Clinical trial NCT02538614
Conditions: Chronic Lymphocytic Leukemia (CLL)
Sponsor: Gilead Sciences
Start date: 2015-12-29; Completion date: 2017-07-05
Enrollment: 2 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study consists of 2 parts: Phase 1b and Phase 2. Phase 1b will evaluate the safety and tolerability of the combination of idelallisib with the anti-CD37 monoclonal antibody BI 836826 in participants with relapsed/refractory chronic lymphocytic leukemia (R/R CLL), and establish the high recommended Phase 2 combination dose (highRP2D) as well as an alternate lower recommended Phase 2 combination dose (lowRP2D). Phase 2 will determine the rates of complete response (CR) and of minimal residual disease (MRD) negativity with the combination at the highRP2D and the lowRP2D in participants with R/R CLL.

Detailed description:

Arms: arm 1: Participants will receive escalating dose of idelalisib at dose levels, 50 mg, 100 mg, and 150 mg + BI 836826 10 mg on Day 8, 50 mg on Day 9 and Day 15, and 100 mg on Day 22, every 2 weeks through Week 18, and every 4 weeks through Week 46. 2 dose combinations (highRP2D and lowRP2D) will be determined for further evaluations in Phase 2. arm 2: Participants will be randomly assigned to receive 1 of the 2 dose combinations selected from Phase 1b.
Interventions: intervention 1: Idelalisib intervention 2: BI 836826
Intervention descriptions: intervention 1: Tablets administered orally twice daily intervention 2: Intravenous administration as a rate-controlled infusion

Protocol documents:
Prot_000.pdf: 




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5.3.2.
Packaging and Labeling .......................................................................................................39
5.3.3.
Storage and Stability ............................................................................................................39
5.3.4.
Solution Preparation and Dispensing ...................................................................................39
5.4.
Dosage and Administration....................................................................................................................39
5.4.1.
Idelalisib...............................................................................................................................40
5.4.2.
BI 836826.............................................................................................................................40
5.5.
Dose-Limiting Toxicity..........................................................................................................................44
5.6.
Safety Monitoring and Study Drug Interruption/Dose Modification/Discontinuation...........................45
5.7.
Requirements and Recommendations Regarding Specific Adverse Events or Conditions....................49
5.7.1.
Transaminase Elevations......................................................................................................49
5.7.2.
Gastrointestinal Events.........................................................................................................50
5.7.3.
Dermatological Events .........................................................................................................52
5.7.4.
Pulmonary Events ................................................................................................................52
5.7.5.
Hematological and Immunological Events...........................................................................53
5.7.6.
Infectious Events..................................................................................................................53
5.7.7.
Secondary Malignancies.......................................................................................................54
5.7.8.
Ultraviolet Exposure ............................................................................................................54
5.7.9.
Pregnancy, Lactation, and Reproduction..............................................................................54
5.7.10.
Pneumocystis jirovecii Pneumonia Prophylaxis...................................................................54
5.7.11.
Risk of Hepatitis B Reactivation..........................................................................................55
5.7.12.
Further Safety Information...................................................................................................56
5.8.
Prior and Concomitant Medications.......................................................................................................56
5.8.1.
Idelalisib...............................................................................................................................56
5.8.2.
BI 836826.............................................................................................................................56
5.8.3.
Anticancer or Experimental Therapies Other than Idelalisib or BI 836826 .........................58
5.8.4.
Granulocyte Colony-Stimulating Factors and Erythropoietin..............................................58
5.8.5.
Corticosteroids .....................................................................................................................58
5.8.6.
Drug-Drug Interactions ........................................................................................................58
5.9.
Investigational Medicinal Product Accountability (Idelalisib and BI 836826)......................................58
5.9.1.
Investigational Medicinal Product Return and Disposal 
(Idelalisib and BI 836826)....................................................................................................59
6.
STUDY PROCEDURES ....................................................................................................................................60
6.1.
Description of Study Procedures............................................................................................................60
6.1.1.
Informed Consent.................................................................................................................60
6.1.2.
Subject Enrollment and Treatment Assignment...................................................................60
6.1.3.
Medical & Medication History.............................................................................................61
6.1.4.
Physical Examination...........................................................................................................61
6.1.5.
Vital Signs............................................................................................................................61
6.1.6.
Eastern Cooperative Oncology Group Performance Status..................................................61
6.1.7.
Electrocardiogram Assessment ............................................................................................61
6.1.8.
Laboratory Assessments.......................................................................................................61
6.2.
Disease Assessments..............................................................................................................................65
6.2.1.
CT Scan/MRI .......................................................................................................................65
6.2.2.
Minimal Residual Disease....................................................................................................65
6.3.
Screening................................................................................................................................................66
6.4.
Enrollment..............................................................................................................................................66
6.5.
Treatment and Post-Treatment Period Assessments ..............................................................................67
6.6.
Criteria for Discontinuation from Treatment or Study...........................................................................67
6.6.1.
Criteria for Discontinuation of Study Drug..........................................................................67
6.6.2.
Criteria for Discontinuation from Study...............................................................................68
6.7.
30-Day Follow-up/End of Study Visit ...................................................................................................69
6.8.
Unscheduled Visits.................................................................................................................................69


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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................70
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................70
7.1.1.
Adverse Events.....................................................................................................................70
7.1.2.
Serious Adverse Events........................................................................................................70
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................71
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................72
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................72
7.2.2.
Assessment of Severity ........................................................................................................72
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................73
7.3.1.
Requirements for Collection Prior to Study Drug Initiation.................................................73
7.3.2.
Adverse Events.....................................................................................................................73
7.3.3.
Serious Adverse Events........................................................................................................73
7.3.4.
Electronic Serious Adverse Event (eSAE) Reporting Process .............................................74
7.4.
Gilead Reporting Requirements.............................................................................................................75
7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events..........................................................................................................................75
7.6.
Toxicity Management ............................................................................................................................75
7.7.
Special Situations Reports......................................................................................................................76
7.7.1.
Definitions of Special Situations..........................................................................................76
7.7.2.
Instructions for Reporting Special Situations.......................................................................76
8.
STATISTICAL CONSIDERATIONS................................................................................................................78
8.1.
Primary Endpoint ...................................................................................................................................78
8.2.
Secondary Endpoint ...............................................................................................................................78
8.4.
Analysis Conventions.............................................................................................................................78
8.4.1.
Analysis Sets ........................................................................................................................78
8.5.
Data Handling Conventions ...................................................................................................................79
8.6.
Demographic Data and Baseline Characteristics ...................................................................................79
8.7.
Efficacy Analysis ...................................................................................................................................79
8.7.1.
Primary Analysis..................................................................................................................80
8.7.2.
Secondary Analyses .............................................................................................................80
8.8.
Safety Analysis.......................................................................................................................................80
8.8.1.
Phase 1b Portion of the Study Only .....................................................................................80
8.8.2.
Extent of Exposure...............................................................................................................80
8.8.3.
Adverse Events.....................................................................................................................81
8.8.4.
Laboratory Evaluations ........................................................................................................81
8.8.5.
Other Safety Evaluations......................................................................................................82
8.9.
Pharmacokinetic Analysis......................................................................................................................82
8.11.
Sample Size............................................................................................................................................83
8.12.
Independent Review Committee ............................................................................................................83
9.
RESPONSIBILITIES..........................................................................................................................................84
9.1.
Investigator Responsibilities ..................................................................................................................84
9.1.1.
Good Clinical Practice..........................................................................................................84
9.1.2.
Institutional Review Board/Independent Ethics Committee Review and 
Approval...............................................................................................................................84
9.1.3.
Informed Consent.................................................................................................................84
9.1.4.
Confidentiality......................................................................................................................85
9.1.5.
Study Files and Retention of Records ..................................................................................85
CCI
CCI


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9.1.6.
Case Report Forms...............................................................................................................86
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................87
9.1.8.
Inspections............................................................................................................................87
9.1.9.
Protocol Compliance............................................................................................................87
9.2.
Sponsor Responsibilities ........................................................................................................................87
9.2.1.
Protocol Modifications.........................................................................................................87
9.2.2.
Study Report and Publications .............................................................................................88
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................88
9.3.1.
Payment Reporting...............................................................................................................88
9.3.2.
Access to Information for Monitoring..................................................................................88
9.3.3.
Access to Information for Auditing or Inspections ..............................................................89
9.3.4.
Study Discontinuation..........................................................................................................89
10.
REFERENCES ...................................................................................................................................................90
11.
APPENDICES ....................................................................................................................................................94
Appendix 1.
Investigator Signature Page....................................................................................................95
Appendix 2.
Study Procedures Tables ........................................................................................................96
Appendix 3.
ECOG Performance Status Scoring System.........................................................................100
Appendix 4.
Modified International Workshop on Chronic Lymphocytic Leukemia Criteria for 
Response Assessment...........................................................................................................101
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................109
Appendix 6.
Bayesian Logistic Regression Model ...................................................................................111
LIST OF IN-TEXT TABLES
Table 5-1.
BI 836826 Infusion Rates.......................................................................................................41
Table 5-2.
BI 836826 Management of Infusion-Related Reactions.........................................................43
Table 5-3.
Requirements and Recommendations for Discontinuation or Modification of Study 
Treatment in Response to Adverse Events .............................................................................46
Table 5-4.
Premedication for BI 836826 .................................................................................................57
Table 6-1.
Analytes..................................................................................................................................62
Table 7-1.
Grading of Adverse Event Severity........................................................................................73
LIST OF IN-TEXT FIGURES
Figure 5-1.
Kaplan-Meier Time to Diarrhea or Colitis .............................................................................51


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PROTOCOL SYNOPSIS
333 Lakeside Drive
Foster City, CA 94404
Study Title
Phase 1b/2 Study of Idelalisib in Combination with BI 836826 in Subjects 
with Chronic Lymphocytic Leukemia
IND Number
EudraCT 
Number
101254
Not applicable
Study Centers 
Planned
Approximately 8 centers in the United States
Objectives
Enrollment to this study was closed on 26 April 2017 based on an updated 
feasibility assessment in relation to changes in standard of care. The 
2 subjects enrolled as of this date may remain on study with a modified 
schedule of assessments.
Subjects may remain on study through approximately Week 50 (to include 
30-Day Follow-up after last dose of BI 836826).
Due to the early study termination, the study objectives will not be met and 
the subjects enrolled will be assessed for safety only. 
The primary objectives of this study are as follows:

Phase 1b: To determine the safety and tolerability of the combination of 
idelalisib with BI 836826 in subjects with relapsed and refractory (R/R) 
chronic lymphocytic leukemia (CLL), and to establish the high
recommended Phase 2 combination dose (highRP2D) as well as an 
alternate lower recommended Phase 2 combination dose (lowRP2D)
regimen.

Phase 2: To determine the rates of complete response (CR) and of 
minimal residual disease (MRD) negativity with the combination at the 
highRP2D and the lowRP2D.
The secondary objectives of this study are as follows:

Phase 1b and 2: To evaluate Overall Response Rate (ORR), 
Progression-Free Survival (PFS), Duration of Complete Response 
(DCR), Duration of Response (DOR), and Overall Survival (OS).

Phase 2: To further characterize the safety and tolerability of the 
combination using the highRP2D as well as the lowRP2D regimen.




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Diagnosis and 
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 
modified International Workshop on Chronic Lymphocytic Leukemia 
(IWCLL) criteria and documented within medical records, and having 
received at least 2 prior treatment regimens. 
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
e) Autoimmune anemia and/or thrombocytopenia that is poorly 
responsive to corticosteroids or other standard therapy, or
f)
Constitutional symptoms, defined as any 1 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) Clinically quantifiable disease burden defined as:
a) For Phase 1b subjects: ALC > 5000/μl in peripheral blood. 
b) For Phase 2 subjects: either at least 1 node ≥2 cm on computed 
tomography (CT) or magnetic resonance imaging (MRI) confirmed 
by the Independent Review Committee (IRC), or a bone marrow is 
performed at Screening and demonstrates quantifiable CLL.


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5) Discontinuation of all cytotoxic chemotherapy and anti-CD20 antibody 
therapy for ≥4 weeks, alemtuzumab for ≥8 weeks, targeted therapy for 
≥2 weeks, and investigational therapy for ≥3 weeks before enrollment 
(Phase 1b) or randomization (Phase 2). For subjects with relapsed CLL 
most recently treated with B-cell receptor (BCR) pathway inhibitors 
who, in the opinion of the investigator, will not tolerate waiting 3 weeks, 
a washout period of > 5 half-lives is allowed. If on a systemic 
corticosteroid, the dose must be stable for the prior 4 weeks.
6) All acute non-hematologic toxic effects of any prior antitumor therapy 
resolved to Grade ≤1 before enrollment with the exception of alopecia
or neurotoxicity (Grade 1 or 2 neurotoxicity permitted).
7) Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2.
8) Required baseline laboratory data (within 4 weeks prior to enrollment) as 
shown in the following table:
Organ System
Parameter
Required Value
Hematopoietic
ANCa
≥1 × 109/L
Platelet
≥25 × 109/L
Hepatic
Serum total 
bilirubin
1.5 × ULN (unless elevated due to 
Gilbert’s syndrome or hemolysis)
Serum ALT
≤2.5 × ULN
Serum AST
Renal
CCr
b
≥30 mL/min
Pregnancy
-hCGc
Negative
Infection
HIV
Negative HIV antibody
HBV
Negative HBsAg and negative HBc antibody, or 
positive HBc antibody and negative for HBV 
DNA
HCV
Negative viral RNA
(if HCV antibody is positive)
CMV
Negative viral DNA
a
ANC value to be obtained in the absence of growth factors
b
As calculated by the Cockcroft-Gault formula or measured.
c
For women of child-bearing potential only; serum -hCG must be negative during Screening and 
urine pregnancy test must be negative prior to the first dose of study drug.
-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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9) 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 
idelalisib or 12 months from the last dose of BI 836826 (whichever is 
later).
10) For male subjects of reproductive potential, willingness to use a 
protocol-recommended method of contraception when having 
intercourse with females of child-bearing potential, and to refrain from 
sperm donation, from enrollment (Day 1) throughout the study and for 
90 days following the last dose of idelalisib or 12 months from the last 
dose of BI 836826 (whichever is later).
11) 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.
12) Willingness and ability to comply with scheduled visits, drug 
administration plan, imaging studies, laboratory tests, other study 
procedures, and study restrictions, including mandatory prophylaxis for 
PJP). 
13) 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). 
2) Known presence of myelodysplastic syndrome.
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 enrollment, 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. 


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4) Known hypersensitivity or intolerance to any of the active substances or 
excipients in the formulations for either idelalisib or BI 836826.
5) Evidence of ongoing systemic bacterial, fungal, or viral infection at the 
time of enrollment.
6) Ongoing infection with, or treatment or prophylaxis for, CMV within the 
past 28 days.
7) 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.
8) History of drug-induced pneumonitis.
9) Ongoing inflammatory bowel disease.
10) Ongoing alcohol or drug addiction.
11) Pregnancy or breastfeeding. 
12) History of prior allogeneic bone marrow progenitor cell or solid organ 
transplantation.
13) Ongoing systemic immunosuppressive therapy other than 
corticosteroids. 
14) History of prior therapy with any phosphatidylinositol 3-kinase (PI3K) 
inhibitor (including idelalisib), or any prior anti-CD37 agent. 
15) Concurrent participation in another therapeutic clinical trial.
16) 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
This study has been terminated with 2 subjects enrolled. Subjects may
remain on study through approximately Week 50 (to include 30-Day 
Follow-up after last dose of BI 836826). Study procedures have been 
modified, and the subjects enrolled will be assessed for safety only.
Screening will begin after obtaining subject’s signed informed consent and 
will occur up to 28 days prior to first dose of study drug (Phase 1b) or 
randomization (Phase 2). 
Treatment will begin with a 7-day idelalisib monotherapy run-in period 
starting on Day 1. BI 836826 will be initiated on Day 8. Subjects will be 
hospitalized overnight on Day 9 for monitoring and prophylaxis against 
tumor lysis syndrome (TLS). The investigator will assess disease status at 
Screening, Weeks 14, 26, 38, 50, and every 16 weeks thereafter, based on 
modified IWCLL criteria. Minimal residual disease (MRD) will be assessed
in peripheral blood coinciding with central radiologic evaluation. MRD 
negativity in peripheral blood will be confirmed by bone marrow biopsy.




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Secondary Endpoint:

Description of any DLTs, serious adverse events (SAE), or AEs leading 
to discontinuation of study treatment.
This study has been terminated in Phase 1b and therefore Phase 2 will not 
occur.
Phase 2 
The following endpoints will be evaluated within the highRP2D and 
lowRP2D groups. There will be no formal comparison between the 2 dose 
groups.
Primary Endpoints:

Complete Response Rate (CRR) – defined as the proportion of subjects 
who achieve a CR. 
MRD Negativity Rate in bone marrow by Week 50 – defined as the 
proportion of subjects with MRD level < 10-4 malignant cells, assessed by 
flow cytometry in bone marrow, achieved by Week 50.
Secondary Endpoints:

Description of SAEs or AEs leading to discontinuation of study 
treatment.

Overall Response Rate (ORR) – defined as the proportion of subjects 
who achieve a complete response (CR) or partial response (PR).

Duration of Complete Response (DCR) – defined as the interval from the 
first documentation of CR to the earlier of the first documentation of 
definitive disease progression or death from any cause.

Duration of Response (DOR) – defined as the interval from the 
first documentation of CR or PR to the earlier of the first documentation 
of definitive disease progression or death from any cause.

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.

Overall Survival (OS) – defined as the interval from the randomization
to the date of death from any cause.

Minimal Residual Disease (MRD) negativity rate in blood at any time –
defined as the proportion of subjects with MRD level < 10-4 malignant 
cells, assessed by flow cytometry in blood, at any time on study.

MRD negativity rate in bone marrow at any time – defined as the 
proportion of subjects with MRD level < 10-4 malignant cells, assessed 
by flow cytometry in bone marrow, at any time on study.






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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
ADA
anti-drug antibody
ADCC
antibody-dependent cellular cytotoxicity
AE
adverse event
ALC
absolute lymphocyte count
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATP
adenosine triphosphate
BCR
B-cell receptor
-HCG
beta human chorionic gonadotropin
BID
twice daily
BLRM
Bayesian logistic regression analysis
B-NHL
B-cell non-Hodgkin lymphoma
CBC
complete blood count
CDC
complement-dependent cytotoxicity
CFR
Code of Federal Regulations
CI
confidence interval
CLL
chronic lymphocytic leukemia
CMV
Cytomegalovirus
CR
complete response
CRi
complete response with incomplete marrow recovery
CRO
contract research organization
CRR
complete response rate
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DCR
duration of complete response
DLT
dose limiting toxicity
DNA
deoxyribonucleic acid
DOR
duration of response
DSPH
Drug Safety and Public Health
E2
depressed estradiol
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EOS
end of study


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EOT
end of treatment
EU
European Union
FD&C
Food, Drug, and Cosmetics Act
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
G-CSF
granulocyte colony-stimulating factor
GCP
good clinical practice
GM-CSF
granulocyte-macrophage colony-stimulating factors
HBc antibody
anti-hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HDPE
high-density polyethylene
HiB
Haemophilus influenza Type B
highRP2D
high recommended Phase 2 dose
HIV
human immunodeficiency virus
HLGT
High-Level Group Term
HLT
High-Level Term
HMG-CoA
3-hydroxy-3-methyl-glutaryl-Coenzyme A
HSP
hysterosalpingogram
lowRP2D
low recommended Phase 2 dose
IB
investigator’s brochure
ICH
International Conference on Harmonisation
IEC
independent ethics committee
Ig
immunoglobulin
IHC
immunohistochemsitry
IRB
independent review board
IRC
independent review committee
IRR
infusion-related reaction
ITT
intent-to-treat
IUD
intrauterine device
IV
intravenous
IWCLL
International Working Group on CLL
IWRS
interactive web response system
LD
longest dimension
LLT
Lower-Level Term
Mab
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MRD
minimal residual disease


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MRI
magnetic resonance imaging
MTD
maximum tolerated dose
N
number in analysis set
N
number of subjects
NCI
National Cancer Institute
NCCN
National Comprehensive Cancer Network
ND
no disease
NE
not evaluable
ORR
overall response rate
OS
overall survival
PBMC
peripheral blood mononuclear cells
PCR
polymerase chain reaction
PD
progressive disease
PDE5
phosphodiesterase-5
PE
physical exam
PET
positron-emission tomography
PFS
progression-free survival
PI3K
phosphatidylinositol 3-kinase
PJP
Pneumocystis jirovecii pneumonia
PK
pharmacokinetic
PPD
product of the perpendicular dimensions
PR
partial response
PT
Preferred Term
PVA
polyvinyl alcohol
QA
quality assurance
RNA
ribonucleic acid
R/R
relapsed/refractory
SADR
serious adverse drug reaction
SAE
serious adverse event
SD
stable disease
SOC
System Organ Class
SOP
standard operating procedure
SRT
Safety Review Team
SUSAR
suspected unexpected serious adverse reactions
TEAE
treatment-emergent adverse event
TLS
Tumor Lysis Syndrome
ULN
upper limit of normal
US
United States
WES
whole exome sequencing


