Conditions: Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma
Keywords: Phase 3 CLL/SLL Pi3K
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 319
Healthy volunteers: no

Brief summary:
A Phase 3 clinical trial to examine the efficacy of duvelisib monotherapy versus ofatumumab monotherapy in subjects with relapsed or refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL).

Detailed description:
This is an open-label, two- arm, randomized phase 3, superiority trial designed to evaluate the efficacy and safety of duvelisib compared to ofatumumab administered to patients who have been diagnosed with CLL/SLL whose disease is relapsed or refractory.

Approximately 150 subjects will receive a starting dose of 25 mg duvelisib BID initially over the course of 21-day treatment cycle followed by 28-day treatment cycles for up to 18 cycles or until disease progression or unacceptable toxicity (whichever comes first). After 18 complete cycles of treatment, subjects may receive additional cycles of duvelisib until disease progression or unacceptable toxicity if they, in the judgment of the Investigator, may derive benefit from continued treatment, and if the subject meets the criteria for additional treatment at Cycle 19 Day 1.

Approximately 150 subjects will receive a starting dose of 300 mg ofatumumab on Day 1 followed by seven weekly doses of 2000 mg. Thereafter, subjects will receive 2000 mg ofatumumab once every month for four months. Administration of ofatumumab will not exceed the 12 doses (within 7 cycles).

Arms:
arm 1: Duvelisib is administered orally and supplied as 5 mg and 25 mg formulated capsules. arm 2: Ofatumumab is administered as an intravenous (IV) infusion and is supplied in single-use vials at two strengths, 100 mg/5 mL and 1000 mg/50 mL.

Interventions: intervention 1: Duvelisib intervention 2: Ofatumumab
Intervention descriptions: intervention 1: PI3K Inhibitor intervention 2: monoclonal antibody

Protocol document:
Prot_001.pdf: 
Protocol IPI-145-07 
 
Verastem, Inc. 
Duvelisib (IPI-145) 
09 February 2017 (Amendment 3) 
CONFIDENTIAL 
Page 1 of 110 
 
 
STUDY PROTOCOL 
IPI-145-07 
Not for Distribution – Do Not Copy 
This study protocol contains confidential information and is the proprietary property of Verastem, Inc. The 
protocol is for use by the Principal Investigator and his/her designated representatives participating in this 
investigational trial. This protocol may not be copied or made available for review by an unauthorized person 
or firm without the prior written authorization of Verastem, Inc. 
Protocol Title: 
A Phase 3 Study of IPI-145 versus Ofatumumab in Patients 
with Relapsed or Refractory Chronic Lymphocytic 
Leukemia/Small Lymphocytic Lymphoma  
 
Protocol Number: 
 
IPI-145-07 
 
Phase: 
 
IND Number: 
 
EudraCT: 
Phase 3 
 
112,486  
 
2013-002405-61 
 
Date of Protocol: 
Previous Versions 
Amendment 2: 
Amendment 1: 
Original: 
 
09 February 2017 (Amendment 3) 
 
02 March 2015 
02 April 2014  
21 August 2013 
 
Sponsor: 
 
Verastem, Inc 
117 Kendrick Street, Suite 500 
Needham, MA 02494 


Protocol IPI-145-07 
 
Verastem, Inc. 
Duvelisib (IPI-145) 
09 February 2017 (Amendment 3) 
CONFIDENTIAL 
Page 2 of 110 
INVESTIGATOR PROTOCOL APPROVAL 
A Phase 3 Study of IPI-145 versus Ofatumumab in Patients with Relapsed or Refractory Chronic 
Lymphocytic Leukemia/Small Lymphocytic Lymphoma 
 
I agree to the terms of this study protocol.  I will conduct the study according to the procedures 
specified herein, and according to principles of Good Clinical Practice and local regulations and 
requirements. 
 
Institution/Clinic:  
___________________________________________ 
 
Principal Investigator 
 
Print Name:  ______________________________________ 
 
Signature:  
______________________________________ 
 
Date (mm/dd/yyyy):    ______________________________ 
 
 
 




Protocol IPI-145-07 
 
Verastem, Inc. 
Duvelisib (IPI-145) 
09 February 2017 (Amendment 3) 
CONFIDENTIAL 
Page 4 of 110 
CONTACT INFORMATION 
 
Sponsor: 
Verastem, Inc. 
117 Kendrick Street, Suite 500  
Needham, MA 02494  
 
For urgent study-related questions please call the Medical Monitor at the following number:  
1-877-462-0134  
 
 
 


Protocol IPI-145-07 
 
Verastem, Inc. 
Duvelisib (IPI-145) 
09 February 2017 (Amendment 3) 
CONFIDENTIAL 
Page 5 of 110 
PROTOCOL SYNOPSIS 
 
Study Title: 
A Phase 3 Study of IPI-145 versus Ofatumumab in Patients with 
Relapsed or Refractory Chronic Lymphocytic Leukemia/Small 
Lymphocytic Lymphoma 
Protocol Number: 
IPI-145-07 
Study Phase: 
3 
Investigational Agent: 
Duvelisib (IPI-145) 
Study Objectives: 
Primary Objective: 
• 
To examine the efficacy of duvelisib monotherapy versus 
ofatumumab monotherapy in subjects with relapsed or 
refractory Chronic Lymphocytic Leukemia (CLL) or Small 
Lymphocytic Lymphoma (SLL) 
Secondary Objectives: 
• 
To determine the safety of duvelisib in subjects with CLL or 
SLL 
• 
To evaluate the pharmacokinetics (PK) of duvelisib and, if 
applicable, its metabolite(s) 
Exploratory Objectives: 
• 
To evaluate the health-related quality of life (QoL) of subjects  
• 
To evaluate pharmacodynamic biomarkers of duvelisib  
• 
To evaluate biomarkers that may predict duvelisib clinical 
activity and/or safety 
• 
To evaluate mechanisms of resistance in subjects who exhibit 
disease progression while being treated with duvelisib or 
ofatumumab 
• 
To evaluate genomic features of tumors predictive of response 
in subjects treated with duvelisib or ofatumumab 


Protocol IPI-145-07 
 
Verastem, Inc. 
Duvelisib (IPI-145) 
09 February 2017 (Amendment 3) 
CONFIDENTIAL 
Page 6 of 110 
Study Treatment: 
Treatment Arm A: Duvelisib 
Duvelisib is administered orally and supplied as 5 mg and 25 mg 
formulated capsules.  
Treatment Arm B: Ofatumumab 
Ofatumumab is administered as an intravenous (IV) infusion and is 
supplied in single-use vials at two strengths, 100 mg/5 mL and 
1000 mg/50 mL 
Study Design: 
 
Study IPI-145-07 is a two-arm, randomized (1:1 ratio), open-label, 
phase 3, superiority trial designed to evaluate the efficacy and safety 
of duvelisib compared to ofatumumab. Subjects will be stratified by:  
1. High-risk cytogenetics (presence vs absence of del[17p]) 
2. Refractory/early relapse to purine analog-based therapy 
(defined as progression <12 months after 
fludarabine/pentostatin: yes vs no)  
3. Grade 4 cytopenia(s) (presence vs absence of neutropenia or 
thrombocytopenia at baseline)   
Schedule of Administration Duvelisib (Arm 1) 
Subjects randomized to duvelisib will be given a starting dose of 
duvelisib 25 mg administered orally twice daily (BID) initially in a 21-
day treatment cycle followed by 28-day treatment cycles for up to 
18 cycles or until disease progression or unacceptable toxicity 
(whichever comes first). After 18 complete cycles of treatment, 
subjects may receive additional cycles of duvelisib until disease 
progression or unacceptable toxicity if they, in the judgment of the 
investigator, may derive benefit from continued treatment  
(see Section 4.2.1.2).   
Schedule of Administration Ofatumumab (Arm 2) 
Subjects randomized to ofatumumab will receive treatment consistent 
with the approved product labeling: 8 weekly infusions, starting with 
an initial dose of ofatumumab 300 mg IV on Day 1 followed by seven 
weekly doses of 2000 mg. Thereafter, subjects will receive 
ofatumumab 2000 mg once every month for four months or until 
disease progression or unacceptable toxicity (whichever comes first), 
as outlined in the schedule of assessments. Administration of 
ofatumumab will not exceed the 12 doses (within 7 cycles) as 
described in the prescribing information. 
Disease Response Assessments (All Subjects) 
Disease response assessments will include computed tomography (CT) 
scans, bone marrow biopsy (when indicated), complete blood count 
(CBC) and differential counts, focused physical exams (PE), and 
assessment of disease-related constitutional symptoms. Disease 
Response Assessments will occur at Screening, and Day 1 of Cycles 3, 
5, 7, 11, 15, and 19 for subjects on both treatment arms. After Cycle 


Protocol IPI-145-07 
 
Verastem, Inc. 
Duvelisib (IPI-145) 
09 February 2017 (Amendment 3) 
CONFIDENTIAL 
Page 7 of 110 
19 Day 1, ongoing assessments will be every 6 months for the duration 
of the study or until disease progression, subject withdrawal, or 
initiation of additional anticancer therapy.  
Study Population: 
Approximately 300 subjects with a diagnosis of relapsed and/or 
refractory CLL or SLL will enroll in the study and be randomized 
equally to one of two treatment groups: 
1. Duvelisib 25 mg BID (N=150) 
2. Ofatumumab (N=150) 
Study Duration: 
Study subjects will be followed for survival for up to 6 years from 
randomization.  
It is anticipated that the entire study will accrue subjects over 
approximately 16 months from the randomization of the first subject. 
Study Centers: 
Enrollment is anticipated at approximately 100 sites, with 
approximately 25 sites in the US and 75 sites outside the US. 
Inclusion Criteria: 
Subjects are eligible for inclusion in the study if they meet the 
following criteria: 
1. ≥ 18 years of age  
2. Diagnosis of active CLL or SLL that meets at least one of the 
IWCLL 2008 criteria for requiring treatment (Binet Stage ≥ B 
and/or Rai Stage ≥ I) 
3. Disease that has progressed during or relapsed after at least 
one previous CLL/SLL therapy 
4. Not appropriate for treatment with a purine-based analogue 
regimen (per National Comprehensive Cancer Network 
[NCCN] or European Society for Medical Oncology [ESMO] 
guidelines), including relapse ≤ 36 months from a purine-
based chemoimmunotherapy regimen or relapse ≤ 24 months 
from a purine-based monotherapy regimen 
5. A cytogenetics or fluorescence in situ hybridization (FISH) 
analysis of the leukemic cells within 24 months of 
randomization is required to document the presence or 
absence of del(17p). Note: if a sample from within 24 months 
is not available, it should be evaluated as part of the screening 
laboratory evaluation to inform stratification 
6. Measurable disease with a lymph node or tumor mass 
> 1.5 cm in at least one dimension as assessed by computed 
tomography (CT) 
7. Eastern Cooperative Oncology Group (ECOG) performance 
status of 0 to 2 (corresponds to Karnofsky Performance Status 
[KPS] ≥ 60%) 


Protocol IPI-145-07 
 
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Duvelisib (IPI-145) 
09 February 2017 (Amendment 3) 
CONFIDENTIAL 
Page 8 of 110 
8. Willingness by subject to be randomized to receive either 
ofatumumab or duvelisib at the dose and schedule defined in 
the protocol 
9. Must meet the following laboratory parameters: 
a. Serum aspartate transaminase (AST/SGOT) or alanine 
transaminase (ALT/SGPT) ≤ 3 x upper limit of 
normal (ULN) 
b. Total bilirubin ≤ 1.5 x ULN 
c. Serum creatinine ≤ 2.0 x ULN 
d. Hemoglobin ≥ 8.0 g/dL with or without transfusion 
support 
e. Platelet count ≥ 10,000 µL with or without transfusion 
support 
10. For women of childbearing potential (WCBP): negative serum 
β-human chorionic gonadotropin (βhCG) pregnancy test 
within 1 week before randomization (WCBP defined as a 
sexually mature woman who has not undergone surgical 
sterilization or who has not been naturally post-menopausal 
for at least 24 consecutive months [women ≤ 55 years] or 12 
consecutive months [women > 55 years]) 
11. Willingness of male and female subjects who are not 
surgically sterile or postmenopausal to use medically 
acceptable methods of birth control from the first dose of 
study drug to 30 days after the last dose of duvelisib and for 
12 months after last dose of ofatumumab. Sexually active 
men, and women using oral contraceptive pills, should also 
use barrier contraception 
12. Ability to voluntarily sign consent for and adhere to the entire 
study visit schedule and all protocol requirements 
13. Signed and dated institutional review board (IRB)/independent 
ethics committee (IEC)-approved informed consent form 
(ICF) before any study specific screening procedures are 
performed 
Exclusion Criteria:  
 
Subjects are to be excluded from the study if they meet any of the 
following criteria: 
1. History of Richter's transformation or prolymphocytic 
leukemia 
2. Autoimmune hemolytic anemia (AIHA) or idiopathic 
thrombocytopenic purpura (ITP) that is uncontrolled or 
requiring > 20 mg once daily (QD) of prednisone (or 
equivalent) to maintain hemoglobin > 8.0 g/dL or platelets > 
10,000 µL without transfusion support 


Protocol IPI-145-07 
 
Verastem, Inc. 
Duvelisib (IPI-145) 
09 February 2017 (Amendment 3) 
CONFIDENTIAL 
Page 9 of 110 
3. Refractory to ofatumumab (defined as progression or relapse 
<12 months of receiving ofatumumab monotherapy or < 24 
months of receiving an ofatumumab-containing regimen)  
4. Prior allogeneic transplant (prior autologous stem cell 
transplant >6 months prior to study entry is permitted) 
5. Known central nervous system (CNS) lymphoma or leukemia; 
subjects with symptoms of CNS disease must have a negative 
CT scan or negative diagnostic lumbar puncture prior to 
randomization  
6. Prior exposure to a phosphoinositide-3-kinase (PI3K) inhibitor 
(eg, GS-1101, duvelisib) or a Bruton’s tyrosine kinase (BTK) 
inhibitor 
7. Use of any of the following medications or procedures within 
the specified timeframe: 
− 
Use of live or live attenuated vaccines within 30 days 
prior to randomization  
− 
Chemotherapy, radiation therapy, or ablative therapy 
within 3 weeks of randomization 
− 
Tyrosine kinase inhibitor within 7 days of randomization  
− 
Other investigational therapy (not included above) within 
3 weeks of randomization  
8. Ongoing treatment with chronic immunosuppressants (eg, 
cyclosporine) or systemic steroids > 20 mg prednisone (or 
equivalent) QD 
9. History of tuberculosis treatment within the preceding two 
years 
10. Ongoing systemic bacterial, fungal, or viral infections at the 
time of initiation of study treatment (defined as requiring IV 
antimicrobial, antifungal or antiviral agents) 
− 
Subjects on antimicrobial, antifungal or antiviral 
prophylaxis are not specifically excluded if all other 
inclusion/exclusion criteria are met and there is no 
evidence of active infection at randomization 
11. Human immunodeficiency virus (HIV) infection 
12. Prior, current, or chronic hepatitis B or hepatitis C infection 
13. History of alcohol abuse or chronic liver disease (other than 
metastatic disease to the liver) 
14. Unable to receive prophylactic treatment for pneumocystis or 
herpes simplex virus (HSV) 
15. Baseline QT interval corrected with Fridericia’s method 
(QTcF) > 480 ms (average of triplicate readings) Note: This 


Protocol IPI-145-07 
 
Verastem, Inc. 
Duvelisib (IPI-145) 
09 February 2017 (Amendment 3) 
CONFIDENTIAL 
Page 10 of 110 
criterion does not apply to subjects with a right or left bundle 
branch block (BBB) 
16. Unstable or severe uncontrolled medical condition (eg, 
unstable cardiac function, unstable pulmonary condition), or 
any important medical illness or abnormal laboratory finding 
that would, in the investigator’s judgment, increase the 
subject’s risk while participating in this study 
17. Concurrent active malignancy other than nonmelanoma skin 
cancer or carcinoma in situ of the cervix, bladder, or prostate 
not requiring treatment.  Subjects with previous malignancies 
are eligible provided that they have been disease free for ≥2 
years 
18. History of stroke, unstable angina, myocardial infarction, or 
ventricular arrhythmia requiring medication or mechanical 
control within the last 6 months 
19. Administration of medications or foods that are strong 
inhibitors or inducers of CYP3A within 2 weeks of 
randomization  
20. Prior surgery or gastrointestinal dysfunction that may affect 
drug absorption (eg, gastric bypass surgery, gastrectomy) 
21. Major surgery or invasive intervention within 4 weeks prior to 
randomization 
22. Pregnant or breastfeeding women 
23. Hypersensitivity to ofatumumab or its excipients 
Study Endpoints: 
Primary Endpoint:  
• 
Progression-free survival (PFS), defined as time from 
randomization to the first documentation of progressive 
disease (PD) as determined by independent review or death 
due to any cause  
Secondary Endpoints: 
• 
Overall Response Rate (ORR), with overall response (based 
on independent review) defined as best response of complete 
response/remission (CR), CR with incomplete marrow 
recovery (CRi), partial response/remission (PR), or PR with 
lymphocytosis (PRwL), according to the IWCLL or revised 
IWG Response Criteria, with modification for treatment-
related lymphocytosis 
• 
Lymph node response rate, with lymph node response defined 
as ≥ 50% decrease in the sum of the products (SPD) of target 
lymph nodes  
• 
Overall Survival (OS), defined as time from randomization to 
death 


Protocol IPI-145-07 
 
Verastem, Inc. 
Duvelisib (IPI-145) 
09 February 2017 (Amendment 3) 
CONFIDENTIAL 
Page 11 of 110 
• 
Hematologic improvement rate, with hematologic 
improvement defined as any of following, for at least 60 days 
without transfusion or exogenous growth factors: 
o Neutrophil count > 1,500/µL or an increase ≥ 50% 
from Baseline; or 
o Hemoglobin > 11 g/dL or an increase ≥ 50% from 
Baseline; or  
o Platelet count >100,000/µL or an increase ≥ 50% from 
Baseline  
• 
Duration of Response (DOR), defined as time from the first 
documentation of response to first documentation of PD or 
death due to any cause 
• 
Treatment-emergent adverse events (TEAEs) and changes in 
safety laboratory values  
• 
PK parameters derived from plasma duvelisib concentrations 
and, if applicable, its metabolite(s) 
Exploratory Endpoints: 
• 
Improvement in disease-related symptoms of fatigue, weight 
loss, unexplained fevers and night sweats from Baseline 
• 
Minimal Residual Disease (MRD) in subjects with 
documented CR or CRi 
• 
Health-related QoL of subjects as assessed by the following 
subject-reported questionnaires:  
o EuroQol-5D (EQ-5D) 
o Functional Assessment of Chronic Illness Therapy-
Fatigue (FACIT-F) 
• 
Serum and tissue biomarkers and blood immunophenotype 
• 
Tumor genomic features (eg, DNA sequence variation, DNA 
copy number variation, and/or RNA expression) 
• 
Germline DNA sequence variations 


Protocol IPI-145-07 
 
Verastem, Inc. 
Duvelisib (IPI-145) 
09 February 2017 (Amendment 3) 
CONFIDENTIAL 
Page 12 of 110 
Statistical 
Methodology: 
Sample Size Determination 
The sample size was determined to provide sufficient power to test the 
primary endpoint of PFS in a group sequential design with one 
planned interim analysis. Assuming an exponential distribution for 
PFS, a total number of 185 PFS events (deaths or progressions) will 
provide approximately 93% power to detect a hazard ratio of 0.6 
(median PFS of 9 months in the ofatumumab group vs 15 months in 
the duvelisib group) using a one-sided log-rank test at a 2.5% overall 
significance level (ie, alpha of 0.025). A total of 300 subjects will be 
randomized in a 1:1 ratio to receive either ofatumumab or duvelisib. 
Assuming a peak accrual rate of 30 subjects per month with 11 months 
for accrual ramp-up and a 4% cumulative dropout rate per year, then 
enrollment would complete in 16 months, with the final analysis for 
PFS estimated to occur approximately 27.5 months from the 
randomization of the first subject.   
Analysis Sets 
The Intent-to-Treat (ITT) analysis set will include all subjects who 
were randomized, with treatment group designated according to initial 
randomization. The ITT analysis set will serve as the primary analysis 
set for all efficacy endpoints and demographics.  
The All-Treated (AT) analysis set will include all subjects who 
received any amount of study drug (duvelisib or ofatumumab), with 
treatment group designated according to actual study treatment 
received. The AT analysis set will be the primary analysis set for 
safety endpoints. 
Primary Efficacy Analyses: 
A stratified log-rank test (1-sided) will be used to compare PFS of the 
duvelisib arm against PFS of the ofatumumab arm at the interim and 
final analyses with the overall one-sided significance level controlled 
at 0.025. The nominal p-value required for statistical significance at an 
analysis will be calculated based on the numbers of PFS events at all 
preceding and current analyses. The hazard ratio and the 
corresponding 2-sided 95% confidence interval will be estimated using 
a stratified Cox proportional hazards model. For both the stratified log-
rank test and the stratified Cox model, the strata will be those used for 
stratified randomization, with potential pooling of strata specified in 
the Statistical Analysis Plan (SAP). PFS will be plotted for each 
treatment group using the Kaplan-Meier method. 


Protocol IPI-145-07 
 
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Duvelisib (IPI-145) 
09 February 2017 (Amendment 3) 
CONFIDENTIAL 
 
Page 13 of 110 
Table 1: Screening Assessments Checklist for All Subjects a 
o Informed consent 
o Inclusion/exclusion criteria 
o Medical history & demographics 
o Cancer history 
o Prior Cytogenetics / FISH results b 
o Prior/Concomitant Medications & Procedures 
o Vital signs  
o Physical examination c  
o ECOG Performance status 
o Disease-related symptoms assessment  
o Quality of life (QoL) EQ-5D & FACT-F  
o Electrocardiogram (ECG, 12-lead) c 
o Blood chemistry c 
o Hematology c, d 
o Coagulation tests c  
o Hepatitis, cytomegalovirus (CMV), and Epstein-Barr virus (EBV) 
o HIV e  
o Serum βhCG pregnancy test f  
o CT scans of the chest, abdomen and pelvis g 
o Bone marrow biopsy and/or bone marrow aspiration h 
o Adverse Event (AE)/Serious Adverse Event (SAE) assessment i 
o Randomization j 
a. 
Screening performed ≤ 30 days from dosing (Cycle 1 Day 1). See Section 6 for details on each study assessment. 
b. 
Documentation of prior results within 24 months required for randomization. Can be performed locally during screening.    
c. 
New clinically significant findings after signing informed consent form (ICF) should be captured as an AE.  
d. 
Includes coombs testing (both a direct and indirect). Documentation of hematology labs within 7 days prior to randomization is required to confirm presence or absence 
of Grade 4 cytopenia for stratification at randomization. 
e. 
Subjects without documentation of a prior negative HIV test result (eg, antibody, antigen or PCR-based test) are required to undergo an HIV test during screening. Only 
subjects with a negative HIV result will be randomized. 
f. 
For all women of child bearing potential (WCBP), the screening pregnancy test will be serum and must be performed within 7 days prior to first dose to confirm 
eligibility.  
g. 
Additional scans may be performed (eg, head/neck CT) if clinically indicated or if the area is a site of known disease. Magnetic resonance imaging (MRI) may be 
substituted if clinically indicated, but the modality chosen to evaluate each individual subject should be the same throughout the duration of the study. 
h. 
Bone marrow biopsy and/or aspirate are required at Screening as a baseline for response assessment (unless clinically contraindicated). Sample and corresponding 
pathology report should be sent for biomarker analysis if available. 
i. 
For all subjects AEs should be monitored from time of the signing of the ICF. Any new medical or worsening preexisting conditions arising after signing the ICF will 
be captured as an AE for randomized subjects. SAEs for all subjects will be reported from the signing of the ICF as defined in Section 8.1.3. 
j. 
Dosing should occur within 1 week of randomization after all screening assessments have been obtained and eligibility confirmed.  
 


Protocol IPI-145-07 
 
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Duvelisib (IPI-145) 
09 February 2017 (Amendment 3) 
CONFIDENTIAL 
 
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Table 2: Schedule of Assessments for Subjects Receiving Duvelisib a 
 
Cycle 1 
(21±2 days) o 
Cycle 2 
(28±4 days) o 
Cycles 3 – 
7 
(28±4 
days) o 
Cycle 9-19 
every odd 
cycle  
(28±4 days) o 
> Cycle 19 
every odd 
cycle 
(28±4 days)p 
Early 
Treatment 
Termination 
(ETT) 
from 
Duvelisib q 
Safety 
Follow-up 
 
D1 
D8±2 
D1±2 
D15±
2 
D1±4 
D1±4 
D1±4 
≤7 d from last 
dose 
30+7 d 
from last 
dose  
Concomitant medications & 
Procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE/SAE assessment b  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Focused physical examination  
X 
 
X 
 
X 
X 
X 
X 
 
Blood chemistry  c 
X d 
X 
X 
X 
X 
X 
X 
X 
 
Hematology c 
X d 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation tests c 
X d 
 
 
 
 
 
 
 
 
Serum Immunoglobulins   
X 
 
 
 
X e 
X e 
 
X e 
 
βhCG pregnancy test c, f 
 
 
 
 
X  
X  
X 
X 
 
Blood for Cytogenetics/FISH 
analysis g 
X h, i 
 
 
 
 
 
 
 
 
Blood for IGHV mutation analysis 
g 
X h 
 
 
 
 
 
 
 
 
Blood for Immunophenotyping g, j 
X k 
 
 
 
X e 
X e 
 
X e 
 
Serum for biomarkers g, j 
X k 
 
X 
 
X e 
X e 
 
X e 
 
Blood for biomarkers g 
 
X k  
 
X 
 
X e 
X e 
 
X e 
 
Pharmacogenomics g 
 
X l 
 
 
 
 
 
 
 
 
EQ-5D & FACIT-F  
X d 
  
 
 
X m 
X m 
X m 
X m 
 
ECOG Performance status 
 X d 
See Table 5: Disease Response Assessments 


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09 February 2017 (Amendment 3) 
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a. 
See Section 6.2 and 6.3 for additional information on each assessment. 
b. 
AEs are collected (and SAEs reported) through 30 days post last dose of duvelisib. 
c. 
Additional (unscheduled) assessments should be done as clinically indicated. Blood samples should be drawn and results reviewed within 72 hours of the designated clinic 
visit. 
d. 
Screening evaluations performed within 7 days of Cycle 1 Day 1 can be used and assessments do not need to be repeated at Cycle 1 Day 1 (predose)  
e. 
Drawn only on Day 1 of Cycles 3, 5, 7, 11, 15, 19, and ETT. Blood for immunophenotyping, serum for biomarkers, and blood for biomarkers do not need to be collected 
beyond the ETT visit or treatment discontinuation. 
f. 
May be either urine or serum, and performed every odd cycle while on treatment. 
g. 
To be sent to the central laboratory. 
h. 
Sample may be drawn at screening or Cycle 1 Day 1 (predose). Collection at Cycle 1 Day 1 is preferred. If drawn at screening, a sample is not needed at Cycle 1 Day 1.  
i. 
This sample will be analyzed centrally and is separate from the documentation of prior del(17p) analysis required for eligibility and stratification. 
j. 
Additional blood for immunophenotyping/biomarker serum samples may be requested from any subject receiving duvelisib at qualified sites (when feasible) at the time of a 
drug interruption/hold due to an AE, or for any usual safety event or efficacy event. 
k. 
Samples on Cycle 1 Day 1 should be drawn predose. 
l. 
Pharmacogenomics sample (buccal swab) is optional. 
m. QoL assessments to be captured at on Day 1 of Cycles 3, 5, 7, 11, 15, and 19 until disease progression, subject withdrawal, or initiation of additional anticancer therapy, and 
when possible, at the ETT (if >1 month from last administered questionnaire). 
n. 
Requests for archival tissue (pretreatment sample) should be initiated at Cycle 1 Day 1.  In the event a request is placed but no archival tissue can be located, this sample type 
is not required. 
o. 
Subjects who discontinue treatment from duvelisib prior to Cycle 19 Day 1 for reasons other than PD, will maintain the clinical visit schedule through Cycle 19 Day 1 until 
disease progression, subject withdrawal, or initiation of additional anticancer therapy. 
p. 
Subjects who, in the judgment of the investigator, may derive benefit from continued treatment, may receive additional cycles of duvelisib beyond Cycle 19 Day 1 until 
disease progression or unacceptable toxicity. .  
q. 
The Early Treatment Termination (ETT) Visit should occur for any subject who discontinues duvelisib treatment prior to Cycle 19 Day 1. The ETT assessments need not be 
performed if the subject has had a previous assessment within the previous 2 weeks or previous 30 days for Disease Response Assessments [see Table 5] and the QoL 
assessment.  
 
 
Response assessments 
 
See Table 5: Disease Response Assessments 
Archival tumor tissue  
  X n 
 
Study drug administration  
X 
Continuous Dosing  
 


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09 February 2017 (Amendment 3) 
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Table 3: Pharmacokinetic Assessments for Subjects Receiving Duvelisib Only a 
  
Cycle 2 d 
Cycle 3 
Cycle 7 
Day 1±2 
Day 1±2 
Day 1±2 
Time (h) relative to duvelisib administration 
Predose 
0.5-2h 
3-5h 
Anytime 
Anytime 
Pharmacokinetic blood sample collection b, c 
X 
X  
X 
X  
  X  
a. See Section 6.3.7 for additional information on pharmacokinetic (PK) assessments. 
b. The date and time of the PK samples will be recorded, along with the date and time of the previous two doses of duvelisib. 
c. Additional PK samples may be requested from any subject receiving duvelisib at qualified sites (when feasible) at the time of a drug interruption/hold 
due to an AE, or for any usual safety event or efficacy event.  
d. The morning dose of duvelisib will be administered in the clinic on Cycle 2 Day 1.   
 
 
 


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Duvelisib (IPI-145) 
09 February 2017 (Amendment 3) 
CONFIDENTIAL 
 
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Table 4: 
Schedule of Assessments for Subjects Receiving Ofatumumab a 
 
Cycle 1  
(21±2 days) o 
Cycle 2  
(28±4 days) o 
Cycle 3-7 
(28±4 
days) o 
Early 
Treatment 
Termination 
(ETT) n 
from Ofa  
≤ 7 d from 
last dose 
Safety 
Follow-
up Visit 
30+7d 
from last 
dose 
Clinical 
Assessment 
Period o 
C9-C19 
(28±4 days)  
Day 1±4 
Ofa 
300 mg 
D1 
Ofa 
2000 
mg 
D8±2 
Ofa 
2000 mg 
D15±2 
Ofa 
2000 mg 
D1±2 
Ofa 
2000 mg 
D8±2 
Ofa 
2000 mg 
D15±2 
Ofa 
2000 mg 
D22±2 
Ofa 
2000 mg 
D1±4 
Concomitant Meds & 
Procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE/SAE assessment b  
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
 
Focused physical exam  
X 
 
 
X 
 
 
 
X 
X 
 
X 
Blood chemistry  c  
  X d 
X 
 
X 
 
X 
 
X 
X 
 
X 
Hematology c 
  X d 
X 
 
X 
 
X 
 
X 
X 
 
X 
Coagulation tests c 
  X d 
 
 
 
 
 
 
  
 
 
 
Serum Immunoglobulins   
X 
 
 
 
 
 
 
  X e 
  X e   
 
 X e 
βhCG pregnancy test c, f 
 
 
 
 
 
 
 
X  
X  
 
 
Blood for Cytogenetics 
/FISH analysis g 
     X h, 
i 
 
 
 
 
 
 
 
 
 
 
Blood for IGHV mutation 
analysis g 
 X h 
 
 
 
 
 
 
 
 
 
 
Blood for 
Immunophenotyping g 
  X j 
 
 
 
 
 
 
 X e 
 X e 
 
 X e 
Serum for biomarkers g 
  X j 
 
 
X  
 
 
 
 X e 
 X e 
 
 X e 
Blood for biomarkers g 
  X j 
 
 
X  
 
 
 
 X e 
 X e 
 
 X e 
Pharmacogenomics g 
   X k 
 
 
 
 
 
 
 
 
 
 
EQ-5D & FACIT-F  
  X d 
 
 
 
 
 
 
  X l 
X l 
 
 X l 
ECOG performance status 
  X d 
See Table 5: Disease Response Assessments 
Response assessments 
 
See Table 5: Disease Response Assessments 
Archival tumor tissue  
X m 
 


Protocol IPI-145-07 
 
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09 February 2017 (Amendment 3) 
CONFIDENTIAL 
 
Page 18 of 110 
 
Cycle 1  
(21±2 days) o 
Cycle 2  
(28±4 days) o 
Cycle 3-7 
(28±4 
days) o 
Early 
Treatment 
Termination 
(ETT) n 
from Ofa  
≤ 7 d from 
last dose 
Safety 
Follow-
up Visit 
30+7d 
from last 
dose 
Clinical 
Assessment 
Period o 
C9-C19 
(28±4 days)  
Day 1±4 
Ofa 
300 mg 
D1 
Ofa 
2000 
mg 
D8±2 
Ofa 
2000 mg 
D15±2 
Ofa 
2000 mg 
D1±2 
Ofa 
2000 mg 
D8±2 
Ofa 
2000 mg 
D15±2 
Ofa 
2000 mg 
D22±2 
Ofa 
2000 mg 
D1±4 
Study drug administration  
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
a. 
See Section 6.2 and 6.3 for additional information on each assessment. 
b. 
AEs are collected (and SAEs reported) through 30 days post last dose of ofatumumab.  
c. 
Additional (unscheduled) assessments should be done as clinically indicated. Blood samples should be drawn and results reviewed within 72 hours of the designated clinic 
visit. 
d. 
Screening evaluations performed within 7 days of Cycle 1 Day 1 can be used and assessments don’t need to be repeated at Cycle 1 Day 1 (predose) 
e. 
Drawn at Day 1 of Cycles 3, 5, 7, 11, 15, 19, and ETT. Blood for immunophenotyping, serum for biomarkers, and blood for biomarkers does not need to be collected beyond 
the ETT visit or treatment discontinuation 
f. 
May be either urine or serum, and will be performed every odd cycle while on treatment. 
g. 
To be sent to the central laboratory. 
h. 
This sample may be drawn at screening or Cycle 1 Day 1 (predose). Collection at Cycle 1 Day 1 is preferred. If drawn at screening, a sample is not needed at Cycle 1 Day 1. 
i. 
This sample will be analyzed centrally and is separate from the documentation of prior del(17p) analysis required for eligibility and stratification.  
j. 
Samples on Cycle 1 Day 1 should be drawn predose.   
k. 
Pharmacogenomics sample (buccal swab) is optional. 
l. 
QoL assessments to be captured at on Day 1 of Cycles 3, 5, 7, 11, 15, and 19, until disease progression, subject withdrawal, or initiation of additional anticancer therapy and 
when possible, at the ETT (if >1 month from last administered questionnaire). 
m. Requests for archival tissue (pretreatment sample) should be initiated at Cycle 1 Day 1.  In the event a request is placed but no archival tissue can be located, this sample type 
is not required. 
n. 
The Early Treatment Termination (ETT) Visit should occur for any subject who discontinues ofatumumab treatment prior to Cycle 7 Day 1. ETT assessments need not be 
performed for those assessments performed within the previous 2 weeks (previous 30 days for Disease Response Assessments [see Table 5] and the QoL assessment).  
o. 
The clinical visit schedule should be maintained until Cycle 9 for subjects who discontinue study treatment prior to Cycle 9 for reasons other than PD. The clinical assessment 
period then begins at Cycle 9, with visits occurring every other month until disease progression, subject withdrawal, or initiation of additional anticancer therapy; no 
additional study drug (ofatumumab) will be administered.  
 
 
 
 


Protocol IPI-145-07 
 
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Duvelisib (IPI-145) 
09 February 2017 (Amendment 3) 
CONFIDENTIAL 
 
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Table 5: Disease Response & Follow-up Assessments for All Subjects 
Assessments d 
Screening 
(baseline) 
Cycle 3 
Day 1 
 
Cycles 5, 7, 
11, 15, & 19  
Day 1  
 
Early Termination 
from Study 
Treatment (ETT) a  
≤7 days of last dose 
Disease 
Follow-up b 
Every 6 months 
(±4 weeks) 
Survival 
Follow-up c 
Every 6 
months (± 4 
weeks) 
CT scans of chest, abdomen and pelvis e 
X 
X 
X  
X  
X  
 
Bone marrow biopsy and/or bone marrow 
aspiration f 
 X  
X  
X  
X 
X 
 
Complete blood count (CBC) and differential 
count g 
X 
X 
X 
X 
X i  
 
Blood sample for assessment for minimum 
residual disease (MRD) h 
 
X 
X 
X  
X 
 
Focused physical examination g, disease related 
constitutional symptoms assessment, and 
ECOG performance status 
X 
X 
X 
X 
X 
 
Survival  
 
 
 
 
 
X 
a. 
ETT Disease Response Assessment is not necessary if a Disease Response Assessment was performed within the previous 30 days. In the absence of disease progression or initiation of subsequent 
anticancer therapy, all subjects with ETT prior to Cycle 19 Day 1 will maintain the disease response assessment schedule (Cycles 5, 7, 11, 15, & 19)  
b. 
All subjects with no disease progression by Cycle 19 Day 1 will continue Disease Response Assessments (Section 6.5.3.1) every 6 months until disease progression, subject withdrawal, or 
initiation of additional anticancer therapy. The first disease follow-up assessment after Cycle 19 Day 1 should occur approximately 6 months after last disease assessment. 
c. 
All subjects will have Survival Follow-up for up to 6 years after randomization or until death. This assessment can be conducted by telephone interview.  Information on initiation of other 
anticancer therapy (including start date, therapy type, and response on treatment) will also be collected. 
d. 
On-treatment Disease Response Assessments should be delayed if a subject’s dose (duvelisib or ofatumumab) is held for >1 week at the time of the scheduled assessment; subjects should be on 
treatment for a minimum of 1 week prior to having a response assessment. 
e. 
CT scans of the chest, abdomen and pelvis are required for all subjects in both treatment arms. These assessments may be performed within 7 days (Day -7 to Day 1) of initiating the next cycle of 
therapy. The frequency provided is the minimum required for study participation. Other scans may be performed (eg, head/neck CT) if clinically indicated or if the area is a site of known disease. 
Copies of all scans must be sent for independent review of response assessment. MRI may be substituted if clinically indicated, but the modality chosen to evaluate each individual subject should 
be the same throughout the duration of the study. 
f. 
Bone marrow biopsy and/or bone marrow aspirate are required for all subjects at Screening and in subjects for whom a bone marrow biopsy and/or bone marrow aspirate result is required to meet 
the criteria for a CR or CRi. If bone marrow aspirate and/or bone marrow biopsy is performed, samples and corresponding pathology report should be sent for biomarker analysis if available. The 
bone marrow biopsy/aspirate may be performed within 7 days (Day -7 to Day 1) of initiating the next cycle of therapy.   
g. 
Please see Table 1, Table 2, and Table 4 for the full schedule of assessments. 
h. 
The MRD assessment for subjects with CR and CRi only will include collection of a blood sample to be evaluated via flow cytometry at a central laboratory. This blood sample is to be collected as 
soon as CR is identified and sent to the central laboratory for assessment. 
i. 
CBC to be performed every 3 months during Disease Follow-up. 


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09 February 2017 (Amendment 3)  
CONFIDENTIAL 
Page 20 of 110 
TABLE OF CONTENTS 
Section 
Page 
INVESTIGATOR PROTOCOL APPROVAL .....................................................................2 
SPONSOR PROTOCOL APPROVAL ..................................................................................3 
CONTACT INFORMATION .................................................................................................4 
PROTOCOL SYNOPSIS ........................................................................................................5 
TABLE OF CONTENTS.......................................................................................................20 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.....................................27 
1 
BACKGROUND AND RATIONALE ............................................................33 
1.1 
INTRODUCTION 
33 
1.2 
BACKGROUND 
33 
1.2.1 
Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma 
33 
1.2.2 
Choice of Comparator 
34 
1.2.3 
Ofatumumab Background 
34 
1.2.4 
Functions of PI3K-δ and PI3K-γ 
35 
1.2.5 
Functions of PI3K-δ and PI3K-γ in Hematologic Cancers 
35 
1.3 
DUVELISIB 
36 
1.3.1 
Nonclinical Summary of Duvelisib 
36 
1.3.2 
Clinical Studies in Humans 
36 
1.3.2.1 
Study IPI-145-01 (Phase 1, first-in-human study) 
36 
1.3.2.2 
Study IPI-145-02 (Phase 1, Hematologic Malignancies) 
37 
1.4 
RATIONALE FOR DUVELISIB AS A POTENTIAL THERAPY FOR 
SUBJECTS WITH CLL AND SLL 
39 
1.5 
DETERMINATION OF STARTING DOSE AND REGIMEN 
40 
2 
STUDY OBJECTIVES .....................................................................................43 
2.1 
PRIMARY OBJECTIVE 
43 
2.2 
SECONDARY OBJECTIVES 
43 
2.3 
EXPLORATORY OBJECTIVES 
43 
3 
STUDY ENDPOINTS .......................................................................................43 
3.1 
PRIMARY ENDPOINT 
43 
3.2 
SECONDARY ENDPOINTS 
43 
3.3 
EXPLORATORY ENDPOINTS 
44 


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4 
STUDY DESIGN ...............................................................................................45 
4.1 
SCHEDULE OF ADMINISTRATION 
45 
4.2 
DOSE INTERRUPTION/HOLD/MODIFICATION GUIDELINES 
46 
4.2.1 
Duvelisib Guidelines 
46 
4.2.1.1 
Duvelisib treatment modification guidelines due to duvelisib-related toxicities46 
4.2.1.2 
Duvelisib treatment modification guidelines due to benefit/maximal benefit. 49 
4.2.2 
Ofatumumab Guidelines 
50 
4.2.2.1 
Ofatumumab treatment modification guidelines due to ofatumumab related 
toxicities 
50 
4.3 
TREATMENT DISCONTINUATION 
52 
4.4 
STUDY DISCONTINUATION 
53 
5 
STUDY POPULATION ...................................................................................54 
5.1 
ENTRY CRITERIA 
54 
5.1.1 
Inclusion Criteria 
54 
5.1.2 
Exclusion Criteria 
55 
6 
STUDY PROCEDURES AND ASSESSMENTS ...........................................57 
6.1 
INFORMED CONSENT 
57 
6.2 
SCREENING PERIOD 
57 
6.2.1 
Medical History, Physical Examination, and Screening Assessments 
57 
6.2.2 
Inclusion and Exclusion Criteria 
59 
6.3 
TREATMENT PERIOD 
59 
6.3.1 
Assessments 
59 
6.3.1.1 
Physical Examinations 
59 
6.3.1.2 
Vital Signs 
59 
6.3.1.3 
ECOG Performance Status 
59 
6.3.1.4 
Additional Assessments 
59 
6.3.2 
Clinical Laboratory Tests 
59 
6.3.3 
Study Drug Administration, Criteria for Treatment 
60 
6.3.3.1 
Duvelisib 
60 
6.3.3.2 
Ofatumumab 
61 
6.3.4 
Adverse Events 
61 
6.3.5 
Subject-reported Outcomes Assessment 
61 
6.3.6 
Concomitant Medication and Therapies 
62 
6.3.6.1 
Prohibited: Use of Vaccines 
63 
6.3.6.2 
Prohibited: Immunosuppressants 
63 
6.3.6.3 
Prohibited: PI3K Inhibitors or BTK Inhibitors 
63 
6.3.6.4 
Prohibited: Other Anticancer Therapy or Investigational Agents 
63 
6.3.6.5 
Prohibited: (Duvelisib Subjects Only) 
63 
6.3.6.6 
Use with Caution (Duvelisib Subjects Only): 
64 
6.3.6.7 
Antiemetics and Antidiarrheals 
64 
6.3.6.8 
Hematopoietic Growth Factors 
65 
6.3.6.9 
Other Concomitant Therapies 
65 
6.3.6.10 
Photosafety 
65 
6.3.7 
Pharmacokinetic Sampling 
65 
6.3.8 
Biomarker Assessments 
66 


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6.3.9 
Disease Response Assessments 
66 
6.3.9.1 
CT Scans 
67 
6.3.9.2 
Investigator assessment of response and progression status 
67 
6.3.9.3 
Independent assessment of response and progression status 
71 
6.4 
EARLY TREATMENT TERMINATION OF Duvelisib OR 
OFATUMUMAB 
71 
6.5 
POST-TREATMENT PERIOD 
72 
6.5.1 
Safety Follow-up Visit (30 Days Post-Treatment) 
72 
6.5.1.1 
Duvelisib 
72 
6.5.1.2 
Ofatumumab 
72 
6.5.2 
Clinical Assessment Period 
72 
6.5.2.1 
Duvelisib 
72 
6.5.2.2 
Ofatumumab 
73 
6.5.3 
Follow-up 
73 
6.5.3.1 
Disease Follow-up 
73 
6.5.3.2 
Survival Follow-up 
73 
6.6 
MISSED VISITS 
74 
7 
INVESTIGATIONAL MEDICINAL PRODUCT .........................................75 
7.1 
DESCRIPTION OF INVESTIGATIONAL MEDICINAL PRODUCT 
75 
7.2 
DOSAGE AND ADMINISTRATION 
75 
7.2.1 
Dosage 
75 
7.2.1.1 
Duvelisib 
75 
7.2.1.2 
Ofatumumab 
75 
7.2.2 
Administration 
75 
7.2.2.1 
Duvelisib 
75 
7.2.2.2 
Ofatumumab 
76 
7.3 
PACKAGING AND LABELING 
76 
7.4 
STORAGE AND HANDLING 
76 
7.4.1 
Duvelisib 
76 
7.4.2 
Ofatumumab 
76 
7.5 
INVESTIGATIONAL MEDICINAL PRODUCT ACCOUNTABILITY 
77 
7.5.1 
Duvelisib 
77 
7.5.2 
Ofatumumab 
77 
7.6 
ASSIGNMENT TO TREATMENT 
77 
7.7 
ASSESSMENT OF COMPLIANCE 
78 
7.7.1 
Duvelisib 
78 
7.7.2 
Ofatumumab 
78 
7.8 
TREATMENT OF OVERDOSE 
78 
8 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS .......................79 
8.1 
DEFINITIONS 
79 
8.1.1 
Adverse Event 
79 
8.1.2 
Adverse Reactions and Suspected Adverse Reactions 
79 
8.1.3 
Serious Adverse Event 
79 
8.2 
PROCEDURES FOR ELICITING, RECORDING, AND REPORTING 
ADVERSE EVENTS 
80 


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8.2.1 
Eliciting and Recording Adverse Events 
80 
8.2.1.1 
Relationship to Study Drug 
80 
8.2.1.2 
Adverse event severity 
81 
8.2.2 
Specific Instructions for Recording Adverse Events on the eCRF 
81 
8.2.2.1 
Diagnosis versus Signs and Symptoms 
81 
8.2.2.2 
Adverse Events Occurring Secondary to Other Events 
81 
8.2.2.3 
Persistent or Recurrent Adverse Events 
82 
8.2.2.4 
Abnormal Laboratory Values 
82 
8.2.2.5 
New Cancers 
82 
8.2.2.6 
Medication Errors, Misuse and Abuse of Study Drug 
82 
8.2.3 
Reporting of Serious Adverse Events 
83 
8.2.3.1 
Immediate Reporting of Serious Adverse Events by Investigator to Sponsor 83 
8.2.3.2 
Immediate Reporting of Medical Events of Interest 
84 
8.2.3.3 
Reporting of Serious Adverse Events to the Institutional Review Board (IRBs)/ 
Ethics Committee 
84 
8.2.3.4 
Reporting of Serious Adverse Events to Regulatory Authorities 
84 
8.2.4 
Pregnancy and In Utero Drug Exposure 
85 
9 
STATISTICAL METHODS ............................................................................86 
9.1 
SAMPLE SIZE 
86 
9.2 
ANALYSIS SETS 
86 
9.2.1 
Intent-to-Treat Analysis Set 
86 
9.2.2 
All-treated Analysis Set 
86 
9.3 
DISPOSITION, DEMOGRAPHIC AND BASELINE Characteristics 
86 
9.4 
EFFICACY ANALYSES 
87 
9.4.1 
Analysis of Primary Efficacy Endpoint 
87 
9.4.2 
Analysis of Key Secondary Efficacy Endpoints 
88 
9.4.2.1 
Overall Response Rate (ORR) 
88 
9.4.2.2 
Lymph Node Response Rate 
88 
9.4.2.3 
Overall Survival (OS) 
88 
9.4.2.4 
Hematologic Improvement Rate 
89 
9.4.3 
Analyses of Other Secondary Efficacy Endpoints 
89 
9.4.3.1 
Duration of response (DOR) 
89 
9.4.4 
Analyses of Exploratory Efficacy Endpoints 
89 
9.5 
SAFETY ANALYSES 
89 
9.6 
PHARMACOKINETIC ANALYSES 
90 
9.7 
ANALYSES OF OTHER ENDPOINTS 
90 
9.8 
INTERIM ANALYSIS 
90 
10 
STUDY ADMINISTRATION .........................................................................92 
10.1 
GOOD CLINICAL PRACTICE STATEMENT 
92 
10.2 
INFORMED CONSENT 
92 
10.3 
SUBJECT CONFIDENTIALITY 
92 
10.4 
INSTITUTIONAL REVIEW BOARD/ ETHICS COMMITTEE 
REQUIREMENTS 
93 
10.5 
CASE REPORT FORMS AND SOURCE DOCUMENTATION 
93 
10.6 
SPONSOR MONITORING 
93 


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10.7 
DATA MONITORING COMMITTEE 
93 
10.8 
BLINDING 
94 
10.9 
QUALITY ASSURANCE 
94 
10.10 
STUDY OR CLINICAL SITE TERMINATION 
94 
10.11 
DURATION OF THE STUDY, EXPECTED DURATION OF SUBJECT 
PARTICIPATION, AND END OF STUDY 
95 
10.12 
RECORDS RETENTION 
95 
10.13 
PUBLICATIONS 
95 
11 
REFERENCES ..................................................................................................96 
12 
APPENDICES ...................................................................................................98 
 
Appendix 1: Medications or Foods Known to Inhibit or Induce CYP3A 
98 
Appendix 2: Known CYP3A or CYP2C8 Substrates 
100 
Appendix 3: P-gp Substrates and Medications that are Inhibitors of P-gp 
101 
Appendix 4: ECOG Performance Status 
103 
Appendix 5: QoL Instrument - EQ-5D Questionnaire 
104 
Appendix 6: Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) 106 
 
 
 


Protocol IPI-145-07 
 
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Duvelisib (IPI-145) 
09 February 2017 (Amendment 3)  
CONFIDENTIAL 
Page 25 of 110 
LIST OF TABLES  
Table 1: 
Screening Assessments Checklist for All Subjects a....................................13 
Table 2: 
Schedule of Assessments for Subjects Receiving Duvelisib a .....................14 
Table 3: 
Pharmacokinetic Assessments for Subjects Receiving Duvelisib Only a ...16 
Table 4: 
Schedule of Assessments for Subjects Receiving Ofatumumab a ..............17 
Table 5: 
Disease Response & Follow-up Assessments for All Subjects ...................19 
Table 6: 
The Expression, Role, and Isoform Biochemical Activity of Duvelisib ....36 
Table 7: 
Clinical Responses in Subjects with Relapsed/Refractory CLL/SLL  
(as of 08 October 2014) from Study IPI-145-02 ..........................................38 
Table 8: 
Dose Interruption/Hold/Modifications for Duvelisib-Related  
Toxicities .........................................................................................................47 
Table 9: 
Dosing Levels Duvelisib .................................................................................49 
Table 10: 
Dose Interruption/Hold/Modifications for Ofatumumab-Related  
Toxicities .........................................................................................................51 
Table 11: 
CLL Response Criteria (modified from IWCLL) 1, 22 ................................68 
Table 12: 
SLL Response Criteria (modified from IWG) 2, 22 ......................................70 
Table 13: 
Primary PFS Censoring / Event Methodology ............................................87 
 
 


Protocol IPI-145-07 
 
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09 February 2017 (Amendment 3)  
CONFIDENTIAL 
Page 26 of 110 
 
LIST OF FIGURES 
Figure 1: 
Maximum Change in Adenopathy by CT Scan Assessment in Subjects 
with Relapsed/Refractory CLL (as of 08 October 2014) from  
Study IPI-145-02 ............................................................................................39 
Figure 2: 
Steady State Exposure (AUC0-12) Versus Response (Reduction in 
Adenopathy) in CLL/SLL Subjects  
(Study IPI-145-02; preliminary data) ..........................................................41 
Figure 3: 
Duvelisib (IPI-145) Plasma Concentration Versus Tumor Cell pAKT 
Inhibition Following a Single Dose in CLL/SLL Subjects  
(Study IPI-145-02; preliminary) ...................................................................41 
Figure 4: 
Mean Duvelisib (IPI-145) Plasma Concentration-Time Profiles  
on Cycle 2, Day 1 (Study IPI-145-02; preliminary data) ............................42 
 
 
 


Protocol IPI-145-07 
 
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09 February 2017 (Amendment 3)  
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADL 
Activities of daily living 
ADME 
Absorption, distribution, metabolism, and excretion 
AE 
Adverse Event 
AIHA 
Autoimmune hemolytic anemia 
ALC 
Absolute lymphocyte count 
ALT 
Alanine aminotransferase  
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
AKT (PKB) 
A serine/threonine protein kinase 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase 
AT 
All Treated  
AUC 
Area under the curve 
BBB 
Bundle branch block 
βhCG 
β human chorionic gonadotropin 
BID 
Twice a day 
BTK 
Bruton’s tyrosine kinase 
BUN 
Blood urea nitrogen 
CAL-101  
Idelalisib (GS-1101): a PI3K-δ inhibitor in clinical 
development for patients with hematologic 
malignancies 
CBC 
Complete blood count 
CD20 
B-lymphocyte antigen CD20 
CEC 
Central Ethics Committee 
CI 
Confidence interval 
CLL 
Chronic lymphocytic leukemia 
cm 
Centimeters 
Cmax 
Maximum concentration 
CNS 
Central nervous system 
CMV 
Cytomegalovirus 
CO2 
Chloride bicarbonate 


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Abbreviation 
Definition 
CR 
Complete response 
CRi 
Complete response with incomplete marrow 
recovery 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events  
CYP 
Cytochrome P450 
d 
Day 
DDI 
Drug-drug interaction 
Del(17p) 
Deletion of the 17p13 chromosomal region 
dL 
Deciliter(s) 
DLT 
Dose limiting toxicity 
DMC 
Data monitoring committee 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of response 
Duvelisib (IPI-145) 
(S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-
phenylisoquinolin-1(2H)-one 
EBV 
Epstein-Barr virus 
ECOG 
Eastern Cooperative Oncology Group 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EMA 
European Medicines Agency 
ESMO 
European Society for Medical Oncology 
EQ-5D 
EuroQol – 5D (health-related QoL assessment) 
ETT 
Early treatment termination 
EU 
European Union 
FACIT-F 
Functional Assessment of Chronic Illness Therapy-
Fatigue 
FACT 
Functional Assessment of Cancer Therapy 
FcεRI 
High-affinity IgE receptor 
FCγRII 
Fc fragment of IgG, low affinity IIa, receptor 
(CD32) 
FDA 
Food and Drug Administration 


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Abbreviation 
Definition 
FISH 
Fluorescence in situ hybridization 
FMLP 
N-formyl-leucine-methionine-phenylalanine 
g 
Gram(s) 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte-colony stimulating factor 
GM-CSF 
Granulocyte macrophage-colony stimulating factor 
GPCR 
G-protein coupled receptor 
GRAS 
Generally regarded as safe 
GS-1101 
Idelalisib (see CAL-101) 
h 
Hour(s) 
HBcAb 
Hepatitis B core antibody  
HBsAg 
Hepatitis B surface antigen 
HCV Ab  
Hepatitis C virus antibodies 
HIV 
Human immunodeficiency virus 
HSV 
Herpes simplex virus 
IC50 
Half maximal inhibitory concentration 
IC90 
90% inhibitory concentration 
ICF 
Informed consent form 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin  
IGHV 
Immunoglobulin heavy chain variable 
in 
inches 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITP 
Idiopathic thrombocytopenic purpura 
ITT 
Intent-to-treat 
IV 
Intravenous(ly) 
IWCLL 
International Workshop on Chronic Lymphocytic 
Leukemia  
IWG 
International Working Group 


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Abbreviation 
Definition 
Kd 
Dissociation constant 
kg 
Kilogram(s) 
KPS 
Karnofsky Performance Status 
L 
Liter(s) 
LDH  
Lactate dehydrogenase 
LEC 
Local Ethics Committee 
LLC 
Lewis lung carcinoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEOI 
Medical Events of interest 
mg 
Milligram(s) 
µg 
Microgram(s) 
μL 
Microliter(s) 
mL 
Milliliter(s) 
µM 
Micromolar 
MRD 
Minimum residual disease 
MRI 
Magnetic resonance imaging 
ms 
Millisecond(s) 
MTD 
Maximum tolerated dose 
N 
Number 
NCCN 
National Comprehensive Cancer Network 
ng 
Nanogram(s) 
nM 
Nanomolar 
Ofa 
Ofatumumab 
ORR 
Overall response rate 
OS 
Overall survival 
pAKT 
Phosphorylated AKT 
PCR 
Polymerase chain reaction 
PD 
Progressive disease 
PE 
Physical exam 
PET 
Positron emission tomography 
PDK-1 
3-phosphoinositide dependent protein kinase-1 


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Abbreviation 
Definition 
PE  
Physical examination 
PFS 
Progression-free survival 
P-gp 
P-glycoprotein 
PH 
Pleckstrin homology 
PI3K 
Phosphoinositide-3-kinase 
PIP3 
Phosphatidylinositol (3,4,5)-trisphosphate 
PK 
Pharmacokinetics 
pM 
Picomolar 
PML 
Progressive multifocal leukoencephalopathy 
PR 
Partial response 
PRwL 
Partial response with lymphocytosis 
PT 
Prothrombin time 
PTEN 
Phosphatase and tensin homolog 
QD 
Once a day 
QoL 
Quality of life 
QTcF 
QT interval corrected with Fridericia’s method 
RAS 
Protein subfamily of small GTPases involved in 
cellular signal transduction 
RBC 
Red blood cell 
RNA 
Ribonucleic acid 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
SH2 
Src homology 2 
SLL 
Small lymphocytic lymphoma 
SmPC 
Summary of Product Characteristics 
SPD 
Sum of the products 
T1/2 
Terminal elimination half-life 
TAMs 
Tumor-associated macrophages 
TEAE 
Treatment-emergent adverse events 
TRAP-6 
Thrombin receptor activating peptide-6 
ULN 
Upper limit of normal 


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Abbreviation 
Definition 
US/USA 
United States of America 
USPI 
United States Package Insert 
UV 
Ultraviolet 
VZV 
Varicella zoster virus 
WCBP 
Women of child-bearing potential 
 
 
 
 


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1 
BACKGROUND AND RATIONALE 
1.1 
INTRODUCTION 
Duvelisb is a potent phosphoinositide-3-kinase (PI3K)-δ,γ inhibitor being developed by 
Verastem , Inc. (Verastem).  PI3K-δ and PI3K-γ isoforms are necessary for adaptive and 
innate immunity, and are important mediators in inflammatory disorders and hematologic 
malignancies.  Therefore, duvelisib is being developed as an orally administered potential 
therapeutic in hematologic malignancy and inflammatory disease indications.   
In a Phase 1 study of duvelisib in patients with relapsed or refractory hematologic 
malignancies, clinical activity was observed early in dose-escalation in subjects with relapsed 
or refractory Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma 
(SLL).  In addition, duvelisib was dosed below the maximum tolerated dose (MTD) in a 
cohort of relapsed or refractory CLL/SLL subjects.  The preliminary safety and efficacy 
profile of duvelisib observed to date in this patient population suggests duvelisib has clinical 
activity in patients with CLL/SLL and may have a superior progression-free survival (PFS) 
and/or overall response rate (ORR) compared to ofatumumab, a CD20-directed cytolytic 
therapy recommended for use in treating relapsed or refractory CLL/SLL.  The purpose of this 
study is to evaluate duvelisib compared to ofatumumab in the treatment of subjects with 
relapsed or refractory CLL or SLL. 
1.2 
BACKGROUND 
1.2.1 
Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma  
CLL is the most common adult leukemia in Western countries with an incidence of 4.2 per 
100,000 per year. In the elderly (> 80 years of age), the incidence increases to > 30 per 
100,000 per year.3 The median age at diagnosis is 72 years, with approximately 10% younger 
than 55 years. 4 CLL and SLL are different manifestations of the same disease and are 
managed in much the same way.  The major difference is that in SLL, the abnormal 
lymphocytes are found predominantly in the lymph nodes, while in CLL the abnormal 
lymphocytes are also found in the bone marrow and peripheral blood (≥ 5,000 clonal 
cells/µL).5 
Treatment of CLL/SLL is indicated in the presence of active, symptomatic disease. The 
intensity of the therapy is dependent on patient age, relative comorbidities, and the presence 
or absence of high-risk cytogenetic features (eg, deletion of 17p [del(17p)]).   
In the first-line setting, chemotherapy with alkylating agents has been the treatment of choice 
for patients with advanced and progressive CLL. Since the introduction of 
chemoimmunotherapy regimens using purine nucleoside-analogs (such as fludarabine and 
cladribine) and pentostatin alkylating agents (such as chlorambucil and bendamustine) in 
combination with rituximab, a CD20-directed cytolytic antibody, these have become the 
preferred therapies for patients with low comorbid burden with or without high-risk 
cytogenetic features. In frail or elderly patients, single agent therapies are routinely used and 
include: chlorambucil; bendamustine; or alemtuzumab, a CD52-directed cytolytic antibody. 
Similarly, patients with specific molecular features like del(17p) do not derive as much 


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benefit from chemoimmunotherapy. Therefore, first-line treatment of CLL patients includes 
selection of single agent therapies based on patient age, relative comorbidities, and the 
presence or absence of high-risk cytogenetic features [ie, del(17p)]. Despite available 
treatment options, the majority of patients with CLL will relapse following first-line therapy 
and can acquire high-risk genetic abnormalities. 
In relapsed or refractory CLL/SLL, treatment options are again dependent of the patient age, 
relative comorbidities, and the presence or absence of high risk cytogenetics. Patients are 
often re-treated with previously administered regimens if the relapse occurs ≥12 or 24 months 
after chemotherapy or chemoimmunotherapy, respectively.  However, the majority of patients 
are not cured of their CLL/SLL and will eventually develop high-risk disease for which 
retreatment with prior therapies has no perceived benefit or alternative therapies have little 
clinical benefit (ie, bendamustine in relapsed high risk cytogenetics) or no longer routinely 
available (ie, alemtuzumab).  In this setting, ofatumumab, a humanized CD20-directed 
cytolytic antibody, has demonstrated significant benefit. 
1.2.2 
Choice of Comparator 
Ofatumumab was selected for use in this study based on the evolving treatment patterns 
across the regions intended for participation in this study.  Use of ofatumumab in the patient 
population defined in this study is supported by information obtained from a review of the 
literature, 6, 7 established treatment guidelines 4, 8 and consultation with multiple expert 
advisors.  It is expected that ofatumumab will be an acceptable choice for use at treatment 
centers where subjects with relapsed/refractory CLL who, unless otherwise contraindicated 
per treatment guidelines, would have routinely already received purine-analog based therapy 
(ie, fludarabine or pentostatin). 
1.2.3 
Ofatumumab Background 
Ofatumumab is the first human anti-CD20 monoclonal antibody to be approved for CLL 
patients in the US and European Union (EU). On October 26, 2009 and April 19, 2010, the 
U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) 
granted approval of ofatumumab (ARZERRA®, GlaxoSmithKline) for the treatment of CLL 
in patients who are refractory to fludarabine and alemtuzumab. Approval was based on the 
unmet medical need and provisions allowing early access to promising agents (US approval 
granted under 21 CFR 601, Subpart E; EU approval granted under conditional circumstances). 
Approvals were based on a clinically meaningful and durable ORR observed in a single-arm 
trial.9 
Following an efficacy supplement filed in April 2014, ofatumumab was converted to full 
approval by both the FDA and the EMA on April 17, 2014 and May 22, 2014, respectively.  
Per the FDA, ofatumumab is now also indicated in combination with chlorambucil for the 
treatment of previously untreated patients with CLL for whom fludarabine-based therapy is 
considered inappropriate (the EMA indication statement also includes ofatumumab in 
combination with bendamustine).  The full approval was based on data from the Phase III 
study of ofatumumab in combination with chlorambucil vs. chlorambucil, which 
demonstrated statistically significant improvement in median PFS in patients who received the 


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combination of ofatumumab and chlorambucil, compared to patients who received 
chlorambucil alone.  
The National Comprehensive Cancer Network’s (NCCN's) Drugs & Biologics Compendium 
recommends the use of ofatumumab as a single-agent or combination salvage therapy in 
rituximab-intolerant patients for disease that does not respond to primary therapy or for 
progressive or relapsed disease. For additional information on ofatumumab, please refer to the 
latest product label.10, 11 
1.2.4 
Functions of PI3K-δ and PI3K-γ  
There are four mammalian isoforms of class 1 PI3Ks: PI3K-α, β,δ (class 1a PI3Ks) and 
PI3K-γ (class 1b PI3K).  These PI3Ks catalyze the production of phosphatidylinositol (3,4,5)-
trisphosphate (PIP3), leading to activation of the downstream effector pathways important for 
cellular survival, differentiation, and function.  PI3K-α and PI3K-β are widely expressed, and 
are important mediators of signaling from cell surface receptors.  PI3K-α is the isoform most 
often found mutated in cancers, and has a role in insulin signaling and glucose homeostasis.12, 
13  PI3K-β is activated in cancers where phosphatase and tensin homolog (PTEN) is deleted.  
Both isoforms are targets of small molecule therapeutics in development for cancer.  PI3K-δ 
and P13K-γ are preferentially expressed in leukocytes, and are important in leukocyte 
function.   
PI3K-δ is activated by cellular receptors (eg, receptor tyrosine kinases) through interaction 
with the SH2 domains of the PI3K regulatory subunit (p85), or through direct interaction with 
RAS.   
PI3K-γ is associated with G-protein coupled receptors (GPCRs), is responsible for the very 
rapid induction of PIP3 in response to GPCRs, and can be also activated by RAS downstream 
of other receptors.  PIP3 produced by PI3K activates effector pathways downstream through 
interaction with pleckstrin homology (PH) domain containing enzymes (eg, PDK-1 and AKT 
[PKB]).14   
1.2.5 
Functions of PI3K-δ and PI3K-γ in Hematologic Cancers 
PI3K-δ and PI3K-γ are expressed in hematopoietic cells, and are critical for the ability of 
normal immune cells to respond to survival and differentiation signals in their environment.  
In cancer patients, where the pathways mediated by PI3K-δ,γ contribute to survival, 
proliferation, and differentiation of cancer cells, treatment with duvelisib may be beneficial. 
The tumor microenvironment plays an important role in the development and maintenance of 
cancer cells.15  Cancer cells through the expression of various cytokines, growth factors, and 
chemokines recruit multiple cell types including myeloid cells capable of differentiating into 
tumor-associated macrophages (TAMs) which promote angiogenesis and augment tumor 
growth.16  Therefore, agents that target TAMs as well as other types of infiltrating leukocytes 
are of potential therapeutic interest in oncology.  Recently, it has been demonstrated that 
tumor growth, invasion of CD11b+ myeloid cells, angiogenesis and metastasis of tumors 
implanted into PI3K-γ deficient mice, were substantially suppressed compared to wild-type 
controls.17 Treatment of mice bearing Lewis Lung Carcinoma (LLC) allografts with the 
selective PI3K-γ inhibitor TG100-115, suppressed tumor inflammation, growth and 


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angiogenesis despite having no effect on LLC proliferation in vitro.  Because the expression 
of PI3K-γ is restricted to the hematological lineage, data suggests that PI3K-γ inhibition acts 
in a cancer cell-extrinsic manner to suppress tumor associated inflammation, angiogenesis and 
tumor progression.17 
1.3 
DUVELISIB 
PI3K-δ and PI3K-γ contribute to the development and maintenance of inflammatory and 
autoimmune diseases, and hematologic malignancies.13, 14, 18, 19  Duvelisib is a potent PI3K-δ,γ 
inhibitor being developed as a potential therapeutic in hematologic malignancy and 
inflammatory disease indications. 
1.3.1 
Nonclinical Summary of Duvelisib 
Table 6 below summarizes the expression, role, isoform, and biochemical activity of 
duvelisib. See the duvelisib Investigator’s Brochure for detailed summaries on pharmacology, 
toxicology, and absorption, distribution, metabolism, and excretion (ADME) of duvelisib. 
Table 6: The Expression, Role, and Isoform Biochemical Activity of Duvelisib 
PI3K Isoform 
PI3K-δ 
PI3K-γ 
PI3K-β 
PI3K-α 
Expression 
Primarily 
Leukocytes 
Primarily 
Leukocytes 
Ubiquitous 
Ubiquitous 
Role 
B-cell & T-cell 
activation, 
proliferation, and 
differentiation 
Innate immune 
function  
T-cell development 
and survival  
Innate immune 
function and cell 
trafficking 
Platelet activation 
Metabolic control 
Metabolic control 
Vascular 
homeostasis  
Biochemical 
Activity (Kd) 
23 pM 
243 pM 
1564 pM 
25900 pM 
Whole Blood 
Assay (IC50)  
(Healthy Donors) 
96±76 nM 
Basophils-Anti-
FcεR1 
1028±803 nM 
Basophils-fMLP 
4700±1800 nM 
Platelet-TRAP-6 
Not determined 
FcεRI = high-affinity IgE receptor; fMLP = N-formyl-leucine-methionine-phenylalanine; IC50 = half maximal 
inhibitory concentration; TRAP-6 = thrombin receptor activating peptide-6 
1.3.2 
Clinical Studies in Humans 
1.3.2.1 
Study IPI-145-01 (Phase 1, first-in-human study) 
Study IPI-145-01 was a randomized, double-blind, placebo-controlled, Phase 1 study in 
healthy adult subjects designed to evaluate the safety, tolerability, PK and pharmacodynamics 
of single and multiple ascending doses of duvelisib and to assess the effect of food and 
ketoconazole on the PK of duvelisib. One-hundred and six (106) subjects were enrolled. In 


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this setting duvelisib was well tolerated at the doses evaluated. There were no deaths and no 
serious adverse events (SAEs).   
Pharmacokinetic assessments demonstrated that duvelisib is rapidly absorbed following single 
and multiple oral dose administration, with the maximum plasma concentration observed 
typically 1 hour after dosing.  Across the dose ranges evaluated, duvelisib exposure increased 
proportionally to dose.  The mean elimination half-life ranged from 6.5 to 11.7 hours after 
repeat dosing and did not depend on the dose level administered.  Duvelisib accumulation was 
less than 2-fold following 14 days of Q12 h oral administration.   
Data from the drug-drug interaction (DDI) portion indicated that concomitant administration 
of 200 mg ketoconazole every 12 hours (Q12 h) increased exposure to duvelisib.  On average, 
Cmax, AUC0-last and AUC0-inf increased by approximately 66%, 285% and 295%, respectively, 
in the presence of ketoconazole compared to duvelisib administered alone.   
See the duvelisib Investigator’s Brochure for further information. 
1.3.2.2 
Study IPI-145-02 (Phase 1, Hematologic Malignancies)  
Study IPI-145-02 is a Phase 1, open-label, dose-escalation study of duvelisib administered 
orally twice daily during each 28-day cycles at doses ranging from 8 mg BID to 100 mg BID 
in adult subjects with advanced hematologic malignancies. Enrollment in all phases of the 
study is complete, with follow-up ongoing. As of 08 October 2014, 210 subjects received at 
least one dose of duvelisib including 55 subjects with relapsed/refractory CLL/SLL (8 mg 
[n=1]; 15 mg [n=2]; 25 mg [n=28]; 75 mg [n=24]). The median time on treatment for all 
relapsed/refractory subject doses was 5.9 months (range 0.9 to 34.1 months), and 7.6 months 
(range 0.9 to 34.1 months) for doses ≤ 25 mg.20 
The maximum tolerated dose (MTD) was determined to be 75 mg BID based upon two dose 
limiting toxicities (DLTs) experienced by two subjects receiving 100 mg BID (Grade 3 rash 
and Grade 3 alanine aminotransferase [ALT]/aspartate aminotransferase [AST] elevations). 
Six expansion cohorts were enrolled at 25 mg BID or 75 mg BID to further define the safety 
and efficacy of duvelisib in select diseases. The 25 mg dose was selected for phase 3 
development based on clinical activity.21 
Clinical Safety in Relapsed/Refractory CLL/SLL 
Frequently occurring (≥ 20% subjects) AEs observed in all relapsed/refractory CLL/SLL 
subjects (n=55) included neutropenia (53%), rash (combined terms) (46%), diarrhea (44%),  
cough (38%), fatigue (38%), pneumonia (combined terms) (36%), ALT/AST increased 
(29%), anemia (29%), pyrexia (27%), nausea (26%), decreased appetite (24%), and 
thrombocytopenia (22%).  Serious adverse events occurring in more than 1 relapsed/refractory 
CLL/SLL subject included pneumonia (combined terms) (15 [27%])), febrile neutropenia (8 
[15%]), diarrhea (3 [5%]), constipation (2 [4%]), hypercalcemia (2 [4%]), pyrexia (2 [4%]),  
and stomatitis (2 [4%]).20   
These events are not unexpected based on the patient population and the mechanism of action 
of duvelisib.  Infection prophylaxis and dose modifications included in the IPI-145-07 
protocol are intended to reduce the risk of the frequently occurring events.   


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Clinical Efficacy in Relapsed/Refractory CLL/SLL 
As of 08 October 2014, 52 subjects overall with relapsed/refractory CLL/SLL and 30 subjects 
who received duvelisib ≤ 25 mg BID with relapsed/refractory CLL/SLL had available efficacy 
data.   
The investigator-reported ORR (CR + PR), as defined by the IWCLL/IWG was 58% among 
all relapsed/refractory CLL/SLL subjects with a response assessment, which included 1 CR, 
and 29 PR. The ORR for relapsed/refractory CLL/SLL subjects who received duvelisib 
≤ 25 mg BID was 57%, which included 1 CR and 16 PR (Table 7). The median time to 
IWCLL/IWG response was 1.9 months.20 
Table 7: Clinical Responses in Subjects with Relapsed/Refractory CLL/SLL (as of 08 
October 2014) from Study IPI-145-02 
Population 
Patients 
(n) 
Best Response  
(n) 
ORR 
by 
IWCLL/IWG 
(CR + PR) 
Evaluable 
CR 
PR 
SD* 
PD 
Overall R/R CLL  
52 
1 
29 
21 
1 
58% 
≤ 25 mg BID 
30 
1 
16 
12 
1 
57% 
Includes efficacy evaluable patients only = at least one response assessment or PD without a response 
assessment 
* Stable disease includes patients with PR + lymphocytosis 
 
Figure 1 below shows the proportion of CLL/SLL subjects with a nodal response in Study IPI-
145-02. A nodal response (reduction ≥ 50%) was observed in 83% (25/30) of CLL patients at 
25 mg BID with a baseline CT scan.20 


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Figure 1: Maximum Change in Adenopathy by CT Scan Assessment in Subjects with 
Relapsed/Refractory CLL (as of 08 October 2014) from Study IPI-145-02 
 
Pharmacokinetics 
Preliminary PK data from Study IPI-145-02 demonstrate duvelisib is rapidly absorbed 
following oral dosing in subjects with advanced hematologic malignancies, with the 
maximum plasma concentration (Cmax) generally achieved at approximately 1 hour post-dose.  
Steady state exposure over the dosing interval (AUC0-12) is proportional to dose. Following 
repeat dose administration of 25 mg BID, mean Cmax and AUC0-12 values are 1460 ng/mL and 
8129 ng*h/mL, respectively.  Duvelisib elimination half-life (t1/2) does not appear to vary with 
dose and the mean t1/2 was 4.5 hours following 25 mg BID administration. 
1.4
RATIONALE FOR DUVELISIB AS A POTENTIAL THERAPY FOR 
SUBJECTS WITH CLL AND SLL 
PI3K-δ and PI3K-γ are expressed in hematopoietic cells, and are critical for the ability of 
normal immune cells to respond to survival and differentiation signals in their environment.  
In cancer patients, where the pathways mediated by PI3K-δ,γ contribute to survival, 
proliferation, and differentiation of cancer cells, treatment with duvelisib may be beneficial.  
The tumor microenvironment plays an important role in the development and maintenance of 
cancer cells.15  Cancer cells through the expression of various cytokines, growth factors, and 
chemokines recruit multiple cell types including myeloid cells capable of differentiating into 
TAMs which promote angiogenesis and augment tumor growth.16  Therefore, agents that 
target TAMs as well as other types of infiltrating leukocytes are of potential therapeutic 
interest in oncology.   
PI3Ks play pivotal roles in cell signaling and regulate a variety of cellular functions relevant 
to oncogenesis. Impaired development and function of B and T lymphocytes has been 


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demonstrated in PI3K-δ and PI3K-γ isoform knockout mice, supporting the development of 
PI3K-δ,γ specific inhibitors for B- and T-cell lymphoid malignancies.  
1.5 
DETERMINATION OF STARTING DOSE AND REGIMEN  
Dose levels of duvelisib ranging from 8 mg BID to 100 mg BID were evaluated in 
Study IPI-145-02, a Phase 1, open-label, dose-escalation study in subjects with advanced 
hematologic malignancies where duvelisib was administered BID continuously in 28-day 
cycles as a single agent. At the time this protocol was developed, the dose-escalation phase of 
Study IPI-145-02 was complete and the MTD was determined to be 75 mg BID.  A total of 
193 subjects had been dosed in the study as of 28 October 2013.   
Based on the available data, the following findings were considered in determining the dose 
and schedule (25 mg BID) for this study: 
• Of the 27 relapsed/refractory CLL/SLL subjects with evaluable efficacy data who 
received ≤ 25 mg BID of duvelisib, 1 subject achieved a CR and 12 subjects achieved 
a PR based on IWCLL 2008 response criteria (best response);  
• The median time to response was rapid (1.9 months) with a PR observed in 6 subjects 
after 2 cycles, in 4 subjects after 4 cycles, and in 2 subjects after 6 cycles of duvelisib 
treatment; 
• 85% (11/13) of the relapsed/refractory CLL/SLL subjects with evaluable efficacy data 
who received ≤ 25 mg BID of duvelisib with stable disease have demonstrated a nodal 
response, defined as > 50% reduction in adenopathy based on CT scans.  Eight of 11 
subjects experienced a nodal response after 2 cycles of duvelisib treatment; and  
• After 2 cycles of duvelisib treatment, a nodal response was reported in 4 out of the 6 
subjects who went on to achieve a PR after 4-6 cycles of duvelisib treatment.  These 
data introduce the possibility that nodal responses (> 50% reduction in adenopathy) 
may be a precursor of response as defined by the IWCLL criteria.  In clinical studies 
of other therapies in development in CLL, it has been reported that nodal responses 
have preceded PRs or CRs. 22 
Pharmacodynamics 
Preliminary exposure-response analyses observed in Study IPI-145-02 supported the rationale 
that duvelisib dosed at 25 mg BID is expected to be efficacious.  The relationship between 
steady state exposure (collected at the beginning of Cycle 2) and reduction in lymph node size 
(assessed at the beginning of Cycle 3) in patients with CLL is provided in Figure 2. Increased 
exposure did not result in greater reductions in adenopathy; based on these preliminary data, a 
dose of 25 mg BID provides exposure anticipated to be efficacious.  


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Figure 2: Steady State Exposure (AUC0-12) Versus Response (Reduction in Adenopathy) 
in CLL/SLL Subjects (Study IPI-145-02; preliminary data)  
 
The serine/threonine kinase AKT is directly phosphorylated by PI3Ks, therefore the reduction 
in phosphorylated AKT (pAKT) was used as a pharmacodynamic marker for tumor cell PI3K 
inhibition in subjects with CLL in Study IPI-145-02. Percent pAKT inhibition versus 
duvelisib plasma concentration following a single dose is depicted in Figure 3. Duvelisib 
inhibits phosphorylation of AKT in a concentration-dependent manner, with maximal effects 
observed at concentrations observed following a 25 mg dose of duvelisib. Further elevations 
in duvelisib plasma concentration did not provide additional inhibition of pAKT. 
Figure 3: Duvelisib (IPI-145) Plasma Concentration Versus Tumor Cell pAKT 
Inhibition Following a Single Dose in CLL/SLL Subjects (Study IPI-145-02; 
preliminary)  
 


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The potential of duvelisib to inhibit PI3K-δ and PI3K-γ was evaluated in vitro through 
quantitation of the reduction in CD63 cell surface expression on CCR3+ basophils in donor 
whole blood following stimulation with FcεR1 (PI3K-δ dependent) and fMLP (PI3K-γ 
dependent).  Mean plasma concentrations following 25 mg BID remained at or above the IC90 
for PI3K-δ inhibition and near or above the IC50 for PI3K-γ inhibition throughout the dosing 
interval (Figure 4).   
Figure 4: Mean Duvelisib (IPI-145) Plasma Concentration-Time Profiles on Cycle 2, 
Day 1 (Study IPI-145-02; preliminary data) 
 


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2 
STUDY OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
The primary objective of this trial is to examine the efficacy of duvelisib monotherapy versus 
ofatumumab monotherapy in subjects with relapsed or refractory CLL or SLL. 
2.2 
SECONDARY OBJECTIVES 
• To determine the safety of duvelisib in subjects with CLL or SLL 
• To evaluate the PK of duvelisib and, if applicable, its metabolite(s) 
2.3 
EXPLORATORY OBJECTIVES 
• To evaluate the health-related quality of life (QoL) of subjects 
• To evaluate pharmacodynamic biomarkers of duvelisib  
• To evaluate biomarkers that may predict duvelisib clinical activity and/or safety 
• To evaluate mechanisms of resistance in subjects who exhibit disease progression 
while being treated with duvelisib or ofatumumab 
• To evaluate genomic features of tumors predictive of response in subjects treated with 
duvelisib or ofatumumab 
3 
STUDY ENDPOINTS 
3.1 
PRIMARY ENDPOINT 
The primary endpoint is progression-free survival (PFS), defined as time from randomization 
to first documentation of progressive disease (PD) as determined by independent review or 
death due to any cause. 
3.2 
SECONDARY ENDPOINTS 
The secondary endpoints of the study are: 
• Overall Response Rate (ORR), with overall response (based on independent review)  
defined as the best response of complete response/remission (CR), CR with 
incomplete marrow recovery (CRi), partial response/remission (PR), or PR with 
lymphocytosis (PRwL), according to the IWCLL or revised IWG Response Criteria, 
with modification for treatment-related lymphocytosis 
• Lymph node response rate, with lymph node response defined as ≥ 50% decrease in 
the SPD of target lymph nodes  
• Overall Survival (OS), defined as time from randomization to death 


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• Hematologic improvement rate, with hematologic improvement defined as any of 
following, for at least 60 days without transfusion or exogenous growth factors: 
o Neutrophil count > 1,500/µL or an increase ≥ 50% from Baseline; or 
o Hemoglobin > 11 g/dL or an increase ≥ 50% from Baseline; or  
o Platelet count >100 000/µL or an increase ≥ 50% from Baseline  
• Duration of Response (DOR), defined as time from the first documentation of 
response to first documentation of PD or death due to any cause 
• TEAEs and changes in safety laboratory values  
• PK parameters derived from plasma duvelisib concentrations and, if applicable, its 
metabolite(s) 
3.3 
EXPLORATORY ENDPOINTS 
The exploratory endpoints of the study are: 
• Improvement in disease-related symptoms of fatigue, weight loss, unexplained fevers 
and night sweats from Baseline 
• Minimal Residual Disease (MRD) in subjects with documented CR or CRi  
• Health-related QoL of subjects as assessed by the following subject-reported 
questionnaires:  
o EuroQol-5D (EQ-5D) 
o Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) 
• Serum and tissue biomarkers and blood immunophenotype 
• Tumor genomic features (eg, DNA sequence variation, DNA copy number variation, 
and/or RNA expression) 
• Germline DNA sequence variations 
 
 


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4 
STUDY DESIGN 
Study IPI-145-07 is a two-arm, randomized (1:1 ratio), open label, phase 3, superiority trial 
designed to evaluate the efficacy and safety of duvelisib compared to ofatumumab. Subjects 
will be stratified by:  
1. High-risk cytogenetics (presence vs absence of del[17p]) 
2. Refractory/early relapse to purine analog based therapy (defined as progression < 
12 months after fludarabine/pentostatin: yes vs no)  
3. Grade 4 cytopenia(s) (presence vs absence of neutropenia or thrombocytopenia at 
baseline)   
Eligible subjects will be randomized in a 1:1 ratio to one of two treatment arms:  
• 
Arm 1: Duvelisib, 25 mg BID  
• 
Arm 2: Ofatumumab  
First dose is to occur within 7 days of randomization after all screening assessments have been 
completed. 
4.1 
SCHEDULE OF ADMINISTRATION  
Subjects who meet all the eligibility criteria at Screening will return to the clinic on Day 1 to 
receive their first dose of study drug (either duvelisib or ofatumumab). The first treatment 
cycle for each treatment arm will be 3 weeks (21±2 days). Subsequent treatment cycles will be 
4 weeks (28±4 days). 
Arm 1 (Duvelisib):  Subjects randomized to duvelisib will receive their first dose of study 
drug in clinic on Day 1, initiating Cycle 1 of treatment. These subjects will return for a second 
clinical visit on Day 8±2. Cycle 1 will be 21 days, with all subsequent cycles 28 days in 
length. Cycle 2 will have clinic visits on Day 1 and on Day 15±2. Each subsequent cycle 
(Cycle 3-7) and then every odd cycle (Cycle 9 to 19) will have only one clinic visit on Day 1.  
Subjects will receive duvelisib continuously for 18 cycles or until disease progression or 
unacceptable toxicity, whichever comes first. After completing approximately 18 cycles of 
treatment with duvelisib, subjects who, in the judgment of the investigator, may derive benefit 
from continued treatment may receive additional cycles of duvelisib until disease progression 
or unacceptable toxicity. However, to receive additional cycles of duvelisib beyond 18 cycles, 
subjects must have CLL/SLL requiring treatment by Cycle 19 Day 1 (Reference 4.2.1.2). 
Subjects who receive duvelisib beyond 18 cycles (Cycle 19 Day 1) will maintain clinical 
visits every odd cycle (Cycle 21, 23, etc) until disease progression, subject withdrawal, or 
initiation of additional anticancer treatment. After Cycle 18, disease response assessments will 
continue every 6 cycles for those subjects who have not had disease progression, withdrawn 
consent, or initiated additional anticancer treatment.  
Arm 2 (Ofatumumab):  Subjects randomized to ofatumumab will receive IV treatment 
according to the approved prescribing information.10, 11  Subjects will receive 8 weekly IV 
infusions, starting with an initial dose of ofatumumab of 300 mg followed by seven weekly 
doses of 2000 mg. Thereafter, subjects will receive 2000 mg ofatumumab once every cycle 
for four cycles or until disease progression or unacceptable toxicity, whichever comes first. 


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Administration of ofatumumab will not exceed the 12 doses (within 7 cycles) as described in 
the prescribing information. After dosing with ofatumumab is complete (ie, through Cycle 7 
or ETT), subjects will continue to have clinical assessments every odd cycle 
(Clinical Assessment Period) through Cycle 19 Day 1 or until disease progression, subject 
withdrawal, or initiation of additional anticancer treatment. After Cycle 19 Day 1, disease 
response assessments will continue every 6 cycles until disease progression, subject 
withdrawal, or initiation of additional anticancer treatment. 
If a subject initiates another anticancer therapy following treatment with ofatumumab, then 
the subject will be discontinued from the Clinical Assessment Period and will be followed for 
survival as described in Table 5.    
Subjects who have documentation of PD confirmed centrally at any time during the study may 
be eligible to receive the opposite study medication as part of a separate Verastem-sponsored 
extension protocol (Study IPI-145-12). Additional extension protocol eligibility criteria must 
also be met. 
4.2 
DOSE INTERRUPTION/HOLD/MODIFICATION GUIDELINES 
4.2.1 
Duvelisib Guidelines 
Duvelisib treatment will consist of 25 mg administered orally BID continuously for up to 
18 cycles. Duvelisib may be continued beyond 18 complete cycles, if the subject meets the 
criteria for additional treatment at Cycle 19 Day 1 (see Section 4.2.1.2). Duvelisib dosing may 
be modified due to benefit or toxicity as described below. 
4.2.1.1 
Duvelisib treatment modification guidelines due to duvelisib-related toxicities 
Subjects will be monitored continuously for toxicity while on study treatment. Toxicity will 
be assessed using the National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) Version 4.03. If a subject has an AE at least possibly related to 
duvelisib, then dose interruptions/holds with possible modifications as described below in 
Table 8 may be implemented.  Deviations from these guidelines may occur based on the 
clinical judgment of the Investigator with notification to the Medical Monitor/Sponsor. There 
should be no attempt to make up for missed doses of duvelisib. 


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Table 8: Dose Interruption/Hold/Modifications for Duvelisib-Related Toxicities  
Duvelisib-related Toxicities a, b 
Dose Interruption/Hold/Modification/Recommendation for 
Duvelisib c 
Nonhematologic: 
Grade 2 or higher Pneumonitis/Pneumonia 
Or 
Grade 3 or higher other Nonhematologic  
First occurrence: 
Withhold until return to ≤Grade 1 or baseline level; re-
challenge therapy at original dose level. 
Second occurrence of the same AE:  
Withhold until return to ≤Grade 1 or baseline level; re-initiate 
therapy at one dose level lower from current dose. 
Third occurrence of the same AE: 
Withhold until return to ≤Grade 1 or baseline level; re-initiate 
therapy at one dose level lower from current dose. 
Fourth occurrence of the same AE: 
Discontinue subject from study drug 
Hematologic: 
Grade 3 or higher febrile neutropenia  
Or 
Grade 3 or higher thrombocytopenia with 
Grade ≥2 hemorrhage. 
Recommendations for implementing duvelisib dose interruptions 
 
Immediate hold for Grade 4 or higher nonhematologic toxicity and Grade 3 or higher febrile neutropenia. 
For all other events, reduce from BID dosing to QD for two days, then hold. 
a. 
Duvelisib-related toxicity = possible, probable, or definite relationship to duvelisib as defined in 
Section 8.2.1. 
b. Toxicity grades are defined per CTCAE Version 4.03.  Note if parameter is not defined by CTCAE, then 
AE grading criteria (Section 8.2.1) should be utilized. 
c. 
Refer to Table 9 for duvelisib dose levels. 
Treatment Interruption for Nonhematologic Toxicity 
Treatment with duvelisib should be interrupted for the following nonhematologic toxicities: 
• Grade 2 or higher pneumonitis/pneumonia, defined as symptomatic and requiring 
medical intervention, including oral antimicrobials and/or steroids  
o Subjects who develop new pulmonary symptoms (eg, cough, shortness of 
breath, dyspnea on exertion) or new radiographic findings should have 
duvelisib held and receive empiric antimicrobial coverage while undergoing 
evaluation. Corticosteroids for symptomatic treatment of pneumonitis is 
recommended (and allowed per protocol). Restarting treatment with duvelisib 
is allowed after complete resolution of symptoms.  
• Grade 3 or higher other nonhematologic toxicity including the following: 
o Infections: Subjects who develop infections requiring IV 
antibiotics/antifungals/anti-virals should have duvelisib held until infection 
resolves (subject may restart duvelisib when completing a course of oral 
therapy).  Prophylaxis to prevent recurrence/opportunistic infections will not 
preclude the subject from restarting treatment.  
o Hepatic events: Subjects who develop Grade 3 or higher transaminase 
(ALT/AST) elevations with or without clinical symptoms should have 
duvelisib held until return to baseline. Additional work-up to evaluate viral 
infection/re-activation, exposure to environmental toxins (eg, alcohol/con-
meds), or other causes is recommended before restarting treatment with 
duvelisib. 


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o Gastrointestinal: Subjects who develop Grade 3 or higher nausea, vomiting or 
diarrhea despite optimal treatment should have duvelisib held until resolution 
of symptoms.  Evaluation of concomitant medications, gastrointestinal 
infections or inflammatory bowel (via endoscopy and biopsy) should be 
considered with persistent diarrhea or recurrence with restarting duvelisib. 
Corticosteroids (budesonide) with taper are allowed if colitis is 
suspected/cannot be ruled out. 
o Skin rash: Subjects who develop Grade 3 or higher skin rashes should have 
duvelisib held until resolution of symptoms. In the setting of new Grade 1-2 
skin rash early intervention is recommended to ameliorate risk of worsening 
symptoms. Evaluation of concomitant medications, environmental exposure, 
infections or other contributing factors is recommended. 
o Cardiac: Subjects who develop Grade 3 or higher cardiac events should have 
duvelisib held until resolution of symptoms. This includes ≥ Grade 3 
(≥ 500 ms) QT interval corrected with Fridericia’s method (QTcF) 
prolongation. A ≥ Grade 3 QTcF prolongation requires triplicate ECGs with 
the average measurement used and the use of Fridericia’s correction method 
(QTcF). For subjects with a right or left BBB, a Grade 3 QTc prolongation is 
defined as an increase in QTcF of >100 ms from the pre-dose ECG to any post 
dose ECG as the QRS interval is prolonged at Baseline (by approximately 40 
ms) in subjects with a BBB 
Subjects requiring treatment interruption should be re-evaluated at least weekly until the 
toxicity improves to ≤ Grade 1 or returns to Baseline level. Duvelisib dose will be restarted at 
doses described in Table 9. 
Treatment Interruption for Hematologic Toxicity 
Worsening or transient Grade 3 or higher neutropenia, anemia, and/or thrombocytopenia 
caused by the subject’s existing disease (CLL or SLL) or by duvelisib are to be expected. 
Blood counts should be monitored as prescribed in the protocol with the frequency increased 
as clinically indicated in the setting of new or worsening Grade 3 or higher cytopenias.  
Duvelisib dosing may be interrupted at any time, at the discretion of the treating physician. 
Treatment with duvelisib should be interrupted for the following symptomatic hematologic 
toxicities: 
• Grade 3 or higher febrile neutropenia 
• Grade 3 or higher thrombocytopenia associated with Grade 2 or higher haemorrhage 
The subject should be re-evaluated at least weekly until the toxicity improves to ≤Grade 1 or 
returns to Baseline.  
Duvelisib may be withheld up to 42 days for toxicity.  Doses withheld for > 42 days due to 
treatment-related toxicity will result in permanent discontinuation from treatment.  Any 
subject who requires a dose < 5 mg BID due to treatment-related toxicities will be 
permanently discontinued from treatment.  Dose levels are shown in Table 9. 


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Table 9: Dosing Levels Duvelisib 
Dose Level 
Dose (mg)  
1 
25 BID 
-1 
15 BID 
-2 
10 BID 
-3 
5 BID 
Subjects who have a dose reduction due to a toxicity may be eligible for a dose increase back 
to the dose level prior to the reduction (ie, the starting dose or dose of previous reduction if 
subject was dose reduced more than one level) if the following criteria are met: 
1. Subject has tolerated the lower treatment dose for >1 treatment cycle 
2. Subject has recovered to baseline levels from the toxicity which caused the dose 
reduction 
4.2.1.2 
Duvelisib treatment modification guidelines due to benefit/maximal benefit. 
Treatment discontinuation due to benefit after < 18 complete cycles of duvelisib therapy:   
Prior to completion of 18 cycles of duvelisib therapy, discontinuation of duvelisib may be 
considered, after discussion with the medical monitor, should a CLL subject demonstrate a 
CR/CRi per IWCLL 2008 criteria or an SLL subject demonstrate a CR per IWG 2007 criteria 
(see Section 6.3.9 for definitions). The timing of duvelisib treatment discontinuation relative 
to the duration of a CR should be considered as follows: 
• < 12 months of duvelisib therapy: duration of CR/CRi > 6 months before 
discontinuation 
• ≥ 12 months of duvelisib therapy: duration of CR/CRi > 3 months before 
discontinuation 
Disease response assessments by CT scan will continue every 6 cycles until disease 
progression (see Table 5). 
Treatment discontinuation after 18 or more complete cycles of duvelisib therapy:   
After completion of 18 cycles (beginning on Day 1 Cycle 19) of duvelisib therapy, 
discontinuation of duvelisib may be considered if a subject demonstrates the following 
responses (per modified IWCLL criteria/IWG criteria or as otherwise indicated [see 
Section 6.3.9]) of > 3 months duration: 
• CR or CRi  
• Partial response (that includes all target lesions ≤ 1.5 cm in diameter) but with a 
peripheral blood absolute lymphocyte count (ALC) ≥ 4,000/µL (Rai Stage 0) 


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• Persistent lymphadenopathy > 50% of baseline (with at least 1 target lesion ≥ 1.5 cm 
in diameter) and persistent lymphocytosis ≥ 4,000/µL (and > 50% of baseline) 
Disease response assessments by CT scan will continue every 6 cycles until disease 
progression (see Table 5). 
Treatment continuation after 18 or more complete cycles of duvelisib therapy:   
Duvelisib therapy may continue if there is potential benefit to the subject based on the 
following disease response assessments (per IWCLL criteria /IWG criteria or as otherwise 
indicated [see Section 6.3.9]) at the end of 18 cycles (Day 1 Cycle 19) of duvelisib therapy: 
• CR or CRi < 3 months duration 
• PR with or without lymphocytosis 
• SD 
Disease response assessments by CT scan will continue every 6 cycles while the subject 
remains on duvelisib treatment (see Table 5). 
4.2.2 
Ofatumumab Guidelines 
Ofatumumab treatment guidelines follow the manufacturer recommendations for 12 
ofatumumab infusions administered over 6-7 months: 8 weekly ofatumumab infusions 
followed by an ofatumumab infusion every month for 4 months.  During the 6-7 months of 
ofatumumab infusions, therapy may be modified due to toxicity as described below.  
Ofatumumab dosing will not be extended beyond the 12 ofatumumab infusions, as described 
in Table 4 and the latest ARZERRA® prescribing information.10, 11   
4.2.2.1 
Ofatumumab treatment modification guidelines due to ofatumumab related 
toxicities 
Subjects will be monitored continuously for toxicity while on study treatment.  Toxicity will 
be assessed using the NCI CTCAE Version 4.03.  If a subject has an AE at least possibly 
related to ofatumumab, then dose interruptions/holds with possible modifications are 
described below. If the dose of ofatumumab is reduced, all reductions should be made per 
Prescribing Information.10, 11 Additional details on study drug dosage and administration are 
described in Section 7.2.1 and 7.2.2, respectively.  Deviations from these guidelines may 
occur based on the clinical judgment of the Investigator with notification to the Medical 
Monitor/Sponsor.  There should be no attempt to make up for a missed weekly dose of 
ofatumumab or a monthly dose of ofatumumab if delayed by >3 weeks. 
 
 


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Table 10: Dose Interruption/Hold/Modifications for Ofatumumab-Related Toxicities  
Ofatumumab-related Toxicities a, b 
Dose Interruption/Hold/Modification/Recommendation for 
Ofatumumab  
Infusion Reactions 
Infusion interruptions  
• 
For Grade 1, 2, or 3 infusion reaction, if the infusion reaction 
resolves or remains less than or equal to Grade 2, resume 
infusion with the following modifications according to the 
initial Grade of the infusion reaction. 
o 
Grade 1 or 2: Infuse at one-half of the previous 
infusion rate. 
o 
Grade 3: Infuse at a rate of 12 mL/hour. 
• 
After resuming the infusion, the infusion rate may be increased 
according to the Principal Investigator, based on subject 
tolerance. 
• 
For Grade 4 infusion reactions, do not resume the infusion. 
 
Modifications: 
• 
Grade 3 or 4 infusion reaction with previous infusion:  
o 
Reduce next ofatumumab dose to 300 mg 
• 
Increase subsequent dose(s) to 2000 mg if no Grade 3 or 4 
infusion reaction occurs 
Nonhematologic:  
Grade 3 or higher  
Withhold until return to ≤ Grade 1 or baseline level; re-challenge 
therapy at original dose level. 
Hematologic: 
Grade 3 or higher febrile neutropenia 
 
Withhold until return to ≤ Grade 1 or baseline level; re-challenge 
therapy at original dose level. 
Grade 3 or higher thrombocytopenia 
associated with Grade 2 or higher 
hemorrhage 
Withhold until return to ≤ Grade 1 or baseline level; re-challenge 
therapy at original dose level. 
a. 
Related = possible, probable, or definite relationship to ofatumumab as defined in Section 8.2.1. 
b. Toxicity grades are defined per CTCAE Version 4.03.  Note if parameter is not defined by CTCAE, then 
AE grading criteria (Section 8.2.1) should be utilized. 
 
Treatment Interruption for Infusion-related Toxicity 
The initial dose of ofatumumab will be 300 mg IV to reduce the possibility of infusion 
reactions.  If the subject tolerates this infusion without occurrence of any infusion-associated 
AEs of ≥ Grade 3, subsequent doses of ofatumumab will be at a dose of 2000 mg for the 
duration of study treatment.  If the subject experiences Grade 4 infusion reaction, the infusion 
should be stopped.  If the subject experiences a Grade 1-3 infusion reaction during the first 
infusion, ofatumumab should be interrupted and appropriate supportive care given.  If the 
infusion reaction improves to ≤ Grade 2, then administer at a slower rate (as described in 
Table 10 and the ARZERRA® package insert).  
Appropriate supportive care should also be given, until the infusion reaction improves to 
≤ Grade 1.  Following a Grade 3/4 infusion reaction, the next ofatumumab dose should be 
given at the starting dose of 300 mg. The ofatumumab dose may be escalated to 2000 mg 
following a dose in which no Grade 3/4 infusion reactions are experienced. 
 
 


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Treatment Interruption for Nonhematologic Toxicity 
Treatment with ofatumumab may be interrupted at any time, at the discretion of the treating 
physician. Treatment with ofatumumab should be interrupted for the following 
nonhematologic toxicities: 
• Any Grade 3 or higher nonhematologic toxicity (with the following modifications) 
− Grade 3 or higher diarrhea despite optimal antidiarrheal treatment 
− Grade 3 nausea, or vomiting despite optimal anti-emetic treatment 
− Grade 3 or higher cardiac events including ≥ Grade 3 QTcF prolongation 
(≥ 500 ms). A ≥ Grade 3 QTcF prolongation requires triplicate ECGs with the 
average measurement used and the use of Fridericia’s correction method 
(QTcF). For subjects with a right or left BBB, a Grade 3 QTc prolongation is 
defined as an increase in QTcF of >100 ms from the pre-dose ECG to any post 
dose ECG as the QRS interval is prolonged at Baseline (by approximately 40 
ms) in subjects with a BBB 
− Subjects who develop infections requiring IV antibiotics will have treatment 
held until the infection resolves (subject may restart ofatumumab while 
completing a course of oral therapy).  Requirement of prophylaxis for further 
infection will not prevent the subject from continuing treatment  
Subjects requiring dose interruption should be re-evaluated at least weekly until the toxicity 
improves to ≤ Grade 1 or returns to Baseline level. 
Treatment Interruption for Hematologic Toxicity 
Worsening or transient Grade 3 or higher neutropenia, anemia, and/or thrombocytopenia 
caused by the subject’s existing disease (CLL/SLL) or by ofatumumab are to be expected.  
Blood counts should be monitored as prescribed in the protocol with the frequency increased 
as clinically indicated in the setting of new or worsening Grade 3 or higher cytopenias.   
Ofatumumab dosing may be interrupted at any time, at the discretion of the treating physician.  
Treatment with ofatumumab should be held for the following symptomatic hematologic 
toxicity: 
• Grade 3 or higher febrile neutropenia 
• Grade 3 or higher thrombocytopenia associated with Grade 2 or higher hemorrhage  
The subject should be re-evaluated at least weekly until the toxicity improves to ≤ Grade 1 or 
returns to Baseline.  
Ofatumumab will be discontinued in subjects who develop viral hepatitis or have a diagnosis 
or symptoms suspicious of progressive multifocal leukoencephalopathy (PML).  
4.3 
TREATMENT DISCONTINUATION 
A subject should be withdrawn from the study treatment if, in the opinion of the investigator, 
it is medically necessary, or if it is the wish of the subject.  
Subjects will be withdrawn from treatment in case of any of the following reasons: 


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• An adverse event that requires permanent discontinuation of duvelisib or ofatumumab 
• Protocol-specified disease progression 
• Subject death 
• Subject lost to follow-up 
• Noncompliance to protocol  
• Investigator decision (including for benefit as described in Section 4.2.1.2) 
• Subject becomes pregnant 
• Termination of the study by sponsor 
• Voluntary withdrawal by subject 
• Subject requires additional anticancer therapy 
Adverse events leading to the discontinuation of a subject will be followed until resolution, 
resolution to baseline or until the event is considered stable or chronic. 
If a subject does not complete dosing through Cycle 19 Day 1 (duvelisib) or through Cycle 7 
(ofatumumab), then he/she should attend an Early Treatment Termination (ETT) Visit within 
7 days of last dose or the decision leading to treatment discontinuation (see Section 6.4). 
Assessments collected within 14 days of the ETT (within 30 days for Disease Response 
Assessment and QoLs) Visit do not need to be repeated at the ETT Visit. Following last dose, 
either due to ETT or completion of dosing, all subjects will complete a 30-day safety follow-
up visit (see Section 6.5.1). Scans will be performed at the ETT if a previous scan has not 
been performed within 30 days of the ETT visit. All subjects who discontinue treatment will 
be followed for survival (see Section 6.5.3.2). 
Subjects who discontinue study treatment for reasons other than PD, and have not withdrawn 
consent from overall study participation should enter the Clinical Assessment Period (Section 
6.5.2) and continue Disease Response Assessments (Section 6.5.3.1) as applicable. 
4.4 
STUDY DISCONTINUATION 
Subjects may voluntarily withdraw from the study at any time for any reason without 
prejudice.  
Subjects will be withdrawn from the study in case of any of the following reasons: 
• 
Subject death 
• 
Subject lost to follow-up  
• 
Completion of the follow-up period 
• 
Termination of the study by sponsor 
• 
Voluntary withdrawal by subject 
If the subject withdraws consent from the study overall participation (and not just study 
treatment), no further evaluations should be performed and no attempts should be made to 
collect additional data. 
 


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5 
STUDY POPULATION 
Approximately 300 subjects with a diagnosis of relapsed and/or refractory CLL or SLL will 
enroll in the study and be randomized equally (150 subjects per arm) to one of two treatment 
groups (25 mg duvelisib BID or ofatumumab). 
Approximately 100 sites will be initiated worldwide. It is anticipated that the entire study will 
accrue subjects over approximately16 months from the randomization of the first subject. 
5.1 
ENTRY CRITERIA 
5.1.1 
Inclusion Criteria 
Subjects must meet all of the following criteria: 
1. ≥ 18 years of age  
2. Diagnosis of active CLL or SLL that meets at least one of the IWCLL 2008 criteria for 
requiring treatment (Binet Stage ≥ B and/or Rai Stage ≥ I) 
3. Disease that has progressed during or relapsed after at least one previous CLL/SLL 
therapy 
4. Not appropriate for treatment with a purine-based analogue regimen (per NCCN or 
European Society for Medical Oncology [ESMO] guidelines), including relapse ≤ 36 
months from a purine-based chemoimmunotherapy regimen or relapse ≤ 24 months 
from a purine-based monotherapy regimen 
5. A cytogenetics or FISH analysis of the leukemic cells within 24 months of 
randomization is required to document the presence or absence of del(17p). Note: if a 
sample from within 24 months is not available, it should be evaluated as part of the 
screening laboratory evaluation to inform stratification 
6. Measurable disease with a lymph node or tumor mass > 1.5 cm in at least one 
dimension as assessed by computed tomography (CT) 
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 
(corresponds to Karnofsky Performance Status [KPS] ≥ 60%) 
8. Willingness by subject to be randomized to receive either ofatumumab or duvelisib at 
the dose and schedule defined in the protocol 
9. Must meet the following laboratory parameters: 
− Serum aspartate transaminase (AST/SGOT) or alanine transaminase 
(ALT/SGPT) ≤ 3 x upper limit of normal (ULN) 
− Total bilirubin ≤ 1.5 x ULN 
− Serum creatinine ≤ 2.0 x ULN 
− Hemoglobin ≥ 8.0 g/dL with or without transfusion support 
− Platelet count ≥ 10,000 µL with or without transfusion support 


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10. For women of childbearing potential (WCBP): negative serum β-human chorionic 
gonadotropin (βhCG) pregnancy test within 1 week before randomization (WCBP 
defined as a sexually mature woman who has not undergone surgical sterilization or 
who has not been naturally post-menopausal for at least 24 consecutive months 
[women ≤ 55 years] or 12 consecutive months [women > 55 years]) 
11. Willingness of male and female subjects who are not surgically sterile or 
postmenopausal to use medically acceptable methods of birth control from the first 
dose of study drug to 30 days after the last dose of duvelisib and for 12 months after 
last dose of ofatumumab. Sexually active men, and women using oral contraceptive 
pills, should also use barrier contraception  
12. Ability to voluntarily sign consent for and adhere to the entire study visit schedule and 
all protocol requirements 
13. Signed and dated institutional review board (IRB)/independent ethics committee 
(IEC)-approved informed consent form (ICF) before any study specific screening 
procedures are performed 
5.1.2 
Exclusion Criteria 
Subjects are to be excluded from the study if they meet any of the following criteria: 
1. History of Richter's transformation or prolymphocytic leukemia 
2. Autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP) 
that is uncontrolled or requiring > 20 mg once daily (QD) of prednisone (or 
equivalent) to maintain hemoglobin > 8.0 g/dL or platelets > 10,000 µL without 
transfusion support 
3. Refractory to ofatumumab (defined as progression or relapse < 12 months of receiving 
ofatumumab monotherapy or < 24 months of receiving an ofatumumab-containing 
regimen)  
4. Prior allogeneic transplant (prior autologous stem cell transplant > 6 months prior to 
study entry is permitted) 
5. Known central nervous system (CNS) lymphoma or leukemia; subjects with 
symptoms of CNS disease must have a negative CT scan or negative diagnostic 
lumbar puncture prior to randomization  
6. Prior exposure to a PI3K inhibitor (eg, GS-1101, duvelisib) or a Bruton’s tyrosine 
kinase (BTK) inhibitor  
7. Use of any of the following medications or procedures within the specified timeframe: 
− Use of live or live attenuated vaccines within 30 days prior to randomization  
− Chemotherapy, radiation therapy, or ablative therapy within 3 weeks of 
randomization 
− Tyrosine kinase inhibitor within 7 days of randomization  


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− Other investigational therapy (not included above) within 3 weeks of 
randomization 
8. Ongoing treatment with chronic immunosuppressants (eg, cyclosporine) or systemic 
steroids > 20 mg prednisone (or equivalent) QD. 
9. History of tuberculosis treatment within the preceding two years 
10. Ongoing systemic bacterial, fungal, or viral infections at the time of initiation of study 
treatment (defined as requiring intravenous [IV] antimicrobial, antifungal or antiviral 
agents) 
− Subjects on antimicrobial, antifungal or antiviral prophylaxis are not specifically 
excluded if all other inclusion/exclusion criteria are met and there is no evidence 
of active infection at randomization 
11. Human immunodeficiency virus (HIV) infection 
12. Prior, current or chronic hepatitis B or hepatitis C infection 
13. History of alcohol abuse or chronic liver disease (other than metastatic disease to the 
liver) 
14. Unable to receive prophylactic treatment for pneumocystis or herpes simplex virus 
(HSV) 
15. Baseline QTcF > 480 ms (average of triplicate readings) Note: This criterion does not 
apply to subjects with a right or left bundle branch block (BBB) 
16. Unstable or severe uncontrolled medical condition (eg, unstable cardiac function, 
unstable pulmonary condition), or any important medical illness or abnormal 
laboratory finding that would, in the investigator’s judgment, increase the subject’s 
risk while participating in this study 
17. Concurrent active malignancy other than nonmelanoma skin cancer or carcinoma in 
situ of the cervix, bladder, or prostate not requiring treatment.  Subjects with previous 
malignancies are eligible provided that they have been disease free for ≥ 2 years 
18. History of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia 
requiring medication or mechanical control within the last 6 months 
19. Administration of medications or foods that are strong inhibitors or inducers of 
CYP3A within 2 weeks of randomization 
20. Prior surgery or gastrointestinal dysfunction that may affect drug absorption (eg, 
gastric bypass surgery, gastrectomy) 
21. Major surgery or invasive intervention within 4 weeks prior to randomization 
22. Pregnant or breastfeeding women 
23. Hypersensitivity to ofatumumab or its excipients 
 
 


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6 
STUDY PROCEDURES AND ASSESSMENTS 
The Schedules of Assessments are summarized in Table 1, Table 2, Table 3, Table 4, and 
Table 5. Details related to the assessments are described below. 
6.1 
INFORMED CONSENT 
Subjects potentially eligible for participation must sign an informed consent form (ICF) prior 
to initiating any study specific procedures.  Standard of care assessments that fulfill study 
eligibility requirements may be performed prior to subject signing the ICF. 
6.2 
SCREENING PERIOD 
6.2.1 
Medical History, Physical Examination, and Screening Assessments 
The Investigator at the site is responsible for maintaining a record of all subjects screened and 
those who are enrolled into the study. 
During the screening visit, the following assessments will be performed: 
• Obtain signed ICF 
• Review inclusion/exclusion criteria 
o 
Prior histologic confirmation of CLL or SLL 
• Complete medical history: includes demographics, cancer history and documentation of 
all previous treatments and treatment results (ie, best response to previous disease specific 
treatments) prior procedures, current medications, and all medications used within 30 days 
prior to Screening 
• Obtain/confirm documentation of cytogenetics/FISH results with analysis for del(17p). In 
order to be valid, these previous results must be within 24 months (2 years) of 
randomization. Additional results for other cytogenetic abnormalities will be collected (if 
available)     
• Full physical examination, which includes vital signs (temperature, blood pressure [sitting 
for 5 minutes], pulse rate, and respiratory rate), height, and weight  
• ECOG* performance status (see Appendix 4) 
• Disease-related constitutional symptoms, (fatigue [as measured by ECOG Performance 
Status], fever [ie, temperature >38°C/100.5°F] without evidence of infection, weight loss, 
and drenching night sweats without evidence of infection  
• Subject-reported health-related QoL* questionnaires (EQ-5D and FACIT-F) will be 
administered at Screening.  If these instruments are not captured at Screening (< 7 days 
prior to Day 1 Cycle 1), then these assessments must be assessed at Cycle 1 Day 1 
predose; English language examples of these instruments are shown in Appendix 5 and 
Appendix 6 
• 12-lead ECG which should be conducted following an approximate 10-minute rest period 
in a semi-recumbent or supine position and obtained in triplicate within approximately a 5 


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minute time period. QTc measurements will use the Fridericia’s correction method 
(QTcF). 
• Blood chemistry laboratory parameters* (including liver function tests): sodium, 
potassium, chloride, bicarbonate (or CO2), albumin, total protein, creatinine, blood urea 
nitrogen (BUN) or urea, lipase, amylase, uric acid, calcium, phosphorus, magnesium, 
glucose, LDH, serum ALT, serum AST, total and direct bilirubin, and alkaline 
phosphatase. 
• Hematology laboratory parameters*: red blood cell (RBC) count, hemoglobin, hematocrit, 
platelets, white blood cell count with 5-part differential (neutrophils, lymphocytes, 
monocytes, eosinophils, basophils) such that an absolute neutrophil count (ANC) and an 
ALC can be derived if it is not already provided as part of the laboratory analysis, and 
coombs testing (direct and indirect).  Documentation of hematology labs within 7 days 
prior to randomization is required to confirm presence or absence of Grade 4 cytopenia for 
stratification at randomization. 
• Coagulation laboratory parameters* including prothrombin time (PT), and activated 
partial thromboplastin time (aPTT). For subjects receiving anticoagulation therapy 
affecting the PT, an International normalized ratio (INR) must be obtained. 
• Anti-hepatitis C antibody (HCV Ab), hepatitis B surface antigen (HBsAg) and hepatitis B 
core antibody (HBcAb).  
• Laboratory studies to assess the status of prior or current Cytomegalovirus (CMV) and 
Epstein-Barr virus (EBV) infection. These may include any or all of the following: CMV 
Ab (via a serology) and antigen [viral load detection via polymerase chain reaction (PCR)] 
or immunohistochemistry (pp65 CMV) and Epstein-Barr virus serology. 
• Serum pregnancy test for WCBP (must be performed within 7 days of randomization) 
• HIV test for all subjects without documentation of a prior negative HIV test  
• Baseline disease assessments, which include: 
− CT scans of chest, abdomen and pelvis are required for all subjects.  Other scans may 
be performed (eg, head/neck CT) if clinically indicated or if the area is a site of known 
disease.  Copies of all imaging/radiology films will be sent to a central laboratory for 
independent review.   
o Note: Magnetic resonance imaging (MRI) may be substituted if clinically 
indicated, but the modality chosen to evaluate each individual subject should 
be the same throughout the duration of the study. 
− Bone marrow aspirate and/or bone marrow biopsy (unless clinically contraindicated). 
* ECOG, QoL, hematology, liver function tests, blood chemistry, or coagulation evaluations 
may be performed within 7 days prior to study treatment (predose Cycle 1 Day 1).  If these 
Screening evaluations are performed within 7 days of Cycle 1 Day 1, these Screening 
results can be used in place of the Cycle 1 Day 1 assessments. 


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6.2.2 
Inclusion and Exclusion Criteria 
Inclusion and exclusion criteria (Section 5.1.1, Section 5.1.2, respectively) will be reviewed 
for each potential subject and documented in the source and electronic Case Report Form 
(eCRF). During the screening period a subject number will be assigned by the Interactive 
Response Technology (IRT). At randomization, the dose and schedule of study drug 
(duvelisib or ofatumumab) will be assigned by the IRT (see Section 7.6 for treatment 
assignment).   
6.3 
TREATMENT PERIOD 
6.3.1 
Assessments 
6.3.1.1 
Physical Examinations 
A focused physical exam should be performed at all clinic visits indicated in Table 2 and 
Table 4 and is to include assessment of liver/spleen size, clinical assessment of tumor masses 
(if accessible) and other clinically significant findings (new or previously noted at Screening). 
Results from the focused physical exams as outlined above will be utilized for disease status 
assessments at time points specific in Table 5.  Any new clinically significant abnormality 
from baseline should be recorded as an AE. 
6.3.1.2 
Vital Signs 
Vital signs should be performed throughout the study only if clinically indicated. Clinically 
significant changes should be recorded on the AE eCRF. 
6.3.1.3 
ECOG Performance Status 
For Cycle 1 Day 1 (predose), the ECOG performance evaluation may be performed within 7 
days prior to study treatment (Cycle 1, Day 1).  If the ECOG performance evaluation is 
performed within 7 days of Cycle 1 Day 1, this Screening result can be used in place of the 
Cycle 1 Day 1 ECOG performance. 
6.3.1.4 
Additional Assessments 
• Adverse events collection (Section 6.3.4) 
• Concomitant medication collection (Section 6.3.6) 
• Pharmacokinetic sample collection (Section 6.3.7) 
• Biomarker sample collection (Section 6.3.8) 
• CLL/SLL Disease Response Status Assessment (Section 6.3.9) 
6.3.2 
Clinical Laboratory Tests 
The following laboratory parameters will be conducted according to Table 1, Table 2, and 
Table 4: 


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• A serum pregnancy test at screening and urine or serum pregnancy tests while on 
treatment will be collected from all women of childbearing potential (WCBP).  
• Hematology laboratory parameters include RBC, hemoglobin, hematocrit, platelets, 
and white blood cell count with 5-part differential (neutrophils, lymphocytes, 
monocytes, eosinophils, basophils) such that an ANC and an ALC can be derived if it 
is not already provided as part of the laboratory analysis. Blood samples should be 
drawn and results reviewed within 72 hours of the designated clinic visit.  
• Coagulation laboratory parameters include prothrombin time (PT) and activated partial 
thromboplastin time (aPTT). The INR must be obtained for subjects receiving 
anticoagulation therapy.  Blood samples should be drawn and results reviewed within 
72 hours of the designated clinic visit. 
• Blood chemistry laboratory parameters include: albumin, total protein, uric acid, 
sodium, potassium, calcium, phosphorous, chloride, bicarbonate (or CO2), BUN or 
urea, creatinine, lipase, amylase, magnesium, and glucose. Liver function tests include 
lactate dehydrogenase (LDH), serum ALT, serum AST, total and direct bilirubin, and 
alkaline phosphatase. Blood samples should be drawn and results reviewed within 72 
hours of the designated clinic visit. 
• Serum quantitative Immunoglobulins (includes IgA, IgM, and IgG).   
For Cycle 1 Day 1 (predose), hematology, liver function tests, blood chemistry, or coagulation 
evaluations may be performed within 7 days prior to study treatment (Cycle 1, Day 1).  If 
these Screening evaluations are performed within 7 days of Cycle 1, Day 1, these Screening 
results can be used in place of the Cycle 1, Day 1 results. 
Clinically significant laboratory findings, including but not limited to those findings resulting 
in a drug interruption/reduction/discontinuation or medical intervention should be reported as 
an AE (see protocol Section 8.1.1 for definition of an AE). In the presence of Grade 3 or 
higher cytopenias, more frequent monitoring per institutional guidelines is recommended.  
6.3.3 
Study Drug Administration, Criteria for Treatment 
6.3.3.1 
Duvelisib 
Beginning on Cycle 1 Day 1, duvelisib 25 mg BID will be administered daily in an initial 21-
day cycle BID, followed by 28-day cycles. Subjects are required to receive pneumocystis 
prophylaxis concomitant with treatment with study drug per institutional guidelines. Subjects 
who are found to be intolerant of pneumocystis prophylaxis may continue with study 
treatment at the discretion of the Investigator. Herpes (HSV/VSV) or CMV prophylaxis 
concomitant with study drug is also recommended (Section 6.3.5).   
For a twice daily schedule, doses should be taken every 12 hours within ±2 hours of the 
scheduled dose. If reduced to a once daily dosing, doses must be taken once every 24 hours 
within ±4 hours of the scheduled dose.  Missed doses outside this window or vomited doses 
should not be taken or repeated. Duvelisib doses will be dispensed to the subject so that the 
subject has enough duvelisib doses until at least the next dispensation visit, taking into 


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account the dispensation visit window. Additional details on study drug dosage and 
administration are described in Section 7.2.1 and 7.2.2, respectively.   
An attempt should be made to enable each dose to be taken at approximately the same time of 
day.     
For dose modifications due to adverse events and laboratory abnormalities, see Section 4.2.1. 
6.3.3.2 
Ofatumumab 
Ofatumumab will be administered in accordance with the ARZERRA® Prescribing 
Information. Each subject randomized to ofatumumab will receive no more than 12 doses as 
described in Table 4. Refer to Section 6.3.5 for recommended prophylactic treatment. 
If the dose of ofatumumab is reduced, all reductions should be made per Table 10 (based on 
Prescribing Information). Additional details on study drug dosage and administration are 
described in Section 7.2.1 and 7.2.2, respectively.   
The date, time, and quantity of each infusion will be recorded in the source documents. 
For dose modifications due to adverse events and laboratory abnormalities, see Section 4.2.2 
and the ARZERRA® package insert. 
6.3.4 
Adverse Events 
For all subjects (including screen-failures), monitoring of AEs will be performed from the 
signing of the ICF. For randomized subjects, AEs will be collected on the AE eCRF from the 
signing of the ICF through 30 days after the final dose of either duvelisib or ofatumumab.   
See Section 8.2 for a full description of the collection and reporting of AEs during this study. 
6.3.5 
Subject-reported Outcomes Assessment 
The health outcomes assessment surveys are for the purpose of exploring the subject’s own 
perceptions about his or her QoL.  Every effort should be made to maintain an unbiased 
assessment. If the subject cannot complete the health outcomes assessments because of 
illiteracy or other documented reason, a proxy (such as a caregiver) cannot complete the 
questionnaires, as these questionnaires are intended to be subject-reported measures only.   
The Functional Assessment of Cancer Therapy (FACT) is a modular approach to assess 
patient health status using a ‘core’ set of questions (FACT-G), as well as a cancer site specific 
module.  The FACIT-Fatigue is a 13-item questionnaire derived from the FACT-G designed 
to assess patient concerns relating to the symptoms of fatigue.   
The EuroQol-5D is a standardized instrument that provides a simple descriptive profile and a 
single index value for health status, and patient preference or utility for a health state. It 
comprises 5 items, covering the domains of mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each of these domains is rated on 3 levels, higher 
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6.3.6 
Concomitant Medication and Therapies 
At every clinic visit, assessment of concomitant medications and procedures will occur. At 
screening, concomitant / previous medications will be assessed and includes all 
medications/procedures that have occurred within the previous 30 days.   
For all subjects during treatment 
• 
Antimicrobial prophylaxis:  
Infection is a recognized complication in patients with relapsed/refractory CLL leading to 
many treatment centers to employ antimicrobial prophylaxis.  Based on the duvelisib clinical 
experience to date and the ofatumumab product label (ARZERRA®) the following are 
required or recommended: 
o Pneumocystis infections have been reported in clinical studies with duvelisib and 
ofatumumab, therefore subjects are required to receive pneumocystis prophylaxis 
concomitant with treatment with study drug. Please follow institutional guidelines. 
Subjects who are found to be intolerant of pneumocystis prophylaxis may continue 
with study treatment at the discretion of the Investigator. 
o Herpes simplex (HSV) and herpes zoster (VZV) infections have been observed 
with duvelisib and ofatumumab; therefore, subjects are recommended to receive 
herpes (HSV/VZV) prophylaxis concomitant treatment per investigator discretion.  
Please follow institutional guidelines. 
o For subjects with history of CMV infection that required treatment, prophylactic 
treatment per institutional guidelines is recommended. 
 Subjects with history of CMV or EBV infection and/or who enter the study 
while receiving antiviral prophylaxis should be monitored for reactivation 
via serology or viral load detection per institutional guidelines while on 
study treatment  
o Other antimicrobial prophylaxis based on the individual subject’s medical history 
may be considered if no contraindications based on drug-drug interactions (DDI).  
See below. 
• Transfusion support (prophylaxis or supportive care):  
At study entry or during any time on treatment, blood cell transfusions (packed red blood cells 
or platelets) to maintain a subject’s hemoglobin ≥8.0 mg/dL or platelets ≥10,000 per µL is 
recommended.  Transfusions may be used at any time as clinically indicated.   
For subjects treated with ofatumumab 
• Premedication: 
Premedicate 30 minutes to 2 hours prior to each dose with oral acetaminophen 1,000 mg (or 
equivalent), oral or intravenous antihistamine (diphenhydramine 50 mg or equivalent), and 
intravenous corticosteroid (prednisolone 100 mg or equivalent). Do not reduce corticosteroid 
dose for Doses 1, 2, and 9. Corticosteroid dose may be reduced as follows for Doses 3 through 
8 and 10 through 12: 


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− Doses 3 through 8: Gradually reduce corticosteroid dose with successive infusions if a 
Grade 3 or greater infusion reaction did not occur with the preceding dose. 
− Doses 10 through 12: Administer prednisolone 50 mg to 100 mg or equivalent if a 
Grade 3 or greater infusion reaction did not occur with Dose 9. 
6.3.6.1 
Prohibited: Use of Vaccines 
For all subjects, the use of live or live attenuated vaccines is prohibited during the treatment 
with either study drug.  
The use of inactivated (or killed) vaccines is allowed during the study, however subjects and 
their physicians should be aware that the effectiveness of any vaccine administered 
concomitantly with duvelisib and ofatumumab may be diminished. The ability to generate an 
immune response to any vaccine following the administration of either duvelisib or 
ofatumumab has not been studied. 
6.3.6.2 
Prohibited: Immunosuppressants 
Subjects are not to receive ongoing treatment with chronic immunosuppressants (eg, 
cyclosporine) or systemic steroids for >1 week at doses > the equivalent of 20 mg prednisone 
QD. 
6.3.6.3 
Prohibited: PI3K Inhibitors or BTK Inhibitors 
Subjects are not to have received any prior exposure to any PI3K or BTK inhibitor prior to 
study entry. 
6.3.6.4 
Prohibited: Other Anticancer Therapy or Investigational Agents 
During the Clinical Assessment Period (through Cycle 19 Day 1 for both treatment arms), 
subjects are not to receive any additional anticancer therapy or other investigational agents 
(including BTK inhibitors and other PI3K inhibitors) not outlined in the protocol during the 
study. 
6.3.6.5 
Prohibited: (Duvelisib Subjects Only) 
• Medications or Food that Inhibit or Induce CYP3A4: 
In vitro data indicate that oxidative metabolism may play an important role in the elimination 
of duvelisib, with CYP3A4 identified as a primary contributor to drug metabolism.  Data from 
a drug-drug interaction study with ketoconazole (a potent CYP3A inhibitor) indicate exposure 
to duvelisib increased approximately 4-fold in the presence of ketoconazole. Similarly, 
exposure to duvelisib was reduced approximately 80% when coadministered with rifampin, a 
recognized CYP3A inducer.  Based on these data, the concomitant use of drugs or foods 
that are strong inhibitors or inducers of CYP3A are not allowed during study treatment 
with duvelisib. 


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Appendix 1 provides a list of medications known to be strong inhibitors or inducers of 
CYP3A. Please note that Appendix 1 is not a comprehensive list of all medications which 
may modulate CYP3A activity. 
Subjects should avoid eating grapefruits or grapefruit-containing products.  In addition, 
subjects should avoid herbal supplements including, but not limited to, St. John’s wort 
throughout the study as this is known to be a strong inducer of CYP3A.   
The Sponsor should be contacted with any questions regarding concomitant use of 
medications that are thought to modulate CYP3A activity.  The concomitant use of moderate 
or weak inhibitors may be allowed in selected circumstances after consultation with the 
medical monitor. 
6.3.6.6 
Use with Caution (Duvelisib Subjects Only):  
• Medications that are Substrates of CYP3A or CYP2C8  
In vitro studies in human liver microsomes have demonstrated duvelisib is an inhibitor of 
cytochrome P450 (CYP) enzymes CYP2C8 and CYP3A4. Coadministration of duvelisib with 
midazolam, a probe CYP3A substrate, resulted in an approximate 4-fold increase in 
midazolam systemic exposure (AUC). Systemic exposure to other medications that are 
substrates for CYP3A4 may be increased in subjects receiving duvelisib. The in vivo effect of 
duvelisib on the exposure of CYP2C8 substrates is not known. Caution should be used if 
duvelisib is used concomitantly with drugs or foods that are substrates of CYP2C8 and 
CYP3A4, particularly those with a narrow therapeutic index.  
Appendix 2 provides a list of medications known to be substrates of CYP3A or CYP2C8.  
Please note that Appendix 2 is not a comprehensive list of all medications which may be 
substrates of CYP3A or CYP2C8.  The Sponsor should be contacted with any questions 
regarding concomitant use of medications that are CYP3A or CYP2C8 substrates. 
• Medications that are Substrates or Inhibitors of P-glycoprotein 
In vitro data indicate that duvelisib is a substrate for P-glycoprotein (P-gp).  Concomitant 
medications that inhibit P-gp may cause the steady state concentration of duvelisib to be 
reached more quickly than usual.  Additionally, in vitro studies demonstrated that duvelisib 
has the potential to inhibit the active transport of other P-gp substrates. These medications 
may be used as medically indicated but with caution. 
Appendix 3 provides a list of medications that are substrates or inhibitors of P-gp.  Please note 
that Appendix 3 is not a comprehensive list of all medications which may be substrates of 
P-gp or may modulate P-gp activity.  The Sponsor should be contacted with any questions 
regarding concomitant use of medications that are thought to modulate P-gp activity.  
6.3.6.7 
Antiemetics and Antidiarrheals 
Antiemetic and antidiarrheal treatments may be used at the discretion of the Investigator and 
in accordance with the American Society of Clinical Oncology (ASCO) guidelines.  The 
choice of antiemetic or antidiarrheal treatment, if required, will be made at the discretion of 
the Investigator.  Subjects on stable doses of antiemetics and/or antidiarrheals to treat baseline 
conditions may continue on these therapies at the baseline dose. 


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6.3.6.8 
Hematopoietic Growth Factors 
Hematopoietic growth factors may be used at the discretion of the Investigator and in 
accordance with the ASCO guidelines. Prophylactic use of growth factors such as 
granulocyte-colony stimulating factor (G-CSF) and granulocyte macrophage-colony 
stimulating factor (GM-CSF) may be implemented if clinically indicated, in accordance with 
local guidelines and medical practice (eg, if a subject has Grade 4 neutropenia for ≥7 days, 
Grade 4 febrile neutropenia, or according to the NCCN practice guidelines for myeloid 
factors).  Subjects on a stable dose of erythropoietin to treat baseline anemia may continue on 
this therapy at this dose. 
6.3.6.9 
Other Concomitant Therapies 
Any other medication which is considered necessary for the subject’s welfare, and which is 
not expected to interfere with the evaluation of duvelisib or ofatumumab, may be given at the 
discretion of the Investigator. 
6.3.6.10 
Photosafety 
The effect of this medication on the skin, especially when in direct sunlight or with artificial 
ultraviolet (UV) light (eg, tanning booths) is not known.  As a general precaution, subjects 
should be advised to use appropriate protective measures to minimize exposure to direct 
sunlight or UV light sources during the treatment period and for at least 30 days after the last 
dose of duvelisib. 
6.3.7 
Pharmacokinetic Sampling 
Peripheral blood will be collected from all subjects at qualified sites who are randomized to 
the duvelisib study treatment arm to characterize the PK profile of duvelisib and, if applicable, 
its metabolites.  Samples will be collected at the following time points, as describe in Table 3. 
• Cycle 2 Day 1: ≤ 2 hours predose, 0.5 to 2 hours postdose, and 3 to 5 hours postdose. 
The morning dose of study medication will be administered in the clinic  
• Cycle 3 Day 1: anytime during the visit 
• Cycle 7 Day 1: anytime during the visit 
The exact date and time of the PK blood draws will be recorded, along with the date and time 
of the previous 2 doses of study medication. Additionally, collection of a PK sample is 
requested when feasible at the time of drug interruption/hold for an AE. If a subject 
permanently discontinues study treatment prior to Cycle 7, Day 1, PK blood samples no 
longer need to be collected. 
Subjects who have an unusual safety or efficacy event (ie, an AE different in type and severity 
from that which is expected in the setting of duvelisib use or an exceptional response to 
treatment) may be asked to have additional PK samples collected. These blood draws for 
pharmacokinetic analysis will only be performed after discussion between the Medical 
Monitor and the Principal Investigator. 


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6.3.8 
Biomarker Assessments  
The following biomarker samples will be collected throughout the study (time points 
described in Table 2 and Table 4) from subjects randomized to duvelisib or ofatumumab: 
• Serum 
• Blood 
• Buccal swab (if optional ICF is signed) 
• Archival tumor tissue (if available at any time during the study – not required for 
enrollment) 
• Bone marrow biopsies and/or aspirates (if obtained as part of clinical disease response 
assessments and tissue is remaining after clinical analysis, including pathology 
reports) 
The biomarker samples may be analyzed at a central laboratory, the Sponsor, or a specialized 
laboratory vendor for the various markers outlined below: 
• Serum for pharmacodynamic and predictive biomarkers such as chemokines, 
cytokines, and matrix metalloproteinases; serum may also be utilized to examine 
levels of known serum drug binding proteins.  
• Blood, archival tissue, and/or bone marrow biopsies for DNA and RNA 
pharmacodynamic and predictive biomarkers (includes genome-wide assessment of 
somatic mutations, DNA copy number changes, and gene expression changes to study 
CLL signaling pathways, disease pathogenesis, and response/resistance to duvelisib 
treatment)  
• Blood for assessment of del(17p), del(11q), del(13q), trisomy 12, and possibly other 
common leukemic cytogenetic abnormalities  
• Blood for tumor immunoglobulin heavy chain variable (IGHV) somatic hypermutation 
status  
• Blood for Immunophenotyping evaluations (eg, B/T-lymphocyte panel and CLL 
markers such as CD38 and ZAP70)  
• Tissue (archival, bone marrow biopsies and aspirates) for immunohistochemistry of 
PI3K pathway components such as PTEN and pS6   
• Buccal swab for germline DNA for pharmacogenomics and confirmation of mutations 
as somatic. (Optional with ICF) 
See the IPI 145-07 Laboratory Manual for biomarker sample handling procedures. 
6.3.9 
Disease Response Assessments 
Response and progression will be measured by the following assessments as indicated in 
Table 5: 
− Bone marrow aspirate and/or bone marrow biopsy 


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− CT scans of chest, abdomen and pelvis (See Section 6.3.9.1) 
− CBC and differential count 
− Blood sample for assessment of MRD in subjects with documented CR or CRi  
− Disease-Related symptoms 
o Focused Physical exam 
o ECOG performance status as a measure of fatigue 
o Disease-related constitutional symptoms (fever [ie, temperature 
>38°C/100.5°F] without evidence of infection, weight loss, and drenching 
night sweats without evidence of infection)  
These evaluations will be done until PD is documented or other anticancer therapy is initiated 
(at which point the subject will enter the Survival Follow-up Period), or death occurs. 
6.3.9.1 
CT Scans 
CT scans (contrast-enhanced preferred) of the chest, abdomen, and pelvis are required for all 
subjects to document measureable disease at baseline and will be performed as outlined in 
Table 5. Other scans may be performed (eg, head CT) if clinically indicated or if the area is a 
site of known disease. MRI may be substituted if clinically indicated, but the modality chosen 
to evaluate each individual subject should be the same throughout the duration of the study.   
If the subject is discontinued early from study treatment (eg, before Day 1 Cycle 7 of 
ofatumumab study treatment or before Day 1 Cycle 19 of duvelisib study treatment) and a 
previous assessment has not been performed within 30 days, CT scans will be also performed 
at the ETT and the subject will continue to undergo assessments as outlined in Disease 
Follow-up in Table 5.    
6.3.9.2 
Investigator assessment of response and progression status 
Assessment of response and progression status will be evaluated by the investigator for 
clinical decision-making using criteria derived from the IWCLL response criteria for subjects 
with CLL (Table 11) and IWG response criteria for subjects with SLL (Table 12).  
The CLL/SLL response definitions for this protocol (provided below) include modifications to 
the IWCLL/IWG response criteria related to PD based on the understanding that agents like 
duvelisib, which target the B-cell receptor signaling pathway, can mobilize CLL/SLL cells 
from tissues into the peripheral blood 23 interfering with their homing.24, 25 Specifically, two 
modifications have been made: (1) an additional category has been added to allow for PR with 
lymphocytosis (PRwL); and (2) the criteria for PD do not include PD based only on 
worsening lymphocytosis or isolated increase in target lesion(s) in the absence of other 
objective evidence of disease progression. 


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Table 11: CLL Response Criteria (modified from IWCLL) 1, 22 
Variable 
Complete Response 
(CR)  
Partial Response (PR)  
Progressive Disease (PD)  
GROUP A  
Lymphadenopathy  
(CT scan) 
None > 1.5 cm 
Decrease ≥ 50%  
New lesions (> 1.5 cm) or 
increase ≥ 50% in diameter of 
any single lesion or the SPD a 
Hepatomegaly 
(CT scan) b 
None 
Decrease ≥ 50% or 
normal 
Increase ≥ 50% of previously 
noted or de novo appearance a 
Splenomegaly 
(CT scan) b  
None 
Decrease ≥ 50% or normal 
Increase ≥ 50% of previously 
noted or de novo appearance a 
Blood lymphocytes 
< 4000/µL 
Decrease ≥ 50% from 
baseline or < 4,000/µL 
Increase ≥ 50% over baseline or 
nadir (whichever is lowest) and 
≥ 5,000 per µL 
Marrow c 
Normocellular, < 30% 
lymphocytes, no B-
lymphoid nodules. 
Hypocellular defines 
CRi in CLL subjects 
only 
If performed: 
50% reduction in 
marrow infiltrate, or 
presence of B-lymphoid 
nodules 
 
GROUP B 
Platelet count 
without transfusions 
or growth factors 
> 100,000/µL 
> 100,000/µL or 
increase ≥ 50% over 
baseline 
Decrease of ≥ 50% from 
baseline secondary to CLL 
Hemoglobin without 
transfusions or 
growth factors 
> 11.0 g/dL 
> 11.0 g/dL or increase 
≥ 50% over baseline 
Decrease of > 2 g/dL from 
baseline secondary to CLL 
Neutrophils without 
growth factors 
> 1500/µL 
> 1500/µL or ≥ 50% 
improvement over 
baseline 
 
Note: Group A criteria define tumor load; Group B criteria define the function of the hematopoietic system (or marrow) 
SPD = Sum of the products of multiple lymph nodes (as evaluated by CT scans). Use of Positron Emission Tomography 
(PET) imaging is not indicated in CLL/SLL. 
a. 
Disease progression confirmed by CT scan is required in the setting of PE findings without other Group A criteria or 
worsening disease-related constitutional symptoms/cytopenia(s). 
b. 
PE is the minimum requirement to meet criteria for PR or SD; CT scan is required for determination of response to 
confirm CR/CRi (CLL subjects only) or if PE is inconclusive.  
c. 
Bone marrow parameters may be irrelevant in the setting of some response categories. 
 
Complete Response/Remission (CR): all of the criteria have been met, and subjects have no 
disease-related constitutional symptoms 
Partial Response/Remission (PR): at least two of Group A criteria plus one Group B criteria 
have to be met.  For subjects with lymphadenopathy at baseline as the only abnormal Group A 
criteria (eg. no organomegaly, blood lymphocyte count < 4,000/µL, and negative bone 
marrow), all Group A criteria plus one Group B criteria have to be met. 


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PR with Lymphocytosis (PRwL): For subjects with lymphadenopathy at baseline as the only 
abnormal Group A criteria (eg. no organomegaly, blood lymphocyte count < 4,000/µL, and 
negative bone marrow) who have a ≥ 50% reduction in lymphadenopathy plus one Group B 
criteria but with isolated progressive lymphocytosis (blood lymphocyte count ≥ 4,000/µL). 
Stable Disease (SD): absence of PD and failure to achieve at least a PR/PRwL 
Progressive Disease (PD): appearance of any new lesions or at least one of the Group A or 
Group B criteria met with the following exceptions: 
− Due to the pharmacologic property of duvelisib to mobilize CLL cells from tissues 
into the peripheral blood, isolated lymphocytosis should not be considered progressive 
disease in the setting of other indications of response such as reduced lymph node size 
or organomegaly or improvement in hemoglobin/platelets22  
− If a new lesion or isolated increase in target lesion(s) may be attributed to another 
cause (eg, infection), these findings alone should not be considered to determine 
progressive disease, especially when observed in the setting of reduced lymph node 
size or organomegaly, or improvement in hemoglobin/platelets. Radiological 
persistence of these findings for >4 weeks is likely to indicate disease progression  
(CT scan confirmation required) 
 
 


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Table 12: SLL Response Criteria (modified from IWG) 2, 22 
Response 
Lymph Nodes a 
Spleen/Liver 
Blood 
Lymphocytes 
Bone Marrow b 
Complete 
Response 
(CR)  
Regression to normal 
size 
Normal size;  
nodules not present 
< 4000/µL 
If infiltrate present at 
screening, infiltrate 
cleared on repeat biopsy 
Partial Response 
(PR) c  
Decrease ≥ 50% in 
SPD of up to 6 
largest masses; no 
increase in size of 
other nodes 
Decrease ≥ 50% in SPD 
of nodules  
(or greatest transverse 
diameter for single 
lesion);  
no increase in size of 
liver or spleen 
Decrease ≥ 50%  
from baseline or  
< 4,000/µL 
Irrelevant if positive 
prior to therapy; cell 
type should be specified 
 
Stable Disease 
(SD) 
Failure to achieve CR/PR criteria or progressive disease 
Progressive 
Disease (PD) d,e,f 
New lesions  
(> 1.5 cm) or 
increase ≥ 50% in 
the SPD from nadir 
of more than 1 node, 
or ≥ 50% increase in 
the longest diameter 
of a node > 1 cm in 
short axis 
> 50% increase from 
nadir in the SPD of any 
previous nodules; 
unequivocal increase in 
liver/spleen size or de 
novo appearance of 
nodules 
Increase ≥ 50% over 
baseline or nadir 
(whichever is lowest) 
and   
≥ 5,000/µL 
 
a. 
Evaluated by CT (or MRI) with sum of the products (SPD) of multiple (up to 6) lymph nodes determined.  Use of 
Positron Emission Tomography (PET) imaging is not indicated in CLL/SLL.   
b. 
Subjects with CR by CT (or MRI) assessment of lymph nodes, liver/spleen, and peripheral blood without a negative 
bone marrow result (at baseline or at time of response assessment) will be considered a PR. 
c. 
PRwL: subjects who have a ≥ 50% reduction in lymphadenopathy, no organomegaly and a negative bone marrow 
(at baseline or at time of response assessment) with isolated progressive lymphocytosis (blood lymphocytes 
≥ 4,000/µL). 
d. 
PD must be confirmed by CT (or MRI) scan 
e. 
Due to the pharmacologic property of duvelisib to mobilize SLL cells from tissues into the peripheral blood, 
isolated lymphocytosis should not be considered progressive disease in the setting of other indications of response 
such as reduced lymph node size or organomegaly or improvement in hemoglobin/platelets22  
f. 
If a new lesion or isolated increase in target lesion(s) may be attributed to another cause (eg, infection), these 
findings alone should not be considered to determine progressive disease, especially when observed in the setting of 
reduced lymph node size or organomegaly, or improvement in hemoglobin/platelets. Radiological persistence of 
these findings for >4 weeks is likely to indicate disease progression (CT scan confirmation is required) 
At each scheduled disease response assessment, the investigator will be asked to provide a 
clinical response based on the parameters provided in Table 11 and Table 12 and assessment 
of disease-related constitutional symptoms. 


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6.3.9.3 
Independent assessment of response and progression status 
Disease progression and response for the primary and secondary endpoints will be evaluated 
by an independent panel of radiologists and oncologists using criteria derived from the 
IWCLL criteria (Table 11) for CLL subjects and the revised IWG criteria (Table 12) for SLL 
subjects. All disease response assessment data, including peripheral blood, physical exam, 
disease-related constitutional symptoms, and CT scans will be utilized in determining 
response and disease progression. Central review of imaging will be utilized to confirm 
investigator-assessed PD at the time of PD determination up to the time of the final analysis.   
6.4 
EARLY TREATMENT TERMINATION OF DUVELISIB OR 
OFATUMUMAB 
If at any time during treatment with study drug (duvelisib or ofatumumab) a subject has an 
AE resulting in permanent discontinuation of study treatment, PD, initiates new anticancer 
therapy, or withdraws consent, then the assessments outlined below will be performed within 
7 days of study treatment discontinuation or the decision to discontinue study treatment. ETT 
assessments include: 
If performed within previous 14 days, do not need to be repeated: 
• Urine or serum pregnancy tests will be collected from all women of childbearing 
potential (WCBP) 
• Concomitant Medications and Procedures collection 
• AE and SAE assessment 
• Blood chemistry 
• Liver function tests 
• Biomarker assessments  
If performed within previous 30 days, do not need to be repeated: 
• Disease response assessments: 
o Focused physical exam /constitutional symptoms 
o Bone marrow biopsy/aspirate (if indicated) 
o Hematology 
o Blood sample for MRD 
o ECOG 
o CT scan  
o Quality of life (QoL) EQ-5D and FACIT-F 
 
 


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6.5 
POST-TREATMENT PERIOD 
6.5.1 
Safety Follow-up Visit (30 Days Post-Treatment) 
6.5.1.1 
Duvelisib 
For subjects randomized to duvelisib, a visit should occur 30+7 days after discontinuation or 
last dose of duvelisib as outlined in Table 2. If possible, this visit should be conducted prior to 
initiation of any subsequent therapy. This visit may be a conducted as a phone screen as long 
as the study subject does not require laboratory and/or other assessments related to any new or 
ongoing AEs, in which case a clinical visit will be required. Assessments should include: 
− AEs/SAEs collection  
− Concomitant medications and procedures collection  
 
Following the last dose of duvelisib, subjects will continue follow-up as described in Table 2 
and Table 5. 
6.5.1.2 
Ofatumumab 
For subjects randomized to ofatumumab, a visit should occur 30+7 days after discontinuation 
or last administration of ofatumumab.  If possible, this visit should be conducted prior to 
initiation of any subsequent therapy. This visit may be a conducted as a phone screen as long 
as the study subject does not require laboratory and/or other assessments related to any new or 
ongoing AEs, in which case a clinical visit will be required.  Assessments include: 
− AEs/SAEs collection  
− Concomitant medications 
 
Following the last dose of ofatumumab, subjects will continue follow-up as described in 
Table 4 and Table 5. 
6.5.2 
Clinical Assessment Period 
6.5.2.1 
Duvelisib 
Subjects who come off treatment with duvelisib prior to Cycle 19 Day 1 for reasons other than 
PD will continue clinic visits every other month through Cycle 19 Day 1. During this period, 
subjects will not receive any additional anticancer therapy (including duvelisib).  
Assessments are outlined in Table 2 and Table 5. 
Note: If a subject experiences PD within this period, then that subject may be offered 
ofatumumab treatment as part of another study (Study IPI-145-12) to evaluate the safety and 
efficacy of ofatumumab therapy after duvelisib therapy.  
All subjects will be followed every 6 months for survival for up to 6 years from 
randomization.  


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6.5.2.2 
Ofatumumab 
Subjects who complete treatment with ofatumumab (Cycle 7) or come off for reasons other 
than PD will enter a Clinical Assessment Period through Cycle 19 Day 1. During this period, 
clinical visits will occur every other (odd) month and subjects will not receive any additional 
anticancer therapy (including ofatumumab).  
Assessments in the Clinical Assessment Period are outlined in Table 4 and Table 5. 
Note: If a subject experiences PD within this period, then that subject may be offered 
duvelisib treatment as part of another study to evaluate the safety and efficacy of duvelisib 
therapy after ofatumumab therapy.  
All subjects will be followed every 6 months for survival for up to 6 years from 
randomization.  
6.5.3 
Follow-up 
6.5.3.1 
Disease Follow-up 
Subjects who discontinue treatment with duvelisib or ofatumumab early (ie, ETT) due to 
reasons other than PD will continue to undergo disease response assessments up until Cycle 
19 Day 1 (ie, Cycles 5, 7, 11, 15 and 19) or until disease progression, subject withdrawal, or 
initiation of additional anticancer therapy. After Cycle 19 Day 1, all subjects without 
progressive disease will enter Disease Follow-up. CBC and differential count will be 
performed approximately 3 months after the last assessment, and every 3 months thereafter 
until disease progression, subject withdrawal, or initiation of additional anticancer therapy. 
All other disease assessments should occur approximately 6 months after the Cycle 19 Day 1 
Disease Response Assessment, and every 6 months thereafter until disease progression, 
subject withdrawal, or initiation of additional anticancer therapy.  The following assessments 
should be performed as outlined in Table 5. 
Every 3 months 
• CBC and differential count  
Every 6 months 
• CT scans of chest, abdomen and pelvis   
• Bone marrow biopsy and/or bone marrow aspiration (when clinically indicated) 
• Blood sample for assessment for minimum residual disease (MRD) in subjects with 
documented CR or CRi 
• Focused physical examination, ECOG performance status, and disease-related 
constitutional symptoms 
6.5.3.2 
Survival Follow-up 
For all subjects, survival follow-up will occur every 6 months for up to 6 years after 
randomization or until death. The first follow-up should occur 6 months (±4 weeks) from 
documentation of PD or treatment discontinuation. For both duvelisib and ofatumumab-
treated subjects, information on initiation of other anticancer therapy will also be collected at 


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each survival follow-up; these assessments may be collected through a telephone interview. 
Please see Table 5 for more details on the follow-up assessments. 
6.6 
MISSED VISITS 
If a subject misses a scheduled visit, the subject will continue on the protocol and attend the 
next scheduled visit.  If a subject misses 2 scheduled visits, then the subject’s continued 
participation in the study must be re-evaluated (see Section 4.3 and Section 4.4).   
 
 


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7 
INVESTIGATIONAL MEDICINAL PRODUCT  
7.1 
DESCRIPTION OF INVESTIGATIONAL MEDICINAL PRODUCT 
Duvelisib drug substance is a white to off-white crystalline powder.  The duvelisib drug 
product is formulated with excipients (Diluent, glidant, disintegrant, and lubricant) that are 
listed in Food and Drug Administration’s (FDA) Inactive Ingredients Database for approved 
drug products and/or Generally Regarded as Safe (GRAS) in two different capsule strengths 
(5 mg and 25 mg) for oral delivery.   
7.2 
DOSAGE AND ADMINISTRATION 
7.2.1 
Dosage 
7.2.1.1 
Duvelisib 
Duvelisib will be administered daily in 28-day cycles (with the exception of Cycle 1 which is 
21 days).  Duvelisib is administered orally as a capsule formulation and will be supplied by 
the Sponsor.  Duvelisib will be administered as a fixed dose in mg/day and should be 
administered using the minimal number of capsules necessary.   
For an individual subject, dose reductions and discontinuations may be based on the clinical 
judgment of the Investigator with notification to the Medical Monitor/Sponsor (see 
Section 4.2.1.1). 
7.2.1.2 
Ofatumumab 
Subjects randomized to ofatumumab will receive treatment consistent with the approved 
product labeling: an initial IV dose of 300 mg ofatumumab on Day 1 followed by seven 
weekly doses of 2000 mg. Thereafter, subjects will receive 2000 mg ofatumumab once every 
month for four months through Cycle 7 or until disease progression or unacceptable toxicity 
(whichever comes first), as outlined in the schedule of assessments. Administration of 
ofatumumab will not exceed the 12 doses (within 7 cycles) as described in the prescribing 
information. For an individual subject, dose reductions (see Table 10) and discontinuations 
may be based on the clinical judgment of the Investigator with notification to the Medical 
Monitor/Sponsor.  
7.2.2 
Administration 
7.2.2.1 
Duvelisib 
Duvelisib should be taken daily BID (every 12 ±2 hours) in 28-day cycles.  Cycle 1 is a 21-
day cycle. 
On Cycle 2 Day 1, the morning dose of study medication will be administered in the clinic to 
accommodate PK sample collection. An attempt should be made to enable each dose to be 


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taken at approximately the same time of day.  Missed doses outside the windows defined 
above or vomited doses should not be taken or repeated.   
Duvelisib doses will be dispensed to the subject so that the subject has enough duvelisib doses 
until at least the next dispensation visit, taking into account the dispensation visit window.   
Duvelisib capsules should be swallowed whole with a glass of water (approximately 8 ounces 
or 240 mL) at approximately the same time(s) each day.  Subjects must avoid grapefruit and 
grapefruit juice.  
Duvelisib may be administered without regard to meals. 
7.2.2.2 
Ofatumumab 
Ofatumumab will be administered via infusion, as described in the ofatumumab 
(ARZERRA®) package insert.10, 11 Please refer to the country-specific package insert for more 
details. 
7.3 
PACKAGING AND LABELING 
Duvelisib will be supplied to the clinical trial site as open-label medication.  Please refer to 
the IPI-145-07 Pharmacy Manual for details regarding packaging and labeling of 
Investigational Product.   
7.4 
STORAGE AND HANDLING 
7.4.1 
Duvelisib 
Duvelisib must be stored at room temperature (15 to 30°C). 
Caution is required when handling duvelisib.  Pharmacists should follow standard procedures 
for the handling of investigational drugs, including avoidance of eye or skin contact with the 
drug product.  If there is exposure to the drug product, provide treatment as necessary for 
physical exposure (skin washing) or inhalation (move to fresh air) and seek medical advice as 
necessary. 
When duvelisib capsules are distributed for self-administration, they should only be handled 
by the study subject.  After handling capsules, the subject should wash their hands 
thoroughly.  If someone who is not enrolled in a clinical trial involving duvelisib swallows a 
capsule or inhales drug powder from a broken capsule of duvelisib, they should contact the 
relevant Principal Investigator to determine whether safety monitoring is necessary.  Capsules 
should always be stored in the container provided to the study subject.  Refer to Section 
8.2.3.2 for details on reporting any exposure. 
7.4.2 
Ofatumumab 
Ofatumumab (ARZERRA®) is supplied as a sterile, clear to opalescent, colorless, 
preservative-free liquid concentrate (20 mg/mL) for dilution and intravenous administration 
provided in single-use glass vials with a latex-free rubber stopper and an aluminum over seal. 


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Each vial contains either 100 mg ofatumumab in 5 mL of solution or 1,000 mg ofatumumab in 
50 mL of solution. 
Store ARZERRA® refrigerated between 2° to 8°C (36° to 46°F). Do not freeze. Vials should 
be protected from light.  
See ARZERRA® package insert for more details.10, 11 
7.5 
INVESTIGATIONAL MEDICINAL PRODUCT ACCOUNTABILITY 
7.5.1 
Duvelisib 
The Investigator or designee is responsible for taking an inventory of each shipment of 
duvelisib investigational supplies received, and comparing it with the accompanying drug 
accountability form. 
All unused duvelisib will be retained at the site.  After full drug accountability and 
reconciliation, the Investigator will dispose of the study drug at the clinical trial site according 
to site procedures, or at the Sponsor’s request will return all duvelisib to the Sponsor, or its 
designee.  If any study drug is lost or damaged, the disposition of the study drug should be 
documented.   
Subjects should be instructed to bring all unused duvelisib to each study visit.  The study site 
should count all capsules that the subject returns, and should take account for taken doses, 
missed doses, doses reduced due to missing or lost capsules, etc., before dispensing new study 
drug to the subject.  Any subject who does not take the prescribed dose should be requested to 
return the remaining drug to the clinical trial site for accountability. 
7.5.2 
Ofatumumab 
For Sponsor supplied Ofatumumab, the Investigator or designee is responsible for taking an 
inventory of each shipment received, and comparing it with the accompanying drug order 
form. 
All unused Ofatumumab will be retained at the site.  After full drug accountability and 
reconciliation, the Investigator will dispose of the study drug at the clinical trial site according 
to site procedures, or at the Sponsor’s request will return all ofatumumab to the Sponsor, or its 
designee.  If any study drug is lost or damaged, the disposition of the study drug should be 
documented. 
7.6 
ASSIGNMENT TO TREATMENT 
Once a subject has met all entry criteria, the IRT will be used to generate a distinct subject 
identifier. Eligible subjects will be randomized within 7 days prior to receipt of first dose of 
study drug. If a subject discontinues from the study, the subject identifier will not be reused 
and the subject will not be allowed to re-enter the study.  
Eligible subjects will be randomized via IRT in a 1:1 ratio to one of two treatment arms:  
• Arm 1: Duvelisib 25 mg BID  


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• Arm 2: Ofatumumab  
In order to ensure subject balance between treatment groups, study subjects will be stratified 
by the following: 
• High risk cytogenetics (presence vs absence of del[17p]) 
• Refractory/early relapse to purine analog based treatment (progression <12 months 
after fludarabine/pentostatin: yes vs no)  
• Grade 4 cytopenia(s) (presence vs absence of neutropenia or thrombocytopenia at 
baseline)   
Randomization is to occur within 7 days of first dose after all screening assessments have 
been completed. 
7.7 
ASSESSMENT OF COMPLIANCE 
7.7.1 
Duvelisib 
At each applicable visit, doses will be dispensed to the subject so that the subject will have 
enough doses until the next applicable visit, taking into account the window for that 
subsequent visit.  Compliance for doses taken outside of the clinic will be assessed by a count 
of the capsules returned to the study trial site by the subject and review with the subject.  
7.7.2 
Ofatumumab 
Ofatumumab will be administered via infusion as described in the package insert by the test 
article administrator.   
7.8 
TREATMENT OF OVERDOSE 
In the case of overdose, clinic staff should be notified immediately and supportive care is to 
be given as indicated.  Subjects should be informed to contact their doctor immediately if they 
have taken an overdose and should stop taking duvelisib. 
No data is available regarding overdosage with ofatumumab.  Supportive care is to be given 
as indicated in the event of an ofatumumab overdosage. 
 
 
 


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8 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.1 
DEFINITIONS 
The definitions of AEs and SAEs are provided below. 
8.1.1 
Adverse Event 
An AE is any untoward medical occurrence associated with the use of a drug or with study 
participation, regardless of the relationship of the occurrence to study drug or protocol.  An 
AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom or disease temporally associated with the use of the drug, whether or not considered 
related to the drug.  An AE can arise from any use of the drug, and from any route of 
administration, formulation or dose, including an overdose.  
Medical conditions present prior to the initiation of the study, as well as ongoing changes in 
laboratory values/conditions that are being treated at baseline, will be captured as an AE if the 
condition worsens. 
8.1.2 
Adverse Reactions and Suspected Adverse Reactions 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered adverse drug reactions.  Suspected adverse reactions are any adverse events for 
which there is a reasonable possibility that the drug caused the adverse event. Adverse 
reactions also include medication errors and uses outside of what is foreseen in the protocol, 
which may include misuse, abuse, and overdose (intentional or unintentional) of the product. 
8.1.3 
Serious Adverse Event 
An adverse event or suspected adverse reaction is considered serious if, in the view of either 
the investigator or Sponsor, it results in any of the following outcomes: 
• Results in death 
• Is immediately life-threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
− Elective or pre-planned treatment for a pre-existing condition that is unrelated to 
the indication under study and has not worsened since signing the ICF (as 
documented as medical history on the eCRF), or 
− Scheduled therapy for the target disease of the study, including admissions for 
transfusion support or convenience 
• Results in persistent or significant disability / incapacity 
• Results in congenital anomaly / birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization, may be considered a serious adverse drug experience when, based upon 


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appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition.  Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
8.2 
PROCEDURES FOR ELICITING, RECORDING, AND REPORTING 
ADVERSE EVENTS 
8.2.1 
Eliciting and Recording Adverse Events 
Subjects will be instructed to report all AEs and will be asked a general health status question 
at each study visit.  All AEs occurring in randomized subjects will be recorded in the eCRF 
from the time of ICF until 30 days after the last dose of study treatment. An AE will be 
followed until it is either resolved, has returned to baseline, or is determined to be a stable or 
chronic condition.  All SAEs occurring from the signing of ICF through 30 days post last 
study drug will be processed as outlined in Section 8.2.3.   
At each required visit during the trial, all AEs that have occurred since the previous visit must 
be reviewed.  The Investigator or appropriate designee must determine if the adverse event is 
serious or non-serious.   
8.2.1.1 
Relationship to Study Drug 
The Investigator is required to provide an assessment of relationship of AEs and SAEs to 
study drug.  A number of factors should be considered in making this assessment including:  
1) the temporal relationship of the event to the administration of study drug; 2) whether an 
alternative etiology has been identified; and/or 3) biological plausibility. The following 
guidelines should be used by Investigators to assess the relationship of an AE to the 
administration of the study drug.   
Relationship assessments that indicate the event is “Not Drug Related”: 
• None:  The event is related to an etiology other than the study product administration 
(the alternative etiology must be documented in the study subject’s medical record). 
• Remote:  The event is unlikely to be related to the study product and likely to be 
related to factors other than study product. 
Relationship assessments that indicate the event is “Drug Related”: 
• Possible:  There is an association between the event and the administration of study 
drug, and there is a plausible mechanism for the event to be related to the study 
product; but there may also be alternative etiology, such as characteristics of the 
subject’s clinical status or underlying disease. 
• Probable:  There is an association between the event and the administration of study 
drug, there is a plausible mechanism for the event to be related to the study product, 
and the event could not be reasonably explained by known characteristics of the 
subject’s clinical status or an alternative etiology is not apparent. 


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• Definite:  There is an association between the event and the administration of study 
drug, there is a plausible mechanism for the event to be related to the study product, 
and causes other than study drug have been ruled out and/or the event re-appeared on 
re-exposure to study drug. 
8.2.1.2 
Adverse event severity 
The Grade of the AE will be assessed according to the NCI-CTCAE Version 4.03.  Toxicities 
that are not specified in NCI-CTCAE Version 4.03 will be defined as follows:  
• Grade 1:  Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
• Grade 2:  Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL). 
• Grade 3:  Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL. 
• Grade 4:  Life-threatening consequences; urgent intervention indicated. 
• Grade 5:  Death related to AE. 
Note: it is important to distinguish between SAEs and severe AEs. Severity is a measure of 
intensity, whereas seriousness is classified by the criteria based on the regulatory definitions 
as described in Section 8.2.1.2 above.  
8.2.2 
Specific Instructions for Recording Adverse Events on the eCRF 
8.2.2.1 
Diagnosis versus Signs and Symptoms 
If a diagnosis is known at the time of reporting, this should be recorded in the eCRF and/or 
SAE Report Form, as applicable, rather than the individual signs and symptoms (eg, record 
only hepatitis rather than elevated transaminases, bilirubin, jaundice).  However, if a 
constellation of signs and/or symptoms cannot be medically characterized as a single 
diagnosis or syndrome at the time of reporting, each individual event should be recorded as an 
SAE or AE on the eCRF (and SAE Report Form, if applicable).  If a diagnosis is subsequently 
established, it should be reported as follow-up on the eCRF (and follow up SAE report, as 
applicable) and should replace the individual signs and/or symptoms as the event term on the 
eCRF (and SAE report form, if applicable), unless the signs/symptoms are clinically 
significant. 
8.2.2.2 
Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (eg, clinical sequelae or a cascade of 
events) should be identified by their primary cause.  For example, if severe vomiting is known 
to result in dehydration, it is sufficient to record only vomiting as the SAE or AE on the eCRF 
(and SAE Report Form, if applicable). However, medically significant AEs occurring 
secondary to an initiating event that are separated in time should be recorded as independent 


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events on the eCRF (and SAE Report Form, if applicable).  For example, if severe vomiting 
leads to acute renal failure, both events should be recorded on the eCRF (SAE Report Form) 
8.2.2.3 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between subject 
evaluation time points.  Such events should only be recorded once on the AE eCRF (and SAE 
Report Form, if applicable).  If a persistent AE changes in grade, it should be recorded as a 
new AE on the eCRF. 
A recurrent AE is one that occurs and resolves between subject evaluation time points, and 
subsequently recurs.  All recurrent AEs should be recorded on the eCRF (and SAE Report 
Form if applicable). 
8.2.2.4 
Abnormal Laboratory Values 
If an abnormal laboratory value or vital sign is associated with clinical signs and/or 
symptoms, the sign or symptom should be reported as an AE or SAE, and the associated 
laboratory value or vital sign should be considered additional information and collected on the 
relevant eCRF.  If the laboratory abnormality is a sign of a disease or syndrome, only the 
diagnosis needs to be recorded on the eCRF (and SAE Report Form, if applicable). Abnormal 
laboratory values will be reported as an AE if the laboratory result: 
• requires an adjustment in the trial drug(s) or discontinuation of treatment  
• require additional testing or surgical intervention  
• is associated with accompanying symptoms  
• is considered to be an AE by the investigator 
8.2.2.5 
New Cancers 
The development of a new primary cancer should be regarded as an AE and will generally 
meet at least one of the serious criteria (see Section 8.1).  New primary cancers are those that 
are not the primary reason for the administration of the trial treatment and have developed 
after the inclusion of the subject into the trial.  They do not include metastases of the original 
cancer.   
Progression of the disease under study (disease progression) is not an AE/SAE, unless fatal.  
8.2.2.6 
Medication Errors, Misuse and Abuse of Study Drug 
Overdose, medication error, misuse and abuse are defined as follows: 
• Overdose: refers to the administration of a quantity of study drug given per 
administration or cumulative, which is above the maximum dose according to the 
protocol.  Clinical judgment should always be applied. 
• Medication error: refers to an unintentional error in dispensing or administration of 
study drug not in accordance with the protocol.   


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• Off-label use: relates to situations where the study drug is intentionally used for 
medical purpose not in accordance with the protocol. 
• Misuse: refers to situations where the study drug is intentionally and inappropriately 
used not in accordance with the protocol. 
• Abuse: corresponds to the persistent or sporadic, intentional excessive use of the study 
drug, which is accompanied by harmful physical or psychological effects. 
• Occupational exposure: refers to the exposure to the study drug as a result of one’s 
professional or non-professional occupation. 
Overdoses, medication errors, abuse or misuse will be collected as part of investigational 
medicinal product dosing information and/or as a protocol violation, as required.   
Any AE associated with an overdose, medication error, misuse or abuse of study drug should 
be recorded on the AE eCRF with the diagnosis of the AE.   
8.2.3 
Reporting of Serious Adverse Events 
8.2.3.1 
Immediate Reporting of Serious Adverse Events by Investigator to Sponsor 
All SAEs (including SAEs occurring in screen failure and randomized subjects) will be 
reported to the Sponsor or designee within 24 hours of the Investigator’s first knowledge of 
the event, even if the experience does not appear to be related to duvelisib or ofatumumab, 
from the time of signing ICF through 30 days after the last dose of study drug.   
Serious adverse events should be communicated on an SAE report form as follows:  
• Email: rtpsafety@ppdi.com 
• Hotline (Phone): 888-483-7729 (USA)  
• Fax: 888-529-3580 (USA)  
• For international numbers, please refer to the SAE Report Form and supporting 
documentation. 
The initial SAE report must be as complete as possible, including details of the current illness 
and (serious) AE, and an assessment of the causal relationship between the event and the 
investigational product(s).  Information not available at the time of the initial report (eg, final 
diagnosis, an end date for the AE, or relevant laboratory values received after the report) must 
be documented on a follow-up SAE Report Form.  All SAE follow-up information must be 
reported in the same timelines as initial information (ie, within 24 hours of the investigator’s 
first knowledge of information). 
At any time after completion of the AE reporting period (ie, 30 days post-treatment), if an 
Investigator becomes aware of an SAE that is suspected by the Investigator to be related to 
study drug, the event must be reported as described above. 


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8.2.3.2 
Immediate Reporting of Medical Events of Interest 
Reports or laboratory results of AST or ALT > 3x ULN in combination with total bilirubin 
> 2x ULN are medical events of interest, and therefore immediately reportable events, even 
if the events do not meet serious adverse event criteria.   
Clinical findings of Grade 3 or higher rash are medical events of interest, and therefore 
immediately reportable events, even if the events do not meet serious adverse event 
criteria.  Pre-existing skin conditions that recur would not meet this definition unless the 
recurrence is of a greater severity/frequency than previously experienced. 
All medical events of interest will be reported to the Sponsor or designee within 24 hours of 
the Investigator’s first knowledge of the event, even if the experience does not appear to be 
related to study drug.  Medical Events of Interest should be communicated on the SAE / 
Medical Events of Interest (MEOI) report form, as described above for SAEs.  
Any occupational exposure or exposure of an individual not enrolled in the study to the 
investigational medicinal product must be reported to the Sponsor or designee within 24 hours 
of the Investigator's first knowledge of the event, even if the exposure does not result in an 
adverse event.  Unintentional exposures should be communicated on the SAE/MEOI report 
form, as described above for SAEs. 
8.2.3.3 
Reporting of Serious Adverse Events to the Institutional Review Board (IRBs)/ 
Ethics Committee 
Verastem or designee shall notify the Investigator and/or the IRBs/ECs per institutional 
guidelines of potential serious risks from clinical trials or any other sources, including the 
following: 
• Suspected adverse reaction that is both serious and unexpected. 
• Any findings from other studies that suggest a significant risk in humans exposed to 
the drug. 
• Any finding from animal or in vitro testing that suggest a significant risk to humans 
exposed to the drug, such as mutagenicity, teratogenicity, or carcinogenicity; or report 
of significant organ toxicity at or near the expected human exposure. 
Verastem or designee shall notify Central Ethics Committees (CEC) of new serious, related, 
and unexpected AE(s) or significant risks to subjects, per country requirements. 
The Investigator will notify Local Ethics Committees (LECs) of serious, related and 
unexpected AE(s) or significant risks to subjects, per local country requirements. 
The Investigator must keep copies of all AE information on file, including correspondence 
with Verastem or Local Ethics Committees.  
8.2.3.4 
Reporting of Serious Adverse Events to Regulatory Authorities 
Verastem or designee shall notify Regulatory Authorities of serious, unexpected adverse 
reactions or other adverse events, per local requirements.  Expectedness will be determined 


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using the current duvelisib Investigator Brochure and the ofatumumab United States Package 
Insert (USPI; 2009) or the Summary of Product Characteristics (SmPC).  
8.2.4 
Pregnancy and In Utero Drug Exposure  
Since duvelisib has not been evaluated in pregnant or nursing women, the treatment of 
pregnant women or women of childbearing potential who are not using effective 
contraception is contraindicated (see Section 5.1.1 and Section 6.2.1 for instructions on 
pregnancy testing and birth control). 
Pregnancies occurring in subjects or partners of male subjects during the study treatment 
period until 30 days after the subject’s last dose of study treatment are considered 
immediately reportable events.  If a pregnancy occurs in a subject, study treatment must be 
discontinued immediately.  The pregnant woman should be referred to an 
obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and 
counseling. 
The pregnancy must be reported to Verastem or designee within 24 hours of the Investigator’s 
knowledge of the pregnancy using the Pregnancy Notification Form as follows: 
• Hotline (Phone): 888-483-7729 (USA)  
• Fax: 888-529-3580 (USA)  
• For International numbers, please refer to the Pregnancy Notification Form and 
supporting documentation. 
The Investigator will follow the pregnant woman until completion of the pregnancy, and must 
notify Verastem of the outcome within 24 hours of the Investigator’s knowledge of the 
pregnancy outcome.  The Investigator will provide this information on the Pregnancy 
Outcome Report Form.  This notification includes pregnancies resulting in live, “normal” 
births. 
If the pregnant subject experiences an SAE during pregnancy, or the outcome of the 
pregnancy meets the criteria for immediate classification as an SAE (ie, spontaneous abortion 
[any congenital anomaly detected in an aborted fetus is to be documented], stillbirth, neonatal 
death, or congenital anomaly), the Investigator should follow the procedures for reporting 
SAEs (ie, report the event to Verastem within 24 hours of the Investigator’s knowledge of the 
event). 
All neonatal deaths and congenital anomalies that occur within 30 days of birth (regardless of 
causality) should be reported as SAEs to Verastem.  In addition, any infant death or congenital 
anomaly occurring after 30 days that the Investigator suspects is related to the in utero 
exposure to the study drug should also be reported to Verastem. 
 
 


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9 
STATISTICAL METHODS 
Details of the statistical methods for this study will be documented in a Statistical Analysis 
Plan (SAP). The SAP may modify the statistical methods outlined in the protocol; however, 
any major modification will also be reflected in a protocol amendment. 
9.1 
SAMPLE SIZE 
This study employs a randomized, open-label, parallel design to assess the potential 
superiority of duvelisib treatment over ofatumumab treatment on PFS in CLL or SLL 
subjects.  
The sample size was determined to provide sufficient power to test the primary endpoint of 
PFS in a group sequential design with one planned interim analysis. 
Assuming an exponential distribution for PFS, a total number of 185 PFS events (deaths or 
progressions) will provide approximately 93% power to detect a hazard ratio of 0.6 (median 
PFS of 9 months in the ofatumumab group versus 15 months in the duvelisib group) using a 
one-sided log-rank test at a 2.5% overall significance level (ie, alpha of 0.025).  The study 
design employs the Lan-DeMets spending function for O’Brien-Fleming boundary as the 
alpha spending function and the Hwang-Shih-DeCani gamma (-4) spending function as the 
beta spending function. A total of 300 subjects will be randomized in a 1:1 ratio to receive 
either ofatumumab or duvelisib. Assuming a peak accrual rate of 30 subjects per month with 
11 months for accrual ramp-up and a 4% cumulative dropout rate per year, then enrollment 
would complete in 16 months, with the final analysis for PFS estimated to occur 
approximately 27.5 months from the randomization of the first subject.   
9.2 
ANALYSIS SETS 
The two most important analysis sets are defined in this section, with additional analysis sets 
to be defined in the SAP. 
9.2.1 
Intent-to-Treat Analysis Set 
The Intent-to-Treat (ITT) analysis set will include all subjects who were randomized, with 
treatment group designated according to initial randomization. The ITT analysis set will serve 
as the primary analysis set for all efficacy endpoints and demographics. 
9.2.2 
All-treated Analysis Set 
The All-Treated (AT) analysis set will include all subjects who received any amount of study 
drug (duvelisib or ofatumumab), with treatment group designated according to actual study 
treatment received. The AT analysis set will be the primary analysis set for safety endpoints.  
9.3 
DISPOSITION, DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
A tabulation of subject disposition will be presented, which will include the number of 
subjects randomized to each treatment, and the number of subjects dosed for each treatment. 


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Discontinuation from study treatment will be summarized by reason for each treatment group. 
Discontinuation from study will also be summarized by reason for each treatment group.    
Details for the summary of demographic and baseline characteristics will be provided in the 
SAP. 
9.4 
EFFICACY ANALYSES 
9.4.1 
Analysis of Primary Efficacy Endpoint  
The primary efficacy endpoint is PFS based on disease status as determined by blinded, 
independent, central review and will be analyzed using the ITT analysis set.  
Censoring of PFS will be performed as detailed in the table below. Additional clarifications 
will be provided in the SAP as needed. 
Table 13: Primary PFS Censoring / Event Methodology 
Situation 
Date of Event or Censoring 
Outcome 
No adequate baseline disease status assessment  
Date of randomization 
Censored 
No adequate post-baseline disease status 
assessment unless death occurs prior to first post-
baseline assessment 
Date of randomization + 1 
Censored 
No documented progression or death before data 
cutoff 
Date of last adequate disease 
status assessment 
Censored 
Documented progression with ≤1 missing 
scheduled disease status assessment before 
progression 
Date of the earliest 
assessment that results in a 
finding of unequivocal 
progression 
Event 
Death before progression being documented with 
≤1 missing scheduled disease status assessment 
before death 
Date of death 
Event 
Documented progression or death following a 
long gap between adequate disease status 
assessments (eg, 2 or more consecutive missed 
scheduled disease status assessments)  
Date of last adequate disease 
status assessment before the 
gap 
Censored 
New anticancer treatment or procedure started 
before documented progression 
Date of last adequate disease 
status assessment 
Censored 
Note: Disease status assessment includes CT scans (chest, abdomen and pelvis), bone marrow aspirate and/or 
biopsy (may not be required of all subjects at all scheduled disease status assessments), CBC and differential 
count, focused physical examination, disease related constitutional symptoms for disease assessment, and ECOG 
performance status. An adequate disease status assessment is any disease status assessment for which the blinded 
independent central review is able to arrive at a disease status (eg, CR, CRi, PR, PRwL, SD, and PD) per 
protocol-defined criteria.   


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A stratified log-rank test (1-sided) will be used to compare PFS of the duvelisib arm against 
PFS of the ofatumumab arm at the interim and final analyses with the overall one-sided 
significance level controlled at 0.025. The nominal p-value required for statistical significance 
at an analysis will be calculated based on the numbers of PFS events at all preceding and 
current analyses. The hazard ratio and the corresponding 2-sided 95% confidence interval (CI) 
will be estimated using a stratified Cox proportional hazards model. For both the stratified 
log-rank test and the stratified Cox model, the strata will be those used for stratified 
randomization, with potential pooling of strata specified in the SAP. PFS will be plotted for 
each treatment group using the Kaplan-Meier method. Median PFS and its associated 95% CI 
will be estimated for each treatment group. 
Analyses of PFS using other censoring rules will be performed as sensitivity analyses. This 
will include a worst-comparison case sensitivity analysis in which surviving, non-progressing 
subjects who were lost to follow-up are treated as being censored at the last adequate disease 
assessment if they were on the ofatumumab arm, and treated as having an event at the time of 
the next scheduled disease assessment following the last adequate disease status assessment if 
they were on the duvelisib arm.  
Analyses of PFS will be performed for subgroups of subjects based on selected baseline 
variables, including stratification factors used for randomization.  The details of the subgroup 
analyses will be provided in the SAP. 
9.4.2 
Analysis of Key Secondary Efficacy Endpoints 
Of the secondary endpoints, ORR, Lymph Node Response Rate, OS, and Hematologic 
Improvement Rate are designated as key secondary efficacy endpoints. If the primary 
endpoint is significant, the four key secondary endpoints will be sequentially tested at the 1-
sided 0.025 significance level in the order listed above. If a null hypothesis is not rejected, 
formal sequential testing will be stopped.  The detailed testing strategy will be specified in the 
SAP. 
9.4.2.1 
Overall Response Rate (ORR) 
ORR will be analyzed using the Cochran-Mantel-Haenszel test (1-sided) to compare the two 
treatment groups.  The strata for the test will be those used for stratified randomization, with 
potential pooling of strata specified in the SAP. 
9.4.2.2 
Lymph Node Response Rate 
Lymph node response rate will be analyzed using the Cochran-Mantel-Haenszel test (1-sided) 
to compare the two treatment groups.  The strata for the test will be those used for stratified 
randomization, with potential pooling of strata specified in the SAP. 
9.4.2.3 
Overall Survival (OS) 
Subjects without documentation of death at the time of the data cutoff for analysis will be 
censored at the date the subject was last known to be alive, or the data cutoff date, whichever 
is earlier.  A stratified one-sided log-rank test will be used to compare OS between the 
2 treatment groups.  The hazard ratios along with the 2-sided 95% CIs will be estimated using 


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a stratified Cox model.  For both the stratified log-rank test and the stratified Cox model, the 
strata will be those used for stratified randomization, with potential pooling of strata specified 
in the SAP. The Kaplan-Meier survival curves and Kaplan-Meier medians (if estimable), 
along with the 2-sided 95% CIs, will be provided for each treatment group. 
9.4.2.4 
Hematologic Improvement Rate 
A subject with a hematologic improvement is one who consistently met the criteria of an 
improvement in neutrophil count, hemoglobin or platelet count for a period of at least 60 days 
during which the subject did not have transfusion or exogenous cytokines. Missing data or 
missing scheduled assessments during a potential 60 day hematologic improvement episode 
will result in categorization of not having a hematologic improvement.  
Hematologic improvement rate will be compared between treatment groups using one-sided 
Cochran–Mantel–Haenszel (CMH) test to adjust for the stratification factors. Details of this 
analysis will be specified in the SAP. 
9.4.3 
Analyses of Other Secondary Efficacy Endpoints 
9.4.3.1 
Duration of response (DOR)  
Duration of response is defined only for subjects demonstrating a response (eg, CR, CRi, PR, 
PRwL), with the response and progression statuses both determined by the blinded, central 
independent review.  The analysis will be descriptive for each treatment group only.  
9.4.4 
Analyses of Exploratory Efficacy Endpoints  
Analyses of exploratory efficacy endpoints such as improvement in disease-related symptoms 
of fatigue, weight loss, unexplained fevers and night sweats from baseline, and minimal 
residual disease in subjects with documented CR or CRi will be specified in the SAP.  
Additional exploratory efficacy endpoints may also be defined in the SAP. 
9.5 
SAFETY ANALYSES 
Safety endpoints will be summarized by treatment using the AT analysis set. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 16.1 or higher and will be graded according to the NCI-CTCAE, version 
4.03 or as described in Section 8.2.1.   
Tabulations of treatment emergent AEs (TEAEs) by System Organ Class and Preferred Terms 
will be produced.  A TEAE is an AE that emerges or worsens in the period from the first dose 
of study treatment to 30 days after the last dose of study treatment. 
Separate tabulations will also be produced for drug-related adverse events, serious adverse 
events, events that led to treatment discontinuation, and adverse events of at least Grade 3 
severity.  


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For laboratory tests with NCI-CTCAE grades, a shift table from baseline grade to the 
maximum post-baseline grade will be provided. Listings will be provided for all laboratory 
test results and for laboratory test results grade 3 and higher.   
9.6 
PHARMACOKINETIC ANALYSES 
Plasma samples will be analyzed for duvelisib and potential metabolite concentrations using a 
validated high performance liquid chromatography-tandem mass spectrometry (LC/MS/MS) 
method.   
The PK data collected will be analyzed by standard population PK methods, using appropriate 
software. The intent of the analysis is to obtain exposure data in subjects with CLL/SLL, to 
characterize the parameters of PK disposition, and to identify relevant covariates affecting 
drug exposure.  Analyses of exposure-response relationships for efficacy and safety endpoints 
may be conducted. The data may be pooled with the results of other studies to perform the 
population PK/pharmacodynamics analysis. 
Additional details on the pharmacokinetic methods and analysis will be provided in the SAP. 
9.7 
ANALYSES OF OTHER ENDPOINTS 
Analyses of other exploratory endpoints such as those for health-related QoL and biomarkers 
may be specified in the SAP or another document. 
9.8 
INTERIM ANALYSIS 
After approximately 50% of the planned PFS events (ie, 93 PFS events) have been observed 
based on the blinded, independent, central review, an interim analysis of efficacy will be 
performed.  
At the interim analysis, PFS will be tested at the alpha level based on the Lan-DeMets alpha 
spending function for O’Brien-Fleming boundary with the opportunity to stop the study (other 
than survival follow-up) for overwhelming evidence of efficacy. If the interim analysis occurs 
at exactly 50% of the planned events, the criterion of stopping for efficacy is one-sided p-
value of 0.0015 (corresponding approximately to a HR of 0.540). In the meantime, PFS will 
also be tested at the alpha level for futility based on the alpha and beta spending functions 
specified for the study design. If the interim analysis occurs at exactly 50% of the planned 
events, the criterion of stopping for futility is one-sided p-value of 0.4791 (corresponding 
approximately to a HR of 0.990). The futility boundary of this study is non-binding, meaning 
that the Type I error is properly controlled even if the study is continued after the futility 
boundary for PFS is crossed at the interim analysis.  Under the protocol design assumptions, 
the interim analysis is expected to occur approximately 17 months after the first subject is 
randomized.  
If the study is not stopped at the interim analysis, the final analysis of PFS will be performed 
when approximately 185 PFS events have occurred in the study.  The criterion of statistical 
significance (ie, boundary for efficacy) is one-sided p-value of 0.0245 (corresponding 
approximately to a HR of 0.748).  


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For the interim analysis, the actual p-value boundaries for efficacy and futility will be 
calculated based on the actual number of PFS events at the analysis. For the final analysis of 
PFS, the actual p-value boundary for efficacy will be calculated based on the actual number of 
PFS events at both the interim analysis and the final analysis. 
The Independent Data Monitoring Committee (IDMC) will review PFS, OS and other efficacy 
data at the interim analysis.  
The interim and final analysis for OS will be specified in the SAP.  
 
 


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10 
STUDY ADMINISTRATION 
10.1 
GOOD CLINICAL PRACTICE STATEMENT 
This study is to be performed in accordance with the protocol, the Declaration of Helsinki, the 
ICH Harmonised Tripartite Guideline for GCP, and all applicable local regulatory 
requirements. 
10.2 
INFORMED CONSENT 
Verastem will provide a sample subject Informed Consent Form (ICF) for modification, as 
appropriate, by the Investigator. The ICF must include all elements required by ICH, GCP, 
and must adhere to the IRB/IEC requirements and the ethical principles that have their origin 
in the Declaration of Helsinki. 
The Investigator or his/her staff will explain the nature of the study, its purpose and associated 
procedures, the expected duration, and the potential risks involved to the subject prior to 
enrollment.  The Investigator or designee will obtain written, informed consent.  The subject 
will have ample time and opportunity to ask questions and will be informed about the right to 
withdraw from the study at any time without any disadvantage and without having to provide 
a reason for this decision.  Following the discussion regarding the study, a subject will be 
asked if they are willing to sign and personally date a statement of informed consent.  Only if 
the subject voluntarily agrees to sign the informed consent statement and has done so, may 
he/she enter the study.  A copy of the signed and dated ICF will be provided to the subject.  
The signed ICF is to remain in the Investigator’s file, per local requirements. 
The ICF and any other written information provided to the subjects will be revised whenever 
important new information becomes available that may be relevant to the subject’s consent, or 
if there is an amendment to the protocol which necessitates a change to the content of the 
subject’s informed consent.  The Investigator will inform the subject of changes in a timely 
manner and will ask the subject to confirm continuation of their participation in the study by 
their signature on the revised informed consent form (if applicable). Any written ICF and 
written information must receive the approval/favorable opinion of the IRB/IEC in advance of 
use.  Any additional approvals from the initial informed consent form should be forwarded to 
the Sponsor. 
10.3 
SUBJECT CONFIDENTIALITY 
The written ICF will explain that study data will be stored in a database, maintaining 
confidentiality in accordance with national data legislation.  All data processed by Verastem 
or its representative(s) will be identified by subject number and study code. 
The written ICF will also explain that for data verification purposes, authorized 
representatives of Verastem, a regulatory authority, and IRB/IEC may require direct access to 
parts of the hospital or clinic records relevant to the study that include the subject’s medical 
history. 
The Investigator must ensure that the subjects’ anonymity is maintained.  On the eCRFs or 
other documents submitted to the Sponsor, subjects should not be identified by their names, 


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but by their assigned subject number and study code.  Documents not for submission to the 
Sponsor, such as signed ICF, should be maintained in strict confidence by the Investigator. 
10.4 
INSTITUTIONAL REVIEW BOARD/ ETHICS COMMITTEE 
REQUIREMENTS 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB/IEC at each clinical trial site.  The Principal 
Investigator must submit written approval to Verastem before he or she can enroll any subject 
into the study. 
The Principal Investigator is responsible for informing the IRB/IEC of any amendment to the 
protocol.  In addition, the IRB/IEC must approve all advertising used to recruit subjects for 
the study.  The protocol must be re-approved by the IRB/IEC annually or as applicable. 
Progress reports and notifications of SAEs will be provided to the IRB/IEC according to 
regulations and guidelines. 
10.5 
CASE REPORT FORMS AND SOURCE DOCUMENTATION 
eCRF will be provided for the recording of all data.  The Principal Investigator / Sub-
Investigator or designee will record data from all observations, tests, and assessments 
specified in the protocol on the eCRFs provided by Verastem. 
10.6 
SPONSOR MONITORING 
Before the first subject is enrolled into the study, a representative of Verastem will visit the 
study site to: 
• Determine the adequacy of the facilities. 
• Discuss with the Investigator(s) (and other personnel involved with the study) their 
responsibilities with regard to the protocol, and the responsibilities of Verastem.   
During the conduct of the study, a representative of Verastem Pharmaceuticals, Inc. will have 
regular contact with the clinical trial site, and have regular visits to the clinical trial site to: 
• Provide information and support the Principal Investigator. 
• Confirm that the facilities remain acceptable. 
• Confirm that the study team is adhering to the protocol, data are being accurately 
recorded in the eCRFs, and the investigational product is being properly maintained 
and accountability records are current. 
• Perform source data verification with access to all original clinical records for each 
subject. 
10.7 
DATA MONITORING COMMITTEE 
An Independent Data Monitoring Committee (IDMC) will be assembled to periodically 
review all available unblinded safety information and recommend whether or not the trial 


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should continue, or should continue with modifications, based on their review of the data.  In 
addition, the IDMC will review PFS and other efficacy data at the time of the interim analysis 
and make a recommendation on overwhelming evidence of efficacy or futility of the study.  
All final decisions regarding study conduct will reside with the Sponsor.  Membership and 
responsibilities of the IDMC will be documented in a separate IDMC Charter. 
10.8 
BLINDING 
This study is open-label and Investigators, site staff, Sponsor and Sponsor designees will have 
access to treatment assignments for individual subjects.  To reduce bias, a blinded 
independent central review of disease status will be conducted, which will be blinded to 
individual subject treatment assignments. Investigators, site staff, Sponsor and Sponsor 
designees will only have access to blinded (pooled) aggregate study data, except for a select 
number of Sponsor staff, who may review aggregate SAEs and MEOI data by treatment 
groups. 
10.9 
QUALITY ASSURANCE 
In compliance with GCP and regulatory requirements, the Sponsor, a third party on behalf of 
the Sponsor, regulatory agencies or IRB/IECs may conduct quality assurance audits at any 
time during or following a study.  The Investigator must agree to allow auditors direct access 
to all study-related documents including source documents, and must agree to allocate his or 
her time and the time of his or her study staff to the auditors in order to discuss findings and 
issues. 
10.10 
STUDY OR CLINICAL SITE TERMINATION 
Sponsor or designee, reserves the right to terminate the study or a clinical trial site at any time.  
Conditions that may warrant termination of the study include, but are not limited to: 
• The discovery of an unexpected, serious, or unacceptable risk to subjects enrolled in 
the study. 
• The decision on the part of Verastem to suspend or discontinue testing or the treatment 
of the study drug. 
• Failure of the Investigator to comply with GCP. 
• Submission of knowingly false information from the clinical trial site to Verastem or 
regulatory authorities. 
• Insufficient adherence to protocol requirements. 
If terminating the study, Verastem and the Investigator(s) will assure that adequate 
consideration is given to the protection of the subjects’ interests. 


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10.11 
DURATION OF THE STUDY, EXPECTED DURATION OF SUBJECT 
PARTICIPATION, AND END OF STUDY 
The study is estimated to complete enrollment within 16 months from randomization of the 
first subject. Subjects will be followed for survival for up to 6 years after randomization. The 
maximum number of months to complete the study is expected to be 72 months.  
10.12 
RECORDS RETENTION 
All correspondence related to this clinical study should be kept in appropriate study files.  
Records of subjects, source documents, eCRFs, drug inventory, IRB, and Sponsor 
correspondence pertaining to the study must be kept on file.  All study documents must be 
kept secured for a period of 2 years after a marketing application is approved for duvelisib; or, 
until 2 years after shipment and delivery of the drug for investigational use is discontinued.  
There may be other circumstances for which the Sponsor is required to maintain study records 
and, therefore, the Sponsor should be contacted prior to removing study records for any 
reason. 
10.13 
PUBLICATIONS 
Publication by the clinical trial site(s) of any data from this study must be carried out in 
accordance with the Clinical Trial Agreement. 


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11 
REFERENCES 
1. 
Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, et 
al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from 
the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer 
Institute–Working Group 1996 guidelines. Blood. 2008 June 15, 2008;111(12):5446-56. 
2. 
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. 
Revised Response Criteria for Malignant Lymphoma. Journal of Clinical Oncology. 2007 
February 10, 2007;25(5):579-86. 
3. 
Howlader N NA, Krapcho M, Neyman N, Aminou R, Altekruse SF, Kosary CL, 
Ruhl J, Tatalovich Z, Cho H, Mariotto A, Eisner MP, Lewis DR, Chen HS, Feuer EJ, Cronin 
KA. SEER Stat Fact Sheets: Chronic Lymphocytic Leukemia.  Bethesda, MD: National 
Cancer Institute; 2009 [updated April 2013; cited 2013 April ]. 
4. 
Eichhorst B, Hallek M, Dreyling M. Chronic lymphocytic leukemia: ESMO 
minimum clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2009 
May;20 Suppl 4:102-4. 
5. 
Tsimberidou AM, Wen S, O'Brien S, McLaughlin P, Wierda WG, Ferrajoli A, et 
al. Assessment of Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma by 
Absolute Lymphocyte Counts in 2,126 Patients: 20 Years of Experience at The University of 
Texas M.D. Anderson Cancer Center. Journal of Clinical Oncology. 2007;25(29):4648-56. 
6. 
Czuczman MS, Gregory SA. The future of CD20 monoclonal antibody therapy in 
B-cell malignancies. Leuk Lymphoma. 2010 Jun;51(6):983-94. 
7. 
Cheson BD. Ofatumumab, a novel anti-CD20 monoclonal antibody for the 
treatment of B-cell malignancies. J Clin Oncol. 2010 Jul 20;28(21):3525-30. 
8. 
National Comprehensive Cancer Network Practice Guidelines in Oncology.  
Chronic lymphocytic leukemia  V 3 2012: National Comprehensive Cancer Network; 2012. 
9. 
Wierda W, O'Brien S, Wen S, Faderl S, Garcia-Manero G, Thomas D, et al. 
Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and 
refractory chronic lymphocytic leukemia. J Clin Oncol. 2005 Jun 20;23(18):4070-8. 
10. 
ARZERRA (Ofatumumab) [Summary of Product Characteristics]. Glaxo Group 
Ltd, Middlesex, United Kingdom; 2014; Available from: 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/001131/WC500093091.pdf. 
11. 
ARZERRA (ofatumumab) Injection for intravenous infusion [Package Insert].  
Greenford, Middlesex, United Kingdom: GlaxoSmithKline; 2014; Available from: 
http://us.gsk.com/products/assets/us_arzerra.pdf. 
12. 
Knight ZA, Gonzalez B, Feldman ME, Zunder ER, Goldenberg DD, Williams O, 
et al. A pharmacological map of the PI3-K family defines a role for p110alpha in insulin 
signaling. Cell. 2006 May 19;125(4):733-47. 
13. 
Vanhaesebroeck B, Vogt PK, Rommel C. PI3K: from the bench to the clinic and 
back. Curr Top Microbiol Immunol. 2011;347:1-19. 


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14. 
Fung-Leung WP. Phosphoinositide 3-kinase delta (PI3Kdelta) in leukocyte 
signaling and function. Cell Signal. 2011 Apr;23(4):603-8. 
15. 
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011 
Mar 4;144(5):646-74. 
16. 
Lewis CE, Pollard JW. Distinct role of macrophages in different tumor 
microenvironments. Cancer Res. 2006 Jan 15;66(2):605-12. 
17. 
Schmid MC, Avraamides CJ, Dippold HC, Franco I, Foubert P, Ellies LG, et al. 
Receptor Tyrosine Kinases and TLR/IL1Rs Unexpectedly Activate Myeloid Cell 
PI3Kgamma, A Single Convergent Point Promoting Tumor Inflammation and Progression. 
Cancer Cell. 2011 Jun 14;19(6):715-27. 
18. 
Clayton E, Bardi G, Bell SE, Chantry D, Downes CP, Gray A, et al. A crucial role 
for the p110delta subunit of phosphatidylinositol 3-kinase in B cell development and 
activation. J Exp Med. 2002 Sep 16;196(6):753-63. 
19. 
Okkenhaug K, Bilancio A, Farjot G, Priddle H, Sancho S, Peskett E, et al. 
Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. 
Science. 2002 Aug 9;297(5583):1031-4. 
20. 
O'Brien S, Patel M, Kahl B, Horwitz S, Foss F, Porcu P, et al. Duvelisib (IPI-145), 
a PI3K-δ,γ Inhibitor, is Clinically Active in Patients with Relapsed/Refractory Chronic 
Lymphocytic Leukemia.  Poster Presented at the 56th ASH Annual Meeting and Exposition, 
December 7, 2014, San Francisco, CA. 
21. 
Flinn I, Patel M, Kahl B, Horowitz S, Foss F, Oki Y, editors. Preliminary safety 
and efficacy of IPI-145, a potent inhibitor of phosphoinositide-3-kinase-δ,γ in patients with 
chronic lymphocytic leukemia. . Oral talk at the 55th ASH Annual Meeting and Exposition; 
2013; New Orleans, LA. 
22. 
Cheson BD, Byrd JC, Rai KR, Kay NE, O'Brien SM, Flinn IW, et al. Novel 
targeted agents and the need to refine clinical end points in chronic lymphocytic leukemia. J 
Clin Oncol. 2012 Aug 10;30(23):2820-2. 
23. 
de Rooij M, Kuil A, Geest CR, Eldering E, Chang BY, Buggy JJ, et al. The 
clinically active BTK inhibitor PCI-32765 targets B-cell receptor - and chemokine-controlled 
adhesion and migration in chronic lymphocytic leukemia. Blood. 2012;119:2590-4. 
24. 
Ponader S, Chen SS, Buggy JJ, Balakrishnan K, Gandhi V, Wierda WG, et al. The 
Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell 
survival and tissue homing in vitro and in vivo. Blood. 2012 Feb 2;119(5):1182-9. 
25. 
Hoellenriegel J, Meadows SA, Sivina M, Wierda WG, Kantarjian H, Keating MJ, 
et al. The phosphoinositide 3'-kinase delta inhibitor, CAL-101, inhibits B-cell receptor 
signaling and chemokine networks in chronic lymphocytic leukemia. Blood. 
2011;118(13):3603-12. 
 
 
 
 


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12 
APPENDICES 
Appendix 1: Medications or Foods Known to Inhibit or Induce CYP3A 
The following list provides medications known to induce or inhibit CYP3A activity.  Note 
that this is not a comprehensive list of all medications which may modulate CYP3A activity.  
Additional information can be found at: 
• http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Dru
gInteractionsLabeling/ucm080499.htm 
Note: Subjects receiving duvelisib are prohibited from concomitant use of medications 
or foods that are known to be strong inhibitors or inducers of CYP3A. 
Classification of In Vivo Inhibitors of CYP3A  
Strong Inhibitors(1)   
Moderate inhibitors(2) 
Weak inhibitors(3)   
Boceprevir, 
clarithromycin, 
conivaptan, 
grapefruit juice,(5) 
indinavir, itraconazole, 
ketoconazole,  
lopinavir/ritonavir, 
mibefradil, (6) 
nefazodone, nelfinavir, 
posaconazole, ritonavir, 
saquinavir,  
telaprevir, 
telithromycin, 
voriconazole 
Amprenavir, aprepitant, 
atazanavir, ciprofloxacin, 
darunavir/ritonavir, 
diltiazem, erythromycin, 
fluconazole, 
fosamprenavir, grapefruit 
juice, (5) 
imatinib, verapamil 
Alprazolam, amiodarone, 
amlodipine, atorvastatin, 
bicalutamide, cilostazol, 
cimetidine, 
cyclosporine, fluoxetine, 
fluvoxamine, ginkgo, (4) 
goldenseal,(4) 
isoniazid, nilotinib, 
oral contraceptives, 
ranitidine, ranolazine, 
tipranavir/ritonavir, 
zileuton 
1. A strong inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a substrate for that 
CYP by equal or more than 5-fold or >80% decrease in CL. 
2. A moderate inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive 
substrate for that CYP by less than 5-fold but equal to or more than 2-fold or 50-80% decrease in CL.  
3. A weak inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate 
for that CYP by less than 2-fold but equal to or more than 5-fold or 20-50% decrease in CL.  
4. Herbal product.  
5. The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-
dependent.  Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain 
preparation was used (eg, high dose, double strength) or as a “moderate CYP3A inhibitor” when another 
preparation was used (eg, low dose, single strength).  
6. Withdrawn from the United States market because of safety reasons.  
 
 


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Appendix 1 (continued) 
Classification of In Vivo Inducers of CYP3A  
Strong Inducers 
≥ 80% decrease in 
AUC 
Moderate Inducers 
50-80% decrease in AUC 
Weak Inducers 
20-50% decrease in AUC 
Avasimibe,(1) 
carbamazepine, 
phenytoin, rifampin, St. 
John’s wort(2) 
Bosentan, efavirenz, 
etravirine, modafinil, 
nafcillin 
Amprenavir, aprepitant, 
armodafinil, echinacea,(3) 
pioglitazone, prednisone, 
rufinamide 
1. Not a marketed drug. 
2. The effect of St. John’s wort varies widely and is preparation-dependent. 
3. Herbal product. 
 
 
 


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Appendix 2: Known CYP3A or CYP2C8 Substrates  
The following lists provide known sensitive CYP3A substrates, CYP3A substrates with a 
narrow therapeutic range, and CYP2C8 substrates.  
Additional information can be found at 
http://www.medicine.iupui.edu/clinpharm/ddis/ClinicalTable.asp and 
http://www.pharmacytimes.com/issue/pharmacy/2008/2008-09/2008-09-8687. 
 
Sensitive CYP3A Substrates 
budesonide 
buspirone 
eplerenone 
eletriptan 
felodipine 
fluticasone 
lovastatin 
 
midazolam 
saquinavir 
sildenafil 
simvastatin 
triazolam 
vardenafil 
 
CYP3A Substrates with a Narrow Therapeutic Range 
alfentanil 
astemizole  
cisapride  
cyclosporine 
diergotamine 
ergotamine 
 
fentanyl 
pimozide 
quinidine  
sirolimus 
tacrolimus 
terfenadine 
CYP2C8 Substrates 
paclitaxel 
torsemide 
amodiaquine 
cervistatin 
repaglinide 
rosiglitazone 
pioglitazone 
 
 
 
 


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Appendix 3: P-gp Substrates and Medications that are Inhibitors of P-gp 
The following list provides medications that are substrates or inhibitors of P-gp.  Note that this is 
not a comprehensive list of all medications which may be substrates of P-gp or may modulate 
P-gp activity. 
 
P-gp Substrates 
Amitriptyline 
Amiodarone 
Atorvastatin 
Cefoperazone 
Chlorpromazine 
Cimetidine 
Ciprofloxacin 
Clarithromycin 
Colchicine 
Cyclosporine 
Dexamethasone 
Digoxin 
Diltiazem 
Erythromycin 
Estradiol 
Fentanyl 
Fexofenadine 
Hydrocortisone 
Itraconazole 
Lansoprazole 
Levofloxacin 
Lidocaine 
 
Loperamide  
Losartan 
Lovastatin 
Methadone 
Methotrexate 
Methylprednisolone 
Morphine 
Nadolol 
Norfloxacin 
Nortriptyline 
Ondansetron 
Omeprazole 
Pantoprazole 
Phenytoin 
Pravastatin 
Propranolol 
Quinidine 
Ranitidine 
Sirolimus 
Tacrolimus 
Timolol 
Trimethoprim 
Verapamil 


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P-gp Inhibitors 
Amiodarone 
Amitriptyline 
Carvedilol 
Chlorpromazine 
Clarithromycin 
Cortisol 
Cyclosporine 
Desipramine 
Diltiazem 
Dipyridamole 
Doxepin 
Erythromycin 
Felodipine 
Fluphenazine 
Grapefruit juice 
Haloperidol 
Itraconazole 
Ketoconazole 
Lovastatin 
Mefloquine 
Nicardipine 
Nifedipine 
Ofloxacin 
Omeprazole 
Pantoprazole 
Progesterone 
Propafenone 
Propranolol 
Quinidine 
Rifampicin (Rifampin) 
Saquinavir 
Simvastatin 
Sirolimus 
Tacrolimus 
Testosterone 
Verapamil 
Source: Atkinson AJ et al. Principles of Clinical Pharmacology, 2nd ed. Academic 
Press, Massachusetts, 2007. 
 
 


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Appendix 4: ECOG Performance Status 
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 
 
Source : Eastern Cooperative Oncology Group : http://www.ecog.org/general/perf_stat.html 
As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And 
Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982 
 
 
 


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Appendix 5: QoL Instrument - EQ-5D Questionnaire 
 


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(English version for the US) 
 
 


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Appendix 6: Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) 
 
Below is a list of statements that other people with your illness have said are important. 
Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days. 
 
 
 
 
 
PHYSICAL WELL-BEING 
 
Not at 
all 
A little bit 
Some-
what 
Quite a 
bit 
Very 
much 
GP1 
I have a lack of energy
 
 
0 
1 
2 
3 
4 
GP2 
I have nausea
 
 
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have 
trouble meeting the needs of my family
 
 
 
0 
 
1 
 
2 
 
3 
 
4 
GP4 
I have pain  
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment
 
 
0 
1 
2 
3 
4 
GP6 
I feel ill 
 
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in bed
 
 
0 
1 
2 
3 
4 


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SOCIAL/FAMILY WELL-BEING 
 
Not at 
all 
A little 
bit 
Some-
what 
Quite a 
bit 
Very 
much 
GS1 
I feel close to my friends
 
 
0 
1 
2 
3 
4 
GS2 
I get emotional support from my family
 
 
0 
1 
2 
3 
4 
GS3 
I get support from my friends
 
 
0 
1 
2 
3 
4 
GS4 
My family has accepted my illness
 
 
0 
1 
2 
3 
4 
GS5 
I am satisfied with family communication about my 
illness 
 
 
0 
 
1 
 
2 
 
3 
 
4 
GS6 
I feel close to my partner (or the person who is my main 
support) 
 
 
0 
 
1 
 
2 
 
3 
 
4 
Q1 
Regardless of your current level of sexual activity, please 
answer the following question. If you prefer not to answer 
it, please mark this box           and go to the next section. 
 
 
 
 
 
GS7 
I am satisfied with my sex life
 
 
0 
1 
2 
3 
4 


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Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days. 
 
 
EMOTIONAL WELL-BEING 
Not at 
all 
A little 
bit 
Some-
what 
Quite a 
bit 
Very 
much 
GE1 
I feel sad 
 
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping with my 
illness 
 
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my illness
 
 
0 
1 
2 
3 
4 
GE4 
I feel nervous
 
 
0 
1 
2 
3 
4 
GE5 
I worry about dying
 
 
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get worse
 
 
0 
1 
2 
3 
4 
 
 
 


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09 February 2017 (Amendment 3) 
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FUNCTIONAL WELL-BEING 
 
Not at 
all 
A little bit 
Some-
what 
Quite a 
bit 
Very 
much 
 
GF1 
I am able to work (include work at home)
 
 
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is fulfilling
 
 
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life
 
 
0 
1 
2 
3 
4 
GF4 
I have accepted my illness
 
 
0 
1 
2 
3 
4 
GF5 
I am sleeping well
 
 
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for fun
 
 
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right now
 
 
0 
1 
2 
3 
4 
 
 
 


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Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days. 
 
 
ADDITIONAL CONCERNS 
 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
HI7 
I feel fatigued
 
 
0 
1 
2 
3 
4 
HI12 
I feel weak all over
 
 
0 
1 
2 
3 
4 
An1 
I feel listless (“washed out”)
 
 
0 
1 
2 
3 
4 
An2 
I feel tired  
0 
1 
2 
3 
4 
An3 
I have trouble starting things because I am tired
 
 
0 
1 
2 
3 
4 
An4 
I have trouble finishing things because I am 
tired 
 
0 
1 
2 
3 
4 
An5 
I have energy
 
 
0 
1 
2 
3 
4 
An7 
I am able to do my usual activities
 
 
0 
1 
2 
3 
4 
An8 
I need to sleep during the day
 
 
0 
1 
2 
3 
4 
An12 
I am too tired to eat
 
 
0 
1 
2 
3 
4 
An14 
I need help doing my usual activities
 
 
0 
1 
2 
3 
4 
An15 
I am frustrated by being too tired to do the 
things I want to do
 
 
 
0 
 
1 
 
2 
 
3 
 
4 
An16 
I have to limit my social activity because I am 
tired 
 
0 
1 
2 
3 
4 
 
 
 

SAP_000.pdf: 
IPI-145-07                                                                                                                         Verastem, Inc. Statistical 
Analysis Plan 
Version 4.0 (9 May 2017) 
CONFIDENTIAL 
Page 1 of 41 
STATISTICAL ANALYSIS PLAN 
 
Protocol IPI-145-07 
A Phase 3 Study of IPI-145 versus Ofatumumab in Subjects with Relapsed or 
Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma 
 
 
 
 
 
 
 
 
 
 
 
This statistical analysis plan contains confidential information and is the proprietary 
property of Verastem, Inc. This document may not be copied or made available for 
review by an unauthorized person or firm without the prior written authorization of 
Verastem, Inc. 
 
 
Protocol Version: 
Amendment 3 
 
Type of Analysis 
Plan: 
Final Analysis 
 
Version: 
4.0 
 
Date: 
9 May 2017 
 
Author: 
Laura Truskowski, MS 




IPI-145-07                                                                                                                         Verastem, Inc. Statistical 
Analysis Plan 
Version 4.0 (9 May 2017) 
CONFIDENTIAL 
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DOCUMENT HISTORY 
 
Version 
Date 
Author(s) 
Brief Summary of Changes 
1.0 
02 Oct 2014 
Shijie Tang 
Original 
2.0 
24 Nov 2015 
Shijie Tang 
Clarified the timing of the 2nd interim 
analysis of overall survival; added 
biomarkers to baseline characteristics; 
other changes. Refer to Section 8.2 for 
Details. 
3.0 
13 Apr 2016 
Shijie Tang 
In Section 3.5.2, the estimated 
numbers of OS events at each of OS 
interim analyses and final analysis are 
provided.  
Lymph node response rate and 
hematological improvement rate are 
removed from the hierarchy of 
inferential testing in secondary 
endpoints. 
4.0 
9 May 2017 
Laura 
Truskowski 
Update to Verstem as Sponsor, 
updates due to protocol amendment 3 
including removal of 3 year limit on 
treatment duration. 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
 
LIST OF ABBREIVATIONS ......................................................................................................... 7 
1 
INTRODUCTION ................................................................................................................ 10 
2 
STUDY OBJECTIVES ......................................................................................................... 10 
2.1 
Primary Objective .......................................................................................................... 10 
2.2 
Secondary Objectives ..................................................................................................... 10 
2.3 
Exploratory Objectives ................................................................................................... 10 
3 
STUDY DESIGN.................................................................................................................. 11 
3.1 
Overview ........................................................................................................................ 11 
3.2 
Sample Size Consideration ............................................................................................. 11 
3.3 
Randomization ............................................................................................................... 12 
3.4 
Blinding .......................................................................................................................... 12 
3.5 
Planned Analyses ........................................................................................................... 12 
3.5.1 
Planned Analyses for PFS ....................................................................................... 13 
3.5.2 
Planned Analyses for OS ........................................................................................ 13 
4 
ANALYSIS SETS ................................................................................................................ 14 
4.1 
Intent-To-Treat (ITT) Analysis Set ................................................................................ 14 
4.2 
All-Treated (AT) Analysis Set ....................................................................................... 14 
4.3 
Per-Protocol (PP) Analysis Set ...................................................................................... 14 
5 
STUDY ENDPOINTS .......................................................................................................... 15 
5.1 
Primary Endpoint ........................................................................................................... 15 
5.2 
Secondary Endpoints ...................................................................................................... 15 
5.3 
Exploratory Endpoints .................................................................................................... 15 
6 
GENERAL STATISTICAL METHODS AND DATA HANDLING ................................. 17 
6.1 
General Methods ............................................................................................................ 17 
6.2 
Handling of Missing Data .............................................................................................. 17 
6.2.1 
Handling of Missing Dates/Months/Years for Adverse Events .............................. 17 
6.2.2 
Handling of Missing Dates/Months/Years for Concomitant Medications ............. 18 


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6.2.3 
Handling of Missing Dates/Months/Years for Disease History and Prior Therapies
 
18 
6.3 
Multiple Comparisons/Multiplicity Adjustment ............................................................ 18 
6.4 
Adjustments for Covariates ............................................................................................ 19 
6.5 
Subgroups ....................................................................................................................... 19 
6.6 
Visit Windows ................................................................................................................ 19 
6.7 
Unscheduled Visits ......................................................................................................... 19 
6.8 
Baseline Values .............................................................................................................. 20 
6.9 
Computing and Coding Standards.................................................................................. 20 
7 
STATISTICAL ANALYSES ............................................................................................... 21 
7.1 
Study Subjects ................................................................................................................ 21 
7.1.1 
Disposition of Subjects ........................................................................................... 21 
7.1.2 
Protocol Deviations ................................................................................................. 21 
7.1.3 
Demographic and Other Baseline Characteristics .................................................. 21 
7.1.4 
Disease History ....................................................................................................... 22 
7.1.5 
Prior Therapies ........................................................................................................ 22 
7.1.6 
Medical History ...................................................................................................... 22 
7.1.7 
Prior and Concomitant Medications ....................................................................... 23 
7.1.8 
Exposure to Study Drug .......................................................................................... 23 
7.2 
Efficacy Analyses ........................................................................................................... 23 
7.2.1 
Analyses of Primary Endpoint ................................................................................ 24 
7.2.2 
Analyses of Secondary Efficacy Endpoints ............................................................ 26 
7.2.3 
Analyses of Exploratory Efficacy Endpoints .......................................................... 29 
7.3 
Safety Analyses .............................................................................................................. 29 
7.3.1 
Adverse Events ....................................................................................................... 29 
7.3.2 
Laboratory Data ...................................................................................................... 31 
7.3.3 
Vital Signs ............................................................................................................... 32 
7.3.4 
Electrocardiogram (ECG) ....................................................................................... 32 
7.3.5 
Concomitant Medications and Procedures .............................................................. 32 
7.3.6 
Deaths ..................................................................................................................... 32 
7.4 
Quality of Life Instruments ............................................................................................ 32 


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7.4.1 
EQ-5D ..................................................................................................................... 32 
7.4.2 
FACIT-F ................................................................................................................. 33 
7.5 
Pharmacokinetic Analyses ............................................................................................. 34 
7.6 
Biomarker Analyses ....................................................................................................... 34 
7.6.1 
Pharmacodynamic and Potentially Predictive Biomarkers ..................................... 34 
7.6.2 
Pharmacogenomics ................................................................................................. 35 
8 
CHANGES IN PLANNED ANALYSES ............................................................................. 36 
8.1 
Changes in Planned Analyses from Protocol Amendment 1 to SAP V1.0 .................... 36 
8.2 
Changes in Planned Analyses from SAP V1.0 to SAP V2.0 ......................................... 36 
8.3 
Changes in Planned Analyses from SAP V2.0 to SAP V3.0 ......................................... 37 
9 
REFERENCES ..................................................................................................................... 38 
10 APPENDICES ...................................................................................................................... 39 
10.1 
Appendix A: Primary PFS Event/Censoring Method ................................................. 39 
10.2 
Appendix B: Event-Free Survival (EFS) Event/Censoring Method .......................... 40 
10.3 
Appendix C: One-Sided Cochran–Mantel–Haenszel (CMH) Test ............................ 41 
 
 


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LIST OF ABBREIVATIONS 
Abbreviation 
Description 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
AT 
All-Treated  
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BID 
Twice a day 
BOR 
Best Overall Response 
BUN 
Blood Urea Nitrogen 
CI 
Confidence Interval 
CLL 
Chronic Lymphocytic Leukemia 
CMH 
Cochran–Mantel–Haenszel 
CO2 
Bicarbonate 
CR 
Complete Response 
CRi 
Complete Response with Incomplete Marrow Recovery 
CS 
Abnormal and Clinically Significant 
CTCAE 
Common Terminology Criteria for Adverse Events 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
Electronic Case Report Form 
eDISH 
Evaluation of Drug Induced Serious Hepatotoxicity 
EQ-5D 
European Quality of Life-5 Dimensions 
FACIT-F 
Functional Assessment of Chronic Illness Therapy-Fatigue 
FACT-G 
The Functional Assessment of Cancer Therapy - General 


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Abbreviation 
Description 
HR 
Hazard Ratio 
IDMC 
Independent Data Monitoring Committee 
IPI-145 
(S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-
phenylisoquinolin-1(2H)-one 
IPCW 
Inverse Probability of Censoring Weighted 
IRC 
Independent Review Committee 
IRT 
Interactive Response Technology 
ITT 
Intent-To-Treat 
IV 
Intravenous 
IWCLL 
International Workshop on Chronic Lymphocytic Leukemia 
IWG 
International Working Group 
LC/MS/MS 
Liquid Chromatography-tandem Mass Spectrometry 
LDH 
Lactate Dehydrogenase 
LFT 
Liver Function Test 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEOI 
Medical Events of interest 
MMRM 
Mixed Effect Repeated Measures 
MRD 
Minimal Residual Disease 
NCI 
National Cancer Institute 
NCS 
Abnormal but Not Clinically Significant 
NED 
No Evidence of Disease 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetics 
PP 
Per-Protocol 
PR 
Partial Response 
PRwL 
PR with Lymphocytosis 


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Abbreviation 
Description 
PT 
Preferred Term 
QoL 
Quality of Life 
RBC 
Red Blood Cell 
RPSFT 
Rank Preserving Structural Failure Time 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SI 
Standard International System of Units 
SLL 
Small Lymphocytic Lymphoma 
SOC 
System Organ Class 
SPD 
Sum of Products 
TEAE 
Treatment Emergent Adverse Event 
TTR 
Time to Response 
UNK 
Unknown 
VAS 
Visual Analog Scale 
WHO 
World Health Organization 
WHO-DD 
World Health Organization Drug Dictionary 
 
 


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1 INTRODUCTION 
This is the statistical analysis plan (SAP) for study IPI-145-07, A phase 3 study of IPI-145 versus 
ofatumumab in subjects with relapsed or refractory chronic lymphocytic leukemia/small 
lymphocytic lymphoma. This SAP is prepared according to Amendment 3 of the protocol, dated 
09 February 2017. 
2 STUDY OBJECTIVES 
2.1 Primary Objective 
The primary objective of this trial is to examine the efficacy of duvelisib (IPI-145) monotherapy 
versus ofatumumab monotherapy in subjects with relapsed or refractory Chronic Lymphocytic 
Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). 
2.2 Secondary Objectives 
• To determine the safety of duvelisib in subjects with CLL or SLL 
• To evaluate the pharmacokinetics (PK) of duvelisib and, if applicable, its metabolite(s) 
2.3 Exploratory Objectives  
• To evaluate the health-related quality of life (QoL) of subjects 
• To evaluate pharmacodynamic biomarkers of duvelisib  
• To evaluate biomarkers that may predict duvelisib clinical activity and/or safety 
• To evaluate mechanisms of resistance in subjects who exhibit disease progression while 
being treated with duvelisib or ofatumumab 
• To evaluate genomic features of tumors predictive of response in subjects treated with 
duvelisib or ofatumumab 
 
 


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3 STUDY DESIGN 
3.1 Overview 
Study IPI-145-07 is a two-arm, randomized (1:1 ratio), open-label, phase 3, superiority trial 
designed to evaluate the efficacy and safety of duvelisib compared to ofatumumab.  
Subjects who meet all the eligibility criteria at Screening will return to the clinic on Day 1 to 
receive their first dose of study drug (randomized to either duvelisib or ofatumumab). The first 
treatment cycle for each treatment arm will be 3 weeks (21±2 days). Subsequent treatment cycles 
will be 4 weeks (28±4 days). 
Subjects randomized to duvelisib will be given a starting dose of 25 mg duvelisib administered 
orally twice daily (BID) initially in a 21-day treatment cycle followed by 28-day treatment cycles 
for up to 18 cycles or until disease progression or unacceptable toxicity (whichever comes first). 
After completing approximately 18 cycles of treatment, subjects who, in the opinion of the 
investigator, may derive benefit from continued treatment may receive additional cycles of 
duvelisib until disease progression or unacceptable toxicity. Subjects randomized to ofatumumab 
will receive treatment consistent with the approved product labeling: 8 weekly infusions, starting 
with an initial IV dose of 300 mg ofatumumab on Day 1 followed by seven weekly doses of 
2000 mg. Thereafter, subjects will receive 2000 mg ofatumumab once every month for four 
months or until disease progression or unacceptable toxicity (whichever comes first), as outlined 
in the schedule of assessments. Administration of ofatumumab will not exceed the 12 doses 
(within 7 cycles) as described in the prescribing information.  
Subjects will be followed for survival for up to 6 years (or other duration as specified by the 
protocol) from randomization or until death. Follow-up visits will occur every 6 months which 
can be conducted through a telephone interview.    
3.2 Sample Size Consideration 
This study employs a randomized, open-label, parallel design to assess the potential superiority 
of duvelisib treatment over ofatumumab treatment on progression-free survival (PFS) in CLL or 
SLL subjects. 
The sample size was determined to provide sufficient power to test the primary endpoint of PFS 
in a group sequential design with one planned interim analysis. 
Assuming an exponential distribution for PFS, a total of 185 PFS events (deaths or progressions) 
will provide approximately 93% power to detect a hazard ratio of 0.6 (median PFS of 9 months 
in the ofatumumab group versus 15 months in the duvelisib group) using a one-sided log-rank 
test at a 2.5% overall significance level (ie, alpha of 0.025). The study design employs the Lan-
DeMets spending function for O’Brien-Fleming boundary as the alpha spending function and the 
Hwang-Shih-DeCani gamma (-4) spending function as the beta spending function. A total of 300 
subjects will be randomized in a 1:1 ratio to receive either ofatumumab or duvelisib. Assuming a 
peak accrual rate of 30 subjects per month with 11 months for accrual ramp-up and a 4% 
cumulative dropout rate per year, the enrollment would complete in 16 months, with the final 


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analysis for PFS estimated to occur approximately 27.5 months from the randomization of the 
first subject. 
3.3 Randomization 
Once a subject has met all entry criteria, the Interactive Response Technology (IRT) will be used 
to generate a distinct subject identifier. If a subject discontinues from the study, the subject 
identifier will not be reused and the subject will not be allowed to re-enter the study.  
Eligible subjects will be randomized via IRT in a 1:1 ratio to one of two treatment arms:  
• Arm 1: duvelisib 25 mg BID  
• Arm 2: Ofatumumab  
In order to ensure subject balance between treatment groups, study subjects will be stratified by 
the following: 
• High risk cytogenetics (presence vs absence of del[17p]) 
• Refractory/early relapse to purine analog based treatment (progression <12 months after 
fludarabine/pentostatin: yes vs no)  
• Grade 4 cytopenia(s) (presence vs absence of neutropenia or thrombocytopenia at 
baseline)   
First dose is to occur within 7 days of randomization after all screening assessments have been 
completed. 
3.4 Blinding  
This study is open-label and Investigators, site staff, Sponsor and Sponsor designees will have 
access to treatment assignments for individual subjects. To reduce bias, a blinded independent 
central review of disease status will be conducted, which will be blinded to individual subject 
treatment assignments. Investigators, site staff, Sponsor and Sponsor designees will only have 
access to blinded (pooled) aggregate study data, except for a select number of Sponsor staff, who 
may review aggregate SAEs and Medical Events of Interest (MEOI) data by treatment groups. 
3.5 Planned Analyses 
Interim and final analyses are planned for PFS and OS. For an interim analysis, the actual p-
value boundaries will be calculated based on the actual number of PFS and OS events at the 
analysis. For the final analysis, the actual p-value boundary for efficacy will be calculated based 
on the actual number of PFS and OS events at the interim analysis (or analyses) and the final 
analysis. 
The Independent Data Monitoring Committee (IDMC) will review PFS, OS and other efficacy 
data at the time of PFS interim analysis. The list of IDMC deliverables, including tables and 
listings, is included in the IDMC charter.  These deliverables will be based on the methods 
described in this SAP.  


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3.5.1 Planned Analyses for PFS 
There will be two planned analyses for PFS, one interim analysis and one final analysis. After 
approximately 50% of the planned PFS events (ie, 93 PFS events) have been observed based on 
the blinded, independent, central review, an interim analysis of efficacy will be performed.  
At the interim analysis, PFS will be tested at the alpha level based on the Lan-DeMets alpha 
spending function for the O’Brien-Fleming boundary with the opportunity to stop the study 
(other than survival follow-up) for overwhelming evidence of efficacy. If the interim analysis 
occurs at exactly 50% of the planned events, the criterion of stopping for efficacy is one-sided p-
value of 0.0015 (corresponding approximately to a HR of 0.540). In the meantime, PFS will also 
be tested at the alpha level for futility based on the alpha and beta spending functions specified 
for the study design. If the interim analysis occurs at exactly 50% of the planned events, the 
criterion of stopping for futility is one-sided p-value of 0.4791 (corresponding approximately to a 
HR of 0.990). The futility boundary of this study is non-binding, meaning that the Type I error is 
properly controlled even if the study is continued after the futility boundary for PFS is crossed at 
the interim analysis.  Under the protocol design assumptions (eg, the study is fully enrolled in 16 
months), the interim analysis is expected to occur approximately 17 months after the first subject 
is randomized.  
If the study is not stopped at the interim analysis, the final analysis will be performed when 
approximately 185 PFS events have occurred in the study.  If the interim analysis and the final 
analysis occur at exactly 93 and 185 PFS events, the criterion of statistical significance  
(ie, boundary for efficacy) is one-sided p-value of 0.0245 (corresponding approximately to a HR 
of 0.748).  
3.5.2 Planned Analyses for OS 
There will be three planned analyses for OS: two interim analyses and one final analysis. The 
first interim analysis of OS will be performed at the time of the planned PFS interim analysis 
after 93 PFS events have occurred. The estimated number of OS events at this first OS interim 
analysis is 24. The second interim analysis of OS will be performed at the planned PFS final 
analysis, after 185 PFS events have occurred. If the planned final analysis of PFS is not 
performed due to an early stop for efficacy, then the second interim analysis of OS will be 
conducted approximately 1 year after the first interim OS analysis. The estimated number of OS 
events at the second OS interim analysis is 58. The final analysis of OS will take place after the 
completion of follow-up for all subjects. The estimated number of OS events at the final OS 
analysis is 161. The information fractions at the two interim OS analyses and the final OS 
analysis will be calculated based on 161 planned OS events at the final OS analysis. The 
cumulative alpha spending at the three analyses will be 0.0001, 0.0249, and 0.0250, respectively.  
If the OS analyses occur at 24, 58, and 161 OS events, the p-value stopping boundaries for the 
three analyses will be 0.0001, 0.0249 and 0.0003, respectively.  The actual p-value stopping 
boundaries will be derived from the actual number of OS events that occurred.  The statistical 


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significance of OS will be claimed based on the hierarchical testing procedure as specified in 
Section 6.3. 
4 ANALYSIS SETS 
4.1 Intent-To-Treat (ITT) Analysis Set 
The intent-to-treat (ITT) analysis set includes all subjects who are randomized, with treatment 
group designated according to randomization. 
This analysis set will serve as the primary analysis set for all efficacy endpoints and 
demographics.  
4.2 All-Treated (AT) Analysis Set 
The all-treated (AT) analysis set includes all subjects who receive any amount of study drug 
(duvelisib or ofatumumab), with treatment group designated according to actual study treatment 
received. The AT analysis set will be the primary analysis set for safety endpoints. 
4.3 Per-Protocol (PP) Analysis Set 
The per-protocol (PP) analysis set includes all subjects in the ITT analysis set who do not violate 
the terms of the protocol in a way that would significantly affect the study outcome, with 
treatment group designated according to randomization. Subjects who meet any of the following 
criteria may be excluded from this analysis set:  
• Do not have documented diagnosis of CLL or SLL  
• Do not have measurable nodal disease at baseline as determined by the IRC 
• ECOG performance status >2 
• History of Richter's transformation or prolymphocytic leukemia  
• Refractory to ofatumumab  (defined as progression or relapse <12 months of receiving 
ofatumumab monotherapy or <24 months of receiving an ofatumumab-containing 
regimen)   
• Prior exposure to a PI3K inhibitor 
• Receive concomitant prohibited anticancer therapy  
• Permanent discontinuation from study drug due to non-compliance 
The PP analysis set will be a secondary analysis set for selected efficacy analyses.  
 
 


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5 STUDY ENDPOINTS  
5.1 Primary Endpoint 
The primary efficacy endpoint PFS is defined as time from randomization to the first 
documentation of progressive disease (PD) as determined by independent review or death due to 
any cause.  
The censoring method of the primary endpoint can be found in Appendix A. The detailed 
algorithm will be specified in the Analysis Data Model (ADaM) specifications.  
5.2 Secondary Endpoints 
The secondary efficacy endpoints of the study are: 
• Overall Response Rate (ORR), with overall response (based on independent review) 
defined as best response of complete response/remission (CR), CR with incomplete 
marrow recovery (CRi), partial response/remission (PR), or PR with lymphocytosis 
(PRwL), according to the IWCLL or revised IWG Response Criteria, with modification 
for treatment-related lymphocytosis  
• Overall Survival (OS), defined as time from randomization to death 
• Lymph node response rate, with lymph node response defined as ≥50% decrease in the 
SPD of target lymph nodes 
• Hematologic improvement rate, defined as any of following hematologic improvement 
sustained for at least 60 days without transfusion or exogenous growth factors: 
o Neutrophil count >1,500/µL or an increase ≥50% from Baseline; or 
o Hemoglobin >11 g/dL or an increase ≥50% from Baseline; or  
o Platelet count >100,000/µL or an increase ≥50% from Baseline  
• Duration of Response (DOR), defined as time from the first documentation of response to 
first documentation of PD or death due to any cause.  
Other secondary endpoints of the study are: 
• TEAEs and changes in safety laboratory values  
• PK parameters derived from plasma duvelisib concentrations and, if applicable, its 
metabolite(s) 
5.3 Exploratory Endpoints 
The exploratory efficacy endpoints of the study are: 
• Improvement in disease-related symptoms of fatigue, weight loss, unexplained fevers and 
night sweats from Baseline 
• Minimal Residual Disease (MRD) in subjects with documented CR or CRi 
• Time to Response (TTR), defined as the time from randomization to the first 
documentation of response (CR, CRi, PR or PRwL)  


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The QoL endpoints of the study are: 
• Health-related QoL of subjects as assessed by the following subject-reported 
questionnaires:  
o EuroQol-5D (EQ-5D) 
o Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) 
The biomarkers of the study are: 
• Serum and tissue biomarkers and blood immunophenotype 
• Tumor genomic features (eg, DNA sequence variation, DNA copy number variation, 
and/or RNA expression) 
• Germline DNA sequence variations 
 
 
 


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6 GENERAL STATISTICAL METHODS AND DATA HANDLING 
6.1 General Methods 
Summary statistics will be presented by treatment group, unless stated otherwise.  
Unless otherwise specified, descriptive statistics for continuous data will include the number of 
subjects with data to be summarized (n), mean, standard deviation, 25% quartile, median, 75% 
quartile, and minimum and maximum. The same number of decimal places as in the raw data 
will be presented when reporting the minimum and maximum, one more decimal place than the 
raw data will be presented when reporting mean and median, and 2 more decimal places than the 
raw data will be presented when reporting standard deviation. 
Descriptive statistics for categorical/qualitative data will include frequency counts and 
percentages. The total number of subjects in the treatment group will be used as the denominator 
for percent calculations, unless stated otherwise. All percentages will be presented with one 
decimal, unless otherwise specified. Percentages equal to 100 will be presented as 100, and 
percentages will not be presented for zero frequencies. 
Descriptive statistics associated with time-to-event analyses will include the number of events, 
the number of subjects censored, 25% quartile, median, 75% quartile, and 95% confidence 
interval for median. These statistics will be presented for all time-to-event analyses, unless stated 
otherwise.  
Listings will be provided for selected endpoints.  
6.2 Handling of Missing Data 
In general, values for missing data will not be imputed unless methods for handling missing data 
are specified. 
6.2.1 Handling of Missing Dates/Months/Years for Adverse Events 
Adverse events (AEs) with incomplete onset dates will be handled as follows for the sole 
purpose of determining treatment emergence (TEAE is defined in Section 7.3.1): 
• If the start/end date of an AE is partially missing, the date will be compared as far as 
possible with the date of the start of administration of study drug and the date of last dose 
of study drug plus 30 days. The AE will be assumed to be treatment emergent if it cannot 
be definitively shown that the AE did not occur or worsen during the treatment-emergent 
period (worst case approach). The detailed algorithm will be specified in ADaM 
specifications.  
• If the start date is completely missing, an AE will be considered treatment-emergent 
unless the stop date is before study drug administration. 
• If the dose start date is missing for a subject at a data-cut, all AEs of the subject will be 
considered treatment-emergent.  
The original partial or missing date will be shown in listings of AEs. 


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6.2.2 Handling of Missing Dates/Months/Years for Concomitant Medications 
Prior or concomitant medications with incomplete start dates will be handled as follows for the 
sole purpose of determining whether a non-study medication is a concomitant medication: 
• If the start/stop date of a medication is partially missing, the date will be compared as far 
as possible with the date of the start of administration of study drug and the date of last 
dose of study drug plus 30 days. The medication will be assumed to be concomitant if it 
cannot be definitively shown that the stop date is before the start of administration of 
study drug, or the start date is more than 30 days after the last date of administration of 
study drug. The detailed algorithm will be specified in ADaM specifications.  
• If the start/stop dates are completely missing, a medication will be considered 
concomitant. 
• If the dose start date is missing for a subject at a data-cut, all non-study medications of 
the subject will be considered concomitant. 
The original partial or missing date will be shown in listings of all non-study medications. 
6.2.3 Handling of Missing Dates/Months/Years for Disease History and Prior Therapies 
For the purpose of calculating the duration from initial diagnosis, most recent relapse/refractory 
diagnosis or most recent prior therapy to randomization, partial/missing dates for diagnosis and 
last prior therapy completion will be imputed as follows:  
 
• If both date and month are missing and the year is prior to the year of screening, the 
imputed date and month will be 01 July.  
• If both date and month are missing and the year is the same as the year of screening, the 
imputed date will be the middle point between 01 Jan of the year and the screening date. 
If the middle point falls between two dates, the first of the two dates will be used.  
• If date is missing and the month and year are prior to the month and year of screening, 
the imputed date will be 15th day of the month.  
• If date is missing and the month and year are the same as the month and year of 
screening, the imputed date will be the middle point between the first date of the month 
and the screening date. If the middle point falls between two dates, the first of the two 
dates will be used.  
• No imputation will be performed if the year is missing.  
6.3 Multiple Comparisons/Multiplicity Adjustment 
Of the secondary endpoints, ORR and OS are designated as key secondary efficacy endpoints. 
The primary endpoint and key secondary endpoints will be tested at an overall one-sided alpha 
level of 0.025 based on a gatekeeping approach.  
If the primary endpoint is significant, the two key secondary endpoints will be sequentially tested 
in the order listed above. ORR will be tested at the one-sided 0.025 level only if PFS is declared 
statistically significant. OS will be tested according to the planned alpha spending specified in 
Section 3.5.2 only if PFS and ORR are declared statistically significant. If any null hypothesis is 
not rejected in this sequence of tests, formal sequential testing will be stopped.  


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6.4 Adjustments for Covariates 
Adjustments for covariates will be considered for analysis of primary and key secondary 
endpoints, with details provided in Sections 7.2.1 and 7.2.2. 
6.5 Subgroups 
PFS, ORR and OS will be examined in the subgroups based on the following baseline 
characteristics or variables: 
• Stratification factors (1. captured from central lab; 2 and 3 captured on the eCRF): 
1 High-risk cytogenetics (presence vs absence of del[17p]) 
2 Refractory/early relapse to purine analog-based therapy (defined as progression 
<12 months after fludarabine/pentostatin: yes vs no)  
3 Grade 4 cytopenia(s) (presence vs absence of neutropenia or thrombocytopenia at 
baseline)   
• Diagnosis (CLL or SLL) 
• Gender (Male or Female) 
• Age group (<65 or ≥65) 
• Race (White or Non-White) 
• Previously treated with ofatumumab (yes vs no, if sample size allows the analysis) 
• Time from last dose of most recent prior anti-cancer therapy to randomization <12 
months: yes vs no  
• del[17p] or TP53 mutation (either or both present vs neither present; del[17p] will be as 
captured from central lab) 
TEAEs (All Causalities) and TEAEs (Treatment-Related) will be examined in the following 
subgroups: 
• Gender (Male or Female) 
• Age group (<65 or ≥65) 
• Race (White or Non-White) 
• Baseline ECOG performance status (0 or 1 vs 2) 
More details will be specified in Sections 7.2.1, 7.2.2 and 7.3.1. 
6.6 Visit Windows 
All data will be categorized based on the scheduled visit at which it was collected.  These visit 
designators are predefined values that appear as part of the visit tab in the eCRF.  There will be 
no additional analysis windowing done based on the assessment date. 
6.7 Unscheduled Visits 
Unscheduled visits will not be included in by-visit summary tables, unless otherwise specified.  
For laboratory tests, data from unscheduled visits will be included in listings and summaries of 
maximum changes from baseline, and the best or worst post-baseline values.  For endpoints 


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based on disease status assessment, data from unscheduled assessments will be included in the 
derivation and analyses of the endpoints. 
6.8 Baseline Values  
Unless otherwise specified, the baseline value is defined as the value collected at the time closest 
to, and prior to, the start of study drug administration.  Values collected at unscheduled visits 
prior to the start of the study drug administration will be included in the calculation of baseline 
values.  
 
6.9 Computing and Coding Standards 
Activities will be performed using the following tools: 
Table, listing, and figure production 
SAS Version 9.3 or higher 
Coding 
 
 
Adverse Events 
MedDRA Version 16.1 or higher 
 
Medical Histories 
MedDRA Version 16.1 or higher 
 
Prior and Concomitant Medications 
WHODrug Version September 2013 
Grading 
 
 
AEs 
CTCAE Version 4.03 
 
Labs 
CTCAE Version 4.03 
 
 
 
 
 
 
 


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7 STATISTICAL ANALYSES 
7.1 Study Subjects 
7.1.1 Disposition of Subjects 
The disposition of subjects will include the number and percentage of subjects for the following 
categories: the number randomized, the number and percentage randomized but not dosed, the 
number and percentage dosed. These categories will be summarized for each treatment arm and 
for the two treatment arms combined (total).  The percentages will be based on all randomized 
subjects (ITT analysis set).   
An end-of-treatment disposition (still on treatment vs discontinued from treatment) will be 
provided for each treatment arm and for the two treatment arms combined (total) based on the 
AT analysis set. The primary reason for treatment discontinuation will be included in the table. A 
listing of these subjects will also be provided, broken down by center and treatment arm. 
An end-of-study disposition (still on study vs discontinued from study) will also be provided for 
each treatment arm and for the two treatment arms combined (total) based on the ITT analysis 
set. The primary reason for study discontinuation will be included in the table. A listing of these 
subjects will also be provided, broken down by center and treatment arm. 
A summary of strata as captured in IRT will be presented by treatment arm and for the two 
treatment arms combined (total) based on the ITT analysis set.  A summary table and a listing of 
the discrepancies in data for stratification factors between those captured in the IRT and those 
reported on the eCRF will be presented. 
7.1.2 Protocol Deviations 
Protocol deviations will be categorized as major or minor prior to data release for the interim or 
final analysis of the primary endpoint. A summary table of the major protocol deviations will be 
provided by treatment arm and for two arms combined (total) for the ITT analysis set. A listing 
of major protocol deviations will be provided, broken down by center and treatment arm. 
7.1.3 Demographic and Other Baseline Characteristics 
Demographic and other baseline variables will be summarized for each treatment arm based on 
all randomized subjects (ITT analysis set) and for the two treatment arms combined (total). The 
variables will include age, age group (<65 versus >=65), sex, race, ethnicity, height, weight and 
the following biomarkers: 
• del[17p] (captured from central lab, presence vs absence vs indeterminate) 
• del[17p] (captured from local lab, presence vs absence vs indeterminate) 
• IgHV status (mutated vs unmutated vs indeterminate) 
• CD38 (Positive (≥30%) vs Negative (<30%) vs indeterminate) 
• ZAP70 (Positive (>19%) vs Negative (≤19%) vs indeterminate) 
• del[17p] and/or TP53 mutation (either or both present vs neither present vs indeterminate; 
del[17p] will be as captured from central lab) 


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• TP53 mutation (presence vs absence vs indeterminate) 
A separate table will be provided to compare del[17p] values captured from central lab and local 
lab. Demographic and other baseline variables will also be summarized based on the PP analysis 
set.  
7.1.4 Disease History 
Disease history will be summarized for each treatment arm and for the two treatment arms 
combined (total) based on the ITT analysis set. The variables will include diagnosis (CLL or 
SLL), risk factors used for randomization that are reported on eCRF (high risk cytogenetics [17p 
deletion: presence vs absence], refractory/early relapse to purine analog based treatment [yes vs 
no], grade 4 cytopenia(s) [presence vs absence]), years from initial diagnosis to randomization, 
months from most recent relapse/refractory diagnosis to randomization, Binet/Rai stage at initial 
diagnosis, type of prior treatment, Binet/Rai stage at baseline, and baseline lymphocyte count.  
The durations to be summarized are defined as follows: 
• Years from initial diagnosis to randomization will be calculated as (date of randomization 
– date of initial diagnosis + 1)/365.25.  
• Months from most recent relapse/refractory diagnosis to randomization will be calculated 
as (date of randomization – date of most recent relapse/refractory diagnosis + 1)/ 
(365.25/12).  
The imputation of partial/missing dates is described in Section 6.2.3. 
7.1.5 Prior Therapies 
Prior therapies will be summarized for each treatment arm and for the two treatment arms 
combined (total) based on the ITT analysis set. The variables will include number of prior 
systemic therapies (summarized as a continuous variable and as a categorical variable) and 
months from most recent prior systemic therapy to randomization. 
The duration to be summarized is defined as follows.  
• Months from most recent prior systemic therapy to randomization will be calculated as 
(date of randomization – stop date of most recent systemic therapy +1)/ (365.25/12).  
The imputation of partial/missing dates is described in Section 6.2.3.  
7.1.6 Medical History 
Medical history will be summarized for each treatment arm and for the two treatment arms 
combined (total) based on the AT analysis set. 
Medical history will be summarized by system organ class (SOC) and preferred term (PT) using 
the number and percentage of subjects who had at least one occurrence of an SOC or PT. The 
summary will be sorted alphabetically in SOC and by decreasing frequency of PT in the 
duvelisib arm within an SOC. 


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7.1.7 Prior and Concomitant Medications  
Medications will be considered as prior if they stopped before the date of first dose of study 
drug.  
Medications will be considered concomitant if they were taken at any time between the date of 
first dose of study drug and 30 days after the date of last dose of study drug, inclusive.  If the 
start date or end date of a medication is completely or partially missing, refer to Section 6.2.2 for 
the algorithm to determine whether a medication is concomitant. 
Prior medications and concomitant medications will be summarized separately. Both summaries 
will be based on the AT analysis set. 
Medications will be summarized by ATC level 1, ATC level 2, and preferred drug name for each 
treatment arm. The summary will be sorted by decreasing frequency in ATC level 1, ATC level 2 
and preferred drug name in the duvelisib arm. A subject taking the same drug multiple times will 
only be counted once. 
A listing will be provided for all non-study medications taken on the study. An identifier will be 
provided to show if a medication is prior or concomitant. Medications that started more than 30 
days after the last dose of study drug will be identified as post-treatment.  
7.1.8 Exposure to Study Drug 
Extent of exposure will be summarized for each treatment arm based on the AT analysis set.  
Extent of exposure will be summarized for the following variables: 
• Duration (weeks): (date of last dose – date of first dose + 1) divided by 7 
• Number of cycles started (continuous and categorical) 
• Ofatumumab arm only: For each infusion (1-12), number and percent of subjects 
receiving the infusion 
• Relative dose intensity, defined as 100% x (total dose received)/ (planned 
cumulative dose for the duration of treatment) 
• Number and percentage of subjects with a dose reduction  
• duvelisib arm only: Number and percentage of subjects with a dose increase  
• Number and percentage of subjects with a dose hold   
• Number and percentage of subjects with study drug discontinued  
A by-subject listing will be presented for exposure to study drug. 
7.2 Efficacy Analyses 
For PFS, ORR, lymph node response rate, DOR and other endpoints derived from progression 
and/or response status, the primary analyses will be based on the endpoints derived from 


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independent central review by Independent Review Committee (IRC). The endpoints derived 
from investigator assessment will be used in sensitivity analyses. 
All efficacy analyses will be based on the ITT analysis set unless stated otherwise.  If analyses 
are performed on more than one analysis set, the analyses on the ITT analysis set will be 
considered primary.   
For stratified analysis of any efficacy endpoint, the following algorithm will be used to pool 
strata if there is insufficient information in any stratum (ie, there are <6 subjects, or there is no 
event for a time-to-event endpoint, or all subject have the same outcome for a binary endpoint in 
a stratum). (1) Strata will be ranked from the smallest to the largest based on the number of 
subjects, and if there is a tie, based on the number of events or responses. If there is still a tie, 
based on the reverse order of strata as determined by the stratification factors and levels (see 
Section 3.3). (2) The smallest stratum will be compared with the criteria of insufficient 
information. (3) If there is insufficient information in the smallest stratum, that stratum will be 
pooled with the smallest of the adjacent strata, which are defined as strata having 2 of the 3 
stratification factors being at the same level as the smallest stratum. At the end of the three steps, 
the pooled stratum will replace the original two contributing strata.  If there is still insufficient 
information in any stratum, the three steps will be repeated with the last pooled stratum assuming 
the stratum label of the larger of the two contributing strata for the purpose of additional pooling. 
The resulting pooled strata will be the strata used for the stratified analysis described in this 
section. 
Listings of all efficacy endpoints will be provided.  
7.2.1 Analyses of Primary Endpoint 
7.2.1.1 Primary Analyses of PFS  
The primary analyses of PFS will use PFS based on IRC assessment in the ITT analysis set. 
Number of subjects with events, types of events (progression or death before progression), 
number of subjects censored, number of subjects for each reason of censoring, estimates and 
95% confidence intervals for the 25th percentile, median, and 75th percentile for PFS will be 
presented by treatment group. Probabilities of event free at selected time points may also be 
presented. 
A stratified log-rank test (one-sided) will be used to compare PFS of the duvelisib arm against 
PFS of the ofatumumab arm at the interim and final analyses with the overall one-sided 
significance level controlled at 0.025. The nominal p-value required for statistical significance at 
an analysis will be calculated based on the numbers of PFS events at all preceding and current 
analyses. The HR (duvelisib/ofatumumab) and the corresponding 2-sided 95% CI will be 
estimated using a stratified Cox proportional hazards model. For both the stratified log-rank test 
and the stratified Cox model, the strata will be those used for stratified randomization, with 
potential pooling of strata specified earlier in Section 7.2.   


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PFS will be plotted for each treatment group using the Kaplan-Meier method. The plot will 
include the number of subjects at risk for each treatment group over time. 
7.2.1.2 Sensitivity Analyses of PFS 
The following sensitivity analyses will be performed: 
• PFS based on investigator assessment: This endpoint will be analyzed using the same 
methods as the primary analyses described for PFS based on IRC assessment. In 
addition, the differences between investigator assessment and IRC assessment will be 
summarized. 
• Worst-case sensitivity analysis: Subjects who are alive and have not had documented 
progression by data cutoff and who are “lost to follow-up” (missing at least one 
disease assessment right before data cut off) will be treated as censored at their last 
adequate disease assessment if they are on the control arm (ofatumumab) and treated 
as having a PFS event at the time of the next scheduled assessment following the last 
adequate disease assessment if they are on the experimental arm (duvelisib). PFS 
based on IRC assessment with the above worst-case censoring/event rule will be 
analyzed using the same methods as the primary analyses for PFS. 
• Event-free survival (EFS): This is defined as time from randomization to the first 
documentation of PD as determined by IRC, start of new anticancer treatment or 
procedure, or death due to any cause.  The event/censoring method is presented in 
Appendix B. EFS will be analyzed using the same methods as the primary analyses 
for PFS except that the summary of types of events will include a category of new 
anticancer treatment or procedure. 
• Analysis using the PP analysis set. 
• Analysis using the AT analysis set. 
• Unstratified analyses: An unstratified log-rank test (one-sided) will be used to 
compare the two trreatment arms. An unstratified Cox regression (one-sided) will be 
used to estimate the hazard ratio (duvelisib/ofatumumab) with its 95% confidence 
interval. Other aspects of the analyses will be the same as the primary analyses of 
PFS. 
• Cox regression with baseline covariates: A stratified Cox regression will be used to 
test treatment effect on PFS, adjusting for demographic and other baseline 
characteristics. The strata will be those used for stratified randomization, with 
potential pooling of strata specified earlier in Section 7.2. A stepwise variable 
selection will be performed to choose the variables in the Cox regression. Candidate 
variables are age, gender, race, disease diagnosis (CLL or SLL), years from initial 
diagnosis, months from most recent relapse/refractory diagnosis, stage at diagnosis, 
stage at baseline, and number of prior systemic therapies. PFS based on IRC 
assessment will be used for this analysis. 


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7.2.1.3 Subgroup analyses of PFS 
Subgroup analyses for PFS will be performed using the subgroups specified in Section 6.5. The 
HR (duvelisib/ofatumumab) with its 95% CI will be calculated based on an unstratified Cox 
regression model for each subgroup. The hazard ratios and their 95% confidence intervals will be 
displayed for all subgroups graphically in a forest plot.  
For selected subgroups, additional analyses of PFS will be performed. Number of subjects with 
events, types of events (progression or death before progression), number of subjects censored, 
number of subjects for each reason of censoring, estimates and 2-sided 95% confidence intervals 
for the 25th percentile, median, and 75th percentile for PFS will be presented by treatment group. 
Probabilities of event free at selected time points may also be presented. PFS will be plotted for 
each treatment group using the Kaplan-Meier method. The plot will include the number of 
subjects at risk for each treatment group over time.   
7.2.2 Analyses of Secondary Efficacy Endpoints 
Of the secondary endpoints, ORR and OS are designated as key secondary efficacy endpoints. 
These endpoints will be tested for statistical significance under an overall one-sided significance 
level of 0.025 if and only if the primary endpoint is significant. Details of multiplicity adjustment 
are provided in Section 6.3. 
The analyses of secondary efficacy endpoints, Lymph Node Response Rate and Hematologic 
Improvement Rate, will include hypothesis testing, but no statistical significance will be claimed. 
The analyses of other secondary efficacy endpoint, Duration of Response (DOR), will be 
nominal only.   
7.2.2.1 Overall Response Rate (ORR) 
The primary analyses of ORR will use ORR based on IRC assessment in the ITT analysis set. 
ORR will be derived from best overall response (BOR), which is defined as the best time point 
response that a subject achieves during the course of the study, with the response ranked 
according to the following order (from best to worst): CR>CRi>PR>PRwL>SD>PD  (CRi 
applies to CLL only).  In addition, the IRC may assign a timepoint response of unknown (UNK) 
due to missing, incomplete, or inadequate data; at baseline, the IRC may assign a timepoint 
response of no evidence of disease (NED) if both radiological and clinical data indicate no 
disease involvement; for a post-baseline timepoint, the IRC may also assign a timepoint response 
of not evaluable (NE) if no target lesions were identified at baseline and the radiological and 
clinical data at the post-baseline timepoint do not support the disease response of PD or UNK; 
these categories will be classified as OTHER in the summary.    
The estimated ORR (percent of subjects with a BOR of CR, CRi, PR or PRwL) and a 2-sided 
95% CI will be provided for each treatment arm.  Number and percent of subjects with BOR in 
each of the response categories (CR, CRi, PR, PRwL, SD, PD, OTHER) will also be presented 
by treatment arm.  All subjects in the analysis set will be included in the denominator in the 
calculation of the percentage for each response category or ORR.  


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ORR will be analyzed using the Cochran-Mantel-Haenszel (CMH) test (one-sided, see Appendix 
C) to compare the two treatment groups. The strata for the test will be those used for stratified 
randomization, with potential pooling of strata specified earlier in Section 7.2. The odds ratio 
and its 95% CI will be estimated. 
The following sensitivity analyses will be performed: 
• ORR based on investigator assessment 
• Overall Confirmed Response Rate (OCRR), with overall confirmed response (based on 
independent review) defined as best confirmed response (time between response and 
confirmation must be ≥8 weeks in duration) of CR, CRi, PR, or PRwL, according to the 
IWCLL or revised IWG Response Criteria, with modification for treatment-related 
lymphocytosis 
• Overall Response Rate without PRwL: with overall response (based on independent 
review) defined as best response of complete response/remission (CR), CR with 
incomplete marrow recovery (CRi), partial response/remission (PR) 
• Overall Confirmed Response Rate without PRwL 
• Overall Response Rate in subset of subjects with baseline assessment other than UNK 
and NED. This analysis will be performed if there are at least 5% subjects with baseline 
assessment of UNK or NED 
• Overall Response Rate in subset of subjects who are on treatment for 60 days or longer 
• Analysis using the PP analysis set 
• Analysis using the AT analysis set 
Subgroup analyses will be performed for ORR using the subgroups specified in Section 6.5.  
The odds ratio (duvelisib/ofatumumab) with its 95% CI will be calculated for each subgroup 
based on unstratified test. The odds ratios and their 95% confidence intervals will be displayed 
for all subgroups graphically in a forest plot. 
For selected subgroups, the estimated ORR and its 2-sided 95% CI will be provided for each 
treatment arm; number and percent of subjects with BOR in each of the response categories (CR, 
CRi, PR, PRwL, SD, PD, OTHER) will also be presented by treatment arm. 
7.2.2.2 Overall Survival (OS) 
The primary analyses of OS will be based on the ITT analysis set.  
Subjects without documentation of death at the time of the data cutoff for analysis will be 
censored at the date the subject was last known to be alive, or the data cutoff date, whichever is 
earlier.  A stratified one-sided log-rank test will be used to compare OS between the 2 treatment 
groups.  The HR along with the 95% CI will be estimated using a stratified Cox model. For both 
the stratified log-rank test and the stratified Cox model, the strata will be those used for stratified 
randomization, with potential pooling of strata specified earlier in Section 7.2. A Kaplan-Meier 
plot for OS will be presented by treatment group. Estimates and 95% confidence intervals for the 


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25th percentile, median, and 75th percentile for OS will be presented by treatment group (if 
estimable).  Probabilities of survival at selected time points may also be presented. 
A majority of subjects can be expected to take subsequent anticancer therapy, especially after 
disease progression. To adjust for the effects of subsequent therapy, the following sensitivity 
analysis may be performed: Primary analyses except additional censoring at the start date of 
subsequent therapy 
Subgroup analyses for OS will be performed using the subgroups specified in section 6.5. The 
HR (duvelisib /ofatumumab) with its 95% CI will be calculated based on an unstratified Cox 
regression model for each subgroup. The HRs and their 95% CIs will be displayed for all 
subgroups graphically in a forest plot. 
OS follow-up time, defined as time from randomization to the date of last procedure or 
assessment (including telephone interview), will be summarized by treatment arm and for the 
two treatment arms combined (total) using the reverse Kaplan-Meier method, which applies 
Kaplan-Meier method to the OS data with the same event/censoring time as the primary OS 
analyses while reversing event/censoring indicator. The 25th percentile, median, and 75th 
percentile of OS follow-up time will be presented.   
7.2.2.3 Lymph Node Response Rate 
The primary analyses of lymph node response rate will be based on IRC assessment in the ITT 
analysis set. The number of subjects with lymph node response, estimated lymph node response 
rate, and a 2-sided 95% CI will be provided for each treatment arm. 
Lymph node response rate will be analyzed using the CMH test (one-sided) to compare the two 
treatment groups. The strata for the test will be those used for stratified randomization, with 
potential pooling of strata specified earlier in Section 7.2. 
A sensitivity analysis will be performed using lymph node response rate based on investigator 
measurements. 
7.2.2.4 Hematologic Improvement Rate 
A subject with a hematologic improvement is one who consistently met the criteria of an 
improvement in neutrophil count, hemoglobin or platelet count for a period of at least 60 days 
during which the subject did not have a transfusion or exogenous cytokines. Missing data or 
missing scheduled assessments during a potential 60-day hematologic improvement episode will 
result in categorization of not having a hematologic improvement.  
The number of subjects with hematologic improvement, estimated hematologic improvement 
rate, and a 2-sided 95% CI will be provided for each treatment arm. 
Hematologic improvement rate will be compared between treatment groups using one-sided 
CMH test. The strata for the test will be those used for stratified randomization, with potential 
pooling of strata specified earlier in Section 7.2.  


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7.2.2.5 Duration of Response (DOR) 
DOR will be presented using the Kaplan-Meier method for each treatment arm based on all 
randomized subjects with a documentation of response (i.e., CR, CRi, PR, or PRwL) as 
determined by IRC assessment. The censoring method will be the same as that for the primary 
endpoint (see Appendix A).  The Kaplan-Meier plot for DOR will be presented by treatment 
group. Estimates and 95% confidence intervals for the 25th percentile, median, and 75th 
percentile for DOR will be presented by treatment group (if estimable). No treatment comparison 
will be performed.  
7.2.3 Analyses of Exploratory Efficacy Endpoints 
7.2.3.1 Improvement in Disease-Related Symptoms 
Disease-related symptoms of fever, weight loss, and drenching night sweats will be assessed as 
present or absent at each timepoint. Improvement in each of the three disease-related symptoms 
from baseline will be analyzed separately.  The summary will display by treatment arm the 
proportion of subjects with an improvement while on treatment. Descriptive analysis of 
improvement in these disease-related symptoms will also be presented over the course of the 
study (eg, for each scheduled assessment) by treatment arm.  
The disease-related symptom of fatigue will be measured by the ECOG performance status. 
Summary statistics will be provided by treatment arm for the ECOG score and the change from 
baseline at each timepoint.  
7.2.3.2 Minimal Residual Disease  
MRD status for subjects with a response of CR or CRi will be determined using flow cytometry 
from a central lab. MRD will be classified as positive or negative. The estimated rates of subjects 
with negative MRD in subjects with a response of CR or CRi will be provided for each treatment 
arm given there are sufficient amount of data.  
7.2.3.3 Time To Response (TTR) 
TTR will be presented for each treatment arm based on all randomized subjects with a 
documentation of response (i.e., CR, CRi, PR, or PRwL). Summary statistics and a 2-sided 
confidence interval for median TTR will be provided by treatment arm. No treatment comparison 
will be performed.  
7.3 Safety Analyses 
All safety analyses will be performed using the AT analysis set. 
7.3.1 Adverse Events  
Adverse events will be coded using MedDRA Version 16.1 or higher. The Grade of the AE will 
be assessed according to the NCI-CTCAE Version 4.03. If an AE is not included in the NCI-
CTCAE Version 4.03, the Grade of the AE will be assessed according to the protocol, Section 
8.2.1.2. 


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The summary of AEs will be focused on treatment-emergent AEs. A treatment-emergent AE 
(TEAE) is defined as any AE that emerges or worsens in the period from the first dose of study 
treatment to 30 days after the last dose of study treatment.  The onset date of an AE will be 
compared to the first dose date and the last dose date plus 30 days to determine whether the AE 
is treatment-emergent or not.  If the onset date of an AE is completely or partially missing, refer 
to Section 6.2.1 for the algorithm to determine whether an AE is treatment emergent. 
TEAEs will be summarized for each treatment arm by MedDRA system organ class (SOC) and 
preferred term (PT), or PT only.  For summary tables by SOC and PT, SOC will be sorted 
alphabetically and PT will be sorted by decreasing frequency in the duvelisib arm within each 
SOC.  For summary tables by PT only, PT will be sorted by decreasing frequency in the 
duvelisib arm.   
If multiple TEAEs of the same PT occur within a subject, only the maximum grade observed for 
this PT will be used in summary of TEAEs by grade, the subject will be counted only once in the 
number of subjects for this PT and only once for the number of subjects for the SOC to which 
this PT belongs.  
An overview TEAE summary table will be provided, which will include the number of subjects 
with AEs in selected categories. In addition, TEAEs will be summarized for the following 
categories, and will be tabulated by SOC and PT, unless otherwise specified.  
• 
Treatment-emergent AEs (All Causalities) 
• 
Treatment-emergent AEs (Treatment-Related) 
• 
Treatment-emergent AEs (All Causalities, by maximum grade) 
• 
Treatment-emergent AEs (Treatment-Related, by maximum grade) 
• 
Grade 3 or higher treatment-emergent AEs (All Causalities) 
• 
Grade 3 or higher treatment-emergent AEs (Treatment-Related) 
• 
Treatment-emergent SAE (All Causalities) 
• 
Treatment-emergent SAE (Treatment-Related) 
• 
Treatment-emergent AEs resulting in discontinuation of study drug (All Causalities) 
• 
Treatment-emergent AEs resulting in dose hold (All Causalities) 
• 
Treatment-emergent AEs resulting in dose reduction (All Causalities) 
• 
Treatment-emergent AEs resulting in dose hold or reduction (All Causalities) 
• 
Treatment-emergent AEs resulting in discontinuation of study drug (Treatment-
Related) 
• 
Treatment-emergent AEs resulting in death (All Causalities) 
• 
Treatment-emergent AEs resulting in death (Treatment-Related) 
• 
Treatment-emergent AEs by PT (All Causalities) 


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• 
Treatment-emergent AEs by PT (AEs with onset date within 24 weeks after the first 
dose of study treatment; All Causalities) 
• 
Grade 3 or higher treatment-emergent AEs by PT (All Causalities) 
• 
Grade 3 or higher treatment-emergent AEs by PT (AEs with onset date within 24 
weeks after the first dose of study treatment; All Causalities) 
• 
Treatment-emergent SAEs by PT (All Causalities) 
• 
Treatment-emergent SAEs by PT (Treatment-Related) 
• 
Treatment-emergent AEs reported in ≥5% of subjects and occurred at ≥2% higher 
incidence in subjects receiving duvelisib (All Causalities) 
• 
Grade 3 or higher treatment-emergent AEs reported in ≥5% of subjects and occurred 
at ≥2% higher incidence in subjects receiving duvelisib (All Causalities) 
A by-subject listing of the following AE categories will be presented.  
• 
All AEs (TEAEs will be flagged) 
• 
All SAEs (TEAEs will be flagged) 
• 
Treatment-emergent AEs resulting in dose hold  
• 
Treatment-emergent AEs resulting in dose reduction 
• 
Treatment-emergent AEs resulting in discontinuation of study drug 
• 
Treatment-emergent AEs resulting in death 
Treatment-emergent AEs (All Causalities) and Treatment-emergent AEs (Treatment-Related) 
will also be tabulated in each subgroup specified in Section 6.5.  
7.3.2 Laboratory Data 
Laboratory tests will be reported separately for hematology and blood chemistry. 
For the purposes of presentation in both tables and listings, the following laboratory test results 
will be converted to the International System of Units (SI) before presentation: sodium, 
potassium, chloride, bicarbonate (or CO2), albumin, total protein, creatinine, uric acid, calcium, 
phosphorus, magnesium, glucose, total and direct bilirubin, and alkaline phosphatase, red blood 
cell (RBC) count, hemoglobin, hematocrit, platelets, white blood cell count with 5-part 
differential performed manually or by flow cytometry (lymphocytes, neutrophils, monocytes, 
basophils, and eosinophils), etc.  
Lab tests performed after the start of the first dose of study treatment, up to 30 days from the last 
dose, will be considered treatment-emergent. Only treatment-emergent lab tests will be included 
in the analyses in this section. 
 


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If a laboratory test value is reported using a non-numeric qualifier (e.g., less than [<] a certain 
value, or greater than [>] a certain value), the given numeric value will be used in the summary 
statistics, ignoring the non-numeric qualifier. 
For laboratory tests with NCI-CTCAE grades, a shift table from baseline grade to the maximum 
post-baseline grade will be provided. Laboratory tests with bi-directional grades (e.g., 
Hyperglycemia and Hypoglycemia) will be presented separately for each direction within the 
shift table.  
Listings will be provided for all laboratory test results and for laboratory test results grade 3 and 
higher.  A listing of subjects with ALT or AST >3xULN with simultaneous total bilirubin 
>2xULN will be presented, where ULN stands for upper limit of normal. The elevations of 
ALT/AST and total bilirubin must occur within 2 days of each other. 
7.3.3 Vital Signs 
The actual values of vital sign parameters, including temperature, heart rate, weight and systolic 
and diastolic blood pressure, will be presented in a by-subject listing.  
7.3.4 Electrocardiogram (ECG) 
A by-subject listing will be presented for baseline ECGs and post-baseline unscheduled ECGs (if 
any).  
7.3.5 Concomitant Medications and Procedures 
Please refer to Section 7.1.7 for the definition and summary of concomitant medications. 
Concomitant procedures will not be summarized. A by-subject listing will be presented. 
 
7.3.6 Deaths 
On-treatment deaths are defined as deaths that occur within 30 days of the last dose of study 
medication. Deaths on treatment and causes for deaths occurring on-treatment, and deaths during 
follow-up will be summarized.  
A by-subject listing of deaths on study will be presented. 
7.4 Quality of Life Instruments 
Analyses of the QoL instruments (EQ-5D and FACIT-F) will be performed on the ITT analysis 
set. Additional analyses may be considered as needed.  
7.4.1 EQ-5D 
The EQ-5D contains a descriptive system with one response for each of 5 dimensions (Mobility, 
Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression). The first response is 
coded as 1 (indicating no problems), the second response is coded as a 2 (indicating some 
problems), and the third response is coded as a 3 (indicating extreme problems). Ambiguous 
responses (eg, more than one response in a dimension) are treated as missing values. The EQ-5D 


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also contains a Visual Analog Scale (VAS) for health state ranging from 0 to 100, where 0 
represents worst imaginable health state and 100 represents the best imaginable health state.  
For each dimension of the descriptive system, the number and percentage of subjects with no 
problems, some problems, and extreme problems will be reported at each visit.  
Summary statistics for the VAS of health state and the change from baseline will be reported for 
each visit.   
7.4.2 FACIT-F 
The FACIT-F contains 5 subscales, Physical Well-Being, Social/Family Well-Being, Emotional 
Well-Being, Functional Well-Being, and Fatigue (Additional Concerns on eCRF). Each subscale 
contains multiple items, and each item has a response of 0 to 4. Scores will be computed for each 
subscale, as well as for the FACIT-F Trial Outcome Index, FACT-G total score, and the FACIT-
F total score.  
The Physical Well-Being subscale contains 7 items. To compute the subscale score, compute the 
item score by subtracting each item response from 4 (item score = 4 – item response), sum the 
item scores, multiply the sum by 7 and divide by the number of items answered. At least 4 
questions must be answered. If fewer than 4 questions are answered, then the subscale score will 
be missing. The Physical Well-Being score ranges from 0 to 28 with higher scores representing 
better quality of life. 
The Social/Family Well-Being score contains 7 questions. To compute the subscale score, sum 
the item responses, multiply the sum by 7 and divide by the number of items answered. At least 4 
questions must be answered. If fewer than 4 questions are answered, then the subscale score will 
be missing. The Social/Family Well-Being score ranges from 0 to 28 with higher scores 
representing better quality of life. 
The Emotional Well-Being subscale contains 6 items. To compute the subscale score, compute 
the item score first. For items 1, 3, 4, 5, and 6, subtract each item response from 4 (item score = 4 
– item response). For item 2, the item score is the same as the item response (no subtraction is 
needed). Sum the item scores, multiply the sum by 6 and divide by the number of items 
answered to compute the subscale score. At least 3 questions must be answered. If fewer than 3 
questions are answered, then the subscale score will be missing. The Emotional Well-Being 
score ranges from 0 to 24 with higher scores representing better quality of life. 
The Functional Well-Being score contains 7 questions. To compute the subscale score, sum the 
item responses, multiply the sum by 7 and divide by the number of items answered. At least 4 
questions must be answered. If fewer than 4 questions are answered, then the subscale score will 
be missing. The Functional Well-Being score ranges from 0 to 28 with higher scores 
representing better quality of life. 
The Fatigue subscale contains 13 items. To compute the subscale score, compute the item score 
first. For all items except An5 and An7, subtract each item response from 4 (item score = 4 – 
item response). For items An5 and An7, the item score is the same as the item response (no 
subtraction is needed). Sum the item scores, multiply the sum by 13 and divide by the number of 


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Analysis Plan 
Version 4.0 (9 May 2017) 
CONFIDENTIAL 
Page 34 of 41 
items answered to compute the subscale score. At least 7 questions must be answered. If fewer 
than 7 questions are answered, then the subscale score will be missing. The Fatigue score ranges 
from 0 to 52 with higher scores representing better quality of life. 
To derive the FACIT-F Trial Outcome Index, sum the subscale scores for Physical Well-Being, 
Functional Well-Being, and Fatigue. If any of these subscale scores is missing, the score for the 
FACIT-F Trial Outcome Index will be missing. The score ranges from 0 to 108.  
To derive the FACT-G score, sum the subscale scores for Physical Well-Being, Social/Family 
Well-Being, Emotional Well-Being, and Functional Well-Being. If any of these subscale scores 
is missing, the FACT-G score will be missing. The score ranges from 0 to 108. 
To derive the FACIT-F total score, sum all 5 subscale scores. If any subscale score is missing, 
the FACIT-F total score will be missing. The score ranges from 0 to 160. 
For each of the five subscale scores and for each of the FACIT-F Trial Outcome Index, the 
FACT-G score, and the FACIT-F total score, summary statistics for the actual values and 
changes from Baseline will be reported at each visit.  
7.5 Pharmacokinetic Analyses 
Plasma samples will be analyzed for duvelisib and IPI-656 (metabolite) concentrations using a 
validated high performance liquid chromatography-tandem mass spectrometry (LC/MS/MS) 
method.  A listing of the duvelisib and IPI-656 concentrations will be provided; the sample 
collection date and time, and the date, time and amount of the preceding duvelisib dose 
administration will be included in the listing. 
The PK data collected will be analyzed by standard population PK methods, using appropriate 
software. Analysis of exposure-response relationships for efficacy and safety endpoints will be 
conducted. If there is only a limited amount of plasma concentration data from this study, the 
data may be pooled with the results of other studies to perform the population PK and exposure-
response analyses.  Further details on these analyses will be outlined in a separate analysis plan. 
Results of the population PK and exposure-response analysis will be summarized in a separate 
technical report. 
7.6 Biomarker Analyses 
The following exploratory analyses may or may not be presented formally. If presented, they will 
be limited to biomarkers for which data from a sufficient number of subjects are available. 
Further details on these analyses may be outlined in a separate analysis plan, and results may be 
summarized in a separate technical report. 
7.6.1 Pharmacodynamic and Potentially Predictive Biomarkers 
The relationship between tumor genomics, gene expression, protein expression, and clinical 
endpoints may be explored as follows: 


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• 
Evaluation of serum biomarkers, blood immunophenotype and tumor biomarkers for 
relationships with duvelisib clinical activity and safety 
• 
Evaluation of tumor genomic features (eg, cytogenetics, FISH, DNA sequence 
variation, DNA copy number variation, and/or RNA expression) for relationships 
with duvelisib clinical activity 
• 
Evaluation of the relationship between serum and/or tumor biomarkers and disease 
progression of duvelisib and ofatumumab 
7.6.2 Pharmacogenomics 
DNA may be extracted from the pharmacogenomics sample in order to evaluate a subject’s 
germline DNA.  This sample may be used to explore the following: 
• Evaluate the relationship between germline DNA sequence variations and PK of 
duvelisib 
• Evaluate germline DNA as a control to verify that tumor sequence variations are 
somatic mutations 
 
 
 


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8 CHANGES IN PLANNED ANALYSES  
8.1 Changes in Planned Analyses from Protocol Amendment 1 to SAP V1.0  
There are no changes from Protocol Amendment 1. More details are provided in the SAP. 
8.2 Changes in Planned Analyses from SAP V1.0 to SAP V2.0 
The main changes from SAP V1.0 to SAP V2.0 are described below. 
1. Section 3.5.2 Clarification 
Old (V1.0): The second analysis of OS will be performed at the PFS final analysis, which 
is expected to happen after 185 PFS events have occurred, or approximately 27.5 months 
after the first subject is randomized. 
New (V2.0): The second interim analysis of OS will be performed at the PFS final 
analysis, which is to happen after 185 PFS events have occurred. If the planned final 
analysis of PFS is not performed due to early stop for efficacy, then the second interim 
analysis of OS will be conducted approximately one year after the first interim analysis of 
OS. 
2. New censoring method for event-free survival were specified.  
3. Prior irradiation and prior surgery were removed from prior therapy summary. 
The following additional analyses/summaries have been added to this version of the SAP: 
1. Analysis of ORR of subjects who are on treatment for 60 days or longer 
2. Time to OS follow up  
3. Time to response 
4. Treatment-emergent AEs reported in ≥5% of CLL/SLL subjects and occurred at ≥2% 
higher incidence in subjects receiving duvelisib (All Causalities) 
5. Grade 3 or higher treatment-emergent AEs reported in ≥5% of CLL/SLL subjects and 
occurred at ≥2% higher incidence in subjects receiving duvelisib (All Causalities) 
6. Treatment-emergent AEs by PT (All Causalities, AE onset date within 24 weeks after 
the first dose of study treatment) 
7. Grade 3 or higher treatment-emergent AEs by PT (All Causalities, AEs with onset 
date within 24 weeks after the first dose of study treatment) 
8. Treatment-emergent AEs resulting in discontinuation of study drug (Treatment-
Related) 
9. Treatment-emergent AEs resulting in death (Treatment-Related) 
10. Treatment-emergent SAEs by PT (All Causalities). 
11. Treatment-emergent SAEs by PT (Treatment-Related) 
12. Deaths on treatment 
13. Deaths during follow-up 


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14. A by-subject listing of treatment-emergent AEs resulting in dose hold  
15. A by-subject listing of treatment-emergent AEs resulting in dose reduction 
16. A by-subject listing of deaths on study 
17. A summary table and a listing of the discrepancies in data for stratification factors 
between those captured in the IRT and those reported on the eCRF  
18. Comparision of del[17p] values captured from central lab and local lab 
19. The following biomarkers will be summarized as baseline characteristics:  
• del[17p] (captured from central lab, presence vs absence vs indeterminate) 
• del[17p] (captured from local lab, presence vs absence vs indeterminate) 
• del[17p] and/or TP53 mutation (del[17p] and/or TP53 mutation, del[17p] 
captured from central lab, either or both present vs neither present vs 
indeterminate) 
• del[17p] and TP53 mutation (del[17p] and TP53 mutation, del[17p] 
captured from central lab, both present vs either vs neither present vs 
indeterminate) 
• TP53 mutation (presence vs absence vs indeterminate) 
• IgHV status (mutated vs unmutated vs indeterminate) 
• CD38 (Positive (≥30%) vs Negative vs indeterminate) 
• ZAP70 (Positive (>19%) vs Negative (<=19%) vs indeterminate) 
20. Subgroup analyses of PFS, OS and ORR based on the following factors: 
• Time from last dose of most recent prior anti-cancer therapy to 
randomization <12 months: yes vs no  
• del[17p] (captured from central lab) or TP53 mutation (either or both 
present vs neither present ) 
 
8.3 Changes in Planned Analyses from SAP V2.0 to SAP V3.0 
The main changes from SAP V2.0 to SAP V3.0 are described below. 
1. In Section 3.5.2, the estimated numbers of OS events at each of OS interim analyses and 
final analysis are provided. 
2. In Section 6.3, Lymph Node Response Rate and Hematological Improvement Rate are 
removed from the list of key secondary efficacy endpoints and removed from the 
hierarchy of inferential testing in secondary endpoints.  
3. In Section 7.2.1.3, for selected subgroups, additional analyses of PFS are added. These 
include the estimate and 95% CI for the median by treatment group, and the Kaplan-
Meier plot by treatment group. 
4. In Section 7.2.2.1, for selected subgroups, summaries of BOR, estimated ORR and its 2-
sided 95% CI for each treatment group are added. 


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9 REFERENCES 
1 O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 
 
1979; 35:549-556. 
2 Robins JM. Information recovery and bias adjustment in proportional hazard 
regression analysis of randomized trials using surrogate markers. Proceedings of the 
Biopharmaceutical Section, American Statistical Association
 
 1993; pp. 24-33.  
3 Robins JM, Finkelstein D.  Correcting for Non-compliance and dependent censoring 
in an AIDS clinical trial with inverse probability of censoring weighted (IPCW) log-
rank tests. Biometrics
 
, 2000; 56(3):779-788. 
4 Robins JM, Tsiatis, AA. Correcting for noncompliance in randomized trials using 
rank preserving structural failure time models. Communications in Statistics
 
, 1991; 
20, 2609-2631. 
 
 


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CONFIDENTIAL 
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10 APPENDICES 
10.1 Appendix A: Primary PFS Event/Censoring Method 
Censoring of PFS will be performed as detailed in the table below.  
 
Situation 
Date of Event or 
Censoring 
Outcome 
No adequate baseline disease status assessment  
Date of randomization 
Censored 
No adequate post-baseline disease status 
assessment unless death occurs prior to first 
post-baseline assessment 
Date of randomization + 1 
Censored 
No documented progression or death before data 
cutoff 
Date of last adequate disease 
status assessment 
Censored 
Documented progression with ≤1 missing 
scheduled disease status assessment before 
progression 
Date of the earliest 
assessment that results in a 
finding of unequivocal 
progression 
Event 
Death before progression being documented 
with ≤1 missing scheduled disease status 
assessment before death 
Date of death 
Event 
Documented progression or death following a 
long gap between adequate disease status 
assessments (eg, 2 or more consecutive missed 
scheduled disease status assessments)  
Date of last adequate disease 
status assessment before the 
gap 
Censored 
New anticancer treatment or procedure started 
before documented progression 
Date of last adequate disease 
status assessment prior to 
new anticancer treatment 
Censored 
Note: Disease status assessment includes CT scans (chest, abdomen and pelvis), bone marrow aspirate and/or biopsy 
(may not be required of all subjects at all scheduled disease status assessments), CBC and differential count, focused 
physical examination, disease related constitutional symptoms for disease assessment, and ECOG performance 
status. An adequate baseline disease status assessment is any baseline disease status assessment that include WBC 
counts and CT scans. An adequate post-baseline disease status assessment is any disease status assessment for which 
a disease status (eg, CR, CRi, PR, PRwL, SD, and PD) is arrived per protocol-defined criteria by the IRC (for IRC 
assessment) or investigator (for investigator assessment).   


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10.2 Appendix B: Event-Free Survival (EFS) Event/Censoring Method 
Situation 
Date of Event or 
Censoring 
Outcome 
No adequate baseline disease status assessment  
Date of randomization 
Censored 
No adequate post-baseline disease status 
assessment unless death or new anticancer 
treatment/procedure occurs prior to first post-
baseline assessment 
Date of randomization + 1 
Censored 
No documented progression, death or new 
anticancer treatment/procedure started before 
data cutoff 
Date of last adequate disease 
status assessment 
Censored 
Documented progression with ≤1 missing 
scheduled disease status assessment before 
progression, and no new anticancer treatment/ 
procedure started before documented 
progression 
Date of the earliest 
assessment that results in a 
finding of unequivocal 
progression 
Event 
Death before progression being documented 
with ≤1 missing scheduled disease status 
assessment before death, and no new anticancer 
treatment/procedure started before death 
Date of death 
Event 
Documented progression, death or new 
anticancer treatment/procedure following a long 
gap between adequate disease status 
assessments (eg, 2 or more consecutive missed 
scheduled disease status assessments)  
Date of last adequate disease 
status assessment before the 
gap 
Censored 
New anticancer treatment/procedure started 
before documented progression with ≤1 missing 
scheduled disease status assessment prior to new 
anticancer treatment/procedure 
Start date of new anticancer 
treatment/procedure 
Event 
 
 
 
 
 


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10.3 Appendix C: One-Sided Cochran–Mantel–Haenszel (CMH) Test 
 
The Cochran–Mantel–Haenszel (CMH) test compares binary responses of two 
treatment groups, adjusting for stratification factors. In the CMH test, the data are 
arranged in a series of associated 2 × 2 contingency tables, the null hypothesis is that the 
observed response is independent of the treatment used in any 2 × 2 contingency table. 
 
Let 
hij
O
 be the observed frequency of treatment i (i=1 or 2) with outcome j (j= 1 or 2) in 
stratum h and 
hij
E
be the expected frequency of treatment i (i=1 or 2) with outcome j (j= 
1 or 2) in stratum h, where 
 
22
21
12
11
2
1
2
1
)
(
)
(
h
h
h
h
j
h
j
h
hi
hi
hij
O
O
O
O
O
O
O
O
E
+
+
+
+
⋅
+
=
 
 
Also, let 
hij
P
be the probability of outcome being j given treatment being i (i=1 or 2, j= 1 
or 2) in stratum h. To test the following hypothesis, 
 
  
 
21
11
0 :
h
h
P
P
H
=
 for all ℎ∈{1, … , 𝐻𝐻}   
versus   
21
11
1 :
h
h
P
P
H
>
 for at least one ℎ∈{1, … , 𝐻𝐻} 
 
The one-sided Cochran-Mantel-Haenszel Test Statistics is constructed as: 
 
Z
V
E
O
Z
H
h
h
h
CMH
~
)
(
11
1
11
11
∑
=
−
=
 
 
Where 
 
 
∑
∑
=
=
−
+
+
+
•
=
−
=
H
h
h
h
h
h
h
h
H
h
h
h
O
O
O
O
E
E
E
O
Var
V
1
22
21
12
11
22
11
1
11
11
11
1
))
(
(
 
 
The test statistic 
CMH
Z
  will be compared with standard normal distribution to 
obtain p-value of the CMH test. 


IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
STATISTICAL ANALYSIS PLAN 
 
Protocol IPI-145-07 
A Phase 3 Study of IPI-145 versus Ofatumumab in Subjects with Relapsed or 
Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma 
 
 
 
 
 
 
 
 
 
 
 
This statistical analysis plan contains confidential information and is the proprietary 
property of Infinity Pharmaceuticals, Inc. This document may not be copied or 
made available for review by an unauthorized person or firm without the prior 
written authorization of Infinity Pharmaceuticals, Inc. 
 
 
 
Protocol Version: 
Amendment 2 
 
Type of Analysis 
Plan: 
Interim and Final Analyses 
 
Version: 
3.0 
 
Date: 
13 Apr 2016 
 
Author: 
Shijie Tang, PhD 
Version 3.0 (13 Apr 2016) 
CONFIDENTIAL 
Page 1 of 41 




IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
 
DOCUMENT HISTORY 
 
Version 
Date 
Author(s) 
Brief Summary of Changes 
1.0 
02 Oct 2014 
Shijie Tang 
Original 
2.0 
24 Nov 2015 
Shijie Tang 
Clarified the timing of the 2nd interim 
analysis of overall survival; added 
biomarkers to baseline characteristics; 
other changes. Refer to Section 8.2 for 
Details. 
3.0 
06 Apr 2016 
Shijie Tang 
In Section 3.5.2, the estimated 
numbers of OS events at each of OS 
interim analyses and final analysis are 
provided.  
Lymph node response rate and 
hematological improvement rate are 
removed from the hierarchy of 
inferential testing in secondary 
endpoints. 
 
 
 
 
 
 
 
 
 
 
Version 3.0 (13 Apr 2016) 
CONFIDENTIAL 
Page 3 of 41 


IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
 
Table of Contents 
 
LIST OF ABBREIVATIONS ......................................................................................................... 7 
1 
INTRODUCTION ................................................................................................................ 10 
2 
STUDY OBJECTIVES ......................................................................................................... 10 
2.1 
Primary Objective .......................................................................................................... 10 
2.2 
Secondary Objectives ..................................................................................................... 10 
2.3 
Exploratory Objectives ................................................................................................... 10 
3 
STUDY DESIGN.................................................................................................................. 11 
3.1 
Overview ........................................................................................................................ 11 
3.2 
Sample Size Consideration............................................................................................. 11 
3.3 
Randomization ............................................................................................................... 12 
3.4 
Blinding .......................................................................................................................... 12 
3.5 
Planned Analyses ........................................................................................................... 12 
3.5.1 
Planned Analyses for PFS ....................................................................................... 13 
3.5.2 
Planned Analyses for OS ........................................................................................ 13 
4 
ANALYSIS SETS ................................................................................................................ 14 
4.1 
Intent-To-Treat (ITT) Analysis Set ................................................................................ 14 
4.2 
All-Treated (AT) Analysis Set ....................................................................................... 14 
4.3 
Per-Protocol (PP) Analysis Set ...................................................................................... 14 
5 
STUDY ENDPOINTS .......................................................................................................... 15 
5.1 
Primary Endpoint ........................................................................................................... 15 
5.2 
Secondary Endpoints ...................................................................................................... 15 
5.3 
Exploratory Endpoints.................................................................................................... 15 
6 
GENERAL STATISTICAL METHODS AND DATA HANDLING ................................. 17 
6.1 
General Methods ............................................................................................................ 17 
6.2 
Handling of Missing Data .............................................................................................. 17 
6.2.1 
Handling of Missing Dates/Months/Years for Adverse Events .............................. 17 
6.2.2 
Handling of Missing Dates/Months/Years for Concomitant Medications ............. 18 
Version 3.0 (13 Apr 2016) 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
6.2.3 
Handling of Missing Dates/Months/Years for Disease History and Prior Therapies
 
18 
6.3 
Multiple Comparisons/Multiplicity Adjustment ............................................................ 18 
6.4 
Adjustments for Covariates ............................................................................................ 19 
6.5 
Subgroups ....................................................................................................................... 19 
6.6 
Visit Windows ................................................................................................................ 19 
6.7 
Unscheduled Visits ......................................................................................................... 20 
6.8 
Baseline Values .............................................................................................................. 20 
6.9 
Computing and Coding Standards ................................................................................. 20 
7 
STATISTICAL ANALYSES ............................................................................................... 21 
7.1 
Study Subjects ................................................................................................................ 21 
7.1.1 
Disposition of Subjects ........................................................................................... 21 
7.1.2 
Protocol Deviations ................................................................................................. 21 
7.1.3 
Demographic and Other Baseline Characteristics .................................................. 21 
7.1.4 
Disease History ....................................................................................................... 22 
7.1.5 
Prior Therapies ........................................................................................................ 22 
7.1.6 
Medical History ...................................................................................................... 22 
7.1.7 
Prior and Concomitant Medications ....................................................................... 23 
7.1.8 
Exposure to Study Drug .......................................................................................... 23 
7.2 
Efficacy Analyses ........................................................................................................... 23 
7.2.1 
Analyses of Primary Endpoint ................................................................................ 24 
7.2.2 
Analyses of Secondary Efficacy Endpoints ............................................................ 26 
7.2.3 
Analyses of Exploratory Efficacy Endpoints .......................................................... 29 
7.3 
Safety Analyses .............................................................................................................. 30 
7.3.1 
Adverse Events ....................................................................................................... 30 
7.3.2 
Laboratory Data ...................................................................................................... 32 
7.3.3 
Vital Signs ............................................................................................................... 32 
7.3.4 
Electrocardiogram (ECG) ....................................................................................... 32 
7.3.5 
Concomitant Medications and Procedures.............................................................. 32 
7.3.6 
Deaths ..................................................................................................................... 33 
7.4 
Quality of Life Instruments ............................................................................................ 33 
Version 3.0 (13 Apr 2016) 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
7.4.1 
EQ-5D ..................................................................................................................... 33 
7.4.2 
FACIT-F ................................................................................................................. 33 
7.5 
Pharmacokinetic Analyses ............................................................................................. 34 
7.6 
Biomarker Analyses ....................................................................................................... 35 
7.6.1 
Pharmacodynamic and Potentially Predictive Biomakers ...................................... 35 
7.6.2 
Pharmacogenomics ................................................................................................. 35 
8 
CHANGES IN PLANNED ANALYSES ............................................................................. 36 
8.1 
Changes in Planned Analyses from Protocol Amendment 1 to SAP V1.0 .................... 36 
8.2 
Changes in Planned Analyses from SAP V1.0 to SAP V2.0 ......................................... 36 
8.3 
Changes in Planned Analyses from SAP V2.0 to SAP V3.0 ......................................... 37 
9 
REFERENCES ..................................................................................................................... 38 
10 APPENDICES ...................................................................................................................... 39 
10.1 
Appendix A: Primary PFS Event/Censoring Method................................................. 39 
10.2 
Appendix B: Event-Free Survival (EFS) Event/Censoring Method .......................... 40 
10.3 
Appendix C: One-Sided Cochran–Mantel–Haenszel (CMH) Test ............................ 41 
 
 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
LIST OF ABBREVIATIONS 
Abbreviation 
Description 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
AT 
All-Treated  
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BID 
Twice a day 
BOR 
Best Overall Response 
BUN 
Blood Urea Nitrogen 
CI 
Confidence Interval 
CLL 
Chronic Lymphocytic Leukemia 
CMH 
Cochran–Mantel–Haenszel 
CO2 
Bicarbonate 
CR 
Complete Response 
CRi 
Complete Response with Incomplete Marrow Recovery 
CS 
Abnormal and Clinically Significant 
CTCAE 
Common Terminology Criteria for Adverse Events 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
Electronic Case Report Form 
eDISH 
Evaluation of Drug Induced Serious Hepatotoxicity 
EQ-5D 
European Quality of Life-5 Dimensions 
FACIT-F 
Functional Assessment of Chronic Illness Therapy-Fatigue 
FACT-G 
The Functional Assessment of Cancer Therapy - General 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Abbreviation 
Description 
HR 
Hazard Ratio 
IDMC 
Independent Data Monitoring Committee 
IPI-145 
(S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-
phenylisoquinolin-1(2H)-one 
IPCW 
Inverse Probability of Censoring Weighted 
IRC 
Independent Review Committee 
IRT 
Interactive Response Technology 
ITT 
Intent-To-Treat 
IV 
Intravenous 
IWCLL 
International Workshop on Chronic Lymphocytic Leukemia 
IWG 
International Working Group 
LC/MS/MS 
Liquid Chromatography-tandem Mass Spectrometry 
LDH 
Lactate Dehydrogenase 
LFT 
Liver Function Test 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEOI 
Medical Events of interest 
MMRM 
Mixed Effect Repeated Measures 
MRD 
Minimal Residual Disease 
NCI 
National Cancer Institute 
NCS 
Abnormal but Not Clinically Significant 
NED 
No Evidence of Disease 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetics 
PP 
Per-Protocol 
PR 
Partial Response 
PRwL 
PR with Lymphocytosis 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Abbreviation 
Description 
PT 
Preferred Term 
QoL 
Quality of Life 
RBC 
Red Blood Cell 
RPSFT 
Rank Preserving Structural Failure Time 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SI 
Standard International System of Units 
SLL 
Small Lymphocytic Lymphoma 
SOC 
System Organ Class 
SPD 
Sum of Products 
TEAE 
Treatment Emergent Adverse Event 
TTR 
Time to Response 
UNK 
Unknown 
VAS 
Visual Analog Scale 
WHO 
World Health Organization 
WHO-DD 
World Health Organization Drug Dictionary 
 
 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
1 INTRODUCTION 
This is the statistical analysis plan (SAP) for study IPI-145-07, A phase 3 study of IPI-145 versus 
ofatumumab in subjects with relapsed or refractory chronic lymphocytic leukemia/small 
lymphocytic lymphoma. This SAP is prepared according to Amendment 2 of the protocol, dated 
02 March 2015. 
2 STUDY OBJECTIVES 
2.1 Primary Objective 
The primary objective of this trial is to examine the efficacy of duvelisib (IPI-145) monotherapy 
versus ofatumumab monotherapy in subjects with relapsed or refractory Chronic Lymphocytic 
Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). 
2.2 Secondary Objectives 
• To determine the safety of duvelisib in subjects with CLL or SLL 
• To evaluate the pharmacokinetics (PK) of duvelisib and, if applicable, its metabolite(s) 
2.3 Exploratory Objectives  
• To evaluate the health-related quality of life (QoL) of subjects 
• To evaluate pharmacodynamic biomarkers of duvelisib  
• To evaluate biomarkers that may predict duvelisib clinical activity and/or safety 
• To evaluate mechanisms of resistance in subjects who exhibit disease progression while 
being treated with duvelisib or ofatumumab 
• To evaluate genomic features of tumors predictive of response in subjects treated with 
duvelisib or ofatumumab 
 
 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
3 STUDY DESIGN 
3.1 Overview 
Study IPI-145-07 is a two-arm, randomized (1:1 ratio), open-label, phase 3, superiority trial 
designed to evaluate the efficacy and safety of duvelisib compared to ofatumumab.  
Subjects who meet all the eligibility criteria at Screening will return to the clinic on Day 1 to 
receive their first dose of study drug (randomized to either duvelisib or ofatumumab). The first 
treatment cycle for each treatment arm will be 3 weeks (21±2 days). Subsequent treatment cycles 
will be 4 weeks (28±4 days). 
Subjects randomized to duvelisib will be given a starting dose of 25 mg duvelisib administered 
orally twice daily (BID) initially in a 21-day treatment cycle followed by 28-day treatment cycles 
for up to 18 cycles or until disease progression or unacceptable toxicity (whichever comes first). 
After completing approximately 18 cycles of treatment, subjects may receive additional cycles of 
duvelisib for up to 3 years (39 cycles of total treatment) if they have documented evidence of 
response and disease requiring continued treatment according to the modified IWCLL/revised 
IWG criteria. 
Subjects randomized to ofatumumab will receive treatment consistent with the approved product 
labeling: 8 weekly infusions, starting with an initial IV dose of 300 mg ofatumumab on Day 1 
followed by seven weekly doses of 2000 mg. Thereafter, subjects will receive 2000 mg 
ofatumumab once every month for four months or until disease progression or unacceptable 
toxicity (whichever comes first), as outlined in the schedule of assessments. Administration of 
ofatumumab will not exceed the 12 doses (within 7 cycles) as described in the prescribing 
information.  
Subjects will be followed for survival for up to 6 years (or other duration as specified by the 
protocol) from randomization or until death. Follow-up visits will occur every 6 months which 
can be conducted through a telephone interview.    
3.2 Sample Size Consideration 
This study employs a randomized, open-label, parallel design to assess the potential superiority 
of duvelisib treatment over ofatumumab treatment on progression-free survival (PFS) in CLL or 
SLL subjects. 
The sample size was determined to provide sufficient power to test the primary endpoint of PFS 
in a group sequential design with one planned interim analysis. 
Assuming an exponential distribution for PFS, a total of 185 PFS events (deaths or progressions) 
will provide approximately 93% power to detect a hazard ratio of 0.6 (median PFS of 9 months 
in the ofatumumab group versus 15 months in the duvelisib group) using a one-sided log-rank 
test at a 2.5% overall significance level (ie, alpha of 0.025). The study design employs the Lan-
DeMets spending function for O’Brien-Fleming boundary as the alpha spending function and the 
Hwang-Shih-DeCani gamma (-4) spending function as the beta spending function. A total of 300 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
subjects will be randomized in a 1:1 ratio to receive either ofatumumab or duvelisib. Assuming a 
peak accrual rate of 30 subjects per month with 11 months for accrual ramp-up and a 4% 
cumulative dropout rate per year, the enrollment would complete in 16 months, with the final 
analysis for PFS estimated to occur approximately 27.5 months from the randomization of the 
first subject. 
3.3 Randomization 
Once a subject has met all entry criteria, the Interactive Response Technology (IRT) will be used 
to generate a distinct subject identifier. If a subject discontinues from the study, the subject 
identifier will not be reused and the subject will not be allowed to re-enter the study.  
Eligible subjects will be randomized via IRT in a 1:1 ratio to one of two treatment arms:  
• Arm 1: duvelisib 25 mg BID  
• Arm 2: Ofatumumab  
In order to ensure subject balance between treatment groups, study subjects will be stratified by 
the following: 
• High risk cytogenetics (presence vs absence of del[17p]) 
• Refractory/early relapse to purine analog based treatment (progression <12 months after 
fludarabine/pentostatin: yes vs no)  
• Grade 4 cytopenia(s) (presence vs absence of neutropenia or thrombocytopenia at 
baseline)   
First dose is to occur within 7 days of randomization after all screening assessments have been 
completed. 
3.4 Blinding  
This study is open-label and Investigators, site staff, Sponsor and Sponsor designees will have 
access to treatment assignments for individual subjects. To reduce bias, a blinded independent 
central review of disease status will be conducted, which will be blinded to individual subject 
treatment assignments. Investigators, site staff, Sponsor and Sponsor designees will only have 
access to blinded (pooled) aggregate study data, except for a select number of Sponsor staff, who 
may review aggregate SAEs and Medical Events of Interest (MEOI) data by treatment groups. 
3.5 Planned Analyses 
Interim and final analyses are planned for PFS and OS. For an interim analysis, the actual p-
value boundaries will be calculated based on the actual number of PFS and OS events at the 
analysis. For the final analysis, the actual p-value boundary for efficacy will be calculated based 
on the actual number of PFS and OS events at the interim analysis (or analyses) and the final 
analysis. 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
The Independent Data Monitoring Committee (IDMC) will review PFS, OS and other efficacy 
data at the time of PFS interim analysis. The list of IDMC deliverables, including tables and 
listings, is included in the IDMC charter.  These deliverables will be based on the methods 
described in this SAP.  
3.5.1 Planned Analyses for PFS 
There will be two planned analyses for PFS, one interim analysis and one final analysis. After 
approximately 50% of the planned PFS events (ie, 93 PFS events) have been observed based on 
the blinded, independent, central review, an interim analysis of efficacy will be performed.  
At the interim analysis, PFS will be tested at the alpha level based on the Lan-DeMets alpha 
spending function for the O’Brien-Fleming boundary with the opportunity to stop the study 
(other than survival follow-up) for overwhelming evidence of efficacy. If the interim analysis 
occurs at exactly 50% of the planned events, the criterion of stopping for efficacy is one-sided p-
value of 0.0015 (corresponding approximately to a HR of 0.540). In the meantime, PFS will also 
be tested at the alpha level for futility based on the alpha and beta spending functions specified 
for the study design. If the interim analysis occurs at exactly 50% of the planned events, the 
criterion of stopping for futility is one-sided p-value of 0.4791 (corresponding approximately to a 
HR of 0.990). The futility boundary of this study is non-binding, meaning that the Type I error is 
properly controlled even if the study is continued after the futility boundary for PFS is crossed at 
the interim analysis.  Under the protocol design assumptions (eg, the study is fully enrolled in 16 
months), the interim analysis is expected to occur approximately 17 months after the first subject 
is randomized.  
If the study is not stopped at the interim analysis, the final analysis will be performed when 
approximately 185 PFS events have occurred in the study.  If the interim analysis and the final 
analysis occur at exactly 93 and 185 PFS events, the criterion of statistical significance  
(ie, boundary for efficacy) is one-sided p-value of 0.0245 (corresponding approximately to a HR 
of 0.748).  
3.5.2 Planned Analyses for OS 
There will be three planned analyses for OS: two interim analyses and one final analysis. The 
first interim analysis of OS will be performed at the time of the planned PFS interim analysis 
after 93 PFS events have occurred. The estimated number of OS events at this first OS interim 
analysis is 24. The second interim analysis of OS will be performed at the planned PFS final 
analysis, after 185 PFS events have occurred. If the planned final analysis of PFS is not 
performed due to an early stop for efficacy, then the second interim analysis of OS will be 
conducted approximately 1 year after the first interim OS analysis. The estimated number of OS 
events at the second OS interim analysis is 58. The final analysis of OS will take place after the 
completion of follow-up for all subjects. The estimated number of OS events at the final OS 
analysis is 161. The information fractions at the two interim OS analyses and the final OS 
analysis will be calculated based on 161 planned OS events at the final OS analysis. The 
cumulative alpha spending at the three analyses will be 0.0001, 0.0249, and 0.0250, respectively.  
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
If the OS analyses occur at 24, 58, and 161 OS events, the p-value stopping boundaries for the 
three analyses will be 0.0001, 0.0249 and 0.0003, respectively.  The actual p-value stopping 
boundaries will be derived from the actual number of OS events that occurred.  The statistical 
significance of OS will be claimed based on the hierarchical testing procedure as specified in 
Section 6.3. 
4 ANALYSIS SETS 
4.1 Intent-To-Treat (ITT) Analysis Set 
The intent-to-treat (ITT) analysis set includes all subjects who are randomized, with treatment 
group designated according to randomization. 
This analysis set will serve as the primary analysis set for all efficacy endpoints and 
demographics.  
4.2 All-Treated (AT) Analysis Set 
The all-treated (AT) analysis set includes all subjects who receive any amount of study drug 
(duvelisib or ofatumumab), with treatment group designated according to actual study treatment 
received. The AT analysis set will be the primary analysis set for safety endpoints. 
4.3 Per-Protocol (PP) Analysis Set 
The per-protocol (PP) analysis set includes all subjects in the ITT analysis set who do not violate 
the terms of the protocol in a way that would significantly affect the study outcome, with 
treatment group designated according to randomization. Subjects who meet any of the following 
criteria may be excluded from this analysis set:  
• Do not have documented diagnosis of CLL or SLL  
• Do not have measurable nodal disease at baseline as determined by the IRC 
• ECOG performance status >2 
• History of Richter's transformation or prolymphocytic leukemia  
• Refractory to ofatumumab  (defined as progression or relapse <12 months of receiving 
ofatumumab monotherapy or <24 months of receiving an ofatumumab-containing 
regimen)   
• Prior exposure to a PI3K inhibitor 
• Receive concomitant prohibited anticancer therapy  
• Permanent discontinuation from study drug due to non-compliance 
The PP analysis set will be a secondary analysis set for selected efficacy analyses.  
 
 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
5 STUDY ENDPOINTS  
5.1 Primary Endpoint 
The primary efficacy endpoint PFS is defined as time from randomization to the first 
documentation of progressive disease (PD) as determined by independent review or death due to 
any cause.  
The censoring method of the primary endpoint can be found in Appendix A. The detailed 
algorithm will be specified in the Analysis Data Model (ADaM) specifications.  
5.2 Secondary Endpoints 
The secondary efficacy endpoints of the study are: 
• Overall Response Rate (ORR), with overall response (based on independent review) 
defined as best response of complete response/remission (CR), CR with incomplete 
marrow recovery (CRi), partial response/remission (PR), or PR with lymphocytosis 
(PRwL), according to the IWCLL or revised IWG Response Criteria, with modification 
for treatment-related lymphocytosis  
• Overall Survival (OS), defined as time from randomization to death 
• Lymph node response rate, with lymph node response defined as ≥50% decrease in the 
SPD of target lymph nodes 
• Hematologic improvement rate, defined as any of following hematologic improvement 
sustained for at least 60 days without transfusion or exogenous growth factors: 
o Neutrophil count >1,500/µL or an increase ≥50% from Baseline; or 
o Hemoglobin >11 g/dL or an increase ≥50% from Baseline; or  
o Platelet count >100,000/µL or an increase ≥50% from Baseline  
• Duration of Response (DOR), defined as time from the first documentation of response to 
first documentation of PD or death due to any cause.  
Other secondary endpoints of the study are: 
• TEAEs and changes in safety laboratory values  
• PK parameters derived from plasma duvelisib concentrations and, if applicable, its 
metabolite(s) 
5.3 Exploratory Endpoints 
The exploratory efficacy endpoints of the study are: 
• Improvement in disease-related symptoms of fatigue, weight loss, unexplained fevers and 
night sweats from Baseline 
• Minimal Residual Disease (MRD) in subjects with documented CR or CRi 
• Time to Response (TTR), defined as the time from randomization to the first 
documentation of response (CR, CRi, PR or PRwL)  
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
The QoL endpoints of the study are: 
• Health-related QoL of subjects as assessed by the following subject-reported 
questionnaires:  
o EuroQol-5D (EQ-5D) 
o Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) 
The biomarkers of the study are: 
• Serum and tissue biomarkers and blood immunophenotype 
• Tumor genomic features (eg, DNA sequence variation, DNA copy number variation, 
and/or RNA expression) 
• Germline DNA sequence variations 
 
 
 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
6 GENERAL STATISTICAL METHODS AND DATA HANDLING 
6.1 General Methods 
Summary statistics will be presented by treatment group, unless stated otherwise.  
Unless otherwise specified, descriptive statistics for continuous data will include the number of 
subjects with data to be summarized (n), mean, standard deviation, 25% quartile, median, 75% 
quartile, and minimum and maximum. The same number of decimal places as in the raw data 
will be presented when reporting the minimum and maximum, one more decimal place than the 
raw data will be presented when reporting mean and median, and 2 more decimal places than the 
raw data will be presented when reporting standard deviation. 
Descriptive statistics for categorical/qualitative data will include frequency counts and 
percentages. The total number of subjects in the treatment group will be used as the denominator 
for percent calculations, unless stated otherwise. All percentages will be presented with one 
decimal, unless otherwise specified. Percentages equal to 100 will be presented as 100, and 
percentages will not be presented for zero frequencies. 
Descriptive statistics associated with time-to-event analyses will include the number of events, 
the number of subjects censored, 25% quartile, median, 75% quartile, and 95% confidence 
interval for median. These statistics will be presented for all time-to-event analyses, unless stated 
otherwise.  
Listings will be provided for selected endpoints. For listings broken down by center and 
treatment arm, site (center) number will be ordered by country. 
6.2 Handling of Missing Data 
In general, values for missing data will not be imputed unless methods for handling missing data 
are specified. 
6.2.1 Handling of Missing Dates/Months/Years for Adverse Events 
Adverse events (AEs) with incomplete onset dates will be handled as follows for the sole 
purpose of determining treatment emergence (TEAE is defined in Section 7.3.1): 
• If the start/end date of an AE is partially missing, the date will be compared as far as 
possible with the date of the start of administration of study drug and the date of last dose 
of study drug plus 30 days. The AE will be assumed to be treatment emergent if it cannot 
be definitively shown that the AE did not occur or worsen during the treatment-emergent 
period (worst case approach). The detailed algorithm will be specified in ADaM 
specifications.  
• If the start date is completely missing, an AE will be considered treatment-emergent 
unless the stop date is before study drug administration. 
• If the dose start date is missing for a subject at a data-cut, all AEs of the subject will be 
considered treatment-emergent.  
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
The original partial or missing date will be shown in listings of AEs. 
6.2.2 Handling of Missing Dates/Months/Years for Concomitant Medications 
Prior or concomitant medications with incomplete start dates will be handled as follows for the 
sole purpose of determining whether a non-study medication is a concomitant medication: 
• If the start/stop date of a medication is partially missing, the date will be compared as far 
as possible with the date of the start of administration of study drug and the date of last 
dose of study drug plus 30 days. The medication will be assumed to be concomitant if it 
cannot be definitively shown that the stop date is before the start of administration of 
study drug, or the start date is more than 30 days after the last date of administration of 
study drug. The detailed algorithm will be specified in ADaM specifications.  
• If the start/stop dates are completely missing, a medication will be considered 
concomitant. 
• If the dose start date is missing for a subject at a data-cut, all non-study medications of 
the subject will be considered concomitant. 
The original partial or missing date will be shown in listings of all non-study medications. 
6.2.3 Handling of Missing Dates/Months/Years for Disease History and Prior Therapies 
For the purpose of calculating the duration from initial diagnosis, most recent relapse/refractory 
diagnosis or most recent prior therapy to randomization, partial/missing dates for diagnosis and 
last prior therapy completion will be imputed as follows:  
 
• If both date and month are missing and the year is prior to the year of screening, the 
imputed date and month will be 01 July.  
• If both date and month are missing and the year is the same as the year of screening, the 
imputed date will be the middle point between 01 Jan of the year and the screening date. 
If the middle point falls between two dates, the first of the two dates will be used.  
• If date is missing and the month and year are prior to the month and year of screening, 
the imputed date will be 15th day of the month.  
• If date is missing and the month and year are the same as the month and year of 
screening, the imputed date will be the middle point between the first date of the month 
and the screening date. If the middle point falls between two dates, the first of the two 
dates will be used.  
• No imputation will be performed if the year is missing.  
6.3 Multiple Comparisons/Multiplicity Adjustment 
Of the secondary endpoints, ORR and OS are designated as key secondary efficacy endpoints. 
The primary endpoint and key secondary endpoints will be tested at an overall one-sided alpha 
level of 0.025 based on a gatekeeping approach.  
If the primary endpoint is significant, the two key secondary endpoints will be sequentially tested 
in the order listed above. ORR will be tested at the one-sided 0.025 level only if PFS is declared 
statistically significant. OS will be tested according to the planned alpha spending specified in 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Section 3.5.2 only if PFS and ORR are declared statistically significant. If any null hypothesis is 
not rejected in this sequence of tests, formal sequential testing will be stopped.  
6.4 Adjustments for Covariates 
Adjustments for covariates will be considered for analysis of primary and key secondary 
endpoints, with details provided in Sections 7.2.1 and 7.2.2. 
6.5 Subgroups 
PFS, ORR and OS will be examined in the subgroups based on the following baseline 
characteristics or variables: 
• Stratification factors (1. captured from central lab; 2 and 3 captured on the eCRF): 
1 High-risk cytogenetics (presence vs absence of del[17p]) 
2 Refractory/early relapse to purine analog-based therapy (defined as progression 
<12 months after fludarabine/pentostatin: yes vs no)  
3 Grade 4 cytopenia(s) (presence vs absence of neutropenia or thrombocytopenia at 
baseline)   
• Diagnosis (CLL or SLL) 
• Gender (Male or Female) 
• Age group (<65 or ≥65) 
• Race (White or Non-White) 
• Previously treated with ofatumumab (yes vs no, if sample size allows the analysis) 
• Time from last dose of most recent prior anti-cancer therapy to randomization <12 
months: yes vs no  
• del[17p] or TP53 mutation (either or both present vs neither present; del[17p] will be as 
captured from central lab) 
TEAEs (All Causalities) and TEAEs (Treatment-Related) will be examined in the following 
subgroups: 
• Gender (Male or Female) 
• Age group (<65 or ≥65) 
• Race (White or Non-White) 
• Baseline ECOG performance status (0 or 1 vs 2) 
More details will be specified in Sections 7.2.1, 7.2.2 and 7.3.1. 
6.6 Visit Windows 
All data will be categorized based on the scheduled visit at which it was collected.  These visit 
designators are predefined values that appear as part of the visit tab in the eCRF.  There will be 
no additional analysis windowing done based on the assessment date. 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
6.7 Unscheduled Visits 
Unscheduled visits will not be included in by-visit summary tables, unless otherwise specified.  
For laboratory tests, data from unscheduled visits will be included in listings and summaries of 
maximum changes from baseline, and the best or worst post-baseline values.  For endpoints 
based on disease status assessment, data from unscheduled assessments will be included in the 
derivation and analyses of the endpoints. 
6.8 Baseline Values  
Unless otherwise specified, the baseline value is defined as the value collected at the time closest 
to, and prior to, the start of study drug administration.  Values collected at unscheduled visits 
prior to the start of the study drug administration will be included in the calculation of baseline 
values.  
 
6.9 Computing and Coding Standards 
Activities will be performed using the following tools: 
Table, listing, and figure production 
SAS Version 9.2 or higher 
Coding 
 
 
Adverse Events 
MedDRA Version 16.1 or higher 
 
Medical Histories 
MedDRA Version 16.1 or higher 
 
Prior and Concomitant Medications 
WHODrug Version September 2013 
Grading 
 
 
AEs 
CTCAE Version 4.03 
 
Labs 
CTCAE Version 4.03 
 
 
 
 
 
 
 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
7 STATISTICAL ANALYSES 
7.1 Study Subjects 
7.1.1 Disposition of Subjects 
The disposition of subjects will include the number and percentage of subjects for the following 
categories: the number randomized, the number and percentage randomized but not dosed, the 
number and percentage dosed. These categories will be summarized for each treatment arm and 
for the two treatment arms combined (total).  The percentages will be based on all randomized 
subjects (ITT analysis set).   
An end-of-treatment disposition (still on treatment vs discontinued from treatment) will be 
provided for each treatment arm and for the two treatment arms combined (total) based on the 
AT analysis set. The primary reason for treatment discontinuation will be included in the table. A 
listing of these subjects will also be provided, broken down by center and treatment arm. 
An end-of-study disposition (still on study vs discontinued from study) will also be provided for 
each treatment arm and for the two treatment arms combined (total) based on the ITT analysis 
set. The primary reason for study discontinuation will be included in the table. A listing of these 
subjects will also be provided, broken down by center and treatment arm. 
A summary of strata as captured in IRT will be presented by treatment arm and for the two 
treatment arms combined (total) based on the ITT analysis set.  A summary table and a listing of 
the discrepancies in data for stratification factors between those captured in the IRT and those 
reported on the eCRF will be presented. 
7.1.2 Protocol Deviations 
Protocol deviations will be categorized as major or minor prior to data release for the interim or 
final analysis of the primary endpoint. A summary table of the major protocol deviations will be 
provided by treatment arm and for two arms combined (total) for the ITT analysis set. A listing 
of major protocol deviations will be provided, broken down by center and treatment arm. 
7.1.3 Demographic and Other Baseline Characteristics 
Demographic and other baseline variables will be summarized for each treatment arm based on 
all randomized subjects (ITT analysis set) and for the two treatment arms combined (total). The 
variables will include age, age group (<65 versus >=65), sex, race, ethnicity, height, weight and 
the following biomarkers: 
• del[17p] (captured from central lab, presence vs absence vs indeterminate) 
• del[17p] (captured from local lab, presence vs absence vs indeterminate) 
• IgHV status (mutated vs unmutated vs indeterminate) 
• CD38 (Positive (≥30%) vs Negative (<30%) vs indeterminate) 
• ZAP70 (Positive (>19%) vs Negative (≤19%) vs indeterminate) 
• del[17p] and/or TP53 mutation (either or both present vs neither present vs indeterminate; 
del[17p] will be as captured from central lab) 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
• TP53 mutation (presence vs absence vs indeterminate) 
A separate table will be provided to compare del[17p] values captured from central lab and local 
lab. Demographic and other baseline variables will also be summarized based on the PP analysis 
set.  
7.1.4 Disease History 
Disease history will be summarized for each treatment arm and for the two treatment arms 
combined (total) based on the ITT analysis set. The variables will include diagnosis (CLL or 
SLL), risk factors used for randomization that are reported on eCRF (high risk cytogenetics [17p 
deletion: presence vs absence], refractory/early relapse to purine analog based treatment [yes vs 
no], grade 4 cytopenia(s) [presence vs absence]), years from initial diagnosis to randomization, 
months from most recent relapse/refractory diagnosis to randomization, Binet/Rai stage at initial 
diagnosis, type of prior treatment, Binet/Rai stage at baseline, and baseline lymphocyte count.  
The durations to be summarized are defined as follows: 
• Years from initial diagnosis to randomization will be calculated as (date of randomization 
– date of initial diagnosis + 1)/365.25.  
• Months from most recent relapse/refractory diagnosis to randomization will be calculated 
as (date of randomization – date of most recent relapse/refractory diagnosis + 1)/ 
(365.25/12).  
The imputation of partial/missing dates is described in Section 6.2.3. 
7.1.5 Prior Therapies 
Prior therapies will be summarized for each treatment arm and for the two treatment arms 
combined (total) based on the ITT analysis set. The variables will include number of prior 
systemic therapies (summarized as a continuous variable and as a categorical variable) and 
months from most recent prior systemic therapy to randomization. 
The duration to be summarized is defined as follows.  
• Months from most recent prior systemic therapy to randomization will be calculated as 
(date of randomization – stop date of most recent systemic therapy +1)/ (365.25/12).  
The imputation of partial/missing dates is described in Section 6.2.3.  
7.1.6 Medical History 
Medical history will be summarized for each treatment arm and for the two treatment arms 
combined (total) based on the AT analysis set. 
Medical history will be summarized by system organ class (SOC) and preferred term (PT) using 
the number and percentage of subjects who had at least one occurrence of an SOC or PT. The 
summary will be sorted alphabetically in SOC and by decreasing frequency of PT in the 
duvelisib arm within an SOC. 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
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7.1.7 Prior and Concomitant Medications  
Medications will be considered as prior if they stopped before the date of first dose of study 
drug.  
Medications will be considered concomitant if they were taken at any time between the date of 
first dose of study drug and 30 days after the date of last dose of study drug, inclusive.  If the 
start date or end date of a medication is completely or partially missing, refer to Section 6.2.2 for 
the algorithm to determine whether a medication is concomitant. 
Prior medications and concomitant medications will be summarized separately. Both summaries 
will be based on the AT analysis set. 
Medications will be summarized by ATC level 1, ATC level 2, and preferred drug name for each 
treatment arm. The summary will be sorted by decreasing frequency in ATC level 1, ATC level 2 
and preferred drug name in the duvelisib arm. A subject taking the same drug multiple times will 
only be counted once. 
A listing will be provided for all non-study medications taken on the study. An identifier will be 
provided to show if a medication is prior or concomitant. Medications that started more than 30 
days after the last dose of study drug will be identified as post-treatment.  
7.1.8 Exposure to Study Drug 
Extent of exposure will be summarized for each treatment arm based on the AT analysis set.  
Extent of exposure will be summarized for the following variables: 
• Duration (weeks): (date of last dose – date of first dose + 1) divided by 7 
• Number of cycles started (continuous and categorical) 
• Ofatumumab arm only: For each infusion (1-12), number and percent of subjects 
receiving the infusion 
• Relative dose intensity, defined as 100% x (total dose received)/ (planned 
cumulative dose for the duration of treatment) 
• Number and percentage of subjects with a dose reduction  
• duvelisib arm only: Number and percentage of subjects with a dose increase  
• Number and percentage of subjects with a dose hold   
• Number and percentage of subjects with study drug discontinued  
A by-subject listing will be presented for exposure to study drug. 
7.2 Efficacy Analyses 
For PFS, ORR, lymph node response rate, DOR and other endpoints derived from progression 
and/or response status, the primary analyses will be based on the endpoints derived from 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
independent central review by Independent Review Committee (IRC). The endpoints derived 
from investigator assessment will be used in sensitivity analyses. 
All efficacy analyses will be based on the ITT analysis set unless stated otherwise.  If analyses 
are performed on more than one analysis set, the analyses on the ITT analysis set will be 
considered primary.   
For stratified analysis of any efficacy endpoint, the following algorithm will be used to pool 
strata if there is insufficient information in any stratum (ie, there are <6 subjects, or there is no 
event for a time-to-event endpoint, or all subject have the same outcome for a binary endpoint in 
a stratum). (1) Strata will be ranked from the smallest to the largest based on the number of 
subjects, and if there is a tie, based on the number of events or responses. If there is still a tie, 
based on the reverse order of strata as determined by the stratification factors and levels (see 
Section 3.3). (2) The smallest stratum will be compared with the criteria of insufficient 
information. (3) If there is insufficient information in the smallest stratum, that stratum will be 
pooled with the smallest of the adjacent strata, which are defined as strata having 2 of the 3 
stratification factors being at the same level as the smallest stratum. At the end of the three steps, 
the pooled stratum will replace the original two contributing strata.  If there is still insufficient 
information in any stratum, the three steps will be repeated with the last pooled stratum assuming 
the stratum label of the larger of the two contributing strata for the purpose of additional pooling. 
The resulting pooled strata will be the strata used for the stratified analysis described in this 
section. 
Listings of all efficacy endpoints will be provided.  
7.2.1 Analyses of Primary Endpoint 
7.2.1.1 Primary Analyses of PFS  
The primary analyses of PFS will use PFS based on IRC assessment in the ITT analysis set. 
Number of subjects with events, types of events (progression or death before progression), 
number of subjects censored, number of subjects for each reason of censoring, estimates and 
95% confidence intervals for the 25th percentile, median, and 75th percentile for PFS will be 
presented by treatment group. Probabilities of event free at selected time points may also be 
presented. 
A stratified log-rank test (one-sided) will be used to compare PFS of the duvelisib arm against 
PFS of the ofatumumab arm at the interim and final analyses with the overall one-sided 
significance level controlled at 0.025. The nominal p-value required for statistical significance at 
an analysis will be calculated based on the numbers of PFS events at all preceding and current 
analyses. The HR (duvelisib/ofatumumab) and the corresponding 2-sided 95% CI will be 
estimated using a stratified Cox proportional hazards model. For both the stratified log-rank test 
and the stratified Cox model, the strata will be those used for stratified randomization, with 
potential pooling of strata specified earlier in Section 7.2.   
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
PFS will be plotted for each treatment group using the Kaplan-Meier method. The plot will 
include the number of subjects at risk for each treatment group over time. 
7.2.1.2 Sensitivity Analyses of PFS 
The following sensitivity analyses will be performed: 
• PFS based on investigator assessment: This endpoint will be analyzed using the same 
methods as the primary analyses described for PFS based on IRC assessment. In 
addition, the differences between investigator assessment and IRC assessment will be 
summarized. 
• Worst-case sensitivity analysis: Subjects who are alive and have not had documented 
progression by data cutoff and who are “lost to follow-up” (missing at least one 
disease assessment right before data cut off) will be treated as censored at their last 
adequate disease assessment if they are on the control arm (ofatumumab) and treated 
as having a PFS event at the time of the next scheduled assessment following the last 
adequate disease assessment if they are on the experimental arm (duvelisib). PFS 
based on IRC assessment with the above worst-case censoring/event rule will be 
analyzed using the same methods as the primary analyses for PFS. 
• Event-free survival (EFS): This is defined as time from randomization to the first 
documentation of PD as determined by IRC, start of new anticancer treatment or 
procedure, or death due to any cause.  The event/censoring method is presented in 
Appendix B. EFS will be analyzed using the same methods as the primary analyses 
for PFS except that the summary of types of events will include a category of new 
anticancer treatment or procedure. 
• Analysis using the PP analysis set. 
• Analysis using the AT analysis set. 
• Unstratified analyses: An unstratified log-rank test (one-sided) will be used to 
compare the two trreatment arms. An unstratified Cox regression (one-sided) will be 
used to estimate the hazard ratio (duvelisib/ofatumumab) with its 95% confidence 
interval. Other aspects of the analyses will be the same as the primary analyses of 
PFS. 
• Cox regression with baseline covariates: A stratified Cox regression will be used to 
test treatment effect on PFS, adjusting for demographic and other baseline 
characteristics. The strata will be those used for stratified randomization, with 
potential pooling of strata specified earlier in Section 7.2. A stepwise variable 
selection will be performed to choose the variables in the Cox regression. Candidate 
variables are age, gender, race, disease diagnosis (CLL or SLL), years from initial 
diagnosis, months from most recent relapse/refractory diagnosis, stage at diagnosis, 
stage at baseline, and number of prior systemic therapies. PFS based on IRC 
assessment will be used for this analysis. 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
7.2.1.3 Subgroup analyses of PFS 
Subgroup analyses for PFS will be performed using the subgroups specified in Section 6.5. The 
HR (duvelisib/ofatumumab) with its 95% CI will be calculated based on an unstratified Cox 
regression model for each subgroup. The hazard ratios and their 95% confidence intervals will be 
displayed for all subgroups graphically in a forest plot.  
For selected subgroups, additional analyses of PFS will be performed. Number of subjects with 
events, types of events (progression or death before progression), number of subjects censored, 
number of subjects for each reason of censoring, estimates and 2-sided 95% confidence intervals 
for the 25th percentile, median, and 75th percentile for PFS will be presented by treatment group. 
Probabilities of event free at selected time points may also be presented. PFS will be plotted for 
each treatment group using the Kaplan-Meier method. The plot will include the number of 
subjects at risk for each treatment group over time.   
7.2.2 Analyses of Secondary Efficacy Endpoints 
Of the secondary endpoints, ORR and OS are designated as key secondary efficacy endpoints. 
These endpoints will be tested for statistical significance under an overall one-sided significance 
level of 0.025 if and only if the primary endpoint is significant. Details of multiplicity adjustment 
are provided in Section 6.3. 
The analyses of secondary efficacy endpoints, Lymph Node Response Rate and Hematologic 
Improvement Rate, will include hypothesis testing, but no statistical significance will be claimed. 
The analyses of other secondary efficacy endpoint, Duration of Response (DOR), will be 
nominal only.   
7.2.2.1 Overall Response Rate (ORR) 
The primary analyses of ORR will use ORR based on IRC assessment in the ITT analysis set. 
ORR will be derived from best overall response (BOR), which is defined as the best time point 
response that a subject achieves during the course of the study, with the response ranked 
according to the following order (from best to worst): CR>CRi>PR>PRwL>SD>PD  (CRi 
applies to CLL only).  In addition, the IRC may assign a timepoint response of unknown (UNK) 
due to missing, incomplete, or inadequate data; at baseline, the IRC may assign a timepoint 
response of no evidence of disease (NED) if both radiological and clinical data indicate no 
disease involvement; for a post-baseline timepoint, the IRC may also assign a timepoint response 
of not evaluable (NE) if no target lesions were identified at baseline and the radiological and 
clinical data at the post-baseline timepoint do not support the disease response of PD or UNK; 
these categories will be classified as OTHER in the summary.    
The estimated ORR (percent of subjects with a BOR of CR, CRi, PR or PRwL) and a 2-sided 
95% CI will be provided for each treatment arm.  Number and percent of subjects with BOR in 
each of the response categories (CR, CRi, PR, PRwL, SD, PD, OTHER) will also be presented 
by treatment arm.  All subjects in the analysis set will be included in the denominator in the 
calculation of the percentage for each response category or ORR.  
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
ORR will be analyzed using the Cochran-Mantel-Haenszel (CMH) test (one-sided, see Appendix 
C) to compare the two treatment groups. The strata for the test will be those used for stratified 
randomization, with potential pooling of strata specified earlier in Section 7.2. The odds ratio 
and its 95% CI will be estimated. 
The following sensitivity analyses will be performed: 
• ORR based on investigator assessment 
• Overall Confirmed Response Rate (OCRR), with overall confirmed response (based on 
independent review) defined as best confirmed response (time between response and 
confirmation must be ≥8 weeks in duration) of CR, CRi, PR, or PRwL, according to the 
IWCLL or revised IWG Response Criteria, with modification for treatment-related 
lymphocytosis 
• Overall Response Rate without PRwL: with overall response (based on independent 
review) defined as best response of complete response/remission (CR), CR with 
incomplete marrow recovery (CRi), partial response/remission (PR) 
• Overall Confirmed Response Rate without PRwL 
• Overall Response Rate in subset of subjects with baseline assessment other than UNK 
and NED. This analysis will be performed if there are at least 5% subjects with baseline 
assessment of UNK or NED 
• Overall Response Rate in subset of subjects who are on treatment for 60 days or longer 
• Analysis using the PP analysis set 
• Analysis using the AT analysis set 
Subgroup analyses will be performed for ORR using the subgroups specified in Section 6.5.  
The odds ratio (duvelisib/ofatumumab) with its 95% CI will be calculated for each subgroup 
based on unstratified test. The odds ratios and their 95% confidence intervals will be displayed 
for all subgroups graphically in a forest plot. 
For selected subgroups, the estimated ORR and its 2-sided 95% CI will be provided for each 
treatment arm; number and percent of subjects with BOR in each of the response categories (CR, 
CRi, PR, PRwL, SD, PD, OTHER) will also be presented by treatment arm. 
7.2.2.2 Overall Survival (OS) 
The primary analyses of OS will be based on the ITT analysis set.  
Subjects without documentation of death at the time of the data cutoff for analysis will be 
censored at the date the subject was last known to be alive, or the data cutoff date, whichever is 
earlier.  A stratified one-sided log-rank test will be used to compare OS between the 2 treatment 
groups.  The HR along with the 95% CI will be estimated using a stratified Cox model. For both 
the stratified log-rank test and the stratified Cox model, the strata will be those used for stratified 
randomization, with potential pooling of strata specified earlier in Section 7.2. A Kaplan-Meier 
plot for OS will be presented by treatment group. Estimates and 95% confidence intervals for the 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
25th percentile, median, and 75th percentile for OS will be presented by treatment group (if 
estimable).  Probabilities of survival at selected time points may also be presented. 
A majority of subjects can be expected to take subsequent anticancer therapy, especially after 
disease progression. To adjust for the effects of subsequent therapy, the following sensitivity 
analysis may be performed: 
1. Primary analyses except additional censoring at the start date of subsequent 
therapy 
2. Rank preserving structural failure time (RPSFT) analysis 
3. Inverse probability of censoring weighted (IPCW) analysis 
The following sensitivity analyses will be performed: 
• Analysis using the PP analysis set. 
• Analysis using the AT analysis set.  
• Unstratified analyses: An unstratified log-rank test (one-sided) will be used to 
compare the two treatment arms. An unstratified Cox regression (one-sided) will be 
used to estimate the hazard ratio (duvelisib /ofatumumab) with its 95% confidence 
interval.  
Subgroup analyses for OS will be performed using the subgroups specified in section 6.5. The 
HR (duvelisib /ofatumumab) with its 95% CI will be calculated based on an unstratified Cox 
regression model for each subgroup. The HRs and their 95% CIs will be displayed for all 
subgroups graphically in a forest plot. 
OS follow-up time, defined as time from randomization to the date of last procedure or 
assessment (including telephone interview), will be summarized by treatment arm and for the 
two treatment arms combined (total) using the reverse Kaplan-Meier method, which applies 
Kaplan-Meier method to the OS data with the same event/censoring time as the primary OS 
analyses while reversing event/censoring indicator. The 25th percentile, median, and 75th 
percentile of OS follow-up time will be presented.   
7.2.2.3 Lymph Node Response Rate 
The primary analyses of lymph node response rate will be based on IRC assessment in the ITT 
analysis set. The number of subjects with lymph node response, estimated lymph node response 
rate, and a 2-sided 95% CI will be provided for each treatment arm. 
Lymph node response rate will be analyzed using the CMH test (one-sided) to compare the two 
treatment groups. The strata for the test will be those used for stratified randomization, with 
potential pooling of strata specified earlier in Section 7.2. 
A sensitivity analysis will be performed using lymph node response rate based on investigator 
measurements. 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
7.2.2.4 Hematologic Improvement Rate 
A subject with a hematologic improvement is one who consistently met the criteria of an 
improvement in neutrophil count, hemoglobin or platelet count for a period of at least 60 days 
during which the subject did not have a transfusion or exogenous cytokines. Missing data or 
missing scheduled assessments during a potential 60-day hematologic improvement episode will 
result in categorization of not having a hematologic improvement.  
The number of subjects with hematologic improvement, estimated hematologic improvement 
rate, and a 2-sided 95% CI will be provided for each treatment arm. 
Hematologic improvement rate will be compared between treatment groups using one-sided 
CMH test. The strata for the test will be those used for stratified randomization, with potential 
pooling of strata specified earlier in Section 7.2.  
7.2.2.5 Duration of Response (DOR) 
DOR will be presented using the Kaplan-Meier method for each treatment arm based on all 
randomized subjects with a documentation of response (i.e., CR, CRi, PR, or PRwL) as 
determined by IRC assessment. The censoring method will be the same as that for the primary 
endpoint (see Appendix A).  The Kaplan-Meier plot for DOR will be presented by treatment 
group. Estimates and 95% confidence intervals for the 25th percentile, median, and 75th 
percentile for DOR will be presented by treatment group (if estimable). No treatment comparison 
will be performed.  
7.2.3 Analyses of Exploratory Efficacy Endpoints 
7.2.3.1 Improvement in Disease-Related Symptoms 
Disease-related symptoms of fever, weight loss, and drenching night sweats will be assessed as 
present or absent at each timepoint. Improvement in each of the three disease-related symptoms 
from baseline will be analyzed separately.  The summary will display by treatment arm the 
proportion of subjects with an improvement while on treatment. Descriptive analysis of 
improvement in these disease-related symptoms will also be presented over the course of the 
study (eg, for each scheduled assessment) by treatment arm.  
The disease-related symptom of fatigue will be measured by the ECOG performance status. 
Summary statistics will be provided by treatment arm for the ECOG score and the change from 
baseline at each timepoint.  
7.2.3.2 Minimal Residual Disease  
MRD status for subjects with a response of CR or CRi will be determined using flow cytometry 
from a central lab. MRD will be classified as positive or negative. The estimated rates of subjects 
with negative MRD and their 95% confidence intervals in subjects with a response of CR or CRi 
will be provided for each treatment arm.  
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
7.2.3.3 Time To Response (TTR) 
TTR will be presented for each treatment arm based on all randomized subjects with a 
documentation of response (i.e., CR, CRi, PR, or PRwL). Summary statistics and a 2-sided 
confidence interval for median TTR will be provided by treatment arm. No treatment comparison 
will be performed.  
7.3 Safety Analyses 
All safety analyses will be performed using the AT analysis set. 
7.3.1 Adverse Events  
Adverse events will be coded using MedDRA Version 16.1 or higher. The Grade of the AE will 
be assessed according to the NCI-CTCAE Version 4.03. If an AE is not included in the NCI-
CTCAE Version 4.03, the Grade of the AE will be assessed according to the protocol, Section 
8.2.1.2. 
The summary of AEs will be focused on treatment-emergent AEs. A treatment-emergent AE 
(TEAE) is defined as any AE that emerges or worsens in the period from the first dose of study 
treatment to 30 days after the last dose of study treatment.  The onset date of an AE will be 
compared to the first dose date and the last dose date plus 30 days to determine whether the AE 
is treatment-emergent or not.  If the onset date of an AE is completely or partially missing, refer 
to Section 6.2.1 for the algorithm to determine whether an AE is treatment emergent. 
TEAEs will be summarized for each treatment arm by MedDRA system organ class (SOC) and 
preferred term (PT), or PT only.  For summary tables by SOC and PT, SOC will be sorted 
alphabetically and PT will be sorted by decreasing frequency in the duvelisib arm within each 
SOC.  For summary tables by PT only, PT will be sorted by decreasing frequency in the 
duvelisib arm.   
If multiple TEAEs of the same PT occur within a subject, only the maximum grade observed for 
this PT will be used in summary of TEAEs by grade, the subject will be counted only once in the 
number of subjects for this PT and only once for the number of subjects for the SOC to which 
this PT belongs.  
An overview TEAE summary table will be provided, which will include the number of subjects 
with AEs in selected categories. In addition, TEAEs will be summarized for the following 
categories, and will be tabulated by SOC and PT, unless otherwise specified.  
• 
Treatment-emergent AEs (All Causalities) 
• 
Treatment-emergent AEs (Treatment-Related) 
• 
Treatment-emergent AEs (All Causalities, by maximum grade) 
• 
Treatment-emergent AEs (Treatment-Related, by maximum grade) 
• 
Grade 3 or higher treatment-emergent AEs (All Causalities) 
• 
Grade 3 or higher treatment-emergent AEs (Treatment-Related) 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
• 
Treatment-emergent SAE (All Causalities) 
• 
Treatment-emergent SAE (Treatment-Related) 
• 
Treatment-emergent AEs resulting in discontinuation of study drug (All Causalities) 
• 
Treatment-emergent AEs resulting in dose hold (All Causalities) 
• 
Treatment-emergent AEs resulting in dose reduction (All Causalities) 
• 
Treatment-emergent AEs resulting in dose hold or reduction (All Causalities) 
• 
Treatment-emergent AEs resulting in discontinuation of study drug (Treatment-
Related) 
• 
Treatment-emergent AEs resulting in death (All Causalities) 
• 
Treatment-emergent AEs resulting in death (Treatment-Related) 
• 
Treatment-emergent AEs by PT (All Causalities) 
• 
Treatment-emergent AEs by PT (AEs with onset date within 24 weeks after the first 
dose of study treatment; All Causalities) 
• 
Grade 3 or higher treatment-emergent AEs by PT (All Causalities) 
• 
Grade 3 or higher treatment-emergent AEs by PT (AEs with onset date within 24 
weeks after the first dose of study treatment; All Causalities) 
• 
Treatment-emergent SAEs by PT (All Causalities) 
• 
Treatment-emergent SAEs by PT (Treatment-Related) 
• 
Treatment-emergent AEs reported in ≥5% of subjects and occurred at ≥2% higher 
incidence in subjects receiving duvelisib (All Causalities) 
• 
Grade 3 or higher treatment-emergent AEs reported in ≥5% of subjects and occurred 
at ≥2% higher incidence in subjects receiving duvelisib (All Causalities) 
A by-subject listing of the following AE categories will be presented.  
• 
All AEs (TEAEs will be flagged) 
• 
All SAEs (TEAEs will be flagged) 
• 
Treatment-emergent AEs resulting in dose hold  
• 
Treatment-emergent AEs resulting in dose reduction 
• 
Treatment-emergent AEs resulting in discontinuation of study drug 
• 
Treatment-emergent AEs resulting in death 
Treatment-emergent AEs (All Causalities) and Treatment-emergent AEs (Treatment-Related) 
will also be tabulated in each subgroup specified in Section 6.5.  
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
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7.3.2 Laboratory Data 
Laboratory tests will be reported separately for hematology and blood chemistry. 
For the purposes of presentation in both tables and listings, the following laboratory test results 
will be converted to the International System of Units (SI) before presentation: sodium, 
potassium, chloride, bicarbonate (or CO2), albumin, total protein, creatinine, uric acid, calcium, 
phosphorus, magnesium, glucose, total and direct bilirubin, and alkaline phosphatase, red blood 
cell (RBC) count, hemoglobin, hematocrit, platelets, white blood cell count with 5-part 
differential performed manually or by flow cytometry (lymphocytes, neutrophils, monocytes, 
basophils, and eosinophils), etc.  
Lab tests performed after the start of the first dose of study treatment, up to 30 days from the last 
dose, will be considered treatment-emergent. Only treatment-emergent lab tests will be included 
in the analyses in this section. 
If a laboratory test value is reported using a non-numeric qualifier (e.g., less than [<] a certain 
value, or greater than [>] a certain value), the given numeric value will be used in the summary 
statistics, ignoring the non-numeric qualifier. 
For laboratory tests with NCI-CTCAE grades, a shift table from baseline grade to the maximum 
post-baseline grade will be provided. Laboratory tests with bi-directional grades (e.g., 
Hyperglycemia and Hypoglycemia) will be presented separately for each direction within the 
shift table.  
Listings will be provided for all laboratory test results and for laboratory test results grade 3 and 
higher.  A listing of subjects with ALT or AST >3xULN with simultaneous total bilirubin 
>2xULN will be presented, where ULN stands for upper limit of normal. The elevations of 
ALT/AST and total bilirubin must occur within 2 days of each other. 
7.3.3 Vital Signs 
The actual values of vital sign parameters, including temperature, heart rate, weight and systolic 
and diastolic blood pressure, will be presented in a by-subject listing.  
7.3.4 Electrocardiogram (ECG) 
A by-subject listing will be presented for baseline ECGs and post-baseline unscheduled ECGs (if 
any).  
7.3.5 Concomitant Medications and Procedures 
Please refer to Section 7.1.7 for the definition and summary of concomitant medications. 
Concomitant procedures will not be summarized. A by-subject listing will be presented. 
 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
7.3.6 Deaths 
On-treatment deaths are defined as deaths that occur within 30 days of the last dose of study 
medication. Deaths on treatment and causes for deaths occurring on-treatment, and deaths during 
follow-up will be summarized.  
A by-subject listing of deaths on study will be presented. 
7.4 Quality of Life Instruments 
Analyses of the QoL instruments (EQ-5D and FACIT-F) will be performed on the ITT analysis 
set. Additional analyses may be considered as needed.  
7.4.1 EQ-5D 
The EQ-5D contains a descriptive system with one response for each of 5 dimensions (Mobility, 
Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression). The first response is 
coded as 1 (indicating no problems), the second response is coded as a 2 (indicating some 
problems), and the third response is coded as a 3 (indicating extreme problems). Ambiguous 
responses (eg, more than one response in a dimension) are treated as missing values. The EQ-5D 
also contains a Visual Analog Scale (VAS) for health state ranging from 0 to 100, where 0 
represents worst imaginable health state and 100 represents the best imaginable health state.  
For each dimension of the descriptive system, the number and percentage of subjects with no 
problems, some problems, and extreme problems will be reported at each visit.  
Summary statistics for the VAS of health state and the change from baseline will be reported for 
each visit.   
7.4.2 FACIT-F 
The FACIT-F contains 5 subscales, Physical Well-Being, Social/Family Well-Being, Emotional 
Well-Being, Functional Well-Being, and Fatigue (Additional Concerns on eCRF). Each subscale 
contains multiple items, and each item has a response of 0 to 4. Scores will be computed for each 
subscale, as well as for the FACIT-F Trial Outcome Index, FACT-G total score, and the FACIT-
F total score.  
The Physical Well-Being subscale contains 7 items. To compute the subscale score, compute the 
item score by subtracting each item response from 4 (item score = 4 – item response), sum the 
item scores, multiply the sum by 7 and divide by the number of items answered. At least 4 
questions must be answered. If fewer than 4 questions are answered, then the subscale score will 
be missing. The Physical Well-Being score ranges from 0 to 28 with higher scores representing 
better quality of life. 
The Social/Family Well-Being score contains 7 questions. To compute the subscale score, sum 
the item responses, multiply the sum by 7 and divide by the number of items answered. At least 4 
questions must be answered. If fewer than 4 questions are answered, then the subscale score will 
be missing. The Social/Family Well-Being score ranges from 0 to 28 with higher scores 
representing better quality of life. 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
The Emotional Well-Being subscale contains 6 items. To compute the subscale score, compute 
the item score first. For items 1, 3, 4, 5, and 6, subtract each item response from 4 (item score = 4 
– item response). For item 2, the item score is the same as the item response (no subtraction is 
needed). Sum the item scores, multiply the sum by 6 and divide by the number of items 
answered to compute the subscale score. At least 3 questions must be answered. If fewer than 3 
questions are answered, then the subscale score will be missing. The Emotional Well-Being 
score ranges from 0 to 24 with higher scores representing better quality of life. 
The Functional Well-Being score contains 7 questions. To compute the subscale score, sum the 
item responses, multiply the sum by 7 and divide by the number of items answered. At least 4 
questions must be answered. If fewer than 4 questions are answered, then the subscale score will 
be missing. The Functional Well-Being score ranges from 0 to 28 with higher scores 
representing better quality of life. 
The Fatigue subscale contains 13 items. To compute the subscale score, compute the item score 
first. For all items except An5 and An7, subtract each item response from 4 (item score = 4 – 
item response). For items An5 and An7, the item score is the same as the item response (no 
subtraction is needed). Sum the item scores, multiply the sum by 13 and divide by the number of 
items answered to compute the subscale score. At least 7 questions must be answered. If fewer 
than 7 questions are answered, then the subscale score will be missing. The Fatigue score ranges 
from 0 to 52 with higher scores representing better quality of life. 
To derive the FACIT-F Trial Outcome Index, sum the subscale scores for Physical Well-Being, 
Functional Well-Being, and Fatigue. If any of these subscale scores is missing, the score for the 
FACIT-F Trial Outcome Index will be missing. The score ranges from 0 to 108.  
To derive the FACT-G score, sum the subscale scores for Physical Well-Being, Social/Family 
Well-Being, Emotional Well-Being, and Functional Well-Being. If any of these subscale scores 
is missing, the FACT-G score will be missing. The score ranges from 0 to 108. 
To derive the FACIT-F total score, sum all 5 subscale scores. If any subscale score is missing, 
the FACIT-F total score will be missing. The score ranges from 0 to 160. 
For each of the five subscale scores and for each of the FACIT-F Trial Outcome Index, the 
FACT-G score, and the FACIT-F total score, summary statistics for the actual values and 
changes from Baseline will be reported at each visit.  
7.5 Pharmacokinetic Analyses 
Plasma samples will be analyzed for duvelisib and IPI-656 (metabolite) concentrations using a 
validated high performance liquid chromatography-tandem mass spectrometry (LC/MS/MS) 
method.  A listing of the duvelisib and IPI-656 concentrations will be provided; the sample 
collection date and time, and the date, time and amount of the preceding duvelisib dose 
administration will be included in the listing. 
The PK data collected will be analyzed by standard population PK methods, using appropriate 
software. Analysis of exposure-response relationships for efficacy and safety endpoints will be 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
conducted. If there is only a limited amount of plasma concentration data from this study, the 
data may be pooled with the results of other studies to perform the population PK and exposure-
response analyses.  Further details on these analyses will be outlined in a separate analysis plan. 
Results of the population PK and exposure-response analysis will be summarized in a separate 
technical report. 
7.6 Biomarker Analyses 
The following exploratory analyses may or may not be presented formally. If presented, they will 
be limited to biomarkers for which data from a sufficient number of subjects are available. 
Further details on these analyses may be outlined in a separate analysis plan, and results may be 
summarized in a separate technical report. 
7.6.1 Pharmacodynamic and Potentially Predictive Biomarkers 
The relationship between tumor genomics, gene expression, protein expression, and clinical 
endpoints may be explored as follows: 
• 
Evaluation of serum biomarkers, blood immunophenotype and tumor biomarkers for 
relationships with duvelisib clinical activity and safety 
• 
Evaluation of tumor genomic features (eg, cytogenetics, FISH, DNA sequence 
variation, DNA copy number variation, and/or RNA expression) for relationships 
with duvelisib clinical activity 
• 
Evaluation of the relationship between serum and/or tumor biomarkers and disease 
progression of duvelisib and ofatumumab 
7.6.2 Pharmacogenomics 
DNA may be extracted from the pharmacogenomics sample in order to evaluate a subject’s 
germline DNA.  This sample may be used to explore the following: 
• Evaluate the relationship between germline DNA sequence variations and PK of 
duvelisib 
• Evaluate germline DNA as a control to verify that tumor sequence variations are 
somatic mutations 
 
 
 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
8 CHANGES IN PLANNED ANALYSES  
8.1 Changes in Planned Analyses from Protocol Amendment 1 to SAP V1.0  
There are no changes from Protocol Amendment 1. More details are provided in the SAP. 
8.2 Changes in Planned Analyses from SAP V1.0 to SAP V2.0 
The main changes from SAP V1.0 to SAP V2.0 are described below. 
1. Section 3.5.2 Clarification 
Old (V1.0): The second analysis of OS will be performed at the PFS final analysis, which 
is expected to happen after 185 PFS events have occurred, or approximately 27.5 months 
after the first subject is randomized. 
New (V2.0): The second interim analysis of OS will be performed at the PFS final 
analysis, which is to happen after 185 PFS events have occurred. If the planned final 
analysis of PFS is not performed due to early stop for efficacy, then the second interim 
analysis of OS will be conducted approximately one year after the first interim analysis of 
OS. 
2. New censoring method for event-free survival were specified.  
3. Prior irradiation and prior surgery were removed from prior therapy summary. 
The following additional analyses/summaries have been added to this version of the SAP: 
1. Analysis of ORR of subjects who are on treatment for 60 days or longer 
2. Time to OS follow up  
3. Time to response 
4. Treatment-emergent AEs reported in ≥5% of CLL/SLL subjects and occurred at ≥2% 
higher incidence in subjects receiving duvelisib (All Causalities) 
5. Grade 3 or higher treatment-emergent AEs reported in ≥5% of CLL/SLL subjects and 
occurred at ≥2% higher incidence in subjects receiving duvelisib (All Causalities) 
6. Treatment-emergent AEs by PT (All Causalities, AE onset date within 24 weeks after 
the first dose of study treatment) 
7. Grade 3 or higher treatment-emergent AEs by PT (All Causalities, AEs with onset 
date within 24 weeks after the first dose of study treatment) 
8. Treatment-emergent AEs resulting in discontinuation of study drug (Treatment-
Related) 
9. Treatment-emergent AEs resulting in death (Treatment-Related) 
10. Treatment-emergent SAEs by PT (All Causalities). 
11. Treatment-emergent SAEs by PT (Treatment-Related) 
12. Deaths on treatment 
13. Deaths during follow-up 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
14. A by-subject listing of treatment-emergent AEs resulting in dose hold  
15. A by-subject listing of treatment-emergent AEs resulting in dose reduction 
16. A by-subject listing of deaths on study 
17. A summary table and a listing of the discrepancies in data for stratification factors 
between those captured in the IRT and those reported on the eCRF  
18. Comparision of del[17p] values captured from central lab and local lab 
19. The following biomarkers will be summarized as baseline characteristics:  
• del[17p] (captured from central lab, presence vs absence vs indeterminate) 
• del[17p] (captured from local lab, presence vs absence vs indeterminate) 
• del[17p] and/or TP53 mutation (del[17p] and/or TP53 mutation, del[17p] 
captured from central lab, either or both present vs neither present vs 
indeterminate) 
• del[17p] and TP53 mutation (del[17p] and TP53 mutation, del[17p] 
captured from central lab, both present vs either vs neither present vs 
indeterminate) 
• TP53 mutation (presence vs absence vs indeterminate) 
• IgHV status (mutated vs unmutated vs indeterminate) 
• CD38 (Positive (≥30%) vs Negative vs indeterminate) 
• ZAP70 (Positive (>19%) vs Negative (<=19%) vs indeterminate) 
20. Subgroup analyses of PFS, OS and ORR based on the following factors: 
• Time from last dose of most recent prior anti-cancer therapy to 
randomization <12 months: yes vs no  
• del[17p] (captured from central lab) or TP53 mutation (either or both 
present vs neither present ) 
 
8.3 Changes in Planned Analyses from SAP V2.0 to SAP V3.0 
The main changes from SAP V2.0 to SAP V3.0 are described below. 
1. In Section 3.5.2, the estimated numbers of OS events at each of OS interim analyses and 
final analysis are provided. 
2. In Section 6.3, Lymph Node Response Rate and Hematological Improvement Rate are 
removed from the list of key secondary efficacy endpoints and removed from the 
hierarchy of inferential testing in secondary endpoints.  
3. In Section 7.2.1.3, for selected subgroups, additional analyses of PFS are added. These 
include the estimate and 95% CI for the median by treatment group, and the Kaplan-
Meier plot by treatment group. 
4. In Section 7.2.2.1, for selected subgroups, summaries of BOR, estimated ORR and its 2-
sided 95% CI for each treatment group are added. 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
9 REFERENCES 
1 O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 
1979; 35:549-556. 
 
2 Robins JM. Information recovery and bias adjustment in proportional hazard 
regression analysis of randomized trials using surrogate markers. Proceedings of the 
Biopharmaceutical Section, American Statistical Association 1993; pp. 24-33.  
 
3 Robins JM, Finkelstein D.  Correcting for Non-compliance and dependent censoring 
in an AIDS clinical trial with inverse probability of censoring weighted (IPCW) log-
rank tests. Biometrics, 2000; 56(3):779-788. 
 
4 Robins JM, Tsiatis, AA. Correcting for noncompliance in randomized trials using 
rank preserving structural failure time models. Communications in Statistics, 1991; 
20, 2609-2631. 
 
 
 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
10 APPENDICES 
10.1 Appendix A: Primary PFS Event/Censoring Method 
Censoring of PFS will be performed as detailed in the table below.  
 
Situation 
Date of Event or 
Censoring 
Outcome 
No adequate baseline disease status assessment  Date of randomization 
Censored 
No adequate post-baseline disease status 
assessment unless death occurs prior to first 
post-baseline assessment 
Date of randomization + 1 
Censored 
No documented progression or death before 
data cutoff 
Date of last adequate 
disease status assessment 
Censored 
Documented progression with ≤1 missing 
scheduled disease status assessment before 
progression 
Date of the earliest 
assessment that results in a 
finding of unequivocal 
progression 
Event 
Death before progression being documented 
with ≤1 missing scheduled disease status 
assessment before death 
Date of death 
Event 
Documented progression or death following a 
long gap between adequate disease status 
assessments (eg, 2 or more consecutive missed 
scheduled disease status assessments)  
Date of last adequate 
disease status assessment 
before the gap 
Censored 
New anticancer treatment or procedure started 
before documented progression 
Date of last adequate 
disease status assessment 
Censored 
Note: Disease status assessment includes CT scans (chest, abdomen and pelvis), bone marrow aspirate and/or biopsy 
(may not be required of all subjects at all scheduled disease status assessments), CBC and differential count, focused 
physical examination, disease related constitutional symptoms for disease assessment, and ECOG performance 
status. An adequate baseline disease status assessment is any baseline disease status assessment that include WBC 
counts and CT scans. An adequate post-baseline disease status assessment is any disease status assessment for which 
a disease status (eg, CR, CRi, PR, PRwL, SD, and PD) is arrived per protocol-defined criteria by the IRC (for IRC 
assessment) or investigator (for investigator assessment).   
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
10.2 Appendix B: Event-Free Survival (EFS) Event/Censoring Method 
Situation 
Date of Event or 
Censoring 
Outcome 
No adequate baseline disease status assessment  Date of randomization 
Censored 
No adequate post-baseline disease status 
assessment unless death or new anticancer 
treatment/procedure occurs prior to first post-
baseline assessment 
Date of randomization + 1 
Censored 
No documented progression, death or new 
anticancer treatment/procedure started before 
data cutoff 
Date of last adequate 
disease status assessment 
Censored 
Documented progression with ≤1 missing 
scheduled disease status assessment before 
progression, and no new anticancer treatment/ 
procedure started before documented 
progression 
Date of the earliest 
assessment that results in a 
finding of unequivocal 
progression 
Event 
Death before progression being documented 
with ≤1 missing scheduled disease status 
assessment before death, and no new 
anticancer treatment/procedure started before 
death 
Date of death 
Event 
Documented progression, death or new 
anticancer treatment/procedure following a 
long gap between adequate disease status 
assessments (eg, 2 or more consecutive missed 
scheduled disease status assessments)  
Date of last adequate 
disease status assessment 
before the gap 
Censored 
New anticancer treatment/procedure started 
before documented progression with ≤1 
missing scheduled disease status assessment 
prior to new anticancer treatment/procedure 
Start date of new anticancer 
treatment/procedure 
Event 
 
 
 
 
 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
10.3 Appendix C: One-Sided Cochran–Mantel–Haenszel (CMH) Test 
 
The Cochran–Mantel–Haenszel (CMH) test compares binary responses of two 
treatment groups, adjusting for stratification factors. In the CMH test, the data are 
arranged in a series of associated 2 × 2 contingency tables, the null hypothesis is that the 
observed response is independent of the treatment used in any 2 × 2 contingency table. 
 
Let 
hij
O
 be the observed frequency of treatment i (i=1 or 2) with outcome j (j= 1 or 2) in 
stratum h and 
hij
E
be the expected frequency of treatment i (i=1 or 2) with outcome j (j= 
1 or 2) in stratum h, where 
 
22
21
12
11
2
1
2
1
)
(
)
(
h
h
h
h
j
h
j
h
hi
hi
hij
O
O
O
O
O
O
O
O
E
+
+
+
+
⋅
+
=
 
 
Also, let 
hij
P be the probability of outcome being j given treatment being i (i=1 or 2, j= 1 
or 2) in stratum h. To test the following hypothesis, 
 
  
 
21
11
0 :
h
h
P
P
H
=
 for all ℎ∈{1, … , 𝐻𝐻}   
versus   
21
11
1 :
h
h
P
P
H
>
 for at least one ℎ∈{1, … , 𝐻𝐻} 
 
The one-sided Cochran-Mantel-Haenszel Test Statistics is constructed as: 
 
Z
V
E
O
Z
H
h
h
h
CMH
~
)
(
11
1
11
11
∑
=
−
=
 
 
Where 
 
 
∑
∑
=
=
−
+
+
+
•
=
−
=
H
h
h
h
h
h
h
h
H
h
h
h
O
O
O
O
E
E
E
O
Var
V
1
22
21
12
11
22
11
1
11
11
11
1
))
(
(
 
 
The test statistic 
CMH
Z
  will be compared with standard normal distribution to 
obtain p-value of the CMH test. 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Version 2.0 (24 Nov 2015) 
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Page 1 of 41 
STATISTICAL ANALYSIS PLAN 
 
Protocol IPI-145-07 
A Phase 3 Study of IPI-145 versus Ofatumumab in Subjects with Relapsed or 
Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma 
 
 
 
 
 
 
 
 
 
 
 
This statistical analysis plan contains confidential information and is the proprietary 
property of Infinity Pharmaceuticals, Inc. This document may not be copied or 
made available for review by an unauthorized person or firm without the prior 
written authorization of Infinity Pharmaceuticals, Inc. 
 
 
 
Protocol Version: 
Amendment 2 
 
Type of Analysis 
Plan: 
Interim and Final Analyses 
 
Version: 
2.0 
 
Date: 
24 Nov 2015 
 
Author: 
Shijie Tang, PhD 




IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Version 2.0 (24 Nov 2015) 
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Page 3 of 41 
 
DOCUMENT HISTORY 
 
Version 
Date 
Author(s) 
Brief Summary of Changes 
1.0 
02 Oct 2014 
Shijie Tang 
Original 
2.0 
24 Nov 2015 
Shijie Tang 
Clarified the timing of the 2nd interim 
analysis of overall survival; added 
biomarkers to baseline characteristics; 
other changes. Refer to Section 8.2 for 
Details. 
 
 
 
 
 
 
 
 
 
 


IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Version 2.0 (24 Nov 2015) 
CONFIDENTIAL 
Page 4 of 41 
 
Table of Contents 
 
LIST OF ABBREIVATIONS ......................................................................................................... 7 
1 
INTRODUCTION ................................................................................................................ 10 
2 
STUDY OBJECTIVES ......................................................................................................... 10 
2.1 
Primary Objective .......................................................................................................... 10 
2.2 
Secondary Objectives ..................................................................................................... 10 
2.3 
Exploratory Objectives ................................................................................................... 10 
3 
STUDY DESIGN.................................................................................................................. 11 
3.1 
Overview ........................................................................................................................ 11 
3.2 
Sample Size Consideration............................................................................................. 11 
3.3 
Randomization ............................................................................................................... 12 
3.4 
Blinding .......................................................................................................................... 12 
3.5 
Planned Analyses ........................................................................................................... 12 
3.5.1 
Planned Analyses for PFS ....................................................................................... 13 
3.5.2 
Planned Analyses for OS ........................................................................................ 13 
4 
ANALYSIS SETS ................................................................................................................ 14 
4.1 
Intent-To-Treat (ITT) Analysis Set ................................................................................ 14 
4.2 
All-Treated (AT) Analysis Set ....................................................................................... 14 
4.3 
Per-Protocol (PP) Analysis Set ...................................................................................... 14 
5 
STUDY ENDPOINTS .......................................................................................................... 15 
5.1 
Primary Endpoint ........................................................................................................... 15 
5.2 
Secondary Endpoints ...................................................................................................... 15 
5.3 
Exploratory Endpoints.................................................................................................... 15 
6 
GENERAL STATISTICAL METHODS AND DATA HANDLING ................................. 17 
6.1 
General Methods ............................................................................................................ 17 
6.2 
Handling of Missing Data .............................................................................................. 17 
6.2.1 
Handling of Missing Dates/Months/Years for Adverse Events .............................. 17 
6.2.2 
Handling of Missing Dates/Months/Years for Concomitant Medications ............. 18 


IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
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6.2.3 
Handling of Missing Dates/Months/Years for Disease History and Prior Therapies
 
18 
6.3 
Multiple Comparisons/Multiplicity Adjustment ............................................................ 18 
6.4 
Adjustments for Covariates ............................................................................................ 19 
6.5 
Subgroups ....................................................................................................................... 19 
6.6 
Visit Windows ................................................................................................................ 20 
6.7 
Unscheduled Visits ......................................................................................................... 20 
6.8 
Baseline Values .............................................................................................................. 20 
6.9 
Computing and Coding Standards ................................................................................. 20 
7 
STATISTICAL ANALYSES ............................................................................................... 21 
7.1 
Study Subjects ................................................................................................................ 21 
7.1.1 
Disposition of Subjects ........................................................................................... 21 
7.1.2 
Protocol Deviations ................................................................................................. 21 
7.1.3 
Demographic and Other Baseline Characteristics .................................................. 21 
7.1.4 
Disease History ....................................................................................................... 22 
7.1.5 
Prior Therapies ........................................................................................................ 22 
7.1.6 
Medical History ...................................................................................................... 23 
7.1.7 
Prior and Concomitant Medications ....................................................................... 23 
7.1.8 
Exposure to Study Drug .......................................................................................... 23 
7.2 
Efficacy Analyses ........................................................................................................... 24 
7.2.1 
Analyses of Primary Endpoint ................................................................................ 24 
7.2.2 
Analyses of Secondary Efficacy Endpoints ............................................................ 26 
7.2.3 
Analyses of Exploratory Efficacy Endpoints .......................................................... 29 
7.3 
Safety Analyses .............................................................................................................. 29 
7.3.1 
Adverse Events ....................................................................................................... 30 
7.3.2 
Laboratory Data ...................................................................................................... 31 
7.3.3 
Vital Signs ............................................................................................................... 32 
7.3.4 
Electrocardiogram (ECG) ....................................................................................... 32 
7.3.5 
Concomitant Medications and Procedures.............................................................. 32 
7.3.6 
Deaths ..................................................................................................................... 32 
7.4 
Quality of Life Instruments ............................................................................................ 32 


IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
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7.4.1 
EQ-5D ..................................................................................................................... 33 
7.4.2 
FACIT-F ................................................................................................................. 33 
7.5 
Pharmacokinetic Analyses ............................................................................................. 34 
7.6 
Biomarker Analyses ....................................................................................................... 34 
7.6.1 
Pharmacodynamic and Potentially Predictive Biomakers ...................................... 35 
7.6.2 
Pharmacogenomics ................................................................................................. 35 
8 
CHANGES IN PLANNED ANALYSES ............................................................................. 36 
8.1 
Changes in Planned Analyses from Protocol Amendment 1 to SAP V1.0 .................... 36 
8.2 
Changes in Planned Analyses from SAP V1.0 to SAP V2.0 ......................................... 36 
9 
REFERENCES ..................................................................................................................... 38 
10 APPENDICES ...................................................................................................................... 39 
10.1 
Appendix A: Primary PFS Event/Censoring Method................................................. 39 
10.2 
Appendix B: Event-Free Survival (EFS) Event/Censoring Method .......................... 40 
10.3 
Appendix C: One-Sided Cochran–Mantel–Haenszel (CMH) Test ............................ 41 
 
 


IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Version 2.0 (24 Nov 2015) 
CONFIDENTIAL 
Page 7 of 41 
LIST OF ABBREIVATIONS 
Abbreviation 
Description 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
AT 
All-Treated  
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BID 
Twice a day 
BOR 
Best Overall Response 
BUN 
Blood Urea Nitrogen 
CI 
Confidence Interval 
CLL 
Chronic Lymphocytic Leukemia 
CMH 
Cochran–Mantel–Haenszel 
CO2 
Bicarbonate 
CR 
Complete Response 
CRi 
Complete Response with Incomplete Marrow Recovery 
CS 
Abnormal and Clinically Significant 
CTCAE 
Common Terminology Criteria for Adverse Events 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
Electronic Case Report Form 
eDISH 
Evaluation of Drug Induced Serious Hepatotoxicity 
EQ-5D 
European Quality of Life-5 Dimensions 
FACIT-F 
Functional Assessment of Chronic Illness Therapy-Fatigue 
FACT-G 
The Functional Assessment of Cancer Therapy - General 


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Version 2.0 (24 Nov 2015) 
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Page 8 of 41 
Abbreviation 
Description 
HR 
Hazard Ratio 
IDMC 
Independent Data Monitoring Committee 
IPI-145 
(S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-
phenylisoquinolin-1(2H)-one 
IPCW 
Inverse Probability of Censoring Weighted 
IRC 
Independent Review Committee 
IRT 
Interactive Response Technology 
ITT 
Intent-To-Treat 
IV 
Intravenous 
IWCLL 
International Workshop on Chronic Lymphocytic Leukemia 
IWG 
International Working Group 
LC/MS/MS 
Liquid Chromatography-tandem Mass Spