-baseline, to confirm CR or PD; if the subject 
does not otherwise meet criteria for CR or if the nature of PD does not require bone marrow confirmation, it is not necessary to obtain a follow-up bone marrow 
biopsy/aspirate. 
d
Only subjects who are HBc antibody positive and HBV DNA negative at screening. Subjects will be tested monthly for the duration of ofatumumab therapy and every 
3 months thereafter for 1 year from the last dose of ofatumumab .
Abbreviations: -HCG=beta human chorionic gonadotropin, CIRS=chronic illness rating scale, CLL=chronic lymphocytic leukemia, CR=complete response, 
CT=computed tomography, ECG=electrocardiogram, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, 
HRQL= health-related quality of life, Ig=immunoglobulin, IWRS=interactive web response system, MRI= magnetic resonance imaging


Idelalisib (IDELA)
GS-US-312-0119
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09 September 2014
Appendix 2.
Testing Strategy for secondary endpoints 
The primary endpoint of Study 312-0119, PFS, will be analyzed using the group sequential 
O’Brien Fleming method with 2 interim analyses and 1 final analysis. Even though 2-sided alpha 
level is used in this study, for simplicity, 1-sided alpha level is used in Appendix 2 as 2-sided 
type I error is 2 times 1-sided type I error in testing superiority of the active arm over the 
control arm. The overall 1-sided family-wise type I error rate for this study is set to be 0.025. 
Given the OF boundaries and the pre-specified gate-keeping procedure for primary and 
secondary endpoints, we here justify the use of 1-sided boundary of 0.015 for the testing of 
secondary endpoints in both the interim and final analyses following the methods in
Hung et al (2007) {26737}, and Tamhane et al (2010) {30874}.
Per Hung et al {26737} the type I error rate for the secondary endpoint in the hierarchical testing 
strategy is:
)
|
,
,
Pr(
)
|
,
Pr(
02
22
22
12
12
11
11
02
21
21
11
11
2
H
C
T
C
T
C
T
H
C
T
C
T








(1)
where the first subscript pertains to the endpoint (1=primary, 2=secondary) and the 
second subscript pertains to the analysis (1=interim, 2=final). 
11
T
and 
11
C are the test statistic and 
critical value for the primary endpoint (PFS) at the first analysis, respectively. Similarly,
21
T
and
21
C is the test statistic and the critical value for OS at the first analysis.
12
T
and 
12
C are the test statistic and the critical value for PFS at the second analysis, respectively,
and 
22
T
and 
22
C are the test statistic and the critical value for OS at the second analysis ,
respectively.
02
H
is the null hypothesis for OS. This was given in a setting of 1 interim analysis 
and 1 final analysis, where analysis 1 refers to the interim analysis and 2 refers to the final 
analysis. Accordingly it can be written as:
)
|
,
,
Pr(
)
|
,
Pr(
02
22
22
12
12
11
11
02
21
21
11
11
2
H
z
Z
z
Z
z
Z
H
z
Z
z
Z








(2)
where 
11
Z
and 
11
z
are the corresponding test statistics and critical values expressed in the setting 
of the standard normal distribution (ie, after standardization).
Extend this to the setting of Study 312-0119, where there were to be 2 interims and 
1 final analyses (3 analyses in total):
)
|
,
,
,
Pr(
)
|
,
,
Pr(
)
|
,
Pr(
02
33
33
13
13
12
12
11
11
02
22
22
12
12
11
11
02
21
21
11
11
2
H
z
Z
z
Z
z
Z
z
Z
H
z
Z
z
Z
z
Z
H
z
Z
z
Z













(3)


Idelalisib (IDELA)
GS-US-312-0119
Final
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29 September 2014
Assume
)
,
,
,
,
,
(
~
23
13
22
12
21
11
Z
Z
Z
Z
Z
Z
Z 
follows a multivariate normal distribution, it can be 
derived that:
















































































1,
,
,
,
,
,1,
,
,
,
,
,1,
,
/
,
/
,
,
,1,
/
,
/
,
,
/
,
/
,1,
,
,
/
,
/
,
,1
,
~
2
2
1
1
2
2
1
1
2
2
2
1
2
1
2
2
2
1
2
1
1
1
2
1
2
1
1
1
2
1
2
1
23
13
22
12
21
11
23
13
22
12
21
11
























t
t
t
t
t
t
t
t
t
t
t
t
t
t
t
t
t
t
t
t
t
t
t
t
t
t
t
t
t
t
t
t
MVN
Z
Z
Z
Z
Z
Z
(4)
where 
)
,
,
(
13
12
11



are the normalized mean treatment effect on the primary endpoint for the data 
up to the first interim, the second interim, and the final analysis; and 
)
,
,
(
23
22
21



are the 
normalized mean treatment effect on the secondary endpoint for the data up to the first 
pre-specified interim, the second pre-specified interim, and the final analysis. 
)
,
,
(
13
12
11



depend 
on the assumed true treatment effect on the primary endpoint, 
)
,
,
(
23
22
21



=
)
0
,0
,0
(
under the 
null hypothesis. denotes the correlation of test statistics between the primary and the 
secondary test statistics at each analysis stage, with range from 0 to 1 by assuming a 
non-negative correlation between the primary and the secondary endpoints. 
5.0
1 
t
and 
75
.0
2 
t
are 
the information fractions at the first and second pre-specified interim analyses in our study. 
The one-sided OF boundaries for primary endpoints are given, z11=z0.0015, z12=z0.009 and 
z13=z0.022. Hence, equation (3) can be calculated used the pmvnorm function in the 
R package mvtnorm based on the covariance structure specified in equation (4).
Appendix Figure 1 below shows the analytically calculated type I error rate for the secondary 
endpoint when α2 ≤0.025. It demonstrates that the use of 1-sided boundary of 0.015 for the 
testing of secondary endpoints in both the interims and final analyses controls the Type I 
error rate regardless of the correlation between the primary and the secondary test statistics and 
the magnitude of treatment effect of primary endpoint.


Idelalisib (IDELA)
GS-US-312-0119
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Appendix Figure 1. Type I Error Rate of Secondary Endpoint in a GS design with OF 
boundaries for Primary Endpoints and One-sided Boundary of 
Alpha Level 0.015 for the Secondary Endpoints at Two Interim
Analyses and One Final Analysis
C) 
<") 
q 
C) 
c 
10 
·o 
N 
a. 
q 
u c 
C) 
w 
2:'-
ro 
C) 
u c 
N 
0 
q 
<.> 
Q) 
C) 
(f) 
0 
2 
10 
ro 
q 
0::: 
C) 
2 w 
C) 
Q) 
a. 
q 
>-
I-
C) 
u 
Q) 
u 
10 
.<f 
C) 
Q) 
q 
c 
C) 
0 
C) 
C) 
q 
C) 
0 
1 
2 
3 
4 
5 
Treatment Effect of Primary Endpoint on Z Scale 


Idelalisib (IDELA)
GS-US-312-0119
Final
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Appendix 3.
Table of Contents for Statistical Tables, Figures, and Listings
Table Number
Title
Analysis Set
Interim
1.1.1
Subject Study Disposition
ITT

1.1.2
Subject Study Disposition
PP

1.1.3
Subject Study Disposition by 12-weeks Interval
ITT
1.1.4
Subject Study Treatment Disposition
ITT

1.1.5
Subject Study Treatment Disposition
PP

1.2
Summary of Enrollment by Site
ITT

1.3
Analysis Set
ITT

1.4
Important Protocol Deviations
ITT

1.5
Subject Distribution by Stratification Factors
ITT

1.6
Subject Demographics and Baseline Characteristics
ITT

1.6.1
Subject Demographics and Baseline Characteristics -
del17p/TP53 Mutation (Either)
ITT

1.6.2
Subject Demographics and Baseline Characteristics -
del17p/TP53 Mutation (Neither)
ITT

1.6.3
Subject Demographics and Baseline Characteristics – IgHV 
Mutated
ITT

1.6.4
Subject Demographics and Baseline Characteristics – IgHV 
Unmutated
ITT

1.7
CLL Disease History
ITT

1.8
Prior Therapy
ITT

1.9
Prior Radiation Therapy
ITT

1.10
Cumulative Illness Rating Scale (CIRS) Scores
ITT

1.10.1
Estimated Creatinine Clearance  (eCcr) at Baseline
ITT

1.11
Study Drug (IDELA) Exposure
Safety

1.12
Ofatumumab Exposure
Safety

1.13
Summary of Dose Modification of IDELA
Safety

1.14
Duration of Study
ITT

1.15
Time to Discontinuation from Study
ITT
.
2.1.1
Progression-free Survival by IRC Assessment
ITT

2.1.1.1
Progression-free Survival by IRC Assessment -
del17p/TP53 Mutation (Either)
ITT

2.1.1.2
Progression-free Survival by IRC Assessment -
del17p/TP53 Mutation (Neither)
ITT



Idelalisib (IDELA)
GS-US-312-0119
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Table Number
Title
Analysis Set
Interim
2.1.1.3
Progression-free Survival by IRC Assessment – IgHV 
Mutated
ITT

2.1.1.4
Progression-free Survival by IRC Assessment – IgHV 
Unmutated
ITT

2.1.1.5
Progression-free Survival by IRC Assessment - 17p deletion
ITT

2.1.1.6
Progression-free Survival by IRC Assessment – No 17p 
deletion
ITT

2.1.1.7
Progression-free Survival by IRC Assessment –
Refractory Status
ITT

2.1.1.8
Progression-free Survival by IRC Assessment –
Relapsed Status
ITT

2.1.1.9
Progression-free Survival by IRC Assessment - Male
ITT

2.1.1.10
Progression-free Survival by IRC Assessment - Female
ITT

2.1.1.11
Progression-free Survival by IRC Assessment –
Age < 65 (years)
ITT

2.1.1.12
Progression-free Survival by IRC Assessment –
Age >= 65 (years)
ITT

2.1.1.13
Progression-free Survival by IRC Assessment - Race White
ITT

2.1.1.14
Progression-free Survival by IRC Assessment - Race 
Non-White
ITT

2.1.1.15
Cox Regression for Progression-free Survival by IRC 
Assessment
ITT
2.1.2
Progression-free Survival by IRC Assessment
PP

2.1.2.1
Progression-free Survival by IRC Assessment -
del17p/TP53 Mutation (Either)
PP

2.1.2.2
Progression-free Survival by IRC Assessment -
del17p/TP53 Mutation (Neither)
PP

2.1.2.3
Progression-free Survival by IRC Assessment - IgHV 
Mutated
PP

2.1.2.4
Progression-free Survival by IRC Assessment - IgHV 
Unmutated
PP

2.1.2.5
Progression-free Survival by IRC Assessment - Relapsed 
Disease Status
PP

2.1.2.6
Progression-free Survival by IRC Assessment - Refractory 
Disease Status
PP

2.1.2.7
Progression-free Survival Sensitivity Analysis by IRC 
Assessment
ITT
2.1.3.1
Progression-free Survival Using the Unstratified Log-rank 
Test (Sensitivity Analysis) by IRC Assessment
ITT



Idelalisib (IDELA)
GS-US-312-0119
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Page 66
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Table Number
Title
Analysis Set
Interim
2.1.3.2
Progression-free Survival (Worst Case Sensitivity Analysis) 
by IRC Assessment
ITT

2.1.4
Progression-free Survival by IRC Assessment with Inverse 
Probability Censoring Weighted
ITT
2.1.5
Progression-free Survival by Investigator Assessment
ITT

2.1.6
Disease Progression Criteria
ITT
2.2.1
Overall Response Rate (ORR) by IRC Assessment
ITT

2.2.1.1
Overall Response Rate (ORR) by IRC Assessment -
del17p/TP53 Mutation (Either)
ITT

2.2.1.2
Overall Response Rate (ORR) by IRC Assessment -
del17p/TP53 Mutation (Neither)
ITT

2.2.1.3
Overall Response Rate (ORR) by IRC Assessment - IgHV 
Mutated
ITT

2.2.1.4
Overall Response Rate (ORR) by IRC Assessment - IgHV 
Unmutated
ITT

2.2.1.5
Overall Response Rate (ORR) by IRC Assessment -
17p deletion
ITT

2.2.1.6
Overall Response Rate (ORR) by IRC Assessment –
No 17p deletion
ITT

2.2.1.7
Overall Response Rate (ORR) by IRC Assessment -
Refractory Disease Status
ITT

2.2.1.8
Overall Response Rate (ORR) by IRC Assessment -
Relapsed Disease Status
ITT

2.2.1.9
Overall Response Rate (ORR) by IRC Assessment - Male
ITT

2.2.1.10
Overall Response Rate (ORR) by IRC Assessment - Female
ITT

2.2.1.11
Overall Response Rate (ORR) by IRC Assessment –
Age < 65 (years)
ITT

2.2.1.12
Overall Response Rate (ORR) by IRC Assessment –
Age >= 65 (years)
ITT

2.2.1.13
Overall Response Rate (ORR) by IRC Assessment - Race 
White
ITT

2.2.1.14
Overall Response Rate (ORR) by IRC Assessment - Race 
Non-White
ITT

2.2.1.15
Logistic Regression for Overall Response Rate (ORR) by 
IRC Assessment
ITT
2.2.4
Overall Response Rate (ORR) Sensitivity Analysis by IRC 
Assessment
ITT

2.2.4.1
Overall Response Rate (ORR) Sensitivity Analysis by IRC 
Assessment - del17p/TP53  Mutation (Either)
ITT



Idelalisib (IDELA)
GS-US-312-0119
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CONFIDENTIAL
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Table Number
Title
Analysis Set
Interim
2.2.4.2
Overall Response Rate (ORR) Sensitivity Analysis by IRC 
Assessment - del17p/TP53  Mutation (Neither)
ITT

2.2.4.3
Overall Response Rate (ORR) Sensitivity Analysis by IRC 
Assessment - IgHV Mutated
ITT

2.2.4.4
Overall Response Rate (ORR) Sensitivity Analysis by IRC 
Assessment - IgHV Unmutated
ITT

2.2.4.5
Overall Response Rate (ORR) Sensitivity Analysis by IRC 
Assessment - 17p deletion
ITT

2.2.4.6
Overall Response Rate (ORR) Sensitivity Analysis by IRC 
Assessment - No 17p deletion
ITT

2.2.4.7
Overall Response Rate (ORR) Sensitivity Analysis by IRC 
Assessment - Refractory Disease Status
ITT

2.2.4.8
Overall Response Rate (ORR) Sensitivity Analysis by IRC 
Assessment - Relapsed Disease Status
ITT

2.2.4.9
Overall Response Rate (ORR) Sensitivity Analysis by IRC 
Assessment - Male
ITT

2.2.4.10
Overall Response Rate (ORR) Sensitivity Analysis by IRC 
Assessment - Female
ITT

2.2.4.11
Overall Response Rate (ORR) Sensitivity Analysis by IRC 
Assessment - Age < 65 (years)
ITT

2.2.4.12
Overall Response Rate (ORR) Sensitivity Analysis by IRC 
Assessment - Age >= 65 (years)
ITT

2.2.4.13
Overall Response Rate (ORR) Sensitivity Analysis by IRC 
Assessment - Race White
ITT

2.2.4.14
Overall Response Rate (ORR) Sensitivity Analysis by IRC 
Assessment - Race Non-White
ITT

2.2.4.15
Logistic Regression for Overall Response Rate (ORR) 
Sensitivity Analysis by IRC Assessment
ITT
2.2.2
Overall Response Rate (ORR) by IRC Assessment
PP

2.2.2.1
Overall Response Rate (ORR) by IRC Assessment -
del17p/TP53 Mutation (Either)
PP

2.2.2.2
Overall Response Rate (ORR) by IRC Assessment -
del17p/TP53 Mutation (Neither)
PP

2.2.2.3
Overall Response Rate (ORR) by IRC Assessment - IgHV 
Mutated
PP

2.2.2.4
Overall Response Rate (ORR) by IRC Assessment - IgHV 
Unmutated
PP

2.2.2.5
Overall Response Rate (ORR) by IRC Assessment -
17p deletion
PP



Idelalisib (IDELA)
GS-US-312-0119
Final
Statistical Analysis Plan
Version 2.0
CONFIDENTIAL
Page 68
29 September 2014
Table Number
Title
Analysis Set
Interim
2.2.2.6
Overall Response Rate (ORR) by IRC Assessment - No 
17p deletion
PP

2.2.2.7
Overall Response Rate (ORR) by IRC Assessment -
Refractory Disease Status
PP

2.2.2.8
Overall Response Rate (ORR) by IRC Assessment -
Relapsed Disease Status
PP

2.2.3
Overall Response Rate (ORR) by IRC Assessment
ITT with at least 
One Post Baseline 
Assessment

2.2.3.1
Overall Response Rate (ORR) by IRC Assessment -
del17p/TP53  Mutation (Either)
ITT with at least 
One Post Baseline 
Assessment

2.2.3.2
Overall Response Rate (ORR) by IRC Assessment -
del17p/TP53  Mutation (Neither)
ITT with at least 
One Post Baseline 
Assessment

2.2.3.3
Overall Response Rate (ORR) by IRC Assessment - IgHV 
Mutated
ITT with at least 
One Post Baseline 
Assessment

2.2.3.4
Overall Response Rate (ORR) by IRC Assessment - IgHV 
Unmutated
ITT with at least 
One Post Baseline 
Assessment

2.2.3.5
Overall Response Rate (ORR) by IRC Assessment -
17p deletion
ITT with at least 
One Post Baseline 
Assessment

2.2.3.6
Overall Response Rate (ORR) by IRC Assessment - No 
17p deletion
ITT with at least 
One Post Baseline 
Assessment

2.2.3.7
Overall Response Rate (ORR) by IRC Assessment -
Relapsed Disease Status
ITT with at least 
One Post Baseline 
Assessment

2.2.3.8
Overall Response Rate (ORR) by IRC Assessment -
Refractory Disease Status
ITT with at least 
One Post Baseline 
Assessment

2.2.3.9
Overall Response Rate (ORR) by IRC Assessment - Male
ITT with at least 
One Post Baseline 
Assessment

2.2.3.10
Overall Response Rate (ORR) by IRC Assessment - Female
ITT with at least 
One Post Baseline 
Assessment

2.2.3.11
Overall Response Rate (ORR) by IRC Assessment –
Age < 65 (years)
ITT with at least 
One Post Baseline 
Assessment



Idelalisib (IDELA)
GS-US-312-0119
Final
Statistical Analysis Plan
Version 2.0
CONFIDENTIAL
Page 69
29 September 2014
Table Number
Title
Analysis Set
Interim
2.2.3.12
Overall Response Rate (ORR) by IRC Assessment –
Age >= 65 (years)
ITT with at least 
One Post Baseline 
Assessment

2.2.3.13
Overall Response Rate (ORR) by IRC Assessment - Race 
White
ITT with at least 
One Post Baseline 
Assessment

2.2.3.14
Overall Response Rate (ORR) by IRC Assessment - Race 
Non-White
ITT with at least 
One Post Baseline 
Assessment

2.2.5
Overall Response Rate (ORR) by Investigator Assessment
ITT

2.2.5.1
Overall Response Rate (ORR) by Investigator Assessment 
(Without 8 Weeks Confirmation)
ITT

2.2.6
Agreement in Overall Response Rate (ORR) between IRC 
and Investigator Assessment
ITT

2.2.6.1
Agreement in Overall Response Rate (ORR) between IRC 
and Investigator Assessment (Without 8 Weeks 
Confirmation)
ITT

2.3.1
Complete Response Rate (CR) by IRC Assessment
ITT
2.3.1.1
Complete Response Rate (CR)  by IRC Assessment -
del17p/TP53  Mutation (Either)
ITT
2.3.1.2
Complete Response Rate (CR)  by IRC Assessment -
del17p/TP53  Mutation (Neither)
ITT
2.3.1.3
Complete Response Rate (CR)  by IRC Assessment - IgHV 
Mutated
ITT
2.3.1.4
Complete Response Rate (CR)  by IRC Assessment - IgHV 
Unmutated
ITT
2.3.1.5
Complete Response Rate (CR)  by IRC Assessment -
17p deletion
ITT
2.3.1.6
Complete Response Rate (CR)  by IRC Assessment - No 
17p deletion
ITT
2.3.1.7
Complete Response Rate (CR)  by IRC Assessment -
Refractory Disease Status
ITT
2.3.1.8
Complete Response Rate (CR)  by IRC Assessment -
Relapsed Disease Status
ITT
2.3.1.9
Complete Response Rate (CR)  by IRC Assessment - Male
ITT
2.3.1.10
Complete Response Rate (CR)  by IRC Assessment - Female
ITT
2.3.1.11
Complete Response Rate (CR)  by IRC Assessment –
Age < 65 (years)
ITT
2.3.1.12
Complete Response Rate (CR)  by IRC Assessment –
Age >= 65 (years)
ITT


Idelalisib (IDELA)
GS-US-312-0119
Final
Statistical Analysis Plan
Version 2.0
CONFIDENTIAL
Page 70
29 September 2014
Table Number
Title
Analysis Set
Interim
2.3.1.13
Complete Response Rate (CR)  by IRC Assessment - Race 
White
ITT
2.3.1.14
Complete Response Rate (CR)  by IRC Assessment - Race 
Non-White
ITT
2.3.1.15
Logistic Regression for Complete Response Rate (CR)  by 
IRC Assessment
ITT
2.3.2
Complete Response Rate (CR)  by IRC Assessment
PP
2.3.2.1
Complete Response Rate (CR)  by IRC Assessment -
del17p/TP53 Mutation (Either)
PP
2.3.2.2
Complete Response Rate (CR)  by IRC Assessment -
del17p/TP53 Mutation (Neither)
PP
2.3.2.3
Complete Response Rate (CR)  by IRC Assessment - IgHV 
Mutated
PP
2.3.2.4
Complete Response Rate (CR)  by IRC Assessment - IgHV 
Unmutated
PP
2.3.2.5
Complete Response Rate (CR) by IRC Assessment -
17p deletion
PP
2.3.2.6
Complete Response Rate (CR) by IRC Assessment - No 
17p deletion
PP
2.3.2.7
Complete Response Rate (CR) by IRC Assessment -
Refractory Disease Status 
PP
2.3.2.8
Complete Response Rate (CR) by IRC Assessment -
Relapsed Disease Status
PP
2.3.3
Complete Response Rate (CR)  by IRC Assessment
ITT with at least 
One Post Baseline 
Assessment
2.3.3.1
Complete Response Rate (CR)  by IRC Assessment -
del17p/TP53  Mutation (Either)
ITT with at least 
One Post Baseline 
Assessment
2.3.3.2
Complete Response Rate (CR)  by IRC Assessment -
del17p/TP53  Mutation (Neither)
ITT with at least 
One Post Baseline 
Assessment
2.3.3.3
Complete Response Rate (CR)  by IRC Assessment - IgHV 
Mutated
ITT with at least 
One Post Baseline 
Assessment
2.3.3.4
Complete Response Rate (CR)  by IRC Assessment - IgHV 
Unmutated
ITT with at least 
One Post Baseline 
Assessment
2.3.3.5
Complete Response Rate (CR)  by IRC Assessment -
17p deletion
ITT with at least 
One Post Baseline 
Assessment


Idelalisib (IDELA)
GS-US-312-0119
Final
Statistical Analysis Plan
Version 2.0
CONFIDENTIAL
Page 71
29 September 2014
Table Number
Title
Analysis Set
Interim
2.3.3.6
Complete Response Rate (CR)  by IRC Assessment –
No 17p deletion
ITT with at least 
One Post Baseline 
Assessment
2.3.3.7
Complete Response Rate (ORR) by IRC Assessment -
Refractory Disease Status
ITT with at least 
One Post Baseline 
Assessment
2.3.3.8
Complete Response Rate (ORR) by IRC Assessment -
Relapsed Disease Status
ITT with at least 
One Post Baseline 
Assessment
2.3.3.9
Complete Response Rate (CR) by IRC Assessment - Male
ITT with at least 
One Post Baseline 
Assessment
2.3.3.10
Complete Response Rate (CR  by IRC Assessment - Female
ITT with at least 
One Post Baseline 
Assessment
2.3.3.11
Complete Response Rate (CR) by IRC Assessment –
Age < 65 (years)
ITT with at least 
One Post Baseline 
Assessment
2.3.3.12
Complete Response Rate (CR) by IRC Assessment –
Age >= 65 (years)
ITT with at least 
One Post Baseline 
Assessment
2.3.3.13
Complete Response Rate (CR) by IRC Assessment - Race 
White
ITT with at least 
One Post Baseline 
Assessment
2.3.3.14
Complete Response Rate (CR) by IRC Assessment - Race 
Non-White
ITT with at least 
One Post Baseline 
Assessment
2.3.4
Complete Response Rate (CR) by Investigator Assessment
ITT
2.3.5
Agreement in Complete Response Rate (CR)  between IRC 
and Investigator Assessment
ITT
2.4.1
Lymph Node Response (LNR) Rate by IRC Assessment
ITT

2.4.1.1
Lymph Node Response (LNR) Rate by IRC Assessment -
del17p/TP53 Mutation (Either)
ITT

2.4.1.2
Lymph Node Response (LNR) Rate by IRC Assessment -
del17p/TP53 Mutation (Neither)
ITT

2.4.1.3
Lymph Node Response (LNR) Rate by IRC Assessment -
IgHV Mutated
ITT

2.4.1.4
Lymph Node Response (LNR) Rate by IRC Assessment -
IgHV Unmutated
ITT

2.4.1.5
Lymph Node Response (LNR) Rate by IRC Assessment -
17p deletion
ITT



Idelalisib (IDELA)
GS-US-312-0119
Final
Statistical Analysis Plan
Version 2.0
CONFIDENTIAL
Page 72
29 September 2014
Table Number
Title
Analysis Set
Interim
2.4.1.6
Lymph Node Response (LNR) Rate by IRC Assessment -
No 17p deletion
ITT

2.4.1.7
Lymph Node Response (LNR) Rate by IRC Assessment -
Refractory Disease Status
ITT

2.4.1.8
Lymph Node Response (LNR) Rate by IRC Assessment -
Relapsed Disease Status
ITT

2.4.1.9
Lymph Node Response (LNR) Rate by IRC Assessment -
Male
ITT

2.4.1.10
Lymph Node Response (LNR) Rate by IRC Assessment -
Female
ITT

2.4.1.11
Lymph Node Response (LNR) Rate by IRC Assessment -
Age < 65 (years)
ITT

2.4.1.12
Lymph Node Response (LNR) Rate by IRC Assessment -
Age >= 65 (years)
ITT

2.4.1.13
Lymph Node Response (LNR) Rate by IRC Assessment -
Race White
ITT

2.4.1.14
Lymph Node Response (LNR) Rate by IRC Assessment -
Race Non-White
ITT

2.4.1.15
Logistic Regression for Lymph Node Response (LNR) Rate 
by IRC Assessment
ITT
2.4.2
Lymph Node Response (LNR) Rate by IRC Assessment
PP

2.4.2.1
Lymph Node Response (LNR) Rate by IRC Assessment -
del17p/TP53  Mutation (Either)
PP

2.4.2.2
Lymph Node Response (LNR) Rate by IRC Assessment -
del17p/TP53  Mutation (Neither)
PP

2.4.2.3
Lymph Node Response (LNR) Rate by IRC Assessment -
IgHV Mutated
PP

2.4.2.4
Lymph Node Response (LNR) Rate by IRC Assessment -
IgHV Unmutated
PP

2.4.2.5
Lymph Node Response (LNR) Rate by IRC Assessment -
17p deletion
PP

2.4.2.6
Lymph Node Response (LNR) Rate by IRC Assessment -
No 17p deletion
PP

2.4.2.7
Lymph Node Response (LNR) Rate by IRC Assessment -
Refractory Disease Status
PP

2.4.2.8
Lymph Node Response (LNR) Rate by IRC Assessment -
Relapsed Disease Status
PP

2.5.1
Overall Survival (OS)
ITT

2.5.1.1
Overall Survival (OS) - del17p/TP53 Mutation (Either)
ITT



Idelalisib (IDELA)
GS-US-312-0119
Final
Statistical Analysis Plan
Version 2.0
CONFIDENTIAL
Page 73
29 September 2014
Table Number
Title
Analysis Set
Interim
2.5.1.2
Overall Survival (OS) - del17p/TP53 Mutation (Neither)
ITT

2.5.1.3
Overall Survival (OS) - IgHV Mutated
ITT

2.5.1.4
Overall Survival (OS) - IgHV Unmutated
ITT

2.5.1.5
Overall Survival (OS) - 17p deletion
ITT

2.5.1.6
Overall Survival (OS) - No 17p deletion
ITT

2.5.1.7
Overall Survival (OS) - Refractory Disease Status
ITT

2.5.1.8
Overall Survival (OS) - Relapsed Disease Status
ITT

2.5.1.9
Overall Survival (OS) - Male
ITT

2.5.1.10
Overall Survival (OS) - Female
ITT

2.5.1.11
Overall Survival (OS) - Age < 65 (years)
ITT

2.5.1.12
Overall Survival (OS) - Age >= 65 (years)
ITT

2.5.1.13
Overall Survival (OS) - Race White
ITT

2.5.1.14
Overall Survival (OS) - Race Non-White
ITT

2.5.1.15
Cox Regression for Overall Survival (OS)
ITT
2.6.1
Time to Response (TTR) by IRC Assessment
ITT

2.6.1.1
Time to Response (TTR) by IRC Assessment -
del17p/TP53 Mutation (Either)
ITT

2.6.1.2
Time to Response (TTR) by IRC Assessment -
del17p/TP53 Mutation (Neither)
ITT

2.6.1.3
Time to Response (TTR) by IRC Assessment - IgHV 
Mutated
ITT

2.6.1.4
Time to Response (TTR) by IRC Assessment - IgHV 
Unmutated
ITT

2.6.1.5
Time to Response (TTR) by IRC Assessment - 17p deletion
ITT

2.6.1.6
Time to Response (TTR) by IRC Assessment - No 
17p deletion
ITT

2.6.1.7
Time to Response (TTR) by IRC Assessment - Refractory 
Disease Status
ITT

2.6.1.8
Time to Response (TTR) by IRC Assessment - Relapsed 
Disease Status
ITT

2.6.1.9
Time to Response (TTR) by IRC Assessment - Male
ITT

2.6.1.10
Time to Response (TTR) by IRC Assessment - Female
ITT

2.6.1.11
Time to Response (TTR) by IRC Assessment –
Age < 65 (years)
ITT



Idelalisib (IDELA)
GS-US-312-0119
Final
Statistical Analysis Plan
Version 2.0
CONFIDENTIAL
Page 74
29 September 2014
Table Number
Title
Analysis Set
Interim
2.6.1.12
Time to Response (TTR) by IRC Assessment –
Age >= 65 (years)
ITT

2.6.1.13
Time to Response (TTR) by IRC Assessment - Race White
ITT

2.6.1.14
Time to Response (TTR) by IRC Assessment - Race 
Non-White
ITT

2.6.2
Time to Response (TTR) Sensitivity Analysis by IRC 
Assessment
ITT

2.6.2.1
Time to Response (TTR) Sensitivity Analysis by IRC 
Assessment - del17p/TP53 Mutation (Either)
ITT

2.6.2.2
Time to Response (TTR) Sensitivity Analysis by IRC 
Assessment - del17p/TP53 Mutation (Neither)
ITT

2.6.2.3
Time to Response (TTR) Sensitivity Analysis by IRC 
Assessment - IgHV Mutated
ITT

2.6.2.4
Time to Response (TTR) Sensitivity Analysis by IRC 
Assessment - IgHV Unmutated
ITT

2.6.2.5
Time to Response (TTR) Sensitivity Analysis by IRC 
Assessment - 17p deletion
ITT

2.6.2.6
Time to Response (TTR) Sensitivity Analysis by IRC 
Assessment - No 17p Deletion
ITT

2.6.2.7
Time to Response (TTR) Sensitivity Analysis Sensitivity 
Analysis by IRC Assessment - Refractory Disease Status
ITT

2.6.2.8
Time to Response (TTR) Sensitivity Analysis by IRC 
Assessment - Relapsed Disease Status
ITT

2.6.2.9
Time to Response (TTR) Sensitivity Analysis by IRC 
Assessment - Male
ITT

2.6.2.10
Time to Response (TTR) Sensitivity Analysis by IRC 
Assessment - Female
ITT

2.6.2.11
Time to Response (TTR) Sensitivity Analysis by IRC 
Assessment - Age < 65 (years)
ITT

2.6.2.12
Time to Response (TTR) Sensitivity Analysis by IRC 
Assessment - Age >= 65  (years)
ITT

2.6.2.13
Time to Response (TTR) Sensitivity Analysis by IRC 
Assessment - Race White
ITT

2.6.2.14
Time to Response (TTR) Sensitivity Analysis by IRC 
Assessment - Race Non-White
ITT

2.6.3
Time to Response (TTR) by IRC Assessment
PP

2.6.4.1
Time to Response (TTR) by Investigator Assessment 
(Without 8 Weeks Confirmation)
ITT

2.7.1
Duration of Response (DOR) by IRC Assessment
ITT



Idelalisib (IDELA)
GS-US-312-0119
Final
Statistical Analysis Plan
Version 2.0
CONFIDENTIAL
Page 75
29 September 2014
Table Number
Title
Analysis Set
Interim
2.7.1.1
Duration of Response (DOR) by IRC Assessment -
del17p/TP53 Mutation (Either)
ITT

2.7.1.2
Duration of Response (DOR) by IRC Assessment -
del17p/TP53 Mutation (Neither)
ITT

2.7.1.3
Duration of Response (DOR) by IRC Assessment - IgHV 
Mutated
ITT

2.7.1.4
Duration of Response (DOR) by IRC Assessment - IgHV 
Unmutated
ITT

2.7.1.5
Duration of Response (DOR) by IRC Assessment -
17p deletion
ITT

2.7.1.6
Duration of Response (DOR) by IRC Assessment - No 
17p deletion
ITT

2.7.1.7
Duration of Response (DOR) by IRC Assessment -
Refractory Disease Status
ITT

2.7.1.8
Duration of Response (DOR) by IRC Assessment - Relapsed 
Disease Status
ITT

2.7.1.9
Duration of Response (DOR) by IRC Assessment - Male
ITT

2.7.1.10
Duration of Response (DOR) by IRC Assessment - Female
ITT

2.7.1.11
Duration of Response (DOR) by IRC Assessment –
Age < 65 (years)
ITT

2.7.1.12
Duration of Response (DOR) by IRC Assessment –
Age >= 65 (years)
ITT

2.7.1.13
Duration of Response (DOR) by IRC Assessment - Race 
White
ITT

2.7.1.14
Duration of Response (DOR) by IRC Assessment - Race 
Non-White
ITT

2.7.2
Duration of Response (DOR) Sensitivity Analysis by IRC 
Assessment
ITT

2.7.2.1
Duration of Response (DOR) Sensitivity Analysis by IRC 
Assessment - del17p/TP53 Mutation (Either)
ITT

2.7.2.2
Duration of Response (DOR) Sensitivity Analysis by IRC 
Assessment - del17p/TP53 Mutation (Neither)
ITT

2.7.2.3
Duration of Response (DOR) Sensitivity Analysis by IRC 
Assessment - IgHV Mutated
ITT

2.7.2.4
Duration of Response (DOR) Sensitivity Analysis by IRC 
Assessment - IgHV Unmutated
ITT

2.7.2.5
Duration of Response (DOR) Sensitivity Analysis by IRC 
Assessment - 17p deletion
ITT

2.7.2.6
Duration of Response (DOR) Sensitivity Analysis by IRC 
Assessment - No 17p deletion
ITT



Idelalisib (IDELA)
GS-US-312-0119
Final
Statistical Analysis Plan
Version 2.0
CONFIDENTIAL
Page 76
29 September 2014
Table Number
Title
Analysis Set
Interim
2.7.2.7
Duration of Response (DOR) Sensitivity Analysis by IRC 
Assessment - Refractory Disease Status
ITT

2.7.2.8
Duration of Response (DOR) Sensitivity Analysis by IRC 
Assessment - Relapsed Disease Status
ITT

2.7.2.9
Duration of Response (DOR) Sensitivity Analysis by IRC 
Assessment - Male
ITT

2.7.2.10
Duration of Response (DOR) Sensitivity Analysis by IRC 
Assessment - Female
ITT

2.7.2.11
Duration of Response (DOR) Sensitivity Analysis by IRC 
Assessment - Age < 65 (years)
ITT

2.7.2.12
Duration of Response (DOR) Sensitivity Analysis by IRC 
Assessment - Age >= 65 (years)
ITT

2.7.2.13
Duration of Response (DOR) Sensitivity Analysis by IRC 
Assessment - Race White
ITT

2.7.2.14
Duration of Response (DOR) Sensitivity Analysis by IRC 
Assessment - Race Non-White
ITT

2.7.3
Duration of Response (DOR) Sensitivity Analysis by IRC 
Assessment
PP

2.7.4.1
Duration of Response (DOR) Sensitivity Analysis by 
Investigator Assessment (Without 8 Weeks Confirmation)
ITT

2.8
Best Percent Change in SPD - IRC assessment
ITT

2.8.1
Best Percent Change in SPD by IRC Assessment -
del17p/TP53 Mutation (Either)
ITT

2.8.2
Best Percent Change in SPD by IRC Assessment -
del17p/TP53 Mutation (Neither)
ITT

2.8.3
Best Percent Change in SPD by IRC Assessment - IgHV 
Mutated
ITT

2.8.4
Best Percent Change in SPD by IRC Assessment - IgHV 
Unmutated
ITT

2.8.5
Best Percent Change in SPD by IRC Assessment -
17p deletion
ITT

2.8.6
Best Percent Change in SPD by IRC Assessment - No 
17p deletion
ITT

2.8.7
Best Percent Change in SPD by IRC Assessment -
Refractory Disease Status
ITT

2.8.8
Best Percent Change in SPD by IRC Assessment - Relapsed 
Disease Status
ITT

2.9.1
Baseline Abnormality Status for Efficacy Response 
Assessment
ITT

2.9.2
Splenomegaly Response Rate - IRC Assessment
ITT



Idelalisib (IDELA)
GS-US-312-0119
Final
Statistical Analysis Plan
Version 2.0
CONFIDENTIAL
Page 77
29 September 2014
Table Number
Title
Analysis Set
Interim
2.9.3
Hepatomegaly Response Rate - IRC Assessment
ITT

2.9.4
ALC Response Rate
ITT

2.9.5
Platelet Response Rate
ITT

2.9.6
Hemoglobin Response Rate
ITT

2.9.7
Neutrophil (ANC) Response Rate
ITT

2.10.1
CT/MRI Assessment by Investigator 
ITT

2.10.2
CLL Assessment by Physical Examination
ITT

2.11.1.1
Functional Assessment of Cancer Therapy: 
Leukemia (FACT-Leu) - Actual and Change from Baseline
ITT

2.11.1.2
Mixed Model for Functional Assessment of Cancer Therapy: 
Leukemia (FACT-Leu) 
ITT
2.11.1.3
Functional Assessment of Cancer Therapy: 
Leukemia (FACT-Leu) - Compliance
ITT

2.11.2.1
Karnofsky Performance Status - Observed and Change from 
Baseline
ITT

2.11.3.1
Summary of EuroQoL Five Dimension Descriptive System 
(EQ-5D) by Dimension
ITT

2.11.3.2
Summary of EuroQol Visual Analogue Score (VAS) -
Actual Values and Change from Baseline
ITT

2.11.3.3
Summary of EuroQol Five Dimension Questionnaire Utility 
Index - Actual Values and Change from Baseline
ITT
2.11.3.4
Mixed Model for EuroQoL Five Dimension Questionnaire 
(EQ-5D)
ITT
2.11.3.5
Mixed Model for EuroQoL Five Dimension Questionnaire 
Utility Index (EQ-5D)
ITT
2.11.3.6
EuroQEuroQoL Five Dimension Questionnaire (EQ-5D) -
Compliance
ITT

3.1.1
Overall Summary of Adverse Events
Safety

3.1.1.1
Overall Summary of Adverse Events - Male
Safety

3.1.1.2
Overall Summary of Adverse Events - Female
Safety

3.1.1.3
Overall Summary of Adverse Events - Age < 65 (years)
Safety

3.1.1.4
Overall Summary of Adverse Events - Age >= 65 (years)
Safety

3.1.1.5
Overall Summary of Adverse Events - Race White
Safety

3.1.1.6
Overall Summary of Adverse Events - Race Non-White
Safety

3.1.2
Treatment-Emergent Adverse Events by MedDRA SOC, 
HLT and PT
Safety



Idelalisib (IDELA)
GS-US-312-0119
Final
Statistical Analysis Plan
Version 2.0
CONFIDENTIAL
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Table Number
Title
Analysis Set
Interim
3.1.2.1
Treatment-Emergent Adverse Events by MedDRA SOC, 
HLT and PT - Male
Safety

3.1.2.2
Treatment-Emergent Adverse Events by MedDRA SOC, 
HLT and PT - Female
Safety

3.1.2.3
Treatment-Emergent Adverse Events by MedDRA SOC, 
HLT and PT - Age < 65 (years)
Safety

3.1.2.4
Treatment-Emergent Adverse Events by MedDRA SOC, 
HLT and PT - Age >=65 (years)
Safety

3.1.2.5
Treatment-Emergent Adverse Events by MedDRA SOC, 
HLT and PT - Race White
Safety

3.1.2.6
Treatment-Emergent Adverse Events by MedDRA SOC, 
HLT and PT - Race Non-White
Safety

3.1.3
Treatment-Emergent Adverse Events by MedDRA SOC, 
HLT, PT and CTCAE Grade
Safety

3.1.3.1
Treatment-Emergent Adverse Events by MedDRA SOC, 
HLT, PT and CTCAE Grade - Male
Safety

3.1.3.2
Treatment-Emergent Adverse Events by MedDRA SOC, 
HLT, PT and CTCAE Grade - Female
Safety

3.1.3.3
Treatment-Emergent Adverse Events by MedDRA SOC, 
HLT, PT and CTCAE Grade - Age < 65 (years)
Safety

3.1.3.4
Treatment-Emergent Adverse Events by MedDRA SOC, 
HLT, PT and CTCAE Grade - Age >=65 (years)
Safety

3.1.3.5
Treatment-Emergent Adverse Events by MedDRA SOC, 
HLT, PT and CTCAE Grade - Race White
Safety

3.1.3.6
Treatment-Emergent Adverse Events by MedDRA SOC, 
HLT, PT and CTCAE Grade - Race Non-White
Safety

3.1.4
Treatment-Emergent Adverse Events Related to IDELA by 
MedDRA SOC, HLT, PT and CTCAE Grade
Safety

3.1.4.1
Treatment-Emergent Adverse Events Related to IDELA  by 
MedDRA SOC, HLT, PT and CTCAE Grade - Male
Safety

3.1.4.2
Treatment-Emergent Adverse Events Related to IDELA  by 
MedDRA SOC, HLT, PT and CTCAE Grade - Female
Safety

3.1.4.3
Treatment-Emergent Adverse Events Related to IDELA by 
MedDRA SOC, HLT, PT and CTCAE Grade - Age 
< 65 (years)
Safety

3.1.4.4
Treatment-Emergent Adverse Events Related to IDELA by 
MedDRA SOC, HLT, PT and CTCAE Grade –
Age >= 65 (years)
Safety

3.1.4.5
Treatment-Emergent Adverse Events Related to IDELA by 
MedDRA SOC, HLT, PT and CTCAE Grade - Race White
Safety



Idelalisib (IDELA)
GS-US-312-0119
Final
Statistical Analysis Plan
Version 2.0
CONFIDENTIAL
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Table Number
Title
Analysis Set
Interim
3.1.4.6
Treatment-Emergent Adverse Events Related to IDELA by 
MedDRA SOC, HLT, PT and CTCAE Grade - Race 
Non-White
Safety

3.1.5
Treatment-Emergent Adverse Events Related to 
Ofatumumab by MedDRA SOC, HLT, PT, and CTCAE 
Grade
Safety

3.1.5.1
Treatment-Emergent Adverse Events Related to 
Ofatumumab by MedDRA SOC, HLT, PT, and CTCAE 
Grade - Male
Safety

3.1.5.2
Treatment-Emergent Adverse Events Related to 
Ofatumumab by MedDRA SOC, HLT, PT, and CTCAE 
Grade - Female
Safety

3.1.5.3
Treatment-Emergent Adverse Events Related to 
Ofatumamub by MedDRA SOC, HLT, PT, and CTCAE 
Grade -  Age < 65 (years)
Safety

3.1.5.4
Treatment-Emergent Adverse Events Related to 
Ofatumumab by MedDRA SOC, HLT, PT, and CTCAE 
Grade - Age >= 65 (years)
Safety

3.1.5.5
Treatment-Emergent Adverse Events Related to 
Ofatumumab by MedDRA SOC, HLT, PT, and CTCAE 
Grade - Race White
Safety

3.1.5.6
Treatment-Emergent Adverse Events Related to 
Ofatumumab by MedDRA SOC, HLT, PT, and CTCAE 
Grade - Race Non-White
Safety

3.1.6
Grade >= 3 Treatment-Emergent Adverse Events by 
MedDRA SOC, HLT and PT
Safety

3.1.6.1
Grade >= 3 Treatment-Emergent Adverse Events by 
MedDRA SOC, HLT and PT - Male
Safety

3.1.6.2
Grade >= 3 Treatment-Emergent Adverse Events by 
MedDRA SOC, HLT and PT - Female
Safety

3.1.6.3
Grade >= 3 Treatment-Emergent Adverse Events by 
MedDRA SOC, HLT and PT - Age < 65 (years)
Safety

3.1.6.4
Grade >= 3 Treatment-Emergent Adverse Events by 
MedDRA SOC, HLT and PT - Age >=65 (years)
Safety

3.1.6.5
Grade >= 3 Treatment-Emergent Adverse Events by 
MedDRA SOC, HLT and PT - Race White
Safety

3.1.6.6
Grade >= 3 Treatment-Emergent Adverse Events by 
MedDRA SOC, HLT and PT - Race Non-White
Safety

3.1.7
Grade >= 3 Treatment-Emergent Adverse Events Related to 
IDELA by MedDRA SOC, HLT and PT
Safety

3.1.7.1
Grade >= 3 Treatment-Emergent Adverse Events Related to 
IDELA by MedDRA SOC, HLT and PT - Male
Safety



Idelalisib (IDELA)
GS-US-312-0119
Final
Statistical Analysis Plan
Version 2.0
CONFIDENTIAL
Page 80
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Table Number
Title
Analysis Set
Interim
3.1.7.2
Grade >= 3 Treatment-Emergent Adverse Events Related to 
IDELA by MedDRA SOC, HLT and PT - Female
Safety

3.1.7.3
Grade >= 3 Treatment-Emergent Adverse Events Related to 
IDELA by MedDRA SOC, HLT and PT - Age < 65 (years)
Safety

3.1.7.4
Grade >= 3 Treatment-Emergent Adverse Events Related to 
IDELA by MedDRA SOC, HLT and PT - Age >= 65 (years)
Safety

3.1.7.5
Grade >= 3 Treatment-Emergent Adverse Events Related to 
IDELA by MedDRA SOC, HLT and PT - Race White
Safety

3.1.7.6
Grade >= 3 Treatment-Emergent Adverse Events Related to 
IDELA by MedDRA SOC, HLT and PT - Race Non-White
Safety

3.1.8
Grade >= 3 Treatment-Emergent Adverse Events Related to 
Ofatumumab by MedDRA SOC, HLT and PT
Safety

3.1.8.1
Grade >= 3 Treatment-Emergent Adverse Events Related to 
Ofatumumab by MedDRA SOC, HLT and PT - Male
Safety

3.1.8.2
Grade >= 3 Treatment-Emergent Adverse Events Related to 
Ofatumumab by MedDRA SOC, HLT and PT - Female
Safety

3.1.8.3
Grade >= 3 Treatment-Emergent Adverse Events Related to 
Ofatumumab by MedDRA SOC, HLT and PT –
Age < 65 (years)
Safety

3.1.8.4
Grade >= 3 Treatment-Emergent Adverse Events Related to 
Ofatumumab by MedDRA SOC, HLT and PT –
Age >=65 (years)
Safety

3.1.8.5
Grade >= 3 Treatment-Emergent Adverse Events Related to 
Ofatumumab by MedDRA SOC, HLT and PT - Race White
Safety

3.1.8.6
Grade >= 3 Treatment-Emergent Adverse Events Related to 
Ofatumumab by MedDRA SOC, HLT and PT - Race
Non-White
Safety

3.1.9
Serious Treatment-Emergent Adverse Events by MedDRA 
SOC, HLT and PT
Safety

3.1.9.1
Serious Treatment-Emergent Adverse Events by MedDRA 
SOC, HLT and PT - Male
Safety

3.1.9.2
Serious Treatment-Emergent Adverse Events by MedDRA 
SOC, HLT and PT - Female
Safety

3.1.9.3
Serious Treatment-Emergent Adverse Events by MedDRA 
SOC, HLT and PT - Age < 65 (years)
Safety

3.1.9.4
Serious Treatment-Emergent Adverse Events by MedDRA 
SOC, HLT and PT - Age >= 65 (years)
Safety

3.1.9.5
Serious Treatment-Emergent Adverse Events by MedDRA 
SOC, HLT and PT - Race White
Safety

3.1.9.6
Serious Treatment-Emergent Adverse Events by MedDRA 
SOC, HLT and PT - Race Non-White
Safety



Idelalisib (IDELA)
GS-US-312-0119
Final
Statistical Analysis Plan
Version 2.0
CONFIDENTIAL
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Table Number
Title
Analysis Set
Interim
3.1.10
Serious Treatment-Emergent Adverse Events Related to 
IDELA by MedDRA SOC, HLT and PT
Safety

3.1.10.1
Serious Treatment-Emergent Adverse Events Related to 
IDELA by MedDRA SOC, HLT and PT - Male
Safety

3.1.10.2
Serious Treatment-Emergent Adverse Events Related to 
IDELA by MedDRA SOC, HLT and PT - Female
Safety

3.1.10.3
Serious Treatment-Emergent Adverse Events Related to 
IDELA by MedDRA SOC, HLT and PT - Age < 65 (years)
Safety

3.1.10.4
Serious Treatment-Emergent Adverse Events Related to 
IDELA by MedDRA SOC, HLT and PT - Age >= 65 (years)
Safety

3.1.10.5
Serious Treatment-Emergent Adverse Events Related to 
IDELA by MedDRA SOC, HLT and PT - Race White
Safety

3.1.10.6
Serious Treatment-Emergent Adverse Events Related to 
IDELA by MedDRA SOC, HLT and PT - Race Non-White
Safety

3.1.11
Serious Treatment-Emergent Adverse Events Related to 
Ofatumamub by MedDRA SOC, HLT and PT
Safety

3.1.11.1
Serious Treatment-Emergent Adverse Events Related to 
Ofatumumab by MedDRA SOC, HLT and PT - Male
Safety

3.1.11.2
Serious Treatment-Emergent Adverse Events Related to 
Ofatumumab by MedDRA SOC, HLT and PT - Female
Safety

3.1.11.3
Serious Treatment-Emergent Adverse Events Related to 
Ofatumumab by MedDRA SOC, HLT and PT –
Age < 65 (years)
Safety

3.1.11.4
Serious Treatment-Emergent Adverse Events Related to 
Ofatumumab by MedDRA SOC, HLT and PT –
Age >= 65 (years)
Safety

3.1.11.5
Serious Treatment-Emergent Adverse Events Related to
Ofatumumab by MedDRA SOC, HLT and PT - Race White
Safety

3.1.11.6
Serious Treatment-Emergent Adverse Events Related to 
Ofatumumab by MedDRA SOC, HLT and PT - Race 
Non-White
Safety

3.1.12
Treatment-Emergent Adverse Events Leading to Reduction/ 
Interruption of IDELA by MedDRA SOC, HLT, PT and 
CTCAE Grade
Safety

3.1.12.1
Treatment-Emergent Adverse Events Leading to Reduction/ 
Interruption of IDELA by MedDRA SOC, HLT, PT and 
CTCAE Grade - Male
Safety

3.1.12.2
Treatment-Emergent Adverse Events Leading to Reduction/ 
Interruption of IDELA by MedDRA SOC, HLT, PT and 
CTCAE Grade - Female
Safety



Idelalisib (IDELA)
GS-US-312-0119
Final
Statistical Analysis Plan
Version 2.0
CONFIDENTIAL
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Table Number
Title
Analysis Set
Interim
3.1.12.3
TEAEs Leading to Reduction/ Interruption of IDELA by 
MedDRA SOC, HLT, PT and CTCAE Grade –
Age < 65 (years)
Safety

3.1.12.4
TEAEs Leading to Reduction/ Interruption of IDELA by 
MedDRA SOC, HLT, PT and CTCAE Grade –
Age >= 65 (years)
Safety

3.1.12.5
Treatment-Emergent Adverse Events Leading to Reduction/ 
Interruption of IDELA by MedDRA SOC, HLT, PT and 
CTCAE Grade - Race White
Safety

3.1.12.6
Treatment-Emergent Adverse Events Leading to Reduction/ 
Interruption of IDELA by MedDRA SOC, HLT, PT and 
CTCAE Grade - Race Non-White
Safety

3.1.13
Treatment-Emergent Adverse Events Leading to IDELA 
Discontinuation by MedDRA SOC, HLT and PT
Safety

3.1.13.1
Treatment-Emergent Adverse Events Leading to IDELA 
Discontinuation by MedDRA SOC, HLT and PT - Male
Safety

3.1.13.2
Treatment-Emergent Adverse Events Leading to IDELA 
Discontinuation by MedDRA SOC, HLT and PT - Female
Safety

3.1.13.3
Treatment-Emergent Adverse Events Leading to IDELA 
Discontinuation by MedDRA SOC, HLT and PT –
Age < 65 (years)
Safety

3.1.13.4
Treatment-Emergent Adverse Events Leading to IDELA 
Discontinuation by MedDRA SOC, HLT and PT –
Age >= 65 (years)
Safety

3.1.13.5
Treatment-Emergent Adverse Events Leading to IDELA 
Discontinuation by MedDRA SOC, HLT and PT - Race 
White
Safety

3.1.13.6
Treatment-Emergent Adverse Events Leading to IDELA 
Discontinuation by MedDRA SOC, HLT and PT - Race 
Non-White
Safety

3.1.28
Treatment-Emergent Adverse Events Leading to 
Ofatumumab Delay by MedDRA SOC, HLT and PT
Safety

3.1.28.1
Treatment-Emergent Adverse Events Leading to 
Ofatumumab Delay by MedDRA SOC, HLT and PT - Male
Safety

3.1.28.2
Treatment-Emergent Adverse Events Leading to 
Ofatumumab Delay by MedDRA SOC, HLT and PT -
Female
Safety

3.1.28.3
Treatment-Emergent Adverse Events Leading to 
Ofatumumab Delay by MedDRA SOC, HLT and PT –
Age < 65 (years)
Safety

3.1.28.4
Treatment-Emergent Adverse Events Leading 
toOfatumumab Delay by MedDRA SOC, HLT and PT –
Age >= 65 (years)
Safety



Idelalisib (IDELA)
GS-US-312-0119
Final
Statistical Analysis Plan
Version 2.0
CONFIDENTIAL
Page 83
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Table Number
Title
Analysis Set
Interim
3.1.28.5
Treatment-Emergent Adverse Events Leading to 
Ofatumumab Delay by MedDRA SOC, HLT and PT - Race 
White
Safety

3.1.28.6
Treatment-Emergent Adverse Events Leading to 
Ofatumumab Delay by MedDRA SOC, HLT and PT - Race 
Non-White
Safety

3.1.29
Treatment-Emergent Adverse Events Leading to 
Ofatumumab Discontinuation by MedDRA SOC, HLT and 
PT
Safety

3.1.29.1
Treatment-Emergent Adverse Events Leading to 
Ofatumumab  Discontinuation by MedDRA SOC, HLT and 
PT - Male
Safety

3.1.29.2
Treatment-Emergent Adverse Events Leading to 
Ofatumumab  Discontinuation by MedDRA SOC, HLT and 
PT - Female
Safety

3.1.29.3
Treatment-Emergent Adverse Events Leading to 
Ofatumumab Discontinuation by MedDRA SOC, HLT and 
PT - Age < 65 (years)
Safety

3.1.29.4
Treatment-Emergent Adverse Events Leading to 
Ofatumumab  Discontinuation by MedDRA SOC, HLT and 
PT - Age >= 65 (years)
Safety

3.1.29.5
Treatment-Emergent Adverse Events Leading to 
Ofatumumab   Discontinuation by MedDRA SOC, HLT and 
PT - Race White
Safety

3.1.29.6
Treatment-Emergent Adverse Events Leading to 
Ofatumumab   Discontinuation by MedDRA SOC, HLT and 
PT - Race Non-White
Safety

3.1.14
Treatment-Emergent Adverse Events Leading to Death by 
MedDRA SOC, HLT and PT
Safety

3.1.14.1
Treatment-Emergent Adverse Events Leading to Death by 
MedDRA SOC, HLT and PT - Male
Safety

3.1.14.2
Treatment-Emergent Adverse Events Leading to Death by 
MedDRA SOC, HLT and PT - Female
Safety

3.1.14.3
Treatment-Emergent Adverse Events Leading to Death by 
MedDRA SOC, HLT and PT - Age < 65 (years)
Safety

3.1.14.4
Treatment-Emergent Adverse Events Leading to Death by 
MedDRA SOC, HLT and PT - Age >= 65 (years)
Safety

3.1.14.5
Treatment-Emergent Adverse Events Leading to Death by 
MedDRA SOC, HLT and PT - Race White
Safety

3.1.14.6
Treatment-Emergent Adverse Events Leading to Death by 
MedDRA SOC, HLT and PT - Race Non-White
Safety



Idelalisib (IDELA)
GS-US-312-0119
Final
Statistical Analysis Plan
Version 2.0
CONFIDENTIAL
Page 84
29 September 2014
Table Number
Title
Analysis Set
Interim
3.1.15
Treatment-Emergent Adverse Events by MedDRA PT and 
CTCAE Grade
Safety

3.1.15.1
Treatment-Emergent Adverse Events by MedDRA PT and 
CTCAE Grade - Male
Safety

3.1.15.2
Treatment-Emergent Adverse Events by MedDRA PT and 
CTCAE Grade - Female
Safety

3.1.15.3
Treatment-Emergent Adverse Events by MedDRA PT and 
CTCAE Grade - Age < 65 (years)
Safety

3.1.15.4
Treatment-Emergent Adverse Events by MedDRA PT and 
CTCAE Grade - Age >= 65 (years)
Safety

3.1.15.5
Treatment-Emergent Adverse Events by MedDRA PT and 
CTCAE Grade - Race White
Safety

3.1.15.6
Treatment-Emergent Adverse Events by MedDRA PT and 
CTCAE Grade - Race Non-White
Safety

3.1.16
All Grades and Grade >= 3 Treatment-Emergent Adverse 
Events by MedDRA PT 
Safety

3.1.16.1
All Grades and Grade >= 3 Treatment-Emergent Adverse 
Events by MedDRA PT - Male
Safety

3.1.16.2
All Grades and Grade >= 3 Treatment-Emergent Adverse 
Events by MedDRA PT - Female
Safety

3.1.16.3
All Grades and Grade >= 3 Treatment-Emergent Adverse 
Events by MedDRA PT - Age < 65 (years)
Safety

3.1.16.4
All Grades and Grade >= 3 Treatment-Emergent Adverse 
Events by MedDRA PT - Age >= 65 (years)
Safety

3.1.16.5
All Grades and Grade >= 3 Treatment-Emergent Adverse 
Events by MedDRA PT - Race White
Safety

3.1.16.6
All Grades and Grade >= 3 Treatment-Emergent Adverse 
Events by MedDRA PT - Race Non-White
Safety

3.1.16.7
All Grades and Grade >= 3 Treatment-Emergent Adverse 
Events by MedDRA PT (0 to 12 Weeks)
Safety
3.1.16.8
All Grades and Grade >= 3 Treatment-Emergent Adverse 
Events by MedDRA PT (12 to 24 Weeks)
Safety at 12 Weeks
3.1.16.9
All Grades and Grade >= 3 Treatment-Emergent Adverse 
Events by MedDRA PT (24 to 36 Weeks)
Safety  at 24 Weeks
3.1.16.10
All Grades and Grade >= 3 Treatment-Emergent Adverse 
Events by MedDRA PT (36 to 48 Weeks)
Safety  at 36
3.1.16.11
All Grades and Grade >= 3 Treatment-Emergent Adverse 
Events by MedDRA PT (>= 48 Weeks)
Safety  at 48 Weeks
3.1.16.12
All Grades and Grade >= 3 Treatment-Emergent Adverse 
Events by MedDRA PT (0 to 6 month)
Safety


Idelalisib (IDELA)
GS-US-312-0119
Final
Statistical Analysis Plan
Version 2.0
CONFIDENTIAL
Page 85
29 September 2014
Table Number
Title
Analysis Set
Interim
3.1.17
All Grades and Grade >= 3 Treatment-Emergent Adverse 
Events Related to IDELA by MedDRA PT
Safety

3.1.17.1
All Grades and Grade >= 3 Treatment-Emergent Adverse 
Events Related to IDELA by MedDRA PT - Male
Safety

3.1.17.2
All Grades and Grade >= 3 Treatment-Emergent Adverse 
Events Related to IDELA by MedDRA PT - Female
Safety

3.1.17.3
All Grades and Grade >= 3 Treatment-Emergent Adverse 
Events Related to IDELA by MedDRA PT –
Age < 65 (years)
Safety

3.1.17.4
All Grades and Grade >= 3 Treatment-Emergent Adverse 
Events Related to IDELA by MedDRA PT –
Age >=65 (years)
Safety

3.1.17.5
All Grades and Grade >= 3 Treatment-Emergent Adverse 
Events Related to IDELA by MedDRA PT - Race White
Safety

3.1.17.6
All Grades and Grade >= 3 Treatment-Emergent Adverse 
Events Related to IDELA by MedDRA PT - Race 
Non-White
Safety

3.1.18
Serious Treatment-Emergent Adverse Events by MedDRA 
PT 
Safety

3.1.18.1
Serious Treatment-Emergent Adverse Events by MedDRA 
PT - Male
Safety

3.1.18.2
Serious Treatment-Emergent Adverse Events by MedDRA 
PT - Female
Safety

3.1.18.3
Serious Treatment-Emergent Adverse Events by MedDRA 
PT - Age < 65 (years)
Safety

3.1.18.4
Serious Treatment-Emergent Adverse Events by MedDRA 
PT - Age >= 65 (years)
Safety

3.1.18.5
Serious Treatment-Emergent Adverse Events by MedDRA 
PT - Race White
Safety

3.1.18.6
Serious Treatment-Emergent Adverse Events by MedDRA 
PT - Race Non-White
Safety

3.1.19
Treatment-Emergent Adverse Events Leading to Reduction/ 
Interruption of IDELA by MedDRA PT and CTCAE grade
Safety

3.1.19.1
Treatment-Emergent Adverse Events Leading to Reduction/ 
Interruption of IDELA by MedDRA PT and CTCAE grade -
Male
Safety

3.1.19.2
Treatment-Emergent Adverse Events Leading to Reduction/ 
Interruption of IDELA by MedDRA PT and CTCAE grade -
Female
Safety

3.1.19.3
Treatment-Emergent Adverse Events Leading to Reduction/ 
Interruption of IDELA by MedDRA PT and CTCAE grade -
Age < 65 (years)
Safety



Idelalisib (IDELA)
GS-US-312-0119
Final
Statistical Analysis Plan
Version 2.0
CONFIDENTIAL
Page 86
29 September 2014
Table Number
Title
Analysis Set
Interim
3.1.19.4
Treatment-Emergent Adverse Events Leading to Reduction/ 
Interruption of IDELA by MedDRA PT and CTCAE grade -
Age >= 65 (years)
Safety

3.1.19.5
Treatment-Emergent Adverse Events Leading to Reduction/ 
Interruption of IDELA by MedDRA PT and CTCAE grade -
Race White
Safety

3.1.19.6
Treatment-Emergent Adverse Events Leading to Reduction/ 
Interruption of IDELA by MedDRA PT and CTCAE grade -
Race Non-White
Safety

3.1.19.7
Treatment-Emergent Adverse Events Leading to Interruption 
of IDELA by MedDRA PT and CTCAE grade
Safety
3.1.19.8
Treatment-Emergent Adverse Events Leading to Interruption 
of IDELA by MedDRA PT and CTCAE grade - Male
Safety
3.1.19.9
Treatment-Emergent Adverse Events Leading to Interruption 
of IDELA by MedDRA PT and CTCAE grade - Female
Safety
3.1.19.10
Treatment-Emergent Adverse Events Leading to Interruption 
of IDELA by MedDRA PT and CTCAE grade –
Age <65 (years)
Safety
3.1.19.11
Treatment-Emergent Adverse Events Leading to Interruption 
of IDELA by MedDRA PT and CTCAE grade –
Age >=65 (years)
Safety
3.1.19.12
Treatment-Emergent Adverse Events Leading to Interruption 
of IDELA by MedDRA PT and CTCAE grade - Race White
Safety
3.1.19.13
Treatment-Emergent Adverse Events Leading to Interruption 
of IDELA by MedDRA PT and CTCAE grade - Race 
Non-White
Safety
3.1.19.14
Treatment-Emergent Adverse Events Leading to Reduction 
of IDELA by MedDRA PT and CTCAE grade
Safety
3.1.19.15
Treatment-Emergent Adverse Events Leading to Reduction 
of IDELA by MedDRA PT and CTCAE grade - Male
Safety
3.1.19.16
Treatment-Emergent Adverse Events Leading to Reduction 
of IDELA by MedDRA PT and CTCAE grade - Female
Safety
3.1.19.17
Treatment-Emergent Adverse Events Leading to Reduction 
of IDELA by MedDRA PT and CTCAE grade –
Age <65 (years)
Safety
3.1.19.18
Treatment-Emergent Adverse Events Leading to Reduction 
of IDELA by MedDRA PT and CTCAE grade –
Age >=65 (years)
Safety
3.1.19.19
Treatment-Emergent Adverse Events Leading to Reduction 
of IDELA by MedDRA PT and CTCAE grade - Race White
Safety


Idelalisib (IDELA)
GS-US-312-0119
Final
Statistical Analysis Plan
Version 2.0
CONFIDENTIAL
Page 87
29 September 2014
Table Number
Title
Analysis Set
Interim
3.1.19.20
Treatment-Emergent Adverse Events Leading to Reduction 
of IDELA by MedDRA PT and CTCAE grade - Race 
Non-White
Safety
3.1.20
Treatment-Emergent Adverse Events Leading to IDELA 
Discontinuation by MedDRA PT
Safety

3.1.20.1
Treatment-Emergent Adverse Events Leading to IDELA 
Discontinuation by MedDRA PT - Male
Safety

3.1.20.2
Treatment-Emergent Adverse Events Leading to IDELA 
Discontinuation by MedDRA PT - Female
Safety

3.1.20.3
Treatment-Emergent Adverse Events Leading to IDELA 
Discontinuation by MedDRA PT - Age < 65 (years)
Safety

3.1.20.4
Treatment-Emergent Adverse Events Leading to IDELA 
Discontinuation by MedDRA PT - Age >= 65 (years)
Safety

3.1.20.5
Treatment-Emergent Adverse Events Leading to IDELA 
Discontinuation by MedDRA PT - Race White
Safety

3.1.20.6
Treatment-Emergent Adverse Events Leading to IDELA 
Discontinuation by MedDRA PT - Race Non-White
Safety

3.1.21
Treatment-Emergent Adverse Events Leading to Death by 
MedDRA PT
Safety

3.1.21.1
Treatment-Emergent Adverse Events Leading to Death by 
MedDRA PT - Male
Safety

3.1.21.2
Treatment-Emergent Adverse Events Leading to Death by 
MedDRA PT - Female
Safety

3.1.21.3
Treatment-Emergent Adverse Events Leading to Death by 
MedDRA PT - Age < 65 (years)
Safety

3.1.21.4
Treatment-Emergent Adverse Events Leading to Death by 
MedDRA PT - Age >= 65 (years)
Safety

3.1.21.5
Treatment-Emergent Adverse Events Leading to Death by 
MedDRA PT - Race White
Safety

3.1.21.6
Treatment-Emergent Adverse Events Leading to Death by 
MedDRA PT - Race Non-White
Safety

3.1.22.1
Treatment-Emergent Adverse Events with >=2% Difference 
Between Two Groups by MedDRA PT 
Safety
3.1.22.2
Grade >= 3 Treatment-Emergent Adverse Events with >=2% 
Difference Between Two Groups by MedDRA PT 
Safety
3.1.22.3
Relative Risk of Treatment-Emergent Adverse Events by 
MedDRA PT 
Safety

3.1.22.4
Exposure-Adjusted Incidence Rate of Treatment-Emergent 
Adverse Events
Safety



Idelalisib (IDELA)
GS-US-312-0119
Final
Statistical Analysis Plan
Version 2.0
CONFIDENTIAL
Page 88
29 September 2014
Table Number
Title
Analysis Set
Interim
3.1.23.1
Treatment-Emergent Adverse Events of Interest by CTCAE 
Grade
Safety

3.1.23.2
Treatment-Emergent Adverse Events of Interest Leading to 
Reduction/ Interruption of IDELA by CTCAE Grade
Safety

3.1.23.3
Treatment-Emergent Adverse Events of Interest Leading to 
Reduction of IDELA by CTCAE Grade
Safety

3.1.23.4
Treatment-Emergent Adverse Events of Interest Leading to 
Interruption of IDELA by CTCAE Grade
Safety
3.1.23.5
Treatment-Emergent Adverse Events of Interest Leading to 
IDELA Discontinuation 
Safety
3.1.23.6
Incidence of Treatment-Emergent Adverse Events of Interest 
by 12-weeks Intevals
Safety
3.1.23.7
Prevalence of Treatment-Emergent Adverse Events of 
Interest by 12-weeks Intevals
Safety
3.1.23.8
Exposure-Adjusted Incidence Rate of Treatment-Emergent 
Adverse Events of Interest
Safety
3.1.23.9
Time to First Onset and Resolution of Treatment-Emergent 
Adverse Events of Interest
Safety
3.1.23.10
Summary of Treatment-Emergent Adverse Events of Interest
Safety
3.1.24
Summary of Infusion-Related Reaction per Preferred Term 
and MST
Safety
3.1.25
Summary of  On-Study Ricther's Transformation and Second
Malignancies
Safety

3.1.26
Summary of Deaths
Safety

3.2.1
Hematology: Summary of Actual Values and Change from 
Baseline
Safety

3.2.2
Hematology: Summary of Treatment-Emergent Laboratory 
Abnormalities
Safety

3.2.2.1
Hematology: Summary of Treatment-Emergent Laboratory 
Abnormalities - Male
Safety

3.2.2.2
Hematology: Summary of Treatment-Emergent Laboratory 
Abnormalities - Female
Safety

3.2.2.3
Hematology: Summary of Treatment-Emergent Laboratory 
Abnormalities - Age < 65 (years)
Safety

3.2.2.4
Hematology: Summary of Treatment-Emergent Laboratory 
Abnormalities - Age >= 65 (years)
Safety

3.2.2.5
Hematology: Summary of Treatment-Emergent Laboratory 
Abnormalities - Race White
Safety

3.2.2.6
Hematology: Summary of Treatment-Emergent Laboratory 
Abnormalities - Race Non-White
Safety



Idelalisib (IDELA)
GS-US-312-0119
Final
Statistical Analysis Plan
Version 2.0
CONFIDENTIAL
Page 89
29 September 2014
Table Number
Title
Analysis Set
Interim
3.2.3
Hematology: Shift from Baseline to worst CTCAE Severity 
Grade
Safety

3.2.4.1
Hematology: Treatment-Emergent Laboratory Abnormalities 
with >=5% Difference Between Two Groups
Safety

3.2.4.2
Hematology: Grade >= 3 Treatment-Emergent Laboratory 
Abnormalities with >=2% Difference Between Two Groups
Safety

3.2.5
Hematology: Exposure-adjusted Incidence Rate of 
Treatment-Emergent Lab Abnormalities
Safety

3.2.6
Serum Chemistry: Summary of Actual Values and Change 
from Baseline
Safety

3.2.7
Serum Chemistry: Summary of Treatment-Emergent 
Laboratory Abnormalities 
Safety

3.2.7.1
Serum Chemistry: Summary of Treatment-Emergent 
Laboratory Abnormalities  - Male
Safety

3.2.7.2
Serum Chemistry: Summary of Treatment-Emergent 
Laboratory Abnormalities  - Female
Safety

3.2.7.3
Serum Chemistry: Summary of Treatment-Emergent 
Laboratory Abnormalities - Age < 65 (years)
Safety

3.2.7.4
Serum Chemistry: Summary of Treatment-Emergent 
Laboratory Abnormalities - Age >= 65 (years)
Safety

3.2.7.5
Serum Chemistry: Summary of Treatment-Emergent 
Laboratory Abnormalities - Race White
Safety

3.2.7.6
Serum Chemistry: Summary of Treatment-Emergent 
Laboratory Abnormalities - Race Non-White
Safety

3.2.8
Serum Chemistry: Shift from Baseline to worst CTCAE 
Severity Grade
Safety

3.2.9.1
Serum Chemistry: Treatment-Emergent Laboratory 
Abnormalities with >=5% Difference Between Two Groups
Safety
3.2.9.2
Serum Chemistry: Grade >= 3 Treatment-Emergent 
Laboratory Abnormalities with >=2% Difference Between 
Two Groups
Safety
3.2.10
Serum Chemistry: Exposure-adjusted Incidence Rate of 
Treatment-Emergent Lab Abnormalities
Safety

3.2.11
Summary of Liver-related Laboratory Abnormalities
Safety
3.2.12
Urinalysis: Summary of Actual Values at Baseline
Safety

3.2.13
Treatment-Emergent Transaminase Elevations 
Safety

3.2.14
Time to First Onset and Resolution of Treatment-Emergent 
Transaminase Elevation
Safety

3.2.15
Immunoglobulin: Summary of Actual Values and Change 
from Baseline
Safety



Idelalisib (IDELA)
GS-US-312-0119
Final
Statistical Analysis Plan
Version 2.0
CONFIDENTIAL
Page 90
29 September 2014
Table Number
Title
Analysis Set
Interim
3.3
Summary of 12-Lead Electrocardiograms at Screening
Safety

3.4.1
Oxygen Saturation: Actual Value and Change from Baseline 
Safety
3.4.2
Lowest Oxygen Saturation
Safety
3.5
Concomitant Medications
Safety

4.1.1
Idelalisib Plasma Pharmacokinetic Concentration (ng/mL)
PK
4.1.2
Idelalisib Metabolite GS-563117 Plasma Pharmacokinetic 
Concentration (ng/mL)
PK


Idelalisib (IDELA)
GS-US-312-0119
Final
Statistical Analysis Plan
Version 2.0
CONFIDENTIAL
Page 91
29 September 2014
Listing Number
Title
Analysis Set
Interim
1.1.1
Screen Failures

1.1.2
Eligibility - IRC Assessment

1.2
Subject Disposition
ITT

1.3
Stratification Factors
ITT

1.4
Subjects Excluded From Any 
ITT

1.5
Important Protocol Deviations
ITT

1.6
Subject Demographics and Baseline Characteristics
ITT

1.7
CLL Disease History
ITT

1.8.1
Prior Therapy
ITT

1.8.2
Prior Radiation Therapy
ITT

1.9
Medical History
ITT

1.10.1
Subject Listing of IDELA Modification 
(Interruption and Reduction)
Safety

1.10.2
Subject Listing of IDELA Dispense and Return with IDELA 
Adherence
Safety

1.10.3
Study Drug (IDELA and Ofatumumab) Administration in 
Clinic
Safety

1.10.4
Study Drug (IDELA) Assignment by IWRS
ITT

1.10.5
Continuous Dosing Records of IDELA
Safety

2.1.1
Radiographic Assessments of Index Lesions by IRC
ITT

2.1.2
Radiographic Assessments of Non-Index Lesions by IRC
ITT

2.1.3
Radiographic Assessments of Spleen and Liver by IRC
ITT

2.1.4
Overall Radiographic and Clinical Response by IRC 
ITT

2.1.5
CT/MRI Assessment Dates
ITT

2.2.1
CLL Assessment by Physical Examination - Investigator 
Assessment
ITT

2.2.2
CLL Assessment by CT/MRI Scan - Investigator Assessment
ITT

2.2.3
Overall CLL Assessment - Investigator Assessment
ITT

2.3
Progression-free Survival
ITT

2.4
Overall Survival
ITT

2.5
Time to First Response and Duration of Response
ITT

2.6
Other Efficacy Response Assessment
ITT

2.7
Bone Marrow Aspirate and Biopsy
ITT

2.8
Organ Biopsy
ITT



Idelalisib (IDELA)
GS-US-312-0119
Final
Statistical Analysis Plan
Version 2.0
CONFIDENTIAL
Page 92
29 September 2014
Listing Number
Title
Analysis Set
Interim
2.9
Functional Assessment of Cancer Therapy: 
Leukemia (FACT-Leu) Scores
ITT

2.10
Karnofsky Performance Status
ITT

2.11
EuroQoL Five-Dimension
ITT

3.1.1
Laboratory Tests: Hematology
Safety

3.1.2
Laboratory Tests: Chemistry
Safety

3.1.3
Laboratory Tests: Urinalysis
Safety

3.1.4
Laboratory Tests: Immunoglobulin
Safety

3.1.5
Laboratory Tests: Hematological Endpoints (ANC)
Safety

3.1.6
Laboratory Tests: Hematological Endpoints (ALC)
Safety

3.1.7
Laboratory Tests: Hematological Endpoints (Platelet)
Safety

3.1.8
Laboratory Tests: Hematological Endpoints (Hemoglobin)
Safety

3.1.9
Listing of liver-related Laboratory Abnormalities
Safety
3.2
Transaminase Elevations
Safety

3.3.1
All Adverse Events
Safety

3.3.2
Serious Treatment Emergent Adverse Events
Safety

3.3.3
TEAEs Leading to Interruption or Modification of IDELA
Safety

3.3.4
TEAEs Leading to IDELA Discontinuation
Safety

3.3.5
Adverse Events Leading to Death
Safety

3.3.6
Summary of Second Malignancies
Safety

3.4
All Deaths
Safety

3.5
Non-Treatment Emergent Adverse Events
Safety

3.6
12-Lead Electrocardiogram
Safety

3.7
Body Weight and Oxygen Saturation
Safety

3.8
Prior and Concomitant Medications
Safety

3.9
Concomitant Therapy Status
Safety

3.10
Transfusion Log
Safety

3.11
Surgical and Medical Procedures
Safety

3.12
Hospitalization
Safety

3.13
Pregnancy
Safety

3.14
Long-term Follow-up Contact
Safety

3.15
Comment
ITT



Idelalisib (IDELA)
GS-US-312-0119
Final
Statistical Analysis Plan
Version 2.0
CONFIDENTIAL
Page 93
29 September 2014
Figure Number
Title
Analysis Set
Interim
1.1.0
Kaplan-Meier Curve of Time to Discontinuation from Study
ITT
1.1
Kaplan-Meier Curve of Progression-free Survival by IRC 
Assessment
ITT

1.1.1
Kaplan-Meier Curve of Progression-free Survival by IRC 
Assessment - del17p/TP53  Mutation (Either)
ITT

1.1.2
Kaplan-Meier Curve of Progression-free Survival by IRC 
Assessment - del17p/TP53  Mutation (Neither)
ITT

1.1.3
Kaplan-Meier Curve of Progression-free Survival by IRC 
Assessment - IgHV Mutated
ITT

1.1.4
Kaplan-Meier Curve of Progression-free Survival by IRC 
Assessment - IgHV Unmutated
ITT

1.1.5
Kaplan-Meier Curve of Progression-free Survival by IRC 
Assessment - 17p deletion
ITT

1.1.6
Kaplan-Meier Curve of Progression-free Survival by IRC 
Assessment - No 17p deletion
ITT

1.1.7
Kaplan-Meier Curve of Progression-free Survival by IRC 
Assessment - Relapsed Disease Status
ITT

1.1.8
Kaplan-Meier Curve of Progression-free Survival by IRC 
Assessment - Refractory Disease Status
ITT

1.1.9
Kaplan-Meier Curve of Progression-free Survival by IRC 
Assessment - Responders
ITT

1.1.10
Kaplan-Meier Curve of Progression-free Survival by IRC 
Assessment - Non-Responders
ITT

1.2
Kaplan-Meier Curve of Progression-free Survival by IRC 
Assessment
PP

1.2.1
Kaplan-Meier Curve of Progression-free Survival by IRC 
Assessment - del17p/TP53  Mutation (Either)
PP

1.2.2
Kaplan-Meier Curve of Progression-free Survival by IRC 
Assessment - del17p/TP53  Mutation (Neither)
PP

1.2.3
Kaplan-Meier Curve of Progression-free Survival by IRC 
Assessment - IgHV Mutated
PP

1.2.4
Kaplan-Meier Curve of Progression-free Survival by IRC 
Assessment - IgHV Unmutated
PP

1.2.5
Kaplan-Meier Curve of Progression-free Survival by IRC 
Assessment - 17p deletion
PP

1.2.6
Kaplan-Meier Curve of Progression-free Survival by IRC 
Assessment - No 17p deletion
PP

1.2.7
Kaplan-Meier Curve of Progression-free Survival by IRC 
Assessment - Relapsed Disease Status
PP



Idelalisib (IDELA)
GS-US-312-0119
Final
Statistical Analysis Plan
Version 2.0
CONFIDENTIAL
Page 94
29 September 2014
Figure Number
Title
Analysis Set
Interim
1.2.8
Kaplan-Meier Curve of Progression-free Survival by IRC 
Assessment - Refractory Disease Status
PP

1.2.9
Kaplan-Meier Curve of Progression-free Survival by IRC 
Assessment - Responders
PP

1.2.10
Kaplan-Meier Curve of Progression-free Survival by IRC 
Assessment - Non-Responders
PP

1.3
Forest Plot of Hazard Ratio for Progression-free Survival by 
IRC Assessment
ITT

1.3.1
Forest Plot of Hazard Ratio for Progression-free Survival in 
the group of 17p/p53 by IRC Assessment
ITT

1.4
Kaplan-Meier Curve of Overall Survival
ITT

1.4.1
Kaplan-Meier Curve of Overall Survival -
del17p/TP53 Mutation (Either)
ITT

1.4.2
Kaplan-Meier Curve of Overall Survival -
del17p/TP53 Mutation (Neither)
ITT

1.4.3
Kaplan-Meier Curve of Overall Survival - IgHV Mutated
ITT

1.4.4
Kaplan-Meier Curve of Overall Survival - IgHV Unmutated
ITT

1.4.5
Kaplan-Meier Curve of Overall Survival - 17p Deletion
ITT

1.4.6
Kaplan-Meier Curve of Overall Survival - No 17p Deletion
ITT

1.4.7
Kaplan-Meier Curve of Overall Survival - Relapsed Disease 
Status
ITT

1.4.8
Kaplan-Meier Curve of Overall Survival - Refractory 
Disease Status
ITT

1.4.9
Forest Plot of Hazard Ratio for Overall Survival by IRC 
Assessment
ITT

1.5
Forest Plot of Odds Ratio for Overall Response Rate by IRC 
Assessment 
ITT

1.5.1
Forest Plot of Odds Ratio for Overall Response Rate by IRC 
Assessment 
PP

1.6
Forest Plot of Odds Ratio for Lymph Node Response Rate 
by IRC Assessment
ITT

1.7
Kaplan-Meier Curve of Duration of Response by IRC 
Assessment
ITT

1.7.1
Kaplan-Meier Curve of Duration of Response by IRC 
Assessment - del17p/TP53 Mutation (Either)
ITT

1.7.2
Kaplan-Meier Curve of Duration of Response by IRC 
Assessment - del17p/TP53 Mutation (Neither)
ITT

1.7.3
Kaplan-Meier Curve of Duration of Response by IRC 
Assessment - IgHV Mutated
ITT



Idelalisib (IDELA)
GS-US-312-0119
Final
Statistical Analysis Plan
Version 2.0
CONFIDENTIAL
Page 95
29 September 2014
Figure Number
Title
Analysis Set
Interim
1.7.4
Kaplan-Meier Curve of Duration of Response by IRC 
Assessment - IgHV Unmutated
ITT

1.7.5
Kaplan-Meier Curve of Duration of Response by IRC 
Assessment - 17p Deletion
ITT

1.7.6
Kaplan-Meier Curve of Duration of Response by IRC 
Assessment - No 17p Deletion
ITT

1.7.7
Kaplan-Meier Curve of Duration of Response by IRC 
Assessment - Relapsed Disease Status
ITT

1.7.8
Kaplan-Meier Curve of Duration of Response by IRC 
Assessment - Refractory Disease Status
ITT

1.8
Kaplan-Meier Curve of Time to Response by IRC 
Assessment
ITT

1.8.1
Kaplan-Meier Curve of Time to Response by IRC 
Assessment - del17p/TP53 Mutation (Either)
ITT

1.8.2
Kaplan-Meier Curve of Time to Response by IRC 
Assessment - del17p/TP53 Mutation (Neither)
ITT

1.8.3
Kaplan-Meier Curve of Time to Response by IRC 
Assessment - IgHV Mutated
ITT

1.8.4
Kaplan-Meier Curve of Time to Response by IRC 
Assessment - IgHV Unmutated
ITT

1.8.5
Kaplan-Meier Curve of Time to Response by IRC 
Assessment - 17p Deletion
ITT

1.8.6
Kaplan-Meier Curve of Time to Response by IRC 
Assessment - No 17p Deletion
ITT

1.8.7
Kaplan-Meier Curve of Time to Response by IRC 
Assessment - Relapsed Disease Status
ITT

1.8.8
Kaplan-Meier Curve of Time to Response by IRC 
Assessment - Refractory Disease Status
ITT

1.9
Waterfall Plot of Best Percent Change from Baseline in SPD 
by IRC Assessment
ITT

1.9.1
Waterfall Plot of Best Percent Change from Baseline in SPD 
by IRC Assessment - del17p/TP53 Mutation (Either)
ITT

1.9.2
Waterfall Plot of Best Percent Change from Baseline in SPD 
by IRC Assessment - del17p/TP53 Mutation (Neither)
ITT

1.9.3
Waterfall Plot of Best Percent Change from Baseline in SPD 
by IRC Assessment - IgHV Mutated
ITT

1.9.4
Waterfall Plot of Best Percent Change from Baseline in SPD 
by IRC Assessment - IgHV Unmutated
ITT

1.9.5
Waterfall Plot of Best Percent Change from Baseline in SPD 
by IRC Assessment - 17p deletion
ITT



Idelalisib (IDELA)
GS-US-312-0119
Final
Statistical Analysis Plan
Version 2.0
CONFIDENTIAL
Page 96
29 September 2014
Figure Number
Title
Analysis Set
Interim
1.9.6
Waterfall Plot of Best Percent Change from Baseline in SPD 
by IRC Assessment - No 17p deletion
ITT

1.9.7
Waterfall Plot of Best Percent Change from Baseline in SPD 
by IRC Assessment - Relapsed Disease Status
ITT

1.9.8
Waterfall Plot of Best Percent Change from Baseline in SPD 
by IRC Assessment - Refractory Disease Status
ITT

1.11.1
Change from Baseline: FACT-Leu Physical Well-being
ITT
1.11.2
Change from Baseline: FACT-Leu Social/Family Well-being
ITT
1.11.3
Change from Baseline: FACT-Leu Emotional Well-being
ITT
1.11.4
Change from Baseline: FACT-Leu Functional Well-being
ITT
1.11.5
Change from Baseline: FACT-Leu Additional Concerns
ITT
1.11.6
Change from Baseline: FACT-Leu Total Outcome Index
ITT
1.11.7
Change from Baseline: FACT-Leu Total Score
ITT
1.12.1
Change from Baseline: EQ VAS 
ITT
1.12.2
Change from Baseline: EuroQol Five Dimension 
Questionnaire Utility Index
ITT
3.1
Volcano Plot of Any Grade Treatment-Emergent Adverse 
Events
Safety

3.2
Volcano Plot of Any Grade Treatment-Emergent Laboratory 
Abnormalities
Safety

3.3.1
Incidence of Treatment-Emergent Adverse Events of Interest
Safety
3.3.2
Kaplan-Meier Curve of Time to Onset of First 
Treatment-Emergent Adverse Event of Interest
Safety
3.3.3
Prevalence of Treatment-Emergent Adverse Events of 
Interest
Safety
3.4.1
Median Over Time: Hemoglobin (g/L) 
Safety

3.4.1.1
Median Over Time: Hemoglobin (g/L) - Subjects with 
Abnormality at Baseline and at Least One Post-baseline 
Measurements 
Safety

3.4.2
Median Over Time: Platelets (x10^9/L)
Safety

3.4.2.1
Median Over Time: Platelets (x10^9/L) - Subjects with 
Abnormality at Baseline and at Least One Post-baseline 
Measurements 
Safety

3.4.3
Median Over Time: Neutrophils (x10^9/L)
Safety

3.4.3.1
Median Over Time: Neutrophils (x10^9/L) - Subjects with 
Abnormality at Baseline and at Least One Post-baseline 
Measurements 
Safety

3.4.4
Median Over Time: ALT (U/L) 
Safety



Idelalisib (IDELA)
GS-US-312-0119
Final
Statistical Analysis Plan
Version 2.0
CONFIDENTIAL
Page 97
29 September 2014
Figure Number
Title
Analysis Set
Interim
3.4.5
Median Over Time: AST (U/L) 
Safety

3.4.6
Median Over Time: Lymphocytes (x10^9/L)
Safety



Idelalisib (IDELA)
GS-US-312-0119
Final
Statistical Analysis Plan
Version 2.0
CONFIDENTIAL
Page 98
29 September 2014
Figure Number
Title
Analysis Set
Interim
3.4.7
Median Over Time: Total Bilirubin (umol/L) 
Safety

3.4.8
Median Over Time: WBC (x10^9/L) 
Safety

3.4.9
Median Over Time: Triglycerides (mmol/L)
Safety

3.4.10
Median Over Time: Serum Glucose (mmol/L)
Safety

3.4.11
Median Over Time: IgA (g/L)
Safety

3.4.12
Median Over Time: IgG (g/L) 
Safety

3.4.13
Median Over Time: IgM (g/L) 
Safety

3.5.1
Change From Baseline: Hemoglobin (g/L) 
Safety

3.5.1.1
Change From Baseline: Hemoglobin (g/L) - Subjects with 
Abnormality at Baseline and at Least One Post-baseline 
Measurements 
Safety

3.5.2
Change From Baseline: Platelets (x10^9/L)
Safety

3.5.2.1
Change From Baseline: Platelets (x10^9/L) - Subjects with 
Abnormality at Baseline and at Least One Post-baseline 
Measurements 
Safety

3.5.3
Change From Baseline: Neutrophils (x10^9/L)
Safety

3.5.3.1
Change From Baseline: Neutrophils (x10^9/L) - Subjects 
with Abnormality at Baseline and at Least One Post-baseline 
Measurements 
Safety

3.5.4
Change From Baseline: ALT (U/L) 
Safety

3.5.5
Change From Baseline: AST (U/L) 
Safety

3.5.6
Change From Baseline: Lymphocytes (x10^9/L)
Safety

3.5.7
Change From Baseline: Total Bilirubin (umol/L) 
Safety

3.5.8
Change From Baseline: WBC (x10^9/L) 
Safety

3.5.9
Change From Baseline: Triglycerides (mmol/L)
Safety

3.5.10
Change From Baseline: Serum Glucose (mmol/L)
Safety

3.5.11
Change From Baseline: IgA (g/L)
Safety

3.5.12
Change From Baseline: IgG (g/L) 
Safety

3.5.13
Change From Baseline: IgM (g/L) 
Safety

3.6.1
Kaplan-Meier Curve of Time to Onset of First Episode of 
Grade 3 and Above Transaminase Elevation
Safety

3.6.2
Kaplan-Meier Curve of Time to Resolution of First Episode 
of Grade 3 and Above Transaminase Elevation
Safety