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1.
INTRODUCTION
1.1.
Background
1.1.1.
Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia (CLL) is a neoplastic condition resulting from the progressive 
accumulation of functionally incompetent monoclonal B lymphocytes in blood, bone marrow, 
lymph nodes, spleen, and liver {Dighiero 2008}. Chronic lymphocytic leukemia constitutes the 
most commonly occurring leukemia in Europe and the United States (US) {Sant 2010, 
Surveillance Epidemiology and End Results (SEER) Program 2011}. Symptoms may include 
fever, night sweats, weight loss, and there may be lymphadenopathy, splenomegaly, or 
hepatomegaly. The natural history of CLL is highly variable, with a median survival of more 
than 10 years in low-risk patients compared with 2 years in high-risk patients. 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}. New 
cytotoxic-free combinations are needed for patients with relapsed or refractory CLL. In patients 
with treatment-naive 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 an anti-CD20 monoclonal antibody 
(eg, rituximab) and can be effective in providing durable remissions {Byrd 2005, Catovsky 2007, 
Hallek 2010, Robak 2010}. However, these treatments are not curative; the disease will usually 
relapse and further intervention is required to obtain and maintain tumor control. The studies that 
have established the best results in response rate and progression free survival (PFS) in treatment 
naïve patients have generally included subjects who are not representative of the average CLL 
patient in the community. For example, the German CLL Study Group CLL-8 study of FC 
(fludarabine plus cyclophosphamide) vs FCR (FC plus rituximab) {Hallek 2010} included a 
subject population that was only 30% ≥65 years, and 10% ≥70 years. For patients who have 
significant comorbidities (“unfit”) and/or are elderly, the benefit of FCR or bendamustine plus 
rituximab (BR) administered in less than standard dosing/schedule has not been established.
There is also a need for new cytotoxic-free combination therapies for previously untreated CLL 
patients not suitable for intensive chemoimmunotherapy.
1.1.2.
Phosphatidylinositol 3-Kinase in Lymphoid Malignancies
Phosphatidylinositol 3-kinases (PI3Ks) are enzymes that regulate several cellular functions 
including motility, proliferation, survival, metabolism and migration {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 . 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, live a normal life span without an increased susceptibility to 
infections but develop colitis {Okkenhaug 2002}. The B-lymphocyte population in these animals 
shows a decrease in maturation, diminished B-cell receptor-induced proliferation, and deficient 
T-cell dependent and independent immune response. 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
{Herman 2010, Lannutti 2011}.
PI3Kδ is critical for multiple signaling pathways that are hyperactive in B-cell malignancies.
Inhibition of PI3Kδ modulates B-cell receptor (BCR) signaling as well as signaling through 
cytokine and chemokine receptors and integrins. These signaling pathways act via downstream 
enzymes (most importantly Akt) to regulate proliferation, apoptosis, homing, and retention of 
malignant B cells in lymphoid tissues and bone marrow compartments. By inhibiting 
PI3Kδ-dependent signaling, idelalisib inhibits proliferation survival and homing in many 
B-cell malignancies.
Knowledge of the critical importance of PI3Kδ in B-cell biology and neoplasia has encouraged a 
search for selective inhibitors of this enzyme that could provide new options in the therapy of 
lymphoid malignancies, including CLL.
1.1.3.
CD37 in Mature B-cell Malignancies
CD37, a member of the tetraspanin superfamily, is a glycosylated cell surface protein with 
4 transmembrane domains and 2 extracellular loops. 
CD37 is predominantly expressed on B cells with highest expression levels on mature peripheral 
blood B cells and reduced levels on plasma cells {Barrena 2005, Schuurman 1987}. Low level 
expression of CD37 has been reported for monocytes, T cells, macrophages, and granulocytes 
{Moore 1987, Schwartz-Albiez 1988, van Spriel 2004}. The majority of malignant cells in 
patients with B-cell non-Hodgkin lymphoma (B-NHL) and CLL express the CD37 antigen 
{Barrena 2005, Norton 1987, Schuurman 1987, Schwartz-Albiez 1988, Smith 1989}. The 
physiological function of CD37 in humans remains largely unknown {Moldenhauer 2000, 
Schwartz-Albiez 1988}. Mice deficient for CD37 display no changes in development and 
cellular composition of lymphoid organs but have reduced levels of IgG1 and attenuated T-cell 
mediated immune reactions {Knobeloch 2000}. Studies with CD37-/- T cells suggest a role for 
CD37 in T-cell proliferation and regulation of IgA response {van Spriel 2004, van Spriel 2009}. 
Recent data provide evidence that CD37 can function as a death receptor on B cells, which can 
mediate dual signal transduction through its N- and C-terminal intracellular domain 
{Lapalombella 2012}.
CD37 is expressed on normal B cells and in B-cell malignancies such as CLL and B-NHL.


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1.2.
Idelalisib
1.2.1.
General Information
Idelalisib (Zydelig) was first approved in the US on July 23, 2014 for the treatment of relapsed 
CLL, follicular lymphoma, and small lymphocytic lymphoma, followed by approval in the 
European Union (EU) on September 18, 2014 (centrally authorized). Zydelig is currently 
approved in 35 countries, including the US, EU, Switzerland, Australia, and Canada.
Idelalisib is a potent competitive inhibitor of the adenosine triphosphate (ATP) binding site of 
the PI3Kδ catalytic domain, which has been shown to be prominently expressed in cells of 
hematopoietic origin {Okkenhaug 2003a, Vanhaesebroeck 2005}. The effects of p110δ on 
lymphocyte activation/function, cellular proliferation, and protection from apoptosis provide the 
rationale for targeting this isoform as a therapy for hematologic malignancies.
Further details on the preclinical pharmacology, toxicology, metabolism, and PK of idelalisib
can be found in the idelalisib Investigator’s Brochure (IB).
1.3.
BI 836826
1.3.1.
General Information
BI 836826 is a mouse human chimeric monoclonal antibody (Mab) against human CD37.
BI 836826 has a cytotoxic mode of action by directly inducing apoptosis upon binding to the
target cell independent of IgG cross-linking. In addition, BI 836826 harbours a mutation in the 
Fc portion of the molecule which conveys increased antibody-dependent cellular cytotoxicity 
(ADCC). BI 836826 is an investigational compound currently in clinical development in mature 
B-cell neoplasms, including CLL.
1.3.2.
BI 836826 Preclinical Pharmacology and Toxicology
In vitro assays demonstrated that BI 836826 specifically recognizes human CD37 and binds with 
high affinity to this antigen. BI 836826 is a potent inducer of apoptosis and ADCC in vitro, but 
lacks complement-dependent cytotoxicity (CDC) activity. The pro-apoptotic activity of BI 836826 
does not depend on IgG cross-linking. BI 836826 is able to deplete endogenous, normal B cells, 
Ramos Burkitt lymphoma cells, and CLL cells from human blood without affecting endogenous 
T cells and monocytes {Heider 2011, Krause 2012, Zenz 2010}.
The combination of BI 836826 with chemotherapeutics (bendamustine, chlorambucil, 
fludarabine) or with the anti-CD20 Mab rituximab in vitro results in additive or synergistic 
apoptosis induction on lymphoma cell lines and primary CLL cells {Heider 2012}. Combination 
studies with idelalisib in primary CLL cells ex vivo demonstrated that the combination of 
idelalisib and BI 836826 showed more direct cytotoxicity in high risk (p53 dysfunctional) patient 
samples than either agent alone {Stephens 2014}.


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Due to the lack of cross-reactivity of BI 836826 with CD37 in any preclinical species tested, the 
preclinical safety of BI 836826 was investigated in 2 toxicologically relevant models: 
1) Transgenic mouse model, in which the human CD37 protein instead of the murine CD37
protein is expressed (HuCD37 transgenic mice) and 2) Cynomolgus monkeys, in which an 
anti-macaque CD37 surrogate antibody (BI 836847) was used. 
The majority of effects observed in the general toxicity studies with BI 836826 in HuCD37 mice 
and with the surrogate BI 836847 in cynomolgus monkeys were directly related or secondary to 
the pharmacological activity of BI 836826 and BI 836847. The main target organs following 
repeat intravenous (IV) exposure to BI 836826 in HuCD37 mice and to the surrogate BI 836847 
in cynomolgus monkeys were the blood and lymphoid system. BI 836826 induced B- but also 
T-cell reduction in HuCD37 mice in peripheral blood and lymphoid organs at all dose levels with 
the histopathological correlate of lymphoid depletion in B-cell areas in spleen and lymph nodes. 
In contrast, the surrogate BI 836847 induced reduction of lymphocytes, predominantly B cells 
and natural killer (NK) cells at low to moderate doses. T cells, granulocytes, and platelets were 
reduced at higher doses. Severe and sustained immunosuppression in monkeys treated with high 
doses led to several cases of septicaemia. Furthermore, anti-drug antibodies were documented in 
both animal models. They were of neutralizing nature allowing recovery of the 
pharmacodynamic effects in mice within the 5-week study duration and resulted in an 
immune-complex mediated glomerulopathy and uveitis in monkeys. However, anti-drug 
antibodies in the transgenic mouse and the cynomolgus monkey are not considered to be 
predictive for the immunogenic effect in humans. Cytokine release studies demonstrated a 
transient and dose dependent increase in interleukin (IL-) 6 and IL-8 in monkeys and of IL-6 and 
TNFα in the in vitro study using the human blood solid phase assay.
1.3.3.
Clinical Trials of BI 836826
Preliminary data from 2 ongoing Phase 1 monotherapy trials are available, 1 in relapsed CLL and 
the other in relapsed NHL. As of June 2015, 77 subjects have been treated with BI 836826, 36 in 
the CLL trial and 41 in the NHL trial.
In the CLL trial (1270.1) 36 subjects were exposed to BI 836826, administered intravenously at 
escalating doses in a 2-week schedule. The median age of subjects was 68 years 
(range: 44-80 years). BI 836826 was administered at the following dose tiers (n) 1 mg (3), 
3 mg (3), 9 mg (6), 25 mg (6), 50 mg (3), 100 mg (3), 200 mg (6), 400 mg (3) and 800 mg (3). 
The initial treatment schedule employed at dose tiers of 1, 3, and 9 mg contained 1 intravenous 
infusion of BI 836826 at a fixed rate over 3 hours on Day 1 of a 14-day treatment course. Due to
the occurrence of infusion-related reactions (IRR) of maximum Grade 2 the infusion schedule 
was amended to increase tolerability. The amendment included a slow increase of the infusion 
rate and division of the first dose into 2 portions delivered on 2 consecutive treatment days 
(Day 1 and 2 of Course 1) to mitigate the risk for severe IRR. This schedule was applied to 
3 additional subjects at 9 mg, and all subjects treated at dose tiers of 25 mg and above. During 
the dose escalation all subjects were scheduled to receive 4 treatment courses, and upon clinical 
benefit were allowed to proceed to 8 treatment courses. Those with sustained clinical benefit 
were offered prolonged therapy. Eighteen of 36 subjects have completed 8 or more treatment 
courses.


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Infusion-Related Reaction was the most frequent adverse event (AE), reported in 25 subjects 
(69%). With mandatory premedication and an infusion schedule using a split of the first dose 
over 2 consecutive treatment days and a slowly increasing infusion rate the IRRs reported have 
been manageable at all dose tiers. The majority of IRRs were Grade 1 or 2, only 3 subjects 
experienced a Grade 3 reaction, which in 2 cases led to discontinuation of the trial drug.
Decrease in leukocytes, neutrophils, thrombocytes, and haemoglobin have frequently been 
reported in subjects. Drug-related neutropenia was reported in 41% (15/36) of the subjects, with 
a worst Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or 4 in 
14/36 subjects (32%). Drug-related thrombocytopenia was reported in 31% (11/36), with a worst 
CTCAE Grade of 3 or 4 in 8 subjects (22%). Corresponding laboratory data showed that 
neutrophils and thrombocytes declined immediately after the infusion. Anemia was considered 
drug-related in 28% of the subjects and the highest Grade was CTCAE Grade 3. A drug-related 
increase of alanine aminotransferase (ALT) was reported in 4 subjects (11%), and an increase of 
aspartate aminotransferase (AST) was reported in 5 subjects (14%). ALT and AST elevations 
were Grade 1 and 2 in all subjects except for 1 subject with a Grade 3 ALT elevation. The 
corresponding laboratory data in these subjects showed short lasting, reversible elevations of 
AST and/or ALT without concomitant bilirubin elevation. Prior to the next administration of 
BI 836826, ALT and AST had returned spontaneously to normal or pre-treatment values.
Efficacy was observed at doses ≥9 mg. The Overall Response Rate (ORR) was 
40% (12/30 subjects); all responses were partial responses. In addition, the decline in
absolute lymphocyte count (ALC) was analyzed to assess effect of BI 836826 on CLL tumor 
load in 25 subjects treated at doses ≥9 mg, who had an elevated ALC at baseline and received at 
least 1 full dose of BI 836826 at the respective dose tier. A decline in ALC by 50% or more as 
compared to baseline was observed in 80% (20/25 of the subjects) and a reduction to < 4 x 109/L 
were observed in 56% (14/25) of the subjects.
Additional clinical data for BI 836826 is available from an ongoing Phase 1 trial in subjects with 
B-NHL. The treatment schedule involves weekly intravenous infusions of BI 836826 on 
Days 1, 8, 15, and 22 of each treatment cycle. The first 2 treatment cycles have a duration of 
7 weeks, and the third cycle is 12 weeks. Subjects were allowed to receive up to 3 treatment 
cycles (12 administrations of BI 836826). Dose tiers of 1, 9, 25, 50, and 100 mg were completed 
without dose-limiting toxicities (DLT). At the dose tier of 200 mg, 1 subject experienced a DLT 
(oral herpes, stomatitis and febrile neutropenia, all CTCAE Grade 3). Because 4 additional 
subjects at this dose level experienced prolonged Grade 3-4 neutropenia lasting 7 days or more, it 
was decided that the 200 mg dose level exceeded the maximum tolerated dose (MTD). An 
intermediate dose of 150 mg was tested, and a total of 6 subjects were enrolled at this dose. 
One subject at the 150 mg dose experienced Grade 3 hypocalcemia and Grade 3 hypokalemia, 
and an additional 2 subjects experienced hypophosphatemia Grade 4. Based on DLT criteria, 
those laboratory abnormalities were classified as DLTs, and the MTD was established at 100 mg, 
which is the recommended dose for the expansion cohort. 
For further information on BI 836826 please refer to the current IB.


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1.4.
Rationale for This Study
This study has been terminated in Phase 1b based on an updated feasibility assessment in
relation to changes in standard of care. There will be no determination of highRP2D or 
lowRP2D in this study.    
Idelalisib and BI 836826 are 2 agents for which there is a theoretical basis for synergy against 
CLL. This is related to the observation that 2 distinct downstream pathways are activated after 
ligation of the CD37 surface protein by antibodies, a SHP-1 dependent cell death pathway and a 
PI3K-dependent cell survival pathway. Consequently, combination of CD37 ligation and 
PI3Kinhibition may lead to synergistic pro-apoptotic activity {Lapalombella 2012}. Enhanced 
cytotoxicity with the combination of idelalisib and BI 836826 in CLL clinical samples, 
especially in P53 null specimens, has been described {Stephens 2014}. Finally, the largely 
non-overlapping toxicity of idelalisib and BI 836826 makes this combination attractive for 
clinical evaluation.
Two dose combinations will be evaluated in this study. The first, higher recommended Phase 2 
dose (highRP2D), will be the maximally tolerated doses of the 2 agents predicted by the 
Bayesian Logistic Regression Model (BLRM) and assessed by the Safety Review Team (SRT)
as tolerable in the Phase 2 component of the study. The second, lower recommended Phase 2
(lowRP2D), will be chosen to evaluate whether similar efficacy can be achieved with lower 
toxicity.
1.5.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


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2.
OBJECTIVES
Enrollment to this study was closed on 26 April 2017 based on an updated feasibility assessment 
in relation to changes in standard of care. The 2 subjects enrolled as of this date may remain on 
study with a modified schedule of assessments.
Subjects may remain on study through approximately Week 50 (to include 30-Day Follow-up
after last dose of BI 836826). 
Due to the early study termination, the study objectives will not be met and the subjects enrolled 
will be assessed for safety only. 
The primary objectives of this study are as follows:

Phase 1b: To determine the safety and tolerability of the combination of idelalisib with 
BI 836826 in subjects with relapsed/refractory (R/R) CLL, and to establish the maximum
recommended Phase 2 combination dose (highRP2D) as well as an alternate lower 
recommended Phase 2 combination dose (lowRP2D).

Phase 2: To determine the rates of Complete Response (CR) and of minimal residual disease 
(MRD) negativity with the combination at the highRP2D and the lowRP2D.
The secondary objectives of this study are as follows:

Phase 1b and 2: To evaluate ORR, PFS, Duration of Complete Response (DCR), Duration of 
Response (DOR), and Overall Survival (OS).

Phase 2: To further characterize the safety and tolerability of the combination using the 
highRP2D and the lowRP2D.
 
CCI


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3.
STUDY DESIGN
Enrollment to this study was closed on 26 April 2017 based on an updated feasibility assessment 
in relation to changes in standard of care. The 2 subjects enrolled as of this date may remain on 
study with a modified schedule of assessments.
Subjects may remain on study through approximately Week 50 (to include 30-Day Follow-up
after last dose of BI 836826).  
3.1.
Endpoints
Due to the early study termination, the endpoints will not be met and the subjects enrolled will be 
assessed for safety only. Planned analyses will not be performed and only safety related 
endpoints will be analyzed and reported for the subjects enrolled in the study.
The Phase 1b primary endpoint is:

Incidence rate of DLTs during the first 7 weeks of study therapy at each combination dose 
level tested
The Phase 1b secondary endpoint is:

Description of any DLTs, serious adverse events (SAE), or AE leading to discontinuation of 
study treatment.
This study has been terminated in Phase 1b and therefore Phase 2 will not occur.
The Phase 2 primary endpoints are:

Complete Response Rate (CRR) – defined as the proportion of subjects who achieve a 
Complete Response (CR)

Minimal Residual Disease (MRD) Negativity Rate in bone marrow by Week 50 – defined as 
the proportion of subjects with MRD level < 10-4 malignant cells, assessed by flow cytometry 
in bone marrow, achieved by Week 50
The Phase 2 secondary endpoints are:

Description of SAEs, or AEs leading to discontinuation of study treatment

ORR – defined as the proportion of subjects who achieve a CR or Partial Response (PR)

DCR – defined as the interval from the first documentation of CR to the earlier of the first 
documentation of definitive disease progression or death from any cause 




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3.2.1.
Phase 1b
The Phase 1b dose escalation portion of the study will enroll approximately 42 evaluable 
subjects with R/R CLL. Determination of the dose levels tested in each cohort will be based on 
the posterior probability of DLT estimated by a 5-parameter BLRM with overdose control
(Appendix 6). Subjects are evaluable for dose selection analysis during the 7week- safety 
evaluation period if either of the following conditions are met:

A DLT (Section 5.5) occurs at any time during the final 6 weeks of the 7-week safety 
evaluation period (once combination treatment has begun). Events occurring during the 
initial 7-day idelalisib monotherapy run-in period and resolving by Day 8 will not be 
included.

A minimum exposure to each of the drugs has been attained. Minimum exposure for safety 
evaluability during the 7 week safety evaluation period is defined as 4 weeks of the assigned
dose of idelalisib after the first infusion of BI 836826 and 2/3 of the intended dose of 
BI 836826.
A minimum of 3 evaluable subjects will be enrolled into each sequential cohort. For each cohort, 
the BLRM will be run based on data collected through14 days after the second full dose of 
BI 836826 for the final evaluable subject. In each run, the estimate of parameters will be updated 
with accumulated data and the toxicity probability at each dose level will be calculated based on 
the posterior distributions of the model parameters. The BLRM-recommended dose for the 
next cohort will be chosen out of the dose candidates satisfying the overdose control criterion, 
based on the conditions listed in Appendix 6. Overdose control criterion is set as the probability 
of excessive toxicity to be less than 25%; however, the maximum allowable dose increment for 
the subsequent cohort will be no more than 100% for each drug. The SRT will review all safety 
data and the BLRM outputs to confirm the combination of doses for the next cohort.
For the final highRP2D to be declared, more than 6 subjects will be evaluated at that level, 
posterior probability of targeted toxicity will exceed 40% at that level, and a minimum of 
12 subjects will be treated in total at all dose levels. The highRP2D will be determined by the 
SRT based on the dose candidate identified by the BLRM and an assessment of the aggregate 
safety and pharmacokinetic data.  
In addition, a supplemental cohort of approximately 6 subjects will be enrolled to evaluate a 
lowRP2D, determined by assessing the combination of a sub-maximal dose of BI 836826 (yet a 
dose which yields a desirable ALC-lowering and effect on biomarkers), and/or a lower dose of 
idelalisib. For this supplemental cohort, treatment will be initiated at the highRP2D dose and the 
lowRP2D first administered Week 8, following the second 100% dose of BI 836826 at the 
highRP2D.
Following completion of enrollment into the lowRP2D cohort and until the safety and efficacy 
analysis of this cohort is complete, an expansion cohort of up to 6 additional subjects may be 
enrolled at the highRP2D.










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4.
SUBJECT POPULATION
Enrollment to this study was closed on 26 April 2017 based on an updated feasibility assessment 
in relation to changes in standard of care. The 2 subjects enrolled as of this date may remain on 
study with a modified schedule of assessments.
Subjects may remain on study through approximately Week 50 (to include 30-Day Follow-up
after last dose of BI 836826).  
4.1.
Number of Subjects and Subject Selection
Approximately 42 evaluable subjects will be treated during the Phase 1b portion of the study. 
The Phase 2 portion of the study will enroll approximately 50 subjects.
4.2.
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 modified International 
Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria and documented within 
medical records, and having received at least 2 prior treatment regimens. 
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
e) Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids 
or other standard therapy, or


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f)
Constitutional symptoms, defined as any 1 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) Clinically quantifiable disease burden defined as:
a) For Phase 1b subjects: ALC > 5000/µL in peripheral blood. 
b) For Phase 2 subjects: either at least 1 node ≥2 cm on computed tomography (CT) or 
magnetic resonance imaging (MRI) confirmed by the Independent Review Committee 
(IRC), or a bone marrow is performed at Screening and demonstrates quantifiable CLL.
5) Discontinuation of all cytotoxic chemotherapy and anti-CD20 antibody therapy for 
≥4 weeks, alemtuzumab for 8 weeks, targeted therapy for ≥2 weeks, and investigational 
therapy for 3 weeks  before enrollment (Phase 1b) or randomization (Phase 2). For subjects 
with relapsed CLL most recently treated with BCR pathway inhibitors who, in the opinion of 
the investigator, will not tolerate waiting 3 weeks, a washout period of > 5 half-lives is 
allowed.  If on a systemic corticosteroid, the dose must be stable for the previous 4 weeks.
6) All acute non-hematologic toxic effects of any prior antitumor therapy resolved to Grade ≤1 
before enrollment with the exception of alopecia or neurotoxicity (Grade 1 or 2 neurotoxicity 
permitted).
7) Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2.
8) Required baseline laboratory data (within 4 weeks prior to enrollment) as shown in the 
following table:


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Organ System
Parameter
Required Value
Hematopoietic
ANCa
1 × 109/L
Platelets
25 × 109/L
Hepatic
Serum total bilirubin
1.5 × ULN (unless elevated due to Gilbert’s syndrome or 
hemolysis)
Serum ALT
2.5 × ULN
Serum AST
Renal
CCrb
30 mL/min
Pregnancy
-hCGc
Negative
Infection
HIV
Negative HIV antibody
HBV
Negative HBsAg and negative HBc antibody, or positive HBc 
antibody and negative for HBV DNA
HCV
Negative viral RNA (if HCV antibody is positive)
CMV
Negative viral DNA
a
ANC value to be obtained in the absence of growth factors
b
As calculated by the Cockcroft-Gault formula or measured.
c
For women of child-bearing potential only; serum -hCG must be negative during Screening and urine pregnancy test must 
be negative prior to the first dose of study drug
-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
9) For female subjects of child-bearing potential, willingness to use a protocol-recommended 
method of contraception from the Screening visit throughout the study, and for 30 days from 
the last dose of idelalisib or 12 months from the last dose of BI 836826 (whichever is later).
10) For male subjects of reproductive potential a willingness to both: 1) use a 
protocol-recommended method of contraception, when having intercourse with females of 
child bearing potential, and 2) to refrain from sperm donation, from enrollment (Day 1) 
throughout the study and for 90 days following the last dose of idelalisib or 12 months from 
the last dose of BI 836826 (whichever is later).
11) 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.
12) Willingness and ability to comply with scheduled visits, drug administration plan, imaging 
studies, laboratory tests, other study procedures, and study restrictions, including mandatory 
prophylaxis for PJP. 


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13) 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.
4.3.
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). 
2) Known presence of myelodysplastic syndrome.
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 enrollment, 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 BI 836826.
5) Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of enrollment.
6) Ongoing infection with, or treatment or prophylaxis for, CMV within the past 28 days.
7) 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.
8) History of drug-induced pneumonitis.
9) Ongoing inflammatory bowel disease.
10) Ongoing alcohol or drug addiction.
11) Pregnancy or breastfeeding. 
12) History of prior allogeneic bone marrow progenitor cell or solid organ transplantation.


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13) Ongoing systemic immunosuppressive therapy other than corticosteroids. 
14) History of prior therapy with any PI3K inhibitor (including idelalisib), or any anti-CD37 
agent.
15) Concurrent participation in another therapeutic clinical trial.
16) 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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5.
STUDY TREATMENTS
5.1.
Randomization, Blinding, and Treatment Codes
5.1.1.
Interactive Web Response System
An IWRS will be employed to manage the conduct of the trial. In Phase 1b and/or Phase 2, the 
IWRS will be used to maintain a central log documenting enrollment, to implement 
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 drug and 
study participation.
5.2.
Description and Handling of Idelalisib
5.2.1.
Formulation
Idelalisib will be provided in tablets intended for oral administration. Each tablet contains 
150 mg, 100 mg, or 50 mg of active idelalisib. 
The 150 mg tablets are oval and pink; the 100 mg tablets are oval and orange; and the 50 mg 
tablets are round and pink. All tablets are film-coated, and include the following inactive 
excipients: microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, 
sodium starch glycolate, magnesium stearate, FD&C Yellow #6/ Sunset Yellow FCF Aluminum 
Lake (100 mg tablets only), red iron oxide (150 mg and 50 mg only), polyethylene glycol, talc, 
polyvinyl alcohol (PVA), and titanium dioxide.
5.2.2.
Packaging and Labeling
Idelalisib tablets are packaged in white, high density polyethylene (HDPE) bottles. Each bottle 
contains 60 tablets and polyester packing material. Each bottle is enclosed with a white, 
continuous thread, child resistant polypropylene screw cap with an induction-sealed and 
aluminum faced liner.
5.2.3.
Storage and Handling
Idelalisib tablets should be stored at controlled room temperature of 25 °C (77 °F); excursions 
are permitted between 15 °C and 30 °C (59 °F and 86 °F). Storage conditions are specified on 
the label. Until dispensed to the subjects, all bottles of study drugs should be stored in a securely 
locked area, accessible only to authorized site personnel. To ensure the stability and proper 
identification, the study drug should be stored in the containers in which they were supplied.
5.3.
Description and Handling of BI 836826
5.3.1.
Formulation
BI 836826 concentrate for solution for infusion is a clear to slightly opalescent, colourless to
yellowish liquid, with an osmolality of 260 - 340 mOsm/kg and a pH of 5.7 – 6.7. Concentration 
is 10 mg/mL in vials with 10 mL, dilution is required prior to administration.




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5.4.1.
Idelalisib
Idelalisib will be taken orally twice daily (BID). At each dose administration, the idelalisib tablet
is to be swallowed whole with 120 to 240 mL (approximately 4 to 8 ounces) of water. In case of 
breakage of the tablet in the oral cavity, additional water should be taken as a rinse.
During Phase 1b the initial BLRM will use the following dose levels for idelalisib: 50 mg BID, 
100 mg BID, and 150 mg BID; the starting dose level will be idelalisib 50 mg BID.
Idelalisib may be taken with or without food. There are no known dietary restrictions related to 
idelalisib use.
On days of BI 836826 dosing, idelalisib will be administered in the clinic approximately 
60 minutes before the start of the infusion and appropriately timed relative to blood sampling for 
idelalisib PK. Prior to these visits, subjects should be reminded not to take their morning dose of 
study drug before coming into the clinic. Subjects should also be reminded to bring their study 
drug with them to clinic for dosing. 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. At home, 
idelalisib should be taken at approximately the same time each day. Ideally, doses should be 
taken at approximately 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.
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.
5.4.2.
BI 836826
BI 836826 is administered intravenously as a rate controlled infusion. Administration will start 
on Week 2 with an initial of 10 mg on Day 8, 50% of the assigned dose on Days 9 and Day 15, 
and 100% of the assigned dose on Day 22. Thereafter, 100% of the assigned dose will be 
administered every 2 weeks through Week 18, and every 4 weeks through Week 46. During the 
Phase 1b portion of the study, subjects will be hospitalized overnight on Day 9 (first 50% dose) 
for monitoring and prophylaxis against tumor lysis syndrome (TLS).
In the Phase 1b portion of the study, the initial BLRM will use the following dose levels for 
BI 836826: 100 mg, 200 mg, and 400 mg; the starting dose level will be 100 mg. The BLRM 
may subsequently be modified to include additional BI 836826 doses through 600 mg, dependent 
on safety data from this study and from Boehringer Ingelheim study 1270.1. 
Subjects should receive 18 infusions of BI 836826 over the course of the study. There will be no 
intra-subject dose escalation.


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There is no limit on the length of time BI 836826 may be held to allow resolution of toxicity. If 
both idelalisib and BI 836826 are held during the same period, when appropriate both drugs 
should be restarted on the same day rather than dosing with idelalisib for 7 days prior to 
restarting BI 836826. If administration of BI 836826 is delayed by more than 4 weeks, when 
infusions are restarted pre-medication must be administered for the first 8 weeks. The last 
BI 836826 infusion must be administered no later than Week 48.
Surveillance of the subject during and until at least 2 hours after the end of the infusion is 
required for the first 4 BI 836826 infusions (through the first infusion of 100% of the assigned
dose). Surveillance should be prolonged as clinically indicated to monitor or treat AEs. 
Mandatory surveillance can be reduced to at least 1 hour in the fifth and subsequent infusions if 
no AE occurs during the infusion or the 1 hour surveillance period. Prophylaxis against IRR is 
required prior to administration (Section 5.8.2.1).
5.4.2.1.
BI 836826 Infusion Rates
Table 5-1 provides a tabular summary of BI 836826 infusion rates.
Table 5-1.
BI 836826 Infusion Rates
Day of 
Treatment
Dose of
BI 836826
Rate of Infusion
Maximum 
Allowed 
Infusion 
Duration
Maximum 
Allowed Infusion 
Rate
Week 2 
Day 8
10 mg
2 mg/hr x 60 min
Escalate by 1 mg/hr every 30 min as 
tolerated to maximum allowed rate
24 hr
5 mg/hr
Week 2 
Day 9
50% of 
assigned
dose
≤ 50 mg/hr x 60 min
Escalate by ≤ 50 mg/hr every 30 min as 
tolerated to maximum allowed rate
24 hr
400 mg/hr
Week 3 
Day 15
50% of 
assigned
dose
≤ 50 mg/hr x 60 min
Escalate by ≤ 50 mg/hr every 30 min as 
tolerated to maximum allowed rate
24 hr
400 mg/hr
Week 4 
Day 22
100% of 
assigned
dose
≤ 50 mg/hr x 60 min
Escalate by ≤ 50 mg/hr every 30 min as 
tolerated to maximum allowed rate; 
slower start rate or smaller increments 
allowed at investigator’s discretion
24 hr
400 mg/hr
Week 6
Day 36
100% of 
assigned
dose
≤ 50 mg/hr x 30 min, then
≤ 100 mg/hr x 30 min
Escalate by ≤ 100 mg/hr as tolerated to 
maximum allowed rate; slower start rate 
or smaller increments allowed at 
investigator’s discretion
24 hr
500 mg/hr


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
Week 2, Day 8: BI 836826 Initial Dose of 10 mg
BI 836826 administration will start with an initial dose of 10 mg on Week 2, Day 8.
Premedication (Section 5.8.2) is mandatory. The recommended initial infusion rate to mitigate 
the risk for severe IRRs is 2 mg/hr for the first 60 minutes. The rate can be escalated every 
30 minutes by increments of 1 mg/hr to a maximum rate of 5 mg/hr in the absence of IRRs. In 
subjects with high risk for IRRs, occurrence of an IRR during the infusion, or a high risk for 
TLS, the infusion may be given extremely slowly over a longer period of time not exceeding 
24 hours.

Week 2, Day 9 and Week 3, Day 15: BI 836826 to 50% of Assigned Dose
Pre-medication (Section 5.8.2) is mandatory. The recommended initial infusion rate to mitigate 
the risk for severe IRRs should not exceed 50 mg/hr for the first 60 minutes. The rate can be 
escalated every 30 minutes by increments of 50 mg/hr or less to a maximum rate of 400 mg/hr in 
the absence of IRRs. A slower start rate or smaller increments are possible based on individual 
risk assessment. Reductions in the infusion rate may be applied as indicated to ensure 
tolerability. In subjects with high risk for IRRs, occurrence of an IRR during the infusion, or a 
high risk for TLS, the infusion may be given extremely slowly over a longer period of time not 
exceeding 24 hours.

Week 4, Day 22: BI 836826 at the Assigned Dose
Pre-medication (Section 5.8.2) is mandatory. The recommended initial infusion rate to mitigate 
the risk for severe IRRs should not exceed 50 mg/hr for the first 60 minutes. The rate can be 
escalated every 30 minutes by increments of 50 mg/hr or less to a maximum rate of 400 mg/hr in 
the absence of IRRs. A slower start rate or smaller increments are possible based on individual 
risk assessment. Reductions in the infusion rate may be applied as indicated to ensure 
tolerability. 

Week 6, Day 36 and Subsequent Doses of BI 836826
In the absence of infusion related reactions during the administration of the previous full dose, 
subsequent administration of BI 836826 is recommended to start at a rate of 50 mg/hr or less for 
the first 30 minutes, followed by a rate of 100 mg/hr or less for 30 minutes. Incremental steps 
thereafter may be larger depending on individual tolerability, but must not exceed 100 mg/hr. A 
maximum rate of 500 mg/hr is not to be exceeded. A slower start rate and smaller increments are 
possible based on individual risk. Reductions in the infusion rate may be applied as indicated to 
ensure tolerability. Pre-medication should be considered according to Section 5.8.2.
5.4.2.2.
BI 836826 Infusion Rate Response to Infusion-Related Reaction
If symptoms of an IRR occur while BI 836826 is administered, the following instructions for rate 
changes and interruptions of BI 836826 should be followed. Table 5-2 provides a tabular 
summary of procedures that may be employed to manage IRRs.


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Table 5-2.
BI 836826 Management of Infusion-Related Reactions
NCI CTCAE Grade 
of IRR
Action
Continuing BI 836826 1
Grade 1
Reduce infusion rate to 50% 
of the rate at which 
symptoms occurred; 
infusion may be interrupted 
at investigator’s discretion
After resolution of 
symptoms
Increase infusion rate to the 
rate at which the reaction 
occurred
Grade 2
Interrupt infusion; 
supportive treatment may be 
administered as indicated
After resolution of 
symptoms
Resume infusion at a slower 
rate than that at which the
reaction occurred
Grade 3
Interrupt infusion; 
supportive treatment is 
typically indicated, 
glucocorticoids should be 
considered for management
After resolution of 
symptoms
Resume infusion at ≤50% 
of the rate at which the 
reaction occurred 
x 30 minutes
Grade 4
Stop infusion
Do not re-expose
1.
Once subject is stable after reintroduction of initial infusion rate, proceed per Section 5.4.2, Dosage and Administration of
BI 836826

In the case of an IRR of CTCAE Grade 1, the infusion rate of BI 836826 should be reduced 
to 50% of the previous rate, but may also be interrupted. Upon resolution of symptoms, the 
infusion may be resumed at an infusion rate not higher than the rate at which the IRR 
occurred, and escalated at the investigator’s discretion within the limits described above.

In the case of an IRR of CTCAE Grade 2, the infusion of BI 836826 should be interrupted. 
Supportive treatment may be administered as indicated. Upon resolution of symptoms, the 
infusion may be resumed at 50% of the previous infusion rate and infusion rate escalated at 
the investigator’s discretion within the limits described above.

In the case of an IRR of CTCAE Grades 3, the infusion with BI 836826 has to be stopped 
immediately. Supportive therapy is typically indicated, glucocorticoids should be considered 
for management. Once all symptoms have resolved, administration of BI 836826 may be 
resumed for at least 30 minutes at a rate which should not exceed 50% of the rate at which 
the reaction occurred. Re-increase of the infusion rate as tolerated by the subject is possible 
within the limits described above.

In the case of an IRR reaction of CTCAE Grade 4, the infusion has to be stopped 
immediately. Symptoms should be aggressively treated, glucocorticoids should be considered 
for management. Re-exposure after the event is not permitted.


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5.4.2.3.
Criteria for Administration of BI 836826 at 100% of the Assigned Dose 
(Day 22 and Following)
Prior to each administration of a 100% assigned dose of BI 836826, AEs and complete blood 
count (CBC) with differential will be assessed. To continue treatment with a further infusion of 
BI 836826, all of the following criteria must be met:

Neutrophils ≥ 1000 /μL (1.0 × 109/L) 

Platelets ≥ 25,000 /μL (25 × 109/L) 

Acceptable tolerability (Table 5-3)
In case any 1 of these criteria is not fulfilled, blood counts and/or the AE should be regularly 
re-evaluated. See section 5.6 for information on dose modification in response to toxicity.
If an infusion cannot be administered within the protocol-specified procedure window 
(see Appendix Table 1, Visit Window) the dose should be skipped. Doses may be made up if a 
minimum interval of 2 weeks is maintained between infusions. The last infusion of BI 836826 
may be given no later than Week 48.
5.5.
Dose-Limiting Toxicity
All AEs, including SAEs and deaths, will be carefully analyzed by the SRT. Dose-limiting 
toxicities will be those clinically relevant AEs which are unexpected in severity or frequency 
considering the mode of action and known toxicities of the individual agents, are not 
manifestations of underlying disease or background events typical of the study population, and 
are any of the following: debilitating, non-reversible, not manageable, or which lead to a fatal 
outcome, where evidence suggests that there was a reasonable possibility that the drug 
combination caused the AE.
The following drug-related hematologic adverse events will be considered DLT:

Grade 4 neutropenia lasting more than 7 days

Grade 4 febrile neutropenia, and Grade 3 febrile neutropenia not resolving within 48 hrs with
appropriate treatment (antibiotics, antivirals, antifungals, growth factor support) 

Grade 4 thrombocytopenia lasting more than7 days, or Grade 3-4 thrombocytopenia with 
clinically significant bleeding

Grade 4 anemia

Any Grade 5 hematologic AE


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Non-hematologic, drug-related AEs of Grade 3 or higher will be considered DLTs except:

Grade 3 ALT or AST elevation

Grade 3 diarrhea that responds to therapy within 7 days

Grade 3 rash that improves within 7 days following supportive therapy and discontinuation 
of idelalisib

Grade 3 pneumonia or localized infection that responds to therapy within 7 days

Any other Grade ≥3 lab abnormalities that, in the opinion of the investigator, are attributable 
to the underlying disease process

Infusion-related reaction, any grade
5.6.
Safety Monitoring and Study Drug Interruption/Dose 
Modification/Discontinuation
Required and recommended actions for discontinuation or dose modification for both drugs, 
including the combination regimen, are provided in Table 5-3. The requirements and
recommendations are based on the drug and the CTCAE grade of specific toxicities, focusing on 
the types of events most commonly attributed to each of the study agents.
In cases of uncertainty, the study medical monitor should be contacted.
There is no limit on the length of time either idelalisib or BI 836826 may be held during the 
study (eg, to allow resolution of toxicity). If both idelalisib and BI 836826 are held during the 
same period, when appropriate both drugs should be restarted on the same day rather than dosing 
with idelalisib for 7 days prior to restarting BI 836826. During the combination therapy period 
(through Week 46), if either study drug is permanently discontinued, the other study drug should 
also be permanently discontinued. See Section 6.6.1 for recommended follow-up.


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Table 5-3.
Requirements and Recommendations for Discontinuation or
Modification of Study Treatment in Response to Adverse Events
NCI CTCAE Grade1
Idelalisib
BI 836826
HEMATOLOGICAL ADVERSE EVENT
Neutropenia
Grade 2 neutropenia
Maintain current dose and schedule.
Maintain current dose level and schedule.
Grade 3 neutropenia
Required action: Blood counts must be 
monitored at least weekly until 
neutropenia Grade ≤ 2. 
Maintain current dose level and schedule.
Consider G-CSF support.
If febrile neutropenia not resolving within 
48 hrs with appropriate treatment, decrease 
subsequent dose by 50%2.
Grade 4 neutropenia 
(or occurrence of 
neutropenic fever or 
infection)
Required action: Interrupt idelalisib. 
Blood counts must be monitored at least 
weekly until neutropenia is ≤Grade 2.
Recommended action: May resume 
idelalisib at lower dose level when 
neutropenia is Grade ≤32.Neutropenia 
should be managed according to 
established clinical guidelines.
If Gr 4 neutropenia lasts >7 days, or febrile 
neutropenia not resolving within 48 hrs 
with appropriate treatment, decrease 
subsequent dose by 50% 3 Otherwise, 
maintain current dose level and schedule
and consider G-CSF support.
Thrombocytopenia
Grade 2 
thrombocytopenia
Maintain current dose and schedule.
Maintain current dose level and schedule.
Grade 3 thrombocytopenia
Maintain current dose and schedule.
Maintain current dose level and schedule; 
unless associated with significant bleeding, 
in which case decrease subsequent dose by 
50% 3
Grade 4 thrombocytopenia
Required action: During continuing 
single agent therapy period, withhold for 
bruising or bleeding until Grade 3.
Recommended action: During 
combination therapy period, maintain 
current dose level. If withheld during 
continuing therapy period, may resume 
at same or reduced dose level at 
investigator discretion 2.
If lasts > 7 days or associated with 
significant bleeding, decrease subsequent 
dose by 50% 3.
Anemia
Grade ≤3
Maintain current dose and schedule.
Maintain current dose level and schedule.
Grade 4
If all other possible etiologies of anemia 
have been ruled out, idelalisib may be 
withheld at investigator discretion.
Decrease subsequent dose by 50%3.


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NCI CTCAE Grade1
Idelalisib
BI 836826
NON-HEMATOLOGICAL ADVERSE EVENT
Rash
Grade ≤2
Maintain current dose and schedule.
Maintain current dose level and schedule.
Grade ≥3 
Required action: Withhold idelalisib 
until Grade ≤1. 
Recommended action: May resume at 
lower dose or discontinue idelalisib at 
investigator discretion 2.
Delay BI 836826 until Grade ≤1. 
Thereafter, may resume at full dose.
Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis
Any Grade
Required action: Discontinue idelalisib. 
Interrupt coadministered medications 
potentially associated with SJS or TEN. 
Institute treatment per institutional 
standards.
Discontinue BI 836826. Institute treatment
per institutional standards.
Bowel Perforation
Any Grade
Discontinue idelalisib.
Discontinue BI 836826.
Diarrhea or Colitis
Any Grade
(in addition see below for 
response to specific 
CTCAE grades)
Required action: See Section 5.7.2.1
for required assessments.
Recommended action: Ensure good 
hydration status and provide anti-
diarrheal; maintain current dose level. 
See Section 5.7.2.2 for recommended 
evaluations.
See below.
Grade 1
Required action: See Section 5.7.2.1 for 
required assessments.
Recommended action: Provide 
anti-diarrheal (eg, loperamide) and 
maintain current idelalisib dose and 
schedule.
Maintain current dose level and schedule.
Grade 2
(unless clinical diagnosis 
is established from 
medical history and 
physical examination)
Required action: See Section 5.7.2.1 for 
required assessments and 
Section 6.1.8.9 for required testing.
Recommended action: See 
Section 5.7.2.2 for recommended 
evaluations. Maintain current dose level.
Delay BI 836826 until Grade ≤1. 
Thereafter, may resume at full dose.
Grade ≥3
(or persistent Grade 2 
diarrhea or colitis without 
clear etiology)
Required action: Withhold idelalisib.  
See Section 5.7.2.1 for required 
assessments and Section 6.1.8.9 for 
required testing. Consider anti-diarrheal 
(eg, loperamide) and/or addition of 
anti-inflammatory agent 
(eg, sulfasalazine, budesonide). 
Recommended action: See 
Section 5.7.2.2 for recommended 
evaluations. At Grade 1, may resume 
at lower dose level 2 or discontinue 
study drug at investigator discretion.
If diarrhea Grade ≥3 recurs despite 
interruption of idelalisib, reduce BI 836826 
to 50% 3. BI 836826 may be increased to 
100% upon resolution to Grade ≤1 at 
investigator discretion.


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NCI CTCAE Grade1
Idelalisib
BI 836826
Hepatic Adverse Events (elevations in ALT, AST)
Grade ≤1
(ALT/AST ≤ 3 × ULN; 
Bilirubin 1.5xULN)
Maintain current dose and schedule.
Maintain current dose level and schedule.
Grade 2
(ALT/AST ≤3-5 × ULN; 
Bilirubin > 1.5- 3xULN)
Maintain current dose and schedule. 
Recommended action: Monitor ALT,
AST, ALP, and bilirubin at least 1x per 
week until all abnormalities are 
Grade ≤1.
Delay BI 836826 until Grade ≤1. 
Thereafter resume at full dose.
Grade 3 
(ALT/AST > 5-20 × ULN; 
Bilirubin > 3-10xULN)
Recommended action: Withhold 
idelalisib. Monitor ALT, AST, alkaline 
phosphatase (ALP), and bilirubin at 
least 1x per week until all abnormalities 
are Grade 1. If bilirubin abnormality 
was Grade <3 resume idelalisib at same 
dose level. If bilirubin abnormality was
Grade 3, resume at lower dose level 2.
Withhold BI 836826. Monitor ALT/AST at 
least 1x per week until Grade ≤1. 
Thereafter, may resume at full dose. If 
ALT/AST elevation Grade ≥3 recurs with 
BI 836826 at full dose and idelalisib at 
reduced dose, reduce BI 836826 to 50% 3. 
Upon resolution of ALT/AST to Grade 1 
BI 836826 may be re-escalated to 100% at 
investigator discretion.
Grade 4
(ALT/AST > 20 × ULN; 
Bilirubin > 10xULN)
Required action: 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, discontinue idelalisib. 
Recommended action: If bilirubin 
abnormality was Grade <4 resume 
idelalisib at lower dose level2.
Withhold BI 836826. Monitor ALT, AST, 
ALP, and bilirubin at least 1x per week 
until all abnormalities are Grade 1. If 
bilirubin abnormality was Grade 4, 
discontinue BI 836826.
Pneumonitis (with new onset or worsening of baseline dyspnea, cough, or hypoxia without obvious 
infectious cause)
Grade 1
(asymptomatic)
Required action: Withhold idelalisib
until resolution to baseline. May resume 
at lower dose level or discontinue at 
investigator discretion.
Maintain current dose level and schedule. 
Grade ≥2
Required action: Discontinue idelalisib
permanently in subjects with any severity 
of symptomatic pneumonitis and institute 
therapy as clinically appropriate.
Discontinue BI 836826.
Pneumocystis jirovecii pneumonia (PJP)
Any Grade
Required action: Discontinue idelalisib.
Discontinue BI 836826.
CMV Infection/Reactivation 4
Any Grade
Required action: Interrupt idelalisib upon 
unequivocal clinical or laboratory 
evidence of CMV infection. Treat 
according to established clinical 
guidelines. If the benefits of resuming 
idelalisib are judged to outweigh the risks, 
consider pre-emptive CMV therapy.
Discontinue BI 836826.
Hepatitis B Reactivation
Any Grade
Required action: Discontinue idelalisib.
Discontinue BI 836826.


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NCI CTCAE Grade1
Idelalisib
BI 836826
OTHER NONHEMATOLOGICAL ADVERSE EVENTS
Grade ≤2
Maintain current dose level and 
schedule.
Maintain current dose level and schedule.
Grade ≥3
Withhold study drug until Grade 1. 
May resume study drug at initial or next 
lower dose2 or discontinue study drug at 
investigator discretion.
Withhold study drug until Grade 1. May 
resume study drug at initial or at 50% 3 or 
discontinue study drug at investigator 
discretion.
1.
CTCAE, Version 4.03.
2.
If assigned idelalisib dose level is 50 mg BID, dose reduction is not possible and idelalisib should be interrupted.
3.
Dose reduction of BI 836826 by 50% may be performed twice. If still not tolerated, BI 836826 should be discontinued.
4.
CMV should be diagnosed using clinical or laboratory criteria per established institutional standard
5.7.
Requirements and Recommendations Regarding Specific Adverse Events or 
Conditions
5.7.1.
Transaminase Elevations
Consistent with observations in a dog toxicology study, reversible asymptomatic ALT/AST 
increases were 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 are consistent with the ongoing experience with idelalisib 
treatment and transaminase elevations are now well characterized as most frequently 
asymptomatic, transient and occurring within the first 3 months of treatment.
Grade 1 or 2 elevations commonly resolve despite continued idelalisib treatment and Grade 3 or 
4 elevations can be managed by temporarily withholding idelalisib. Successful rechallenge after 
resolution at either the same or lower dose level of idelalisib has been achieved in the majority of 
subjects. There has been no evidence of impaired synthetic function. Close monitoring of hepatic 
laboratory tests during therapy is important to allow for appropriate idelalisib interruption and 
reinstitution so that subjects may continue with study drug treatment.
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.
In selected subjects who experience more complicated hepatic AEs, further workup may be 
warranted particularly in subjects who first experience a serum ALT/AST elevation 12 weeks 
from the start of study drug therapy, who have an elevation in serum bilirubin concentration or 
coagulation parameters, or who have other characteristics that suggest an atypical change in 
transaminase values. Hepatic AEs that require additional workup should be discussed with the 
Gilead Sciences Medical Monitor.


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5.7.2.
Gastrointestinal Events
Isolated cases of gastrointestinal inflammation (eg, stomatitis, colitis, cecitis) have been noted in 
subjects receiving idelalisib. Rare cases of gastrointestinal perforation have occurred, generally 
in the setting of occult carcinoma, mesenteric embolus or diverticular disease.  Study treatment 
must be discontinued in subjects who experience bowel perforation.
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. 
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 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 immunohistochemical (IHC) staining should be considered. For 
Grade ≥ 3 or persistent Grade 2 colitis or diarrhea without clear etiology (eg, C. difficile
enterocolitis), endoscopy with biopsy is strongly recommended. See Section 6.1.8.9 for required 
testing. In the event that an infectious cause is not identified, an antimotility agent 
(eg, loperamide) may lessen symptoms and intervention with enteric steroidal (eg, budesonide) 
or non-steroidal (eg, sulfasalazine) anti-inflammatory agents should be considered. In such 
subjects, rechallenge with idelalisib at a lower dose level has resulted in recurrence of symptoms 
in some but not all subjects and has not been associated with other severe adverse events.
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
{Coutre 2015}.


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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}
5.7.2.1.
Required Assessments for Diarrhea/Colitis
For any grade 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).
5.7.2.2.
Recommended Assessments for Diarrhea/Colitis
Differentiation between small-bowel and large-bowel diarrhea may be possible on a clinical 
basis.  If unclear, consider upper and lower tract endoscopy with biopsy.

Small bowel diarrhea is characterized by large volume diarrhea (more than 1 per day), 
possible associated dehydration weight loss and paraumbilical pain. Consider an endoscopic 
small-bowel biopsy and evaluate other etiologies such as celiac disease.

Large-bowel diarrhea may present with lower pelvic pain, tenesmus, generally smaller stool 
volume with gross blood frquently found in the stool. Consider a colonoscopic evaluation 
and biopsy.
For Grade ≥ 3 or persistent Grade 2 colitis or diarrhea without clear etiology (eg, C. difficile
enterocolitis), endoscopy with biopsy is strongly recommended. All biopsy samples should 
include immunohistochemistry and PCR for CMV, Adenovirus. If ileal biopsy is performed, 
consider Acid Fact Bacillus staining.
 
 
 
   
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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5.7.3.
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 Grade ≥ 3 rash for which an underlying etiology cannot be identified 
(eg, infection, co-suspect drug), study drug must be interrupted. Resumption of study drug 
should be considered once rash resolves.
Severe cutaneous reactions, including fatal events of Stevens-Johnson syndrome (SJS) and 
toxic epidermal necrolysis (TEN), have been reported in subjects receiving idelalisib.
Assessment of potential causal association between idelalisib and the occurrence of SJS or TEN 
has been confounded by the coadministration of antineoplastic agents (eg, bendamustine, 
rituximab) and/or other concomitant medications known to be associated with SJS or TEN 
(eg, allopurinol). If SJS or TEN is suspected, idelalisib must be discontinued and all 
coadministered medications associated with SJS or TEN should be interrupted, and the subject 
treated per institutional standards. 
5.7.4.
Pulmonary Events
Documented bacterial, fungal, viral, and pneumocystis pneumonias have been observed in 
patients receiving idelalisib, primarily in patients with CLL. Some study subjects receiving 
idelalisib alone or in combination have developed evidence of pneumonitis without documented 
pulmonary infection. 
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.
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, dyspnea, 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.


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5.7.5.
Hematological and Immunological Events
In the Phase 1 experience with idelalisib in patients with NHL and CLL, subjects with Grade 3 
neutropenia, anemia, and/or thrombocytopenia were enrolled to clinical trials. Decreased levels 
of neutrophil counts, hemoglobin, or platelet counts during idelalisib administration were largely 
due to minor fluctuations in these parameters among subjects with pre-existing hematological 
abnormalities due to disease or prior therapy. Thus, idelalisib did not appear to induce overt 
myelosuppression. Obvious patterns of drug-mediated reductions in circulating CD4+ 
lymphocyte counts or suppression of serum IgG levels were also not observed.
Treatment-emergent Grade 3 or 4 neutropenia events, including those accompanied by fever or 
infection, have occurred in subjects treated with idelalisib. 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 neutropenia Grade 3, blood counts must be monitored at least weekly until neutropenia
is Grade ≤ 2. For subjects who develop neutropenia Grade 4, idelalisib must be interrupted and blood 
counts monitored at least weekly until neutropenia is Grade ≤ 2. Idelalisib dosing may be resumed at 
lower dose level when neutropenia is Grade ≤ 3.  Neutropenia should be managed according to 
established clinical guidelines.
No modification of either study drug for changes in circulating CD4+ counts or Ig levels is 
planned.
5.7.6.
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 prophylaxis for PJP throughout the course of idelalisib treatment, and for 
2 to 6 months after idelalisib treatment ends (see Section 5.8.1). Subjects must permanently 
discontinue idelalisib upon diagnosis of PJP.
Cytomegalovirus (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, consider pre-emptive CMV therapy.
In high-risk subjects (history of recurrent infection, allogeneic transplant, treatment with 
alemtuzumab, hypogammaglobulinemia) other infection prophylaxis should be considered per 
consensus guidelines. Administration of intravenous immunoglobulin is permitted per standard 
institutional practice {Raanani 2009}. For subjects who develop an infection, appropriate 
medical therapy should be instituted in a timely manner.


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5.7.7.
Secondary Malignancies
Subjects receiving idelalisib for CLL or iNHL have developed pre-malignant and secondary 
malignant diseases, such as basal cell carcinoma, myelodysplastic syndrome, myeloproliferative
disorders, and more aggressive lymphoid malignancies (eg, have had Richter transformation). 
Generally this has occurred in subjects who have received multiple previous lines of therapy and 
when idelalisib is combined with other therapies such as rituximab or bendamustine. The specific 
association of the therapeutic agents with these types of events has not been determined.
5.7.8.
Ultraviolet Exposure
In vitro studies indicate enhanced cytotoxicity when embryonic murine fibroblasts treated with 
GS-563117 (the major metabolite of idelalisib) are simultaneously exposed to ultraviolet light. 
While nonclinical findings suggest the hypothetical potential for phototoxicity in humans, 
available clinical data do not reveal a photosafety concern. Although specific clinical correlates 
for these nonclinical data are not available, investigators and study subjects should be observant 
for the possibility that study participants may have exaggerated sunburn reactions 
(eg, burning, erythema, exudation, vesicles, blistering, edema) involving areas of skin exposed to 
ultraviolet light.
5.7.9.
Pregnancy, Lactation, and Reproduction
Idelalisib has induced embryo lethality and teratogenicity when administered to pregnant female 
rats at maternally toxic doses. However, definitive reproductive toxicology studies in animals 
have not yet been performed and the specific effects of idelalisib on human embryogenesis or 
fetal development are unknown. Whether idelalisib is excreted in human breast milk is unknown.
General toxicology studies of idelalisib in rats and dogs indicated dose-dependent reductions in 
testicular weights, with persistent minimal to mild degeneration of the seminiferous tubules and 
decreased spermatozoa in rats and hypospermatogenesis in dogs. The implications of these 
testicular changes for animal or human fertility are unknown.
Given the potential 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 
sexual intercourse or use an effective form of contraception (see Appendix 5). If a female study 
participant becomes pregnant or decides to breastfeed during the course of the study, all study 
therapy (idelalisib//BI836826) must be discontinued.
5.7.10.
Pneumocystis jirovecii Pneumonia Prophylaxis
Trimethoprim sulfamethoxazole is rated a Pregnancy Category C agent.  In rats, oral doses of 
533 mg/kg or 200 mg/kg produced teratologic effects manifested mainly as cleft palates.
One survey found no congenital abnormalities in 35 children whose mothers had received oral
sulfamethoxazole and trimethoprim at the time of conception or shortly thereafter. Because 
sulfamethoxazole and trimethoprim may interfere with folic acid metabolism it should be used 
during pregnancy only if the potential benefit justifies the potential risk to the fetus.


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Dapsone is rated a Pregnancy Category C agent.  Extensive, but uncontrolled experience and 
2 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 Dapsone, 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; 
however, 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.
5.7.11.
Risk of Hepatitis B Reactivation
Hepatitis B Virus (HBV) reactivation can occur in patients treated with anti-CD20 antibodies, 
and this risk may be assumed to apply also to anti-CD37 antibodies.  Subjects whose Screening 
labs show anti-hepatitis B core antibody (HBc antibody)  positivity, but have negative HBV 
DNA by PCR are eligible to enroll on this study.  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 who are HBc antibody positive at screening should receive Hepatitis B prophylaxis 
with lamivudine, entecavir, or tenofovir per National Comprehensive Cancer Network (NCCN)
infection guidelines. These subjects will also be monitored for potential HBV reactivation 
(manifest as detectable HBV DNA by quantitative PCR).  Subjects will be tested monthly, 


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starting at Week 8, for the duration of BI 836826 therapy and every 3 months thereafter for 
1 year from the last dose of BI 836826 during study participation. Following the completion of
study participation, 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 BI 836826 and idelalisib.
5.7.12.
Further Safety Information
Further safety information regarding the study drug may be found in the idelalisib and BI 836826 
IBs.
5.8.
Prior and Concomitant Medications
5.8.1.
Idelalisib
Subjects must receive trimethoprim-sulfamethoxazole or other established prophylaxis for PJP 
throughout the course of idelalisib treatment.  Prophylaxis will continue for a minimum period of 
2-6 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. 
5.8.2.
BI 836826
5.8.2.1.
Infusion-Related Reactions
Infusion-Related Reactions are related to cytokine-release resulting from the interaction of 
antibody with antigen on circulating hematopoietic cells, with increasing risk at higher infusion 
dose rates or increments. Pre-medication is mandatory 30-120 minutes prior to the administration 
of BI 836826 to mitigate the risk for IRR, see Table 5-4. In case a contra-indication for 1 of the 
drug exists, the drug may be replaced or omitted. 
If BI 836826 has been well tolerated without signs of IRRs during the sixth or a later 
administration (ie, in Week 8 or later), the glucocorticoid dose may be stepwise reduced during 
subsequent infusions while the other drugs are maintained. If BI 836826 is tolerated without IRR 
after pre-medication according to Table 5-4 Level -2, the investigator may individually decide 
whether to administer pre-medication for subsequent treatments and which of the recommended 
drugs to use.
If IRRs are observed at infusions with reduced pre-medication, the pre-medication triplet at 
doses as outlined for the first 4 infusions should continue to be used for all administrations.


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Table 5-4.
Premedication for BI 836826
Week
Subjects Requiring 
Premedication
Premedication
Completion Prior 
to BI 836826
2-8
all subjects
Analgesic/Antipyretic PO or IV 1
Antihistamine PO or IV 2
Glucocorticoid IV, equivalent to prednisolone 100 mg
60-120 minutes
10-46
all subjects with IRR in 
the previous infusion or 
with ALC ≥25000/µL
Analgesic/Antipyretic PO or IV 1
Antihistamine PO or IV 2
Glucocorticoid IV, equivalent to prednisolone 100 mg
60-120 minutes
10-46
subjects without IRR in 
previous infusion and 
ALC < 25000/µL
Premedication Level -1:
Analgesic/Antipyretic PO or IV 1
Antihistamine PO or IV 2
Glucocorticoid IV, equivalent to prednisolone 50 mg
30-120 minutes
10-46
subjects with ALC 
< 25000/µL and 
without IRR and 
premedication at 
level -1 at 
previous infusion
Premedication Level -2:
Analgesic/Antipyretic PO or IV 1
Antihistamine PO or IV 2
Glucocorticoid IV, equivalent to prednisolone 25 mg
30-120 minutes
12-46
subjects with ALC 
< 25000/µL and 
without IRR and 
premedication at 
level -2 at 
previous infusion
Premedication at the discretion of the investigator
1.
equivalent to Acetaminophen/Paracetamol 1000 mg
2.
equivalent to diphenhydramine 50 mg IV
5.8.2.2.
Tumor Lysis Syndrome
Subjects with a high tumor burden or preexisting renal dysfunction should receive prophylaxis 
for TLS prior to the initiation of treatment. These subjects must be well hydrated. It is desirable 
to maintain a fluid intake of approximately 3 liters per day for 1-2 days before the first 50% dose 
of BI 836826. Treatment with allopurinol (≥300 mg p.o./day) or a suitable alternative 
(eg, rasburicase) starting ≥ 24 hours prior to the first infusion should be considered. Subjects
should continue to receive repeated prophylaxis with allopurinol and adequate hydration prior to 
each subsequent infusion, if deemed appropriate by the investigator. Older and frail subjects will 
need special individualized care in fluid management, as 3 liters per day may not be 
tolerated. Rasburicase may be particularly indicated in such subjects. For all subjects, 
electrolytes should be monitored and corrected, fluid balance and renal function should be 
monitored, and supportive care should be administered, including dialysis as indicated.
5.8.2.3.
Hepatitis B
All subjects who are HBc antibody positive at screening should receive Hepatitis B prophylaxis. 
Refer to Section 5.7.11 for specific treatment recommendations.


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5.8.3.
Anticancer or Experimental Therapies Other than Idelalisib or BI 836826
No other anticancer therapies (including systemic chemotherapy, radiation, antibody therapy, 
immunotherapy, or other experimental therapies) of any kind are permitted while the subject is 
participating in the study. Subjects are not allowed to participate concurrently in any other 
therapeutic clinical study.
5.8.4.
Granulocyte Colony-Stimulating Factors and Erythropoietin
Granulocyte-macrophage colony-stimulating factors (GM-CSF) should not be administered 
given the potential for GM-CSF-related inflammatory symptoms. The use of supportive care 
agents such as Granulocyte colony-stimulating factor (G-CSF) agents or erythropoietic agents 
are permitted in compliance with regional prescribing information.
5.8.5.
Corticosteroids
Subjects may receive topical or inhaled corticosteroids while on study. The use of systemic 
corticosteroids is discouraged because their potential antineoplastic activity in subjects with CLL 
may confound interpretation of idelalisib-mediated antitumor effects. However, subjects who 
develop severe or life-threatening conditions that may be alleviated by systemic corticosteroid 
therapy are permitted to receive such drugs and are not required to discontinue study 
participation. Systemic corticosteroids in addition to premedication should be used as indicated 
to treat infusion related reactions. Hydrocortisone for prevention or treatment of IRRs is not 
recommended as it has not been effective in reducing the rate of infusion reactions with other 
Fc-engineered antibodies.
5.8.6.
Drug-Drug Interactions
Consistent with nonclinical data indicating that GS-563117(the major metabolite of idelalisib) is 
a reversible and time-dependent inhibitor of CYP3A, coadministration with idelalisib resulted in 
higher midazolam systemic exposures, 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, certain antiarrhythmics, calcium channel blockers, 
benzodiazepines, HMG-CoA reductase inhibitors, phosphodiesterase-5 [PDE5] inhibitors, and 
warfarin). Avoid coadministration of idelalisib with drugs that are narrow therapeutic index 
CYP3A substrates (eg, alfentanil, cyclosporine, sirolimus, tacrolimus, cisapride, pimozide, 
fentanyl, quinidine, ergotamine, dihydroergotamine, astemizole, and terfenadine).
Data indicate that 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.
5.9.
Investigational Medicinal Product Accountability (Idelalisib and BI 836826)
The investigator is responsible for ensuring adequate accountability of all used and unused study 
drug containers (idelalisib bottles and BI 836826 vials). This includes acknowledgement of 
receipt of each shipment of study drug (quantity and condition).


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Study drug accountability records for idelalisib and BI 836826 will be provided to each study 
site to:

Record receipt into pharmacy: date, quantity, and lot and/or bottle number(s) received.

Record dispensing from the pharmacy: date, subject number, subject initials, and lot and/or 
bottle number dispensed.

Record return: date, quantity of used and unused study drug/containers, along with the 
initials of the person recording the information.
Institution specific accountability records may be used if they capture the same information 
listed above.
5.9.1.
Investigational Medicinal Product Return and Disposal
(Idelalisib and BI 836826)
5.9.1.1.
Idelalisib
Used and unused idelalisib and containers should be retrieved at the end of each dispensing 
interval. The quantity of idelalisib and the date returned by the subject should be recorded in the 
study drug accountability records. All idelalisib and containers returned by the subject should be 
retained for review by the study site monitor prior to destruction.
5.9.1.2.
BI 836826
Used and unused BI 836826 and containers should be retrieved at the end of each infusion. The 
quantity of used/unused BI 836826 and containers should be recorded in the study drug 
accountability records. All BI 836826 and containers remaining after the infusion should be 
retained for review by the study site monitor prior to destruction.




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6.1.3.
Medical & Medication History
A complete medical and surgical history will be obtained prior to enrollment and recorded on the 
eCRF, including a history of the subject’s CLL.
A history of medications taken within the 3 months prior to Screening and during the Screening 
period will be obtained prior to enrollment and recorded on the eCRF.
6.1.4.
Physical Examination
The physical examination (PE) will be performed by a physician, physician’s assistant or nurse 
practitioner qualified to perform the assessment.
At Screening, a complete PE will be performed including height, body weight, and clinical signs, 
and symptoms. Height and body weight assessments will be performed per institutional practice 
and will be recorded in the eCRF. Physical examination findings during the Screening period 
will either be reported as medical history or adverse events based on the requirements in 
Section 7.1.1.
At subsequent study visits, the PE will include body weight and assessment of disease related 
clinical signs and symptoms. 
More frequent examinations may be performed at the investigator’s discretion, if clinically 
indicated.
6.1.5.
Vital Signs
Vital signs will include pulse, systolic and diastolic blood pressure, and body temperature. 
Vital signs should be collected per institutional practice.
6.1.6.
Eastern Cooperative Oncology Group Performance Status
Performance status will be scored using the ECOG criteria (see Appendix 3).
6.1.7.
Electrocardiogram Assessment
A standard 12-lead ECG will be performed at Screening per standard institutional practice, at 
week 26 and 30-Day Follow-Up/End of Study, and whenever clinically indicated at the 
discretion of the Investigator.
6.1.8.
Laboratory Assessments
Due to the early study termination, several blood samples are no longer being collected, 
however the subjects enrolled will continue to be assessed for safety. Refer to the modified 
Table 6-1 and Appendix 2 for changes to Laboratory Assessments. Certain subsections in
Section 6.1.8  may no longer apply.


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Blood samples for laboratory assessments will be sent to a central/local laboratory for analysis.
Analytes to be tested are listed in Table 6-1. Laboratory samples will be collected and analyzed 
on the scheduled day as specified in Appendix 2, even if study medication is being held. More 
frequent examinations may be performed at the investigator’s discretion if medically indicated. 
In addition to the required central laboratory tests, laboratory tests may be performed locally at 
the discretion of the investigator to facilitate treatment decisions.
Any samples collected as specified in Appendix 2 may be analyzed for any tests necessary to 
ensure subject safety. Specific instructions for processing, labeling, and shipping samples will be 
provided in a central laboratory manual.
When abnormal laboratory values or test results constitute an AE, they must be recorded on the 
eCRF AE page.
Table 6-1.
Analytes
Chemistry
Urinalysis
Hematology
Other Analytes
Albumin
Alkaline phosphatase
ALT/SGPT
AST/SGOT
BUN
Calcium
Chloride
Cholesterol
Creatinine a
GGT
Glucose
LDH
Phosphorus
Potassium
Sodium
Total bilirubin
Total protein
Triglycerides
Uric acid
Dipstick
pH
Occult blood
Protein
Glucose
Ketones
Bilirubin
Urobilirubin
Nitrite
Leukocyte esterase
Microscopic c
WBC/HPF
RBC/HPF
RBC
Hematocrit
Hemoglobin
Platelets
WBC
Differential
Neutrophils
Bands/stabs
Eosinophils
Basophils
Lymphocytes
Monocytes
Genotyping
Serum -hCG pregnancy test b
Urine pregnancy test be
-2 microglobulin
Immune monitoringe:
Lymphocyte subset panel
Quantitative immunoglobulins: IgG, IgM, IgA
Total hemolytic complement (CH50)
Hepatitis B surface antigen
Hepatitis B core antibody
Hepatitis B DNAe
Hepatitis C antibody
Hepatitis C viral RNA
HIV antibody
CMV DNA
MRDe
Biomarkers d,e
Plasma concentration of idelalisib and 
BI 836826 e
Anti-drug Antibodies
Coagulation
PT /INR
aPTT
ANC = absolute neutrophil count; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen;
CMV=cytomegalovirus; HiB=Haemophilus influenza Type B; LDH = lactate dehydrogenase; MRD=minimal residual disease;
RBC = red blood cell; WBC = white blood cell
Note: Additional components, abnormal, and/or atypical cells will also be reported if present
a
Estimated creatinine clearance/glomerular filtration rate will be calculated based on the Cockroft-Gault formula
b
If applicable. 
c
To be performed only if the dipstick results are abnormal
d
See Section 3.7
e
These tests have been removed in Amendment 4. The one female subject enrolled is not of child bearing potential. CD4 
monitoring will continue. The 2 subjects enrolled were negative for HBc antibody.






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6.2.
Disease Assessments
The investigator will assess the overall CLL response at timepoints specified in Appendix 2.  
This will be based on modified IWCLL criteria (Appendix 4) and will require consideration of 
the CBC. Physical exam and any imaging to be performed per standard of care.  
6.2.1.
CT Scan/MRI
With the early termination of this study, CT/MRI scans have been discontinued for the rest of the 
study. Imaging assessments should follow standard of care per investigator discretion. 
Subjects will be imaged for neck, chest, abdomen, and pelvis with either contrast-enhanced 
CT or gadolinium-enhanced MRI.  If MRI is chosen, subjects will have an MRI of neck, 
abdomen and pelvis, but will need a non-contrast enhanced CT of the chest. Chest x-ray, 
ultrasound, endoscopy, laparoscopy, positron-emission tomography (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 the study and 
follow-up. Furthermore, the use of IV contrast should be consistent across time points. In the 
event that the Screening/baseline CT scan of the neck, chest, abdomen and pelvis is performed 
without IV contrast, follow-up time points should be performed with IV contrast. Subjects who 
develop an allergy to CT contrast dye may have subsequent scans without contrast. All relevant 
clinical and radiographic information required to make each assessment must be made available 
for source verification and for submission to the IRC (see Section 8.12).
During the Phase 2 portion of the study, the IRC will evaluate the Screening CT/MRI to assess 
for measurable lesions and subjects who do not have a lesion ≥2 cm confirmed by IRC will need 
a bone marrow biopsy demonstrating  quantifiable CLL per inclusion criterion 4).
CT/MRIs performed as standard of care prior to signing the ICF and within 42 days of 
enrollment (Phase 1b) or randomization (Phase 2) may be used to fulfill the Screening 
requirement.  If this option is used, the scans must follow the same conditions set above.
Investigators will assess the status of each subject’s CLL using the criteria in Appendix 4. 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 8.12). The findings of 
the IRC will be considered primary for analyses of efficacy endpoints
6.2.2.
Minimal Residual Disease
With the implementation of Amendment 4, MRD assessments will not be performed.


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Minimal residual disease will be evaluated in peripheral blood and/or bone marrow, depending 
on the time point of the assessment. MRD assessments will be done by multi-parameter flow 
cytometry with a sensitivity of at least 1 leukemic cell per 10,000 leukocytes (10-4 malignant 
cells), the level defined as MRD negative status. The laboratory procedures, instrument settings 
and antibody panels will be fully standardized in order to achieve maximally comparable results 
among the different central labs.
Minimal residual disease will be assessed in peripheral blood at Screening, Weeks 14, 26, 38, 50
and then every 16 weeks through End of Study at the same time as imaging studies and overall 
disease assessment.
Minimal residual disease will be assessed in bone marrow at Week 50.  In addition, if a 
peripheral specimen is MRD negative at any time, a marrow specimen should be obtained within 
30 days following the achievement of peripheral blood MRD negativity at any time point.  Once 
marrow MRD negativity is achieved, the subject will be followed with peripheral blood sampling 
only, according to the schedule of procedures.
6.3.
Screening
The Screening date is defined as the date the subject signs the informed consent form. The 
Screening period starts once a subject has provided written informed consent to participate in the 
study, and ends on the day the subject is enrolled (Phase 1b) or randomized (Phase 2). Screening 
evaluations will be performed within 28 days of confirming eligibility for participation in the 
study (unless specifically noted below or for a particular procedure). CT/MRIs performed as 
standard of care, prior to signing the ICF, and within 42 days of randomization, may be used to 
fulfill this Screening requirement.
Screening tests and procedures indicated in Appendix 2 will be performed to determine 
eligibility. Please refer to the IWRS study reference manual for the process of subject number 
assignment.
Subjects failing to meet eligibility or complete the initial Screening will be registered as a Screen 
Failure and permitted to rescreen 1 time. Laboratory assessments may be repeated 1 time during 
the Screening period for confirmation prior to registering the subject as a Screen Failure. 
Rescreening requirements are the same as the Screening requirements. Assessments from the 
first Screening attempt that fall within the allowed timeframes do not need to be repeated.
From the time of obtaining informed consent through the first administration of investigational 
medicinal product, record all SAEs, as well as any AEs related to protocol-mandated procedures 
on the AE eCRF. All other untoward medical occurrences observed during the Screening period, 
including exacerbation or changes in medical history are to be captured on the medical history 
eCRF. See Section 7 for additional details.
6.4.
Enrollment
This study was terminated in Phase 1b and therefore Phase 2 will not occur.


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It is the responsibility of the investigator to ensure that each subject is eligible for the study 
before enrollment.
During the Phase 2 portion of the study, a site must confirm eligibility by IRC review of imaging 
and, if applicable, bone marrow for quantifiable CLL prior to randomizing the subject. The 
IWRS will assign study medication at the time of randomization. 
The site will train the subject on the dosing schedule for each medication at the time of 
dispensing. Day 1 for the purposes of calculating future visits is defined as the date of the first 
dose of any study drug. The subject’s baseline status for the study is defined by tests and 
procedures done prior to receipt of any study drug. Some of these tests are performed during the 
Screening period and some are performed after enrollment but prior to the first dose of any study 
drug. The following laboratory tests are performed at Week 1, Day 1 after enrollment and prior 
to receipt of any study drug (refer to Appendix 2):

Urine pregnancy test

Physical exam and vital signs

Chemistry

-2 microglobulin

Hematology
6.5.
Treatment and Post-Treatment Period Assessments
Study days will be determined based on the first administration of idelalisib on Week 1, Day 1. 
All subjects will receive 7 days of idelalisib monotherapy followed by a period of combination 
therapy with idelalisib plus intermittent BI 836826 infusions. After the final BI 836826 infusion 
subjects will continue to receive idelalisib monotherapy for 4 weeks, through completion of 
Week 50 assessments. 
6.6.
Criteria for Discontinuation from Treatment or Study
6.6.1.
Criteria for Discontinuation of Study Drug
Study drug may be discontinued in the following instances, in consultation with the 
Gilead Medical Monitor:

Disease progression
CCI
CCI


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
Initiation of non-study specific anti-cancer therapy in the absence of progression

If, in the investigator’s opinion, it is not in the subject’s best interest to continue.

Pregnancy or breastfeeding begins during the study

Subject non-compliance

Subject request to discontinue study drug, for any reason

Any subject is unable to tolerate a second rechallenge for the same AE

Toxicity for which the protocol specifies discontinuation of study drug

Any subject whose benefit-risk profile is not deemed positive by the investigator must
discontinue study drug

During the combination therapy period (through Week 46), if either study drug is 
permanently discontinued, the other study drug should also be permanently discontinued 
End of Treatment (EOT) assessments as specified in Appendix 2 will be performed when a 
subject permanently discontinues both BI 836826 and idelalisib. 
Subjects who permanently discontinue study drug for a reason other than disease progression 
should continue with disease assessments per the schedule of procedures until disease 
progression, study participation has ended, or another anticancer or experimental therapy is 
initiated (see Appendix 2).
6.6.2.
Criteria for Discontinuation from Study
Discontinuation from the study may occur in the following instances:

Disease progression

Initiation of non-study specific systemic anti-cancer therapy in the absence of progression

If, in the investigator’s opinion, and in consultation with Gilead Sciences, it is determined not 
to be in the subject’s best interest to continue.

Pregnancy begins during the study

Death

Discontinuation of the study at the request of Gilead, a regulatory agency, or an 
institutional review board or independent ethics committee (IRB/IEC) occurs


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
Withdrawal of consent

Subject is lost to follow-up
If a subject discontinues the study for reasons other than withdrawal of full consent, lost to 
follow-up, or death, the subject will complete a 30-Day Follow-up/End of Study visit (see
Section 6.7).  Note that pregnancies are monitored until the conclusion of the pregnancy even 
after discontinuation from the study (see Section 7.7.2.1).
6.7.
30-Day Follow-up/End of Study Visit
A 30-Day Follow-up/End of Study assessment will be performed 30 days following the last dose 
of BI 836826 (no later than Week 50) 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.
6.8.
Unscheduled Visits
Unscheduled visits may occur at any time while the subject is enrolled on study. Vital signs, 
laboratory assessments, ECG, physical examination, radiographic assessments, and bone marrow
aspiration/biopsy may be conducted at these visits. Data relevant to the study generated during 
an unscheduled visit will be collected on the eCRF.


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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
7.1.1.
Adverse Events
An AE is any untoward medical occurrence in a clinical study subject administered a medicinal 
product, 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, lack of efficacy, overdose, drug abuse/misuse reports, or occupational 
exposure. 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:

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 (e.g., hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 7.7.1)

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 an 
AE. It is considered to be pre-existing and should be documented on the medical history 
eCRF.
7.1.2.
Serious Adverse Events
An 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.)

In-patient hospitalization or prolongation of existing hospitalization


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
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 1 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. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements.
7.1.2.1.
Protocol-Specific Serious Adverse Event Instructions
The following events related to the disease under study, if assessed as unrelated to study drug,
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 investigational medicinal product (IMP)(s) caused or 
contributed to the disease progression (i.e., by a means other than lack of effect). Unrelated 
disease progression should be captured on the eCRF.
These events will be reported, as appropriate, in the final clinical study report and in any relevant 
aggregate safety reports.
7.1.3.
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 7.1.1 and 7.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (eg, anemia), not the 
laboratory result (ie, decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 7.5.


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7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to each 
study drug independently, 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)
7.2.2.
Assessment of Severity
The severity of AEs will be graded using the CTCAE, Version 4.03 in study manual and 
available at 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf
For each episode, the highest severity grade attained should be reported.
If a CTCAE criterion does not exist, the investigator should use the grade or adjectives: Grade 1 
(mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or Grade 5 (fatal) to 
describe the maximum intensity of the AE. For purposes of consistency with the CTCAE, these 
intensity grades are defined in Table 7-1.


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Table 7-1.
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.
The distinction between the seriousness and the severity of an AE should be noted. Severe is a 
measure of intensity; thus, a severe reaction is not necessarily a serious reaction. 
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead
7.3.1.
Requirements for Collection Prior to Study Drug Initiation
After the subject has signed the informed consent form, but prior to initiation of study 
medication, the following types of events should be reported on the eCRF:

All SAEs, and AEs related to protocol-mandated procedures
7.3.2.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 30 days after last administration of idelalisib or BI 836826 (whichever is discontinued last), 
and report in the eCRF database as instructed.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol defined follow up 
period.
7.3.3.
Serious Adverse Events
All SAEs, regardless of cause or relationship, which 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) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed after informed 
consent is signed.




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7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA 
Code of Federal Regulations (CFR), 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 IRB/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 IB 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.
7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (eg, clinical chemistry, hematology, coagulation, and urinalysis) that require 
medical or surgical intervention or lead to study drug interruption or discontinuation must be 
recorded as an AE, as well as an SAE, if applicable. If the laboratory abnormality is part of a 
syndrome, record the syndrome or diagnosis (eg, anemia) not the laboratory result 
(ie, decreased hemoglobin).
Severity should be recorded and graded according to the CTCAE Version 4.03.
For AEs associated with laboratory abnormalities, the event should be graded on the basis of the 
clinical severity in the context of the underlying conditions; this may or may not be in agreement 
with the grading of the laboratory abnormality.
7.6.
Toxicity Management
Please refer to the current IBs for idelalisib and BI 836826 for information related to toxicity 
management. See Section 5.6 for additional information related to recommended dose 
modifications associated with toxicities.


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7.7.
Special Situations Reports
7.7.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, and pregnancy reports regardless of an 
associated AE. 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 are also considered special situation reports.

A pregnancy report form is used to report any pregnancy in female subjects and 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 and 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).

Product complaint is defined as complaints arising from potential deviations in the 
manufacture, packaging, or distribution of the medicinal product.
7.7.2.
Instructions for Reporting Special Situations
7.7.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study medication and throughout the study, including the post study drug follow-up 
period, to Gilead DSPH 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.


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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 will be reported as described in 
Sections 7.1.1 and 7.1.2. Furthermore, any SAE occurring as an adverse pregnancy outcome post 
study must be reported to Gilead DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead DSPH 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. Gilead DSPH contact information is as follows: 
Email:
 or Fax: 
 
Pregnancies of female partners of male study subjects exposed to idelalisib or BI 836826 must 
also be reported and relevant information should be submitted to Gilead DSPH 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: 
 or Fax:
.
Refer to Appendix 5 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.7.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead DSPH within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study drug and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead concomitant medications does not need to be reported on 
the special situation report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE eCRF. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to the CRF/eCRF completion guidelines for full instructions on the mechanism of special 
situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE CRF/eCRF and/or the SAE report form. Details of the symptoms 
and signs, clinical management, and outcome will be reported, when available.
PPD
PPD
PPD
PPD


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8.
STATISTICAL CONSIDERATIONS
Due to the early study termination, the endpoints will not be met and the subjects enrolled will be 
assessed for safety only. Planned analyses will not be performed and only safety- related 
endpoints will be analyzed and reported for the subjects enrolled in the study.
8.1.
Primary Endpoint
The primary endpoint of the Phase 1b portion of the study is the incidence rate of DLTs during 
the first 7 weeks of study therapy at each combination dose level tested. 
In the Phase 2 portion of the study, the primary endpoints are CRR and MRD negativity rate in 
bone marrow achieved by Week 50 as defined in Section 3.1.
8.2.
Secondary Endpoint
The secondary endpoint of the Phase 1b portion of the study is description of any DLTs, SAEs, 
and AEs leading to discontinuation of study treatment. 
The secondary endpoints of the Phase 2 portion of the study include ORR, DCR, DOR, PFS, OS, 
MRD negativity rate in blood at any time on study, MRD negativity rate in bone marrow at any 
time on study, and safety profile of the combined study drugs. 
8.4.
Analysis Conventions
8.4.1.
Analysis Sets
8.4.1.1.
Intent-to-Treat Analysis Set
The Intent-to-Treat (ITT) Analysis Set will include all subjects who received at least 1 dose of 
any study drug (Phase 1b) or who were randomized (Phase 2). Treatment group for the Phase 2 
portion of the study will be designated according to randomization regardless of whether any 
study drug is administered. This analysis set will be used for the analysis of efficacy endpoints.
8.4.1.2.
Safety Analysis Set
The Safety Analysis Set will consist of all subjects receiving at least 1 dose of any study drug, 
with treatment group designated according to the actual treatment received. This analysis set will 
be used in the analyses of safety endpoints and study treatment exposure.
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8.7.1.
Primary Analysis
In the Phase 2 portion of the study, complete response rate and MRD negativity rate in bone 
marrow by Week 50 will be calculated along with its 95% CIs based on exact method. In the 
analyses of CRR and MRD negativity rate, subjects who do not have sufficient on-study tumor 
assessment to characterize response will be counted in the denominator.
8.7.2.
Secondary Analyses
ORR will be calculated along with its 95% CIs based on exact method. In the analyses of ORR, 
subjects who do not have sufficient on-study tumor assessment to characterize response will be 
counted in the denominator.
For the analyses of DCR, DOR, PFS and OS, the Kaplan-Meier method will be used. For the 
DCR, DOR and PFS analyses, subjects who withdraw from the study or are lost to follow-up 
without disease progression or death will be censored on the date of the last visit that lack of 
disease progression was documented. Subjects who start a new antitumor treatment other than 
study treatment before disease progression will be censored on the last visit that lack of disease 
progression was objectively documented before the start of new antitumor treatment. 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. Subjects without any adequate post-baseline disease assessment 
will be censored on the date of first study dose (Phase 1b) and date of randomization (Phase 2).
8.8.
Safety Analysis
Due to study termination, the endpoints will not be met and the subjects enrolled will be assessed 
for safety. Planned analyses will not be performed and only safety related endpoints will be 
analyzed and reported for the subjects remaining in the study.
8.8.1.
Phase 1b Portion of the Study Only
Five-parameter BLRM will be used with overdose control (Appendix 6). Dose recommendation 
will be based on the posterior distribution of DLT in the highRP2D Analysis Set. The highRP2D 
will be determined by the SRT based on an assessment of the aggregate safety and PK data, and 
the highRP2D as the identified by the BLRM.
8.8.2.
Extent of Exposure
A subject’s extent of exposure to idelalisib and BI 836826 will be generated from the study drug 
administration data. Exposure data and study drug compliance will be summarized based on 
safety analysis set.
Idelalisib compliance will be described in terms of the amount actually taken based on returned 
pill count relative to the amount that was dispensed (taking into account physician-prescribed 
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BI 836826 compliance will be described in terms of the number of doses actually administered 
relative to the expected number of doses planned, and as the cumulative dose of BI actually 
administered relative to the planned cumulative dose.
8.8.3.
Adverse Events
All AEs will be listed. The focus of AE summarization will be on treatment-emergent adverse 
events (TEAEs). A TEAE is defined as an AE that occurs or worsens in the period from the first 
dose of study treatment (idelalisib, BI 836826) to 30 days after the last dose of study treatment.
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). System 
Organ Class (SOC), High-Level Group Term (HLGT), High-Level Term (HLT), Preferred Term
(PT), and Lower-Level Term (LLT) will be attached to the clinical database. 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 for a specific type of AE, the grade corresponding to the 
appropriate adjective will be used by the investigator to describe the maximum intensity of the 
AE: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life threatening), or 
Grade 5 (fatal). The relationship of the AE to the study drug will be categorized as related or 
unrelated. 
Summaries (number and percentage of subjects) of treatment-emergent AEs (by SOC and PT) 
will be provided. A subject who reports multiple treatment-emergent AEs within the same PT
(or SOC) is counted only once for that PT (or SOC) using the worst severity grade. AE 
descriptions will be presented by decreasing frequency for a given SOC and PT.
Following summaries (number and percentage of subjects) of TEAEs will be provided:

All AEs

AEs related to study drug

AEs that are Grade ≥ 3 in severity

AEs leading to study drug modification (interruption/reduction)

AEs leading to study drug discontinuation

AEs leading to death

SAEs

IRRs and related symptoms
8.8.4.
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, 






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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
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 Harmonisation (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 Practice Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of GCP, as outlined in 
21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators,” 21 CFR, part 50, 1998, 
and 21 CFR, part 56, 1998.
The investigator and all applicable subinvestigators will comply with 21 CFR, Part 54, 1998, 
providing documentation of their financial interest or arrangements with Gilead, or proprietary 
interests in the investigational drug under study. This documentation must be provided prior to 
the investigator’s (and any subinvestigator’s) participation in the study. The investigator and 
subinvestigator agree to notify Gilead of any change in reportable interests during the study and 
for 1 year following completion of the study. Study completion is defined as the date when the 
last subject completes the protocol-defined activities.
9.1.2.
Institutional Review Board/Independent Ethics Committee Review and 
Approval
The 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 (for studies conducted in the United States) or IEC (for studies 
conducted outside of the United States). 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 any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/IEC approval, with the exception of those necessary to 
reduce immediate risk to study subjects.
9.1.3.
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 EC-approved consent form for documenting 


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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 
conducting the consent discussion, and also by an impartial witness if required by IRB/IEC or 
local requirements. The consent form will inform subjects about pharmacogenomic testing and 
sample retention, and their right to receive clinically relevant pharmacogenomic analysis results.
9.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, another 
unique identifier (as allowed by local law) and an identification code will be recorded on any 
form or biological sample submitted to the Sponsor, IRB/IEC, or laboratory. Laboratory 
specimens must be labeled in such a way as to protect subject identity while allowing the results 
to be recorded to the proper subject. Refer to specific laboratory instructions. NOTE: The 
investigator must keep a Screening log showing codes, names, and addresses for all subjects 
screened and for all subjects enrolled in the trial. Subject data will be processed in accordance 
with all applicable regulations.
The investigator agrees that all information received from Gilead, including but not limited to the 
investigator brochure, this protocol, CRF, the IMP, and any other study information, remain the 
sole and exclusive property of Gilead 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. 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.
9.1.5.
Study Files and Retention of Records
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 two 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, 
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 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, ie, history, PE, and confirmation of 
diagnosis (to support inclusion and exclusion criteria)

Documentation of the reason(s) a consented subject is not enrolled


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
Participation in study (including study number)

Study discussed and date of informed consent

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 IMP, including dates of dispensing and return

Record of all adverse events and other safety parameters (start and end date, and including 
causality and severity)

Concomitant medication (including start and end date, dose if relevant; dose changes)

Date of study completion and reason for early discontinuation, if it occurs
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region (ie, United States, Europe, or Japan) and until there are no pending or planned 
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 
specified by regulatory requirements, by local regulations, or by an agreement with Gilead. The 
investigator must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site.
9.1.6.
Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. Subsequent to 
data entry, a study monitor will perform source data verification within the electronic data 
capture (EDC) system. Original entries as well as any changes to data fields will be stored in the 
audit trail of the system. Prior to database lock (or any interim time points as described in the 
clinical data management plan), the investigator will use his/her log in credentials to confirm that 
the forms have been reviewed, and that the entries accurately reflect the information in the 


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source documents. The eCRF capture the data required per the protocol schedule of events and 
procedures. System-generated or manual queries will be issued to the investigative site staff as 
data discrepancies are identified by the monitor or internal Gilead staff, who routinely review the 
data for completeness, correctness, and consistency. The site coordinator is responsible for 
responding to the queries in a timely manner, within the system, either by confirming the data as 
correct or updating the original entry, and providing the reason for the update (e.g. data entry 
error). At the conclusion of the trial, Gilead will provide the site with a read-only archive copy of
the data entered by that site. This archive must be stored in accordance with the records retention 
requirements outlined in Section 9.1.5.
9.1.7.
Investigational Medicinal Product Accountability and Return
The study monitor will evaluate each study center’s IMP disposal procedures and provide 
appropriate instruction for destruction of unused IMP supplies. If the site has an appropriate 
standard operating procedure (SOP) for drug destruction as determined by Gilead QA, the site 
may destroy used (empty or partially empty) and unused IMP supplies in accordance with that
site’s approved SOP. A copy of the site’s approved SOP will be obtained for central files. 
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the IMP. Upon study completion, copies of the 
IMP accountability records must be filed at the site. Another copy will be returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRB/IEC, or to regulatory authority or health authority 
inspectors.
9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB/IEC in 
accordance with local requirements and receive documented IRB/IEC approval before 
modifications can be implemented.


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9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency(ies). Gilead 
will ensure that the report meets the standards set out in the ICH Guideline for Structure and 
Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in 
certain cases.
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:

The results of the study in their entirety have been publicly disclosed by or with the consent 
of Gilead in an abstract, manuscript, or presentation form or the study has been completed at 
all study sites for at least 2 years.

The investigator will submit to Gilead any proposed publication or presentation along with 
the respective scientific journal or presentation forum at least 30 days before submission of 
the publication or presentation. 

No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).

The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, e.g. attendance at Investigator's Meetings.  If required under the applicable statutory 
and regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.
9.3.2.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
eCRF.
The monitor is responsible for routine review of the eCRF 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 eCRF. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected through any type of monitoring (central, on site) are resolved.


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9.3.3.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead 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 medical monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.
9.3.4.
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 authority(ies), IRBs, and IECs. In terminating the study, Gilead and the investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.


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10.
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Robak T, Dmoszynska A, Solal-Celigny P, Warzocha K, Loscertales J, Catalano J, et al. 
Rituximab plus fludarabine and cyclophosphamide prolongs progression-free 
survival compared with fludarabine and cyclophosphamide alone in previously 
treated chronic lymphocytic leukemia. J Clin Oncol 2010;28 (10):1756-65.


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Sant M, Allemani C, Tereanu C, De Angelis R, Capocaccia R, Visser O, et al. Incidence of 
hematologic malignancies in Europe by morphologic subtype: results of the 
HAEMACARE project. Blood 2010;116 (19):3724-34.
Schuurman HJ, van Baarlen J, Huppes W, Lam BW, Verdonck LF, van Unnik JA. 
Immunophenotyping of non-Hodgkin's lymphoma. Lack of correlation between 
immunophenotype and cell morphology. Am J Pathol 1987;129 (1):140-51.
Schwartz-Albiez R, Dorken B, Hofmann W, Moldenhauer G. The B cell-associated CD37 
antigen (gp40-52). Structure and subcellular expression of an extensively 
glycosylated glycoprotein. J Immunol 1988;140 (3):905-14.
Smith JL, Jones DB, Bell AJ, Wright DH. Correlation between histology and immunophenotype 
in a series of 322 cases of non-Hodgkin's lymphoma. Hematol Oncol 1989;7 
(1):37-48.
Stephens DM, Beckwith K, Cheney CM, Mo X, Flynn JM, Jones JA, et al. BI 836826, a Novel 
Fc-engineered Antibody in Combination with PI3K Inhibitor for Treatment of 
High-Risk Chronic Lymphocytic Leukemia [Poster]. ASH Annual Meeting; 2014 
December 5-8; Orlando, FL. 
Surveillance Epidemiology and End Results (SEER) Program. SEER Stat Fact Sheets: Chronic 
Lymphocytic Leukemia. Available at: 
http://seer.cancer.gov/statfacts/html/clyl.html. Accessed 12 May 2011.
van Spriel AB, Puls KL, Sofi M, Pouniotis D, Hochrein H, Orinska Z, et al. A regulatory role for 
CD37 in T cell proliferation. J Immunol 2004;172 (5):2953-61.
van Spriel AB, Sofi M, Gartlan KH, van der Schaaf A, Verschueren I, Torensma R, et al. The 
tetraspanin protein CD37 regulates IgA responses and anti-fungal immunity. 
PLoS pathogens 2009;5 (3):e1000338.
Vanhaesebroeck B, Ali K, Bilancio A, Geering B, Foukas LC. Signalling by PI3K isoforms: 
insights from gene-targeted mice. Trends Biochem Sci 2005;30 (4):194-204.
Zenz T, Volden M, Mast T, Nordhausen K, Winkler D, Schnaiter A, et al. Exceptional In Vitro 
Activity of CD37 Antibodies In CLL [Abstract 2460]. ASH Annual Meeting; 
2010 December 4-7; Orlando, FL. 


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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Tables
Appendix 3.
ECOG Performance Status Scoring System
Appendix 4.
Modified International Workshop on Chronic Lymphocytic Leukemia Criteria for 
Response Assessment
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 6.
Bayesian Logistic Regression Model










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Appendix Table 2.
PK and Anti-Drug Antibody Sampling
With the implementation of Amendment 4, PK samples are no longer being collected and 
subjects are past Week 16.
Study 
Day
Study 
Week
BI 836826 PK
ADA analysis
Idelalisib PK
8
2
Before start of BI 836826 
drug infusion
Before start of BI 836826  
drug infusion
Within 30 min prior to 
idelalisib dose
Shortly before end of 
infusion
1.5 hr after idelalisib dose
9
2
Before start of BI 836826 
drug infusion
Shortly before end of 
infusion
15
3
Before start of BI 836826 
drug infusion
Shortly before end of 
infusion
22
4
Before start of BI 836826 
drug infusion
Within 30 min prior to 
idelalisib dose
Shortly before end of 
infusion
1.5 hr after idelalisib dose
8-10 hr after start of drug 
infusion
23
23-25 hr after start of drug 
infusion
[25-27]
72-120 hr after start of drug 
infusion
36 to 
106
6 through 
16
Before start of BI 836826 
drug infusion
Weeks 6, 10, and 14
Before start of BI 836826  
drug infusion
Weeks 6 and 14: within 
30 min prior to, and 1.5 hr 
after idelalisib dose
Shortly before end of 
infusion (Weeks 6, 10, and 
14 only)
120
18
Before start of BI 836826  
drug infusion
176 to 
316
26 through 
46
Weeks 26, 34, and 42
Before start of BI 836826  
drug infusion
344
30d follow 
up/EOS
At any time during the visit


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Appendix 3.
ECOG Performance Status Scoring System
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities.
Up and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead


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Appendix 4.
Modified International Workshop on Chronic Lymphocytic 
Leukemia Criteria for Response Assessment
The determination of CLL response and progression will be based on standardized 
International Workshop on CLL (IWCLL) criteria {Hallek 2008}, as specifically modified for 
this study to reflect current recommendations which consider the study design and mechanism of 
action of idelalisib and similar drugs {Cheson 2012}.
1.1.
Identification and Follow-up of Lesions and Organomegaly
CT/MRI scans are no longer required as of Amendment 4. The following guidelines are 
recommendations for local imaging studies, if done. 
1.1.1.
Index Lesions
For subjects entering the study with lymphadenopathy, 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. The 
cross-sectional dimensions (the largest cross-sectional diameter, ie, the longest diameter (LD) × 
the longest perpendicular diameter (LPD) will be recorded for each index lesion. The product of 
the perpendicular diameters (PPD) for each index lesion and the shortest perpendicular diameter 
(SPD) for all index lesions will be calculated and recorded. The baseline SPD will be used as 
references by which objective disease 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 cm and all PPDs and SPDs 
will be reported in cm2.
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.
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 1 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.
A new node that measures > 1.5 cm in the LD and > 1.0 cm in the LPD will be considered PD.
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.


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If lesions merge, a boundary between the lesions may 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.
1.1.2.
Spleen and Liver
Both the spleen and liver will be assessed by CT/MRI scan at baseline and at the stipulated 
intervals during the study. 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 the study. 
The spleen will be considered enlarged if it is > 12 cm in LVD {Asghar 2011, Bezerra 2005}, 
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). The amount of 
enlargement of a spleen with LVD > 12 cm is equal to the LVD minus 12 cm. For subjects with 
splenomegaly at baseline evaluations of the spleen will consider only changes relative to the 
amount of enlargement at baseline. Splenic progression will be based on increase from the nadir 
measurement, or 12 cm if the nadir is ≤ 12 cm. 
A 50% decrease (minimum 2 cm decrease) from baseline in the enlargement of the spleen or 
decrease in LVD to 12 cm by imaging is required for declaration of a splenomegaly response. 
Conversely, an increase in splenic enlargement by 50% from nadir (minimum increase of 
2 cm) is required for declaration of splenic progression; the spleen must be at least 14 cm in 
LVD to assess splenic progression.  
The liver will be considered enlarged if it is > 18 cm in LVD {Erturk 2006}, with the LVD being 
obtained by multiplying the number of sections on which the liver is visualized by the thickness 
of the sections (eg, if the liver is seen in 36 contiguous cross-sectional images with 0.5-cm 
thickness, the LVD is recorded as 18 cm). The amount of enlargement of a liver with LVD 
> 18 cm is equal to the LVD minus 18 cm. 
A 50% decrease (minimum 2 cm decrease) from baseline in the enlargement of the liver or 
decrease in LVD to 18 cm by imaging is required for declaration of a hepatomegaly response. 
Conversely, an increase in liver enlargement by 50% from nadir (minimum increase of 2 cm)
is required for declaration of hepatic progression; the liver must be at least 20 cm in LVD to 
assess hepatic progression.
1.1.3.
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.


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The presence or absence of non-index disease should be recorded at baseline and at the stipulated 
intervals during the study. 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 disease response during 
treatment. Measurements are not required and these lesions should be followed as “present”, 
“progressed” or “absent”.
1.2.
Definitions of Disease Response and Progression
Responses will be categorized by the IRC as CR, CR with incomplete marrow recovery (CRi), 
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 no evidence of tumor 
either at baseline or on the study.
The best OR will be determined. The best OR is the best response recorded from the start of 
treatment until progressive disease/recurrence (taking as reference for PD the smallest 
measurements recorded since treatment started). Subjects with NE or ND will be included in the 
denominator in the analyses of disease response. 
1.2.1.
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 × 109/L

Regression of all index nodal masses 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 × 109/L without need for exogenous growth factors (eg, G-CSF)
Platelet count 100 × 109/L without need for exogenous growth factors or transfusions
Hemoglobin 110 g/L (11.0 g/dL) without red blood cell transfusions or need for 
exogenous growth factors (eg, erythropoietin)


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1.2.2
Partial Response
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 a CRi.1.2.2. Partial 
Response
To satisfy criteria for a PR, all of the following criteria must be met:

No evidence of new disease

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:
a) ANC > 1.5 × 109/L or 50% increase over baseline without need for exogenous growth 
factors (eg, G-CSF)
b) Platelet count 100 x 109/L or 50% increase over baseline without need for exogenous 
growth factors or transfusions
c) 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)

Change in disease status meeting the following criteria:
Phase 1b:

Subjects entering the study with baseline lymphocytosis, but without lymphadenopathy, 
hepatomegaly, or splenomegaly:
A decrease in peripheral blood ALC by 50% from baseline or a decrease to < 4 × 109/L.

Subjects entering the study with baseline lymphocytosis AND ONLY ONE of the following 
additional abnormal baseline findings: baseline lymphadenopathy OR baseline hepatomegaly 
OR baseline splenomegaly:
In a subject with baseline lymphadenopathy, 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 Appendix 4 Section 1.1.2
In a subject with enlargement of the liver at baseline, a hepatomegaly response as defined 
in Appendix 4 Section 1.1.2
WITH OR WITHOUT a decrease in peripheral blood ALC by 50% from baseline or a 
decrease to < 4 × 109/L.


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
Subjects entering the study with baseline lymphocytosis and AT LEAST TWO of the 
following additional abnormal baseline findings: baseline lymphadenopathy OR baseline 
hepatomegaly OR baseline splenomegaly:
Response demonstrated in AT LEAST TWO of the same additional abnormal baseline 
findings
OR response demonstrated in ONE of the same additional abnormal baseline findings AND 
a decrease in peripheral blood ALC by 50% from baseline or a decrease to < 4 × 109/L
Phase 2:

Subjects entering the study with at least one lymph node with LD ≥20 mm and LPD of 
≥10 mm at baseline:
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 × 109/L), a decrease in peripheral 
blood ALC by 50% from baseline or a decrease to < 4 × 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 Appendix 4 Section 1.1.2.
■
In a subject with enlargement of the liver at baseline, a hepatomegaly response as 
defined in Appendix 4 Section 1.1.2
■
A decrease by 50% from baseline in the CLL marrow infiltrate or in B-lymphoid 
nodules

Subjects entering the study without lymphadenopathy but with quantifiable CLL in bone
marrow at baseline:
Change in disease status meeting 2 of the following criteria, with 2 exceptions in which 
only 1 criterion is needed: (1) Only quantifiable CLL in bone marrow is present at 
baseline; (2) Only quantifiable CLL in bone marrow and lymphocytosis are present at
baseline. In these 2 cases, only quantifiable CLL in bone marrow must improve to the 
extent specified below:
■
In a subject with baseline lymphocytosis (ALC 4 × 109/L), a decrease in peripheral 
blood ALC by 50% from baseline or a decrease to < 4 × 109/L
■
In a subject with enlargement of the spleen at baseline, a splenomegaly response as 
defined in Appendix 4 Section 1.1.2.


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■
In a subject with enlargement of the liver at baseline, a hepatomegaly response as 
defined in Appendix 4 Section 1.1.2
■
A decrease by 50% from baseline in the CLL marrow infiltrate or in B-lymphoid 
nodules
1.2.3.
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
1.2.4.
Definitive Progressive Disease
The occurrence of any of the following events indicates definitive PD: 

Evidence of any new disease:
a) A new node that measures >1.5 cm in the LD and >1.0 cm in the LPD
b) New or recurrent splenomegaly, with a minimum LVD of 14 cm
c) New or recurrent hepatomegaly, with a minimum LVD of 20 cm
d) Unequivocal reappearance of an extra-nodal lesion that had resolved  
e) A new unequivocal extra-nodal lesion of any size
f)
New non-index disease (eg, effusions, ascites, or other organ abnormalities related to 
CLL)
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: 
a) Increase from the nadir by 50% in the SPD of index lesions
b) Increase from the nadir by 50% in the LD if an individual node that now has an 
LD of >1.5 cm and an LPD of > 1.0 cm
c) 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)
d) Hepatic progression defined as an increase in hepatic enlargement by 50% from nadir 
(with a minimum 2 cm increase and minimum LVD of 20 cm)


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e) Unequivocal increase in the size of non-index disease (eg, effusions, ascites, or other 
organ abnormalities related to CLL)
f)
Transformation to a more aggressive histology (eg, Richter syndrome) as established by 
lymph node biopsy 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). 

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:
a) The current platelet count is < 100 × 109/L and there has been a decrease by > 50% from 
the highest on-study platelet count 
b) 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

At any time greater than 4 weeks after the discontinuation of idelalisib: an increase in the 
number of blood lymphocytes by 50% or more with at least 5000 B lymphocytes per 
microliter as measured from the nadir during that time period.
1.2.5.
Non-Evaluable and No Disease
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).
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.
No Disease Subjects have a status of ND if all of the following conditions occur: 

No index disease noted at baseline or on-the study

No non-index disease noted at baseline or on-the study

No enlargement of the liver or spleen at baseline or on-the study

No abnormalities of peripheral blood counts (elevated ALC or abnormally low ANC, 
platelet count, or hemoglobin) and no evidence of CLL in bone marrow (if available) at 
baseline or on the study


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1.3.
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, 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 
treatment as described in Protocol Section 6.


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Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Definitions
a. Definition of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential 
following the initiation of puberty (Tanner stage 2) until becoming post-menopausal, unless 
permanently sterile or with medically documented ovarian failure.  
Women are considered to be in a postmenopausal state when they are > 54 years of age with 
cessation of previously occurring menses for > 12 months without an alternative cause.  In 
addition, women of any age with amenorrhea of > 12 months may also be considered 
postmenopausal if their follicle stimulating hormone (FSH) level is in the postmenopausal range 
and they are not using hormonal contraception or hormonal replacement therapy.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.
b. Definition of Male Fertility
For the purposes of this study, a male born subject is considered of fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
2) Contraception Requirements for Female Subjects
a. Study Drug Effects on Pregnancy and Hormonal Contraception
Idelalisib is contraindicated in pregnancy as a malformation effect has been 
demonstrated/suspected or is unknown, taking into consideration class effects, genotoxic 
potential, or a strong suspicion of human teratogenicity/fetotoxicity in early pregnancy based on 
non-clinical data. Idelalisib has demonstrated/suspected or has insufficient data to exclude the 
possibility of a clinically relevant interaction with hormonal contraception that results in reduced 
contraception efficacy.  Therefore, contraceptive steroids are not recommended as a 
contraceptive method either solely or as a part of a contraceptive regimen. Please refer to the 
latest version of the IB for additional information.
b. Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires the use of highly effective 
contraceptive measures.  They must also not rely on hormone-containing contraceptives as a 
form of birth control during the study.  They must have a negative serum pregnancy test at 
Screening and a negative pregnancy test on the Baseline/Day 1 visit prior to randomization.  
Pregnancy tests will be performed at monthly intervals thereafter.  Female subjects must agree to 
one of the following from the Screening visit throughout the study, and for 30 days from the last 
dose of idelalisib or 12 months from the last dose of BI 836826 (whichever is later). 


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
Complete abstinence from intercourse of reproductive potential.  Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual lifestyle.
Or

Consistent and correct use of 1 of the following methods of birth control listed below. 
Intrauterine device (IUD) with a failure rate of <1% per year
Tubal sterilization
Essure micro-insert system (provided confirmation of success 3 months after procedure)
Vasectomy in the male partner (provided that the partner is the sole sexual partner and 
had confirmation of surgical success 3 months after procedure)
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and for 30 days from the last dose of idelalisib or 12 months from the last dose of BI 836826 
(whichever is later).
3) Contraception Requirements for Male Subjects
It is theoretically possible that a relevant systemic concentration may be achieved in a female 
partner from exposure of the male subject’s seminal fluid.  Therefore, male subjects with female 
partners of childbearing potential must use condoms during treatment and until 90 days 
following the last dose of idelalisib or 12 months from the last dose of BI 836826 (whichever is 
later). Additional contraception recommendations should also be considered if the female partner 
is not pregnant.
Male subjects must also refrain from sperm donation during treatment and until at least 90 days 
following the last dose of idelalisib or 12 months from the last dose of BI 836826 (whichever is 
later). 
Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (eg, calendar, ovulation, 
symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method (LAM).  Female condom and male condom should not be used 
together.
4) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 30 days for females or 90 days for female partners 
of male subjects of last study drug dose. Subjects who become pregnant or who suspect that they 
are pregnant during the study must report the information to the investigator and discontinue 
study drug immediately. Subjects whose partner has become pregnant or suspects she is pregnant 
during the study must report the information to the investigator.  Instructions for reporting 
pregnancy, partner pregnancy, and pregnancy outcome are outlined in Section 7.7.2.1.


,GHODOLVLE
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Idelalisib
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Final
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Amendment 4
CONFIDENTIAL
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15 June 2017
Under dosing: [0.00, 0.20)
Targeted toxicity: [0.20, 0.35)
Excessive toxicity: [0.35, 1.00]
The overdose control criterion is set as the posterior probability of excessive toxicity less than 
25%. The maximum allowable dose increment for the subsequent cohort will be no more than 
100% for each drug. Out of all dose candidates satisfying the overdose control criterion, the dose 
cohort at which the posterior probability for the target toxicity interval is the maximum will be 
chosen for the next dose cohort.
Dose search will continue until one of the following incidences occurs:

Starting dose level is declared to be too toxic.

Maximum number of subjects (N = 36) is reached.

More than 6 subjects have been evaluated at this dose level, posterior probability of targeted 
toxicity exceeds 40% at this dose level, and a minimum of 12 subjects have been treated in 
total at all dose levels. 
1. Planned Dose Levels
The provisional dose levels for idelalisib are 50 mg BID (starting dose), 100 mg BID, and 
150 mg BID, and for BI 836826 are 100 mg (starting dose), 200 mg, and 400 mg. However, dose 
levels for BI 836826 may subsequently be modified to include additional doses through 600 mg, 
dependent on safety data from this study and from Boehringer Ingelheim study 1270.1. 
2. Prior Specification
BLRM model parameters include (α1, β1) for idelalisib, (α2, β2) for BI 836826, and γ for 
interaction between idelalisib and BI 836826.
A bivariate normal prior distribution for (log(α1), log(β1)) will be specified as follows:

The estimated DLT rate at the reference dose (100 mg BID) will be set to 10%.

Doubling the dose level is assumed to double the odds of DLT. 

Variance of log(α1) and log(β1) are set to 2 with correlation of 0 to consider the uncertainty of 
priors.   


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Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
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A bivariate normal prior distribution for (log(α2), log(β2)) corresponding to BI 836826 will be 
specified similarly as follows:

The estimated DLT rate at the reference dose (200 mg BID) will be set to 10%.

Doubling the dose level is assumed to double the odds of DLT. 

Variance of log(α2) and log(β2) are set to 2 with correlation of 0 to consider the uncertainty of 
priors.   
A normal prior will be specified for the interaction parameter γ as follows, in a way that the 
distribution reflects the uncertainty in safety profile by combining idelalisib with BI 836826.

No increase/decrease in odds of DLT is expected by interaction of idelalisib and BI 836826.

Variance of γ is set to 2 to consider the uncertainty of priors.   
In summary, the parameters of the prior distributions for BLRM are provided in 
Appendix Table 3, with the corresponding summaries of prior probability of DLT shown in 
Appendix Table 4. 
Appendix Table 3.
Parameters of the prior distributions 
Parameter
Means
Variances
Correlation
Priors for idelalisib: (log(α1), log(β1))
(-2.197, 0)
(2, 2)
0
Priors for BI 836826: (log(α2), log(β2))
(-2.197, 0)
(2, 2)
0
Prior for interaction: γ
0
2
N/A
Appendix Table 4.
Summary of prior probability of DLT
Dose level
Pr(DLT)
Prior Probability of 
Idelalisib
BI 836826
Median
Excessive
[35%, 100%)
Target
[20%, 35%)
Under
[0%, 20%)
50 mg BID
100 mg
0.111
0.144
0.178
0.678
100 mg BID
100 mg
0.190
0.264
0.217
0.519
150 mg BID
100 mg
0.305
0.460
0.170
0.370
50 mg BID
200 mg
0.181
0.270
0.195
0.535
100 mg BID
200 mg
0.260
0.401
0.174
0.425
150 mg BID
200 mg
0.383
0.527
0.126
0.347
50 mg BID
400 mg
0.346
0.496
0.139
0.365
100 mg BID
400 mg
0.466
0.551
0.092
0.357
150 mg BID
400 mg
0.621
0.592
0.053
0.355


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Amendment 4
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There are safety data available from Study 101-02 in which subjects with previously treated CLL 
received monotherapy idelalisib (Appendix Table 5) and from ongoing Phase 1 dose-escalation 
study 1270.1 in which subjects with R/R CLL received BI 836826 (Appendix Table 6. Assuming 
there is no drug-drug interaction, the predicted DLT probabilities of combination doses are 
summarized in Appendix Table 7. 
The proposed priors have higher probabilities of DLT than the predicted ones using historical 
data at each combination dose level. The study will use more conservative priors for the 
combination therapy.
Appendix Table 5.
Summary of DLTs* from monotherapy idelalisib study
Dose of idelalisib
No of DLTs/No of evaluable subjects
100 mg BID
3/11
150 mg BID
8/52
200 mg BID
3/10
350 mg BID
3/7
* Number of DLTs is retrospectively re-calculated using the definition of DLT in Study GS-US-312-1579
Appendix Table 6.
Summary of DLTs from monotherapy BI 836826 study
Dose of BI 836826
No of DLTs/No of evaluable subjects
1 mg
0/3
3 mg
0/3
9 mg
0/6
25 mg
0/6
50 mg
0/3
100 mg
0/3
200 mg
1/6
400 mg
0/3
800 mg
1/2


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Appendix Table 7.
Summary of DLTs predicted from monotherapy of Idelalisib and 
BI 836826 
Dose level
Pr(DLT)
Idelalisib
BI 836826
Median
50 mg BID
100 mg
0.107
100 mg BID
100 mg
0.169
150 mg BID
100 mg
0.222
50 mg BID
200 mg
0.152
100 mg BID
200 mg
0.211
150 mg BID
200 mg
0.261
50 mg BID
400 mg
0.259
100 mg BID
400 mg
0.311
150 mg BID
400 mg
0.355
3. Operating Characteristics
In order to assess operating characteristics, simulation studies were performed under 2 hypothetical
scenarios. A total of 1000 trials were simulated under each scenario.

Scenario 1: Only lowest dose level is safe

Scenario 2: Only 2 middle dose levels have DLTs in the targeted region
Appendix Table 8.
True underlying probabilities of DLT
Scenario
BI 836826
idelalisib
100 mg
200 mg
400 mg
1
50 mg BID
0.302
0.436
0.525
100 mg BID
0.398
0.466
0.563
150 mg BID
0.428
0.491
0.603
2
50 mg BID
0.092
0.136
0.185
100 mg BID
0.149
0.257
0.322
150 mg BID
0.362
0.411
0.441
* Underlined text indicates doses with true probability of DLT within the target toxicity interval [0.20, 0.35)
* Italicized text indicates doses with true probability of DLT within the target toxicity interval [0.35, 1)


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Simulation parameters
The metrics evaluated to review operating characteristics are:
I.
Proportion of trials that recommend dose levels with true Pr(DLT) in [20%, 35%) as the 
MTD (correct decision)
II. Proportion of trials that recommend dose levels with true Pr(DLT) ≥ 35% as the MTD 
(patient risk)
III. Proportion of trials that recommend dose levels with true Pr(DLT) < 20% as the MTD 
IV. Proportion of trials which stops early because all dose levels are too toxic
V. Average number of subjects evaluated
Results of simulation study
Appendix Table 9 summarizes the operating characteristics of the model for the 2 simulated 
scenarios.
Appendix Table 9.
Simulation results for operating characteristics
Scenario
Metrics
I
II
III
IV
V
1
14.0%
8.9%
NA
77.1%
9
2
44.0%
12.2%
15.4%
28.4%
19
The probability of recommending a correct dose combination (metric I) shows reasonable 
performance of BLRM, with 14.0% for Scenario 1 and 44.0% for Scenario 2. The probability of 
identifying an overly toxic dose combination as MTD (metric II) is low for both scenarios. When 
most dose combinations are set to overly toxic as in Scenario 1, the chance of stopping the study 
with identifying the correct MTD or declaring toxicity of all dose levels is high. 
In conclusion, the simulations illustrate that the model has reasonable operating characteristics.
4. Simulation Trial Conduction
To help understand the algorithm better, we describe a simulated trial conduct of Scenario 2 with 
details on DLT observations, posterior distribution, and dose escalation decisions below. 
Detailed posterior distribution of Pr(DLT) for the candidate combination dose levels are shown 
for cohort 1 and 2 only to illustrate the algorithm of dose selection. Same algorithm is applied for 
other cohorts thus not detailed here.


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Cohort 1: Three patients were treated at the starting dose of idelalisib 50 mg BID + BI 836826
100 mg (50, 100). None of them experienced a DLT. Let Pr(DLT)p represent the posterior 
distribution of Pr(DLT), BLRM provides probabilities of overdose, on target, and underdose for 
each combination dose level. There are 5 dose levels satisfying overdose control criterion as 
listed in the table below. The next dose level to be escalated is (100, 200), which has the highest 
posterior probability for the target toxicity interval out of all the dose candidates.
Dose Level
(idelalisib, BI 836826)
Overdose
Pr(DLT)p ≥35%
On Target
35% >Pr(DLT)p ≥20%
Under Dose
Pr(DLT)p < 20%
100, 200
0.161
0.188
0.651
150, 100
0.221
0.170
0.609
100, 100
0.079
0.158
0.763
50, 200
0.106
0.151
0.743
50, 100
0.031
0.085
0.884
Cohort 2: Three patients were treated at dose level (100, 200), and 1 patient experienced a DLT.
BLRM finds the following dose levels satisfying the overdose criterion, and recommends next 
dose level as (50, 200).
Dose Level
(idelalisib, BI 836826)
Overdose
Pr(DLT)p ≥35%
On Target
35% >Pr(DLT)p ≥20%
Under Dose
Pr(DLT)p < 20%
50, 200
0.146
0.245
0.609
100, 100
0.182
0.226
0.592
50, 100
0.047
0.123
0.830
Cohort 3: Three more patients were treated at dose level (50, 200), and no patient experienced a 
DLT. BLRM recommends dose escalation to (100, 200).
Cohort 4: One DLT was observed in 3 patients treated at dose level (100, 200). BLRM 
recommends staying at dose level (100, 200).
Cohort 5: No patient experienced DLT, and BLRM recommends dose escalation to (150, 200)
Cohort 6: One DLT was observed, and BLRM recommends dose de-escalation to (100, 200).
Cohort 7: Two DLTs were observed. The algorithm stops as it satisfies the stopping rule. The 
MTD is claimed as (100, 200).


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Amendment 4
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Appendix Table 10. Simulated Trial of Scenario 2
Cohort
Dose Level (idelalisib, BI 836826)
DLT/ Number of Patients
1
50, 100
0/3
2
100, 200
1/3
3
50, 200
0/3
4
100, 200
1/3
5
100, 200
0/3
6
150, 200
1/3
7
100, 200
2/3
There are safety data available from Study 101-02 in which subjects with previously treated CLL 
received monotherapy idelalisib (Appendix Table 11) and from ongoing Phase 1 dose-escalation 
study 1270.1 in which subjects with R/R CLL received BI 836826 (Appendix Table 12). 
Assuming there is no drug-drug interaction, the predicted DLT probabilities of combination 
doses are summarized in Appendix Table 13. 
The proposed priors have higher probabilities of DLT than the predicted ones using historical 
data at each combination dose level, which means more conservative priors are used for the 
combination therapy.
Appendix Table 11. Summary of DLTs* from monotherapy idelalisib study
Dose of idelalisib
No of DLTs/No of evaluable subjects
100 mg BID
3/11
150 mg BID
8/52
200 mg BID
3/10
350 mg BID
3/7
* Number of DLTs is retrospectively re-calculated using the definition of DLT in Study GS-US-312-1579


Idelalisib
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Final
Gilead Sciences, Inc.
Amendment 4
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Appendix Table 12. Summary of DLTs from monotherapy BI 836826 study
Dose of BI 836826
No of DLTs/No of evaluable subjects
1 mg
0/3
3 mg
0/3
9 mg
0/6
25 mg
0/6
50 mg
0/3
100 mg
0/3
200 mg
1/6
400 mg
0/3
800 mg
1/2
Appendix Table 13. Summary of DLTs predicted from monotherapy of Idelalisib and 
BI 836826 
Dose level
Pr(DLT)
Idelalisib
BI 836826
Median
50 mg BID
100 mg
0.107
100 mg BID
100 mg
0.169
150 mg BID
100 mg
0.222
50 mg BID
200 mg
0.152
100 mg BID
200 mg
0.211
150 mg BID
200 mg
0.261
50 mg BID
400 mg
0.259
100 mg BID
400 mg
0.311
150 mg BID
400 mg
0.355
50 mg BID
800 mg
0.459
100 mg BID
800 mg
0.497
150 mg BID
800 mg
0.529

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 1b/2 Study of Idelalisib in Combination with BI 836826
in Subjects with Chronic Lymphocytic Leukemia
Name of Test Drug:
Idelalisib
Study Number:
GS-US-312-1579
Protocol Version (Date):
Amendment 4 (15 June 2017)
Analysis Type:
Final Analysis
Analysis Plan Version:
1.0
Analysis Plan Date:
28 November 2017
Analysis Plan Author(s):
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
(fJ GILEAU 


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Statistical Analysis Plan – Final Analysis 
Version 1.0
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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF ABBREVIATIONS........................................................................................................................................4
1.
INTRODUCTION ................................................................................................................................................6
1.1.
Study Objectives ......................................................................................................................................6
1.2.
Study Design............................................................................................................................................6
1.3.
Sample Size and Power............................................................................................................................7
2.
TYPE OF PLANNED ANALYSIS ......................................................................................................................8
2.1.
Interim Analyses ......................................................................................................................................8
2.2.
Final Analysis ..........................................................................................................................................8
2.3.
Follow-up Analysis ..................................................................................................................................8
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES..............................................................................9
3.1.
Analysis Sets............................................................................................................................................9
3.1.1.
Safety Analysis Set.................................................................................................................9
3.2.
Subject Grouping .....................................................................................................................................9
3.3.
Strata and Covariates................................................................................................................................9
3.4.
Examination of Subject Subgroups..........................................................................................................9
3.5.
Multiple Comparisons..............................................................................................................................9
3.6.
Missing Data and Outliers........................................................................................................................9
3.6.1.
Missing Data ..........................................................................................................................9
3.6.2.
Outliers.................................................................................................................................10
3.7.
Data Handling Conventions and Transformations .................................................................................10
3.8.
Analysis Visit Windows.........................................................................................................................10
3.8.1.
Definition of Study Day .......................................................................................................10
3.8.2.
Analysis Visit Windows.......................................................................................................10
4.
SUBJECT DISPOSITION ..................................................................................................................................11
4.1.
Subject Enrollment and Disposition.......................................................................................................11
4.2.
Extent of Study Drug Exposure and Adherence.....................................................................................11
4.2.1.
Duration of Exposure to Study Drug....................................................................................11
4.3.
Protocol Deviations................................................................................................................................11
5.
BASELINE CHARACTERISTICS....................................................................................................................12
5.1.
Demographics ........................................................................................................................................12
5.2.
Other Baseline Characteristics ...............................................................................................................12
5.3.
Medical History......................................................................................................................................12
5.4.
Prior Anticancer Therapy.......................................................................................................................12
6.
EFFICACY ANALYSES ...................................................................................................................................13
6.1.
Primary Efficacy Endpoint.....................................................................................................................13
6.2.
Secondary Efficacy Endpoints ...............................................................................................................13
6.3.
Exploratory Efficacy Endpoints.............................................................................................................13
7.
SAFETY ANALYSES........................................................................................................................................14
7.1.
Adverse Events and Deaths....................................................................................................................14
7.1.1.
Adverse Event Dictionary ....................................................................................................14
7.1.2.
Adverse Event Severity........................................................................................................14
7.1.3.
Relationship of Adverse Events to Study Drug....................................................................14
7.1.4.
Serious Adverse Events........................................................................................................14


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7.1.5.
Treatment-Emergent Adverse Events...................................................................................14
7.1.6.
Summaries of Adverse Events and Deaths...........................................................................15
7.2.
Laboratory Evaluations ..........................................................................................................................15
7.2.1.
Graded Laboratory Values ...................................................................................................16
7.2.2.
Liver-related Laboratory Evaluations...................................................................................16
7.3.
Body Weight , Height, and Vital Signs..................................................................................................16
7.4.
Prior and Concomitant Medications.......................................................................................................16
7.4.1.
Prior Medications .................................................................................................................17
7.4.2.
Concomitant Medications.....................................................................................................17
7.5.
Electrocardiogram Results .....................................................................................................................17
7.5.1.
QT Intervals..........................................................................................................................17
7.5.2.
PR and QRS Intervals...........................................................................................................17
7.6.
Other Safety Measures ...........................................................................................................................18
7.7.
Changes From Protocol-Specified Safety Analyses...............................................................................18
8.
PHARMACOKINETIC (PK) ANALYSES........................................................................................................19
8.1.
PK Sample Collection............................................................................................................................19
8.2.
PK Analyses Related to Intensive PK Sampling....................................................................................19
8.3.
PK Analyses Related to Sparse PK Sampling........................................................................................19
9.
REFERENCES ...................................................................................................................................................20
10.
SOFTWARE.......................................................................................................................................................21
11.
SAP REVISION..................................................................................................................................................22
12.
APPENDICES ....................................................................................................................................................23
Appendix 1.
Schedule of Assessments........................................................................................................23


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LIST OF ABBREVIATIONS
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BID
twice daily
BLQ
below the limit of quantitation
BLRM
Bayesian logistic regression analysis
BMI
body mass index
CLL
chronic lymphocytic leukemia
CR
complete response
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
DCR
duration of complete response
DLT
dose limiting toxicity
DMC
data monitoring committee
DOR
duration of response
DSPH
Drug Safety and Public Health
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
highRP2D
high recommended Phase 2 dose
HLGT
high-level group term
HLT
high-level term
IV
intravenous
LLT
lower-level term
LOQ
limit of quantitation
lowRP2D
low recommended Phase 2 dose
MedDRA
Medical Dictionary for Regulatory Activities
MRD
minimal residual disease
n
number of subjects
ORR
overall response rate
OS
overall survival
PFS
progression-free survival
PT
preferred term
Q1, Q3
first quartile, third quartile
QRS
electrocardiographic deflection between the beginning of the Q wave and termination of 
the S wave representing time for ventricular depolarization


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QT
electrocardiographic interval between the beginning of the Q wave and termination of the 
T wave representing the time for both ventricular depolarization and repolarization to 
occur
R/R
relapsed/refractory
SAE
serious adverse event
SAP
statistical analysis plan
SE
standard error
SOC
system organ class
SRT
Safety Review Team
StD
standard deviation
TEAE
treatment-emergent adverse event
TFLs
tables, figures, and listings
ULN
upper limit of normal


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1.
INTRODUCTION
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) in the clinical study report (CSR) 
for Study GS-US-312-1579. This SAP is based on the study protocol amendment 4 dated 
15 June 2017 and the electronic case report form (eCRF). The SAP will be finalized before 
database finalization. Any changes made after the finalization of the SAP will be documented in 
the CSR.
This study has been terminated. Enrollment to this study was closed on 26 April 2017 based on 
an updated feasibility assessment in relation to changes in the chronic lymphocytic leukemia  
(CLL) treatment landscape. Two subjects were enrolled in the Phase 1b portion of the study and 
no subjects were enrolled in the Phase 2 portion of the study.
1.1.
Study Objectives
The primary objectives of this study are as follows:

Phase 1b: To determine the safety and tolerability of the combination of idelalisib with
BI 836826 in subjects with relapsed and refractory (R/R) CLL, and to establish the high
recommended Phase 2 combination dose (highRP2D) as well as an alternate lower 
recommended Phase 2 combination dose (lowRP2D) regimen.

Phase 2: To determine the rates of complete response (CR) and of minimal residual disease 
(MRD) negativity with the combination at the highRP2D and the lowRP2D.
The secondary objectives of this study are as follows:

Phase 1b and 2: To evaluate overall response rate (ORR), progression-free survival (PFS), 
duration of complete response (DCR), duration of response (DOR), and overall survival 
(OS).

Phase 2: To further characterize the safety and tolerability of the combination using the 
highRP2D as well as the lowRP2D regimen.
Due to the early study termination, the study objectives will not be met and the 2 subjects that 
were enrolled will be assessed for safety only.
1.2.
Study Design
The Phase 1b portion of the study will evaluate various dose combinations of idelalisib and 
BI 836826 in sequential cohorts following an initial 7-day idelalisib monotherapy run-in period. 
The safety data from each cohort will be used as input into the bayesian logistic regression model 
(BLRM). The output from this model will be used by the safety review team (SRT) to choose the 
dose combination for evaluation in the subsequent cohort. At completion of Phase 1b, 2 dose 


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combinations will be selected for fmi her evaluation in Phase 2. In the Phase 2 po1iion of the 
study, subjects with R/R CLL will be randomly assigned in a 1: 1 manner to receive 1 of the 
2 dose combinations selected from Phase l b following an initial 7-day idelalisib monotherapy 
nm-in period. 
Approximately 42 evaluable subjects will be enrolled in the Phase 1 b po1iion of the study and 
50 evaluable subjects will be randomized in the Phase 2 portion of the study. 
Idelalisib tablets will be administered orally twice daily (BID) continuously until disease 
progression or intolerable toxicity. During the Phase 1 b po1iion of the study, the following dose 
levels will be tested: 50 mg BID, 100 mg BID, and 150 mg BID; the staiiing dose level will be 
50 mg BID. BI 836826 will be administered as a rate-controlled intravenous (IV) infusion, with a 
total of 18 doses, from Week 2 through Week 46. During the Phase lb po1iion of the study, the 
staiiing dose level will be 100 mg, and the highest possible dose tested will be 600 mg. 
In both Phase lb and Phase 2, idelalisib will be administered staiiing on Week 1, Day 1. 
Following 7 days of idelalisib, BI 836826 administration will strut during Week 2 with an initial 
dose of 10 mg on Day 8; 50% of the assigned dose will be given on Days 9 and 15, and 100% of 
the assigned dose will be given on Day 22. Thereafter, 100% of the assigned dose will be 
administered eve1y 2 weeks through Week 18, and eve1y 4 weeks through Week 46. 
Dosing Schema: 
idelalisib 
BID continuous starting Day 1 
The schedule of assessments is in Appendix 1 of this SAP. 
100% 
Day 22 
Q2 wk through Wk18 
Q4 wk through Wk46 
Following enrollment of 2 subjects in the Phase 1 b po1iion of the study, the study was tenninated 
and therefore, Phase 2 will not occur. Subjects may remain on study through approximately 
Week 50 (to include 30-day follow up after last dose of BI 836826). Study procedures have been 
modified accordingly. 
1.3. 
Sample Size and Power 
There is no fo1mal hypothesis to be tested in this study; therefore, no fo1mal sample size 
calculation was perfonned. 
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2.
TYPE OF PLANNED ANALYSIS
2.1.
Interim Analyses
This study does not have a data monitoring committee (DMC). Therefore, no analyses will be 
conducted for the DMC.
2.2.
Final Analysis
After all subjects have completed the study, outstanding data queries have been resolved or 
adjudicated as unresolvable, and the data have been cleaned and finalized, the final analysis of 
the data will be performed.
2.3.
Follow-up Analysis
Not applicable


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
By-subject listings will be presented for all subjects in the Safety Analysis Set and sorted by 
subject identification (ID) number, visit date, and time (if applicable). Data collected on log 
forms, such as adverse events (AEs), will be presented in chronological order within the subject. 
The dose cohort to which subjects were initially assigned will be used in the listings. Age, sex at 
birth, race, and ethnicity will be included in the listings.
Due to the early study termination, planned analyses will not be performed and only 
safety-related endpoints will be reported for the subjects enrolled in the study.
3.1.
Analysis Sets
Analysis sets define the subjects to be included in an analysis. Analysis sets and their definitions 
are provided in this section. The analysis set will be identified and included as a subtitle of each 
table, figure, and listing.
3.1.1.
Safety Analysis Set
The Safety Analysis Set includes all subjects who took at least 1 dose of study drug. This is the 
primary analysis set for safety analyses.
3.2.
Subject Grouping
Not Applicable
3.3.
Strata and Covariates
This study does not use a stratified randomization schedule when enrolling subjects. 
No covariates will be included in safety analyses.
3.4.
Examination of Subject Subgroups
There are no prespecified subject subgroupings for safety analyses.
3.5.
Multiple Comparisons
Adjustments for multiplicity will not be made, because no formal statistical testing will be 
performed in this study.
3.6.
Missing Data and Outliers
3.6.1.
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified.


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3.6.2.
Outliers
All data will be included in the data analysis.
3.7.
Data Handling Conventions and Transformations
In general, age (in years) on the first dosing date of study drug will be used for analyses and 
presentation in listings. For screen failures, the date the informed consent was signed will be 
used for age calculation. If only the birth year is collected on the eCRF, “01 July” will be used 
for the unknown birth day and month for the purpose of age calculation. If only birth year and 
month are collected, “01” will be used for the unknown birth day.
3.8.
Analysis Visit Windows
3.8.1.
Definition of Study Day
Study day will be calculated from the first dosing date of study drug and derived as follows:

For postdose study days: Assessment Date – First Dosing Date + 1

For days prior to the first dose: Assessment Date – First Dosing Date
Therefore, study day 1 is the day of first dose of study drug administration.
3.8.2.
Analysis Visit Windows
The nominal visit as recorded on the eCRF will be used.


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
The following by-subject listings will be provided by subject ID number in ascending order:

Reasons for premature study drug or study discontinuation

Reasons for screen failure will be provided by screening ID number in ascending order

Lot number and kit ID
4.2.
Extent of Study Drug Exposure and Adherence
Extent of exposure to study drug will be examined by assessing the total duration of exposure to 
study drug.
4.2.1.
Duration of Exposure to Study Drug
Total duration of exposure to idelalisib will be defined as last dosing date minus first dosing date 
plus 1, regardless of any temporary interruptions in idelalisib administration, and will be 
expressed in days. If the last idelalisib dosing date is missing, the latest date among the study 
drug end date, clinical visit date, laboratory sample collection date, and vital signs assessment 
date that occurred during the on-treatment period will be used.
A by-subject listing of study drug administration will be provided for both idelalisib and 
BI 836826 by subject ID number (in ascending order) and visit (in chronological order).
4.3.
Protocol Deviations 
Protocol deviations occurring after subjects entered the study are documented during routine 
monitoring. A by-subject listing will be provided for those subjects with an important protocol 
deviation.


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5.
BASELINE CHARACTERISTICS  
5.1.
Demographics
A by-subject demographic listing, including age, sex, race, ethnicity, and the informed consent 
date, will be provided by subject ID number in ascending order.
5.2.
Other Baseline Characteristics
Other baseline characteristics include body weight (in kg), height (in cm), body mass index 
(BMI; in kg/m2), and Eastern Cooperative Oncology Group (ECOG) performance status at 
screening.
A by-subject listing of other baseline characteristics will be provided by subject ID number in 
ascending order.
5.3.
Medical History
General medical history data collected at screening will be listed only. Medical history data will 
not be coded. A by-subject listing of general and disease-specific medical history will be 
provided by subject ID number in ascending order.
Time since CLL diagnosis (years) will be calculated by (first dosing date of study drug – date of 
CLL diagnosis). In deriving the time since CLL diagnosis, all partial dates of diagnosis will be 
identified, and the partial dates will be imputed as follows:

If both the day and month are missing but the year is available, then the imputed day and 
month will be 01 Jan.

If only the day is missing but the month and year are available, then the imputed day will be 
the first day of the month.

If the year is missing, a partial date will not be imputed.
5.4.
Prior Anticancer Therapy
The regimens and prior therapies that the subjects received and time since the completion of last 
regimen will be listed based on the Safety Analysis Set. A partial completion date will be 
imputed using the following algorithm for the last regimen:

If both the day and month are missing but the 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 the 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 the year is missing, no imputation will be done and the completion date will be treated as 
missing.
Prior radiation therapy and prior surgery/procedure will be listed.


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6.
EFFICACY ANALYSES
This study was terminated in Phase 1b based on an updated feasibility assessment in relation to 
changes in the CLL treatment landscape. Since only 2 subjects were enrolled at the time of study 
termination, efficacy endpoints will not be evaluated and available data will only be listed. 
6.1.
Primary Efficacy Endpoint
Not applicable
6.2.
Secondary Efficacy Endpoints
Not applicable
6.3.
Exploratory Efficacy Endpoints
Not applicable


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7.
SAFETY ANALYSES
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Clinical and laboratory AEs will be coded using the current version of Medical Dictionary for 
Regulatory Activities (MedDRA). System organ class (SOC), high-level group term (HLGT), 
high-level term (HLT), preferred term (PT), and lower-level term (LLT) will be provided in the 
AE dataset.
7.1.2.
Adverse Event Severity
Adverse events are graded by the investigator as Grade 1, 2, 3, 4, or 5 according to Common 
Toxicity Criteria for Adverse Events (CTCAE) Version 4.03. The severity grade of events for 
which the investigator did not record severity will be categorized as “missing” for data listings.
7.1.3.
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator selected “Related” on the AE eCRF to the 
question of “Related to Study Treatment.” Relatedness will always default to the investigator’s
choice, not that of the medical monitor. Events for which the investigator did not record 
relationship to study drug will be shown as missing in by-subject data listings.
7.1.4.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if the AEs met the 
definitions of SAEs that were specified in the study protocol. SAEs captured and stored in the 
clinical database will be reconciled with the SAE database from the Gilead Drug Safety and 
Public Health (DSPH) Department before data finalization.
7.1.5.
Treatment-Emergent Adverse Events
7.1.5.1.
Definition of Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) are defined as 1 or both of the following:

Any AEs with an onset date on or after the study drug start date and no later than 30 days 
after permanent discontinuation of study drug

Any AEs leading to premature discontinuation of study drug.


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7.1.5.2.
Incomplete Dates
If the onset date of the AE is incomplete and the AE stop date is not prior to the first dosing date 
of study drug, then the month and year (or year alone if month is not recorded) of onset 
determine whether an AE is treatment emergent. The event is considered treatment emergent if 
both of the following 2 criteria are met:

The AE onset is the same as or after the month and year (or year) of the first dosing date of 
study drug, and

The AE onset date is the same as or before the month and year (or year) of the date 
corresponding to 30 days after the date of the last dose of study drug 
An AE with completely missing onset and stop dates, or with the onset date missing and a stop 
date later than the first dosing date of study drug, will be considered to be treatment emergent. In 
addition, an AE with the onset date missing and incomplete stop date with the same or later 
month and year (or year alone if month is not recorded) as the first dosing date of study drug will 
be considered treatment emergent.
If the AE onset date is incomplete and needs to be imputed, the following algorithm will be 
followed:

If the 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.

If the 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.
7.1.6.
Summaries of Adverse Events and Deaths
All AEs and SAEs will be listed based on the Safety Analysis Set.
7.2.
Laboratory Evaluations
By-subject listings of laboratory data will be provided by subject ID number and time point in 
chronological order for hematology, serum chemistry, and urinalysis separately based on the 
Safety Analysis Set. When values are below the LOQ, they will be listed as such, and hemolized 
test results will be included. Values falling outside of the relevant reference range and/or having 
a severity grade of 1 or higher on the CTCAE severity grade will be flagged in the data listings, 
as appropriate.
A baseline laboratory value will be defined as the last measurement obtained on or prior to the 
date/time of first dose of study drug. 


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7.2.1.
Graded Laboratory Values
CTCAE Version 4.03 will be used to assign toxicity grades (0 to 4) to laboratory results for 
analysis. Grade 0 includes all values that do not meet the criteria for an abnormality of at least 
Grade 1. For laboratory tests with criteria for both increased and decreased levels, analyses for 
each direction (ie, increased, decreased) will be presented separately. 
7.2.1.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from baseline at any postbaseline time point, up to and including the date of last 
dose of study drug plus 30 days for subjects who permanently discontinued study drug. If the 
relevant baseline laboratory value is missing, any abnormality of at least Grade 1 observed 
within the time frame specified above will be considered treatment emergent.
7.2.2.
Liver-related Laboratory Evaluations
Liver-related abnormalities after initial study drug dosing will be examined using the following 
laboratory test values for postbaseline measurements:

AST: > 3 times of the upper limit of reference range (ULN)

ALT: > 3 x ULN

Total bilirubin: (a) > 1.5 x ULN; (b) > 2 x ULN

ALP > 1.5 x ULN

ALP < 2 x ULN and total bilirubin > 2 x ULN
The listing will include laboratory data from all postbaseline visits up to 30 days after the last 
dose of study drug. For individual laboratory tests, subjects will be counted once based on the 
most severe postbaseline values. For the composite endpoint, subjects will be counted once when 
the criteria are met at the same postbaseline visit date. 
7.3.
Body Weight , Height, and Vital Signs
A by-subject listing of vital signs will be provided by subject ID number and time point in 
chronological order. Body weight, height, and BMI will be included in the vital signs listing, if 
space permits. If not, they will be provided separately.
7.4.
Prior and Concomitant Medications
Medications collected at screening and during the study will be coded using the current version 
of the World Health Organization Drug dictionary.


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7.4.1.
Prior Medications
Prior medications are defined as any medications taken before a subject took the first study drug.
For the purposes of analysis, any medication with a start date prior to the first dosing date of 
study drug will be included in the prior medication summary regardless of when the stop date is. 
If a partial start date is entered, the medication will be considered prior unless the month and 
year (if day is missing) or year (if day and month are missing) of the start date are after the first 
dosing date. 
7.4.2.
Concomitant Medications
For the purposes of analysis, any medications with a start date prior to or on the first dosing date 
of study drug and continued to be taken after the first dosing date, or started after the first dosing 
date but prior to or on the last dosing date of study drug will be considered concomitant 
medications. Medications started and stopped on the same day as the first dosing date or the last 
dosing date of study drug will also be considered concomitant. Medications with a stop date prior 
to the date of first dosing date of study drug or a start date after the last dosing date of study drug 
will be excluded from the concomitant medication summary. If a partial stop date is entered, any 
medication with the month and year (if day is missing) or year (if day and month are missing) 
prior to the date of first study drug administration will be excluded from the concomitant 
medication summary. If a partial start date is entered, any medication with the month and year 
(if day is missing) or year (if day and month are missing) after the study drug stop date will be 
excluded from the concomitant medication summary. Medications with completely missing start 
and stop dates will be considered as a concomitant medication.
All prior and concomitant medications (other than per-protocol study drugs) will be provided in a 
by-subject listing sorted by subject ID number and administration date in chronological order.
7.5.
Electrocardiogram Results
A by-subject listing for electrocardiogram (ECG) data and assessment results will be provided by 
subject ID number and time point in chronological order.
7.5.1.
QT Intervals
The QT interval (measured in millisecond [msec]) is a measure of the time between the start of 
the Q wave and the end of the T wave in the heart’s electrical cycle. The QT interval represents 
electrical depolarization and repolarization of the ventricles. 
7.5.2.
PR and QRS Intervals
The PR interval (measured in msec) is a measure of the time between the start of the P wave 
(the onset of atrial depolarization) and the beginning of the QRS complex (the onset of 
ventricular depolarization). The QRS interval measures the duration of the QRS complex. 


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7.6.
Other Safety Measures
Since only 2 subjects were enrolled at time of study termination, the dose limiting toxicity (DLT)
will not be evaluated.
7.7.
Changes From Protocol-Specified Safety Analyses
Due to the early study termination, only safety-related endpoints will be listed for the subjects 
enrolled in the study.


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8.
PHARMACOKINETIC (PK) ANALYSES
8.1.
PK Sample Collection
This study was terminated in Phase 1b based on an updated feasibility assessment in relation to 
changes in the CLL treatment landscape. Since only 2 subjects were enrolled at the time of study 
termination, PK samples will not be evaluated. 
8.2.
PK Analyses Related to Intensive PK Sampling
Not Applicable
8.3.
PK Analyses Related to Sparse PK Sampling
Not Applicable


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REFERENCES


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10.
SOFTWARE
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA.


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11.
SAP REVISION
Revision Date
(DD MMM YYYY)
Section
Summary of Revision
Reason for Revision


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12. 
APPENDICES 
Appendix 1. 
Schedule of Assessments 
Appendix Table 1. 
Study Procedures Table 
Shaded columns indicate laborato1y draws only occur on these days 
= 
"' "' 
Version 1.0 
Visit 
... 
Idelalisib Run-in and Combination Treatment through Week 18 
,,: 
Week 
-4 
1 
2 
2 
2 
3 
4 
5 
6 
7 
8 
9 
10 
12 
14 
16 
18 
Study Day 
-28 
1 
8 
9 
15 
22 
36 
50 
64 
78 
92 
106 
120 
Visit Window 
NA 
± 1 day 
± 3 days 
Info1med Consent 
X 
Medical Histo1y 
X 
Medication Histo1y 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG Pe1fon11ance Status 
X 
12-lead ECG 
X 
Chemistiy & Hematology 1 
X 
X 
X 
X 
XXX 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
X 
Urinalysis 
X 
X 
HBV, CMV, HCV, HIV 
X 
Screening 
CMV monitoring 2 
X 
X 
X 
X 
X 
X 
2 microglobulin 
X 
lnimune monitoring (CD4)3 
X 
X 
X 
ADA testing 
4 
X 
X 
X 
X 
X 
Investigator Assessment 
X 
X 
Idelalisib & PJP Prophylaxis 
X 
X 
X 
X 
X 
X 
Dispensing 
Idelalisib Accountability 
X 
X 
X 
X 
Idelalisib Administi-ation 6 
- - - - - - -- - --- - - - -
BI 836826 Administi·ation 7 
10mg 50% 
50% 100% 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ALL FOOTNOTES APPEAR AT END OF PART 2 
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30-Day 
Follow-up 
Visit 
Combination Treatment and Post- Combination Treatment 
End of Study8 
Week 
20 
22 
24 
26 
30 
34 
38 
42 
46 
Study Day 
134 
148 
162 
176 
204 
232 
260 
288 
316 
Visit Window 
± 3 days 
±7 days 
Info1med Consent 
Medical Histo1y 
Medication Histo1y 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
12-lead ECG 
X 
X 
Chemistiy & Hematology 1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
Urinalysis 
X 
X 
CMV monitoring 2 
X 
X 
X 
X 
X 
X 
X 
X 
2 microglobulin 
lnimune monitoring (CD4) 3 
X 
X 
X 
X 
ADA testing 
4 
X 
X 
X 
X 
-------------------------------
Investigator Assessment 
X 
X 
X 
Idelalisib & PJP Prophylaxis 
X 
X 
X 
X 
X 
X 
X 
Dispensing 
Idelalisib Accountability 
X 
X 
X 
X 
X 
X 
X 
Idelalisib Administi-ation 6 
---+ 
---+ 
---+ 
---+ 
---+ 
---+ 
---+ 
BI 836826 Administi·ation 7 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistiy & hematology will be obtained a minimum of 3 times in the first week following completion of the 
first 50% dose of BI 836826 on Day 9; and once after the first foll dose of BI 836826 on Day 22, then a minimum of weekly 
x 6 weeks, then prior to each BI 836826 infusion. All subjects should have blood counts monitored at least eve1y two weeks 
for the first 6 months of idelalisib treatment. For subjects who develop ANC 0.5 to< 1.0 Gi/L, blood counts should be 
monitored at least weekly 
2 
CMV surveillance for active disease must be conducted approximately eve1y 4 weeks throughout the cotu·se of idelalisib 
ti·eatment. 
3 
Samples for immune monitoring were drawn at Baseline prior to the first dose of idelalisib. With the implementation of 
Amendment 4, only CD4 will be collected at the time points specified. 
4 
With the implementation of Amendment 4, PK and biomarker samples are no longer being collected and subjects are past 
Week 16. Samples for BI 836826 anti-dmg antibody testing will be drawn at the time points indicated. For additional 
info1mation see the protocol Appendix Table 2 PK and Anti-Dmg Antibody Sampling and the Laborato1y Manual. 
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Idelalisib 
GS-US-312-1579 
Statistical Analysis Plan - Final Analysis 
r 
Version 1.0 
6 
I e a 1s1 1s ta en BID; on BI 836826 dose days the moming dose is taken in the clinic apprnximately 60 minutes prior to 
sta1ting the BI 836826 infusion 
7 
BI 836826 given via IV infusion at the indicated time points, beginning with IO mg and ramping up thrnugh 50% to 100% 
of the intended dose over 4 weeks 
8 
The 30-day Follow-up assessment will be done following last dose of BI 836826 (no later than Week 50). 
CONFIDENTIAL 
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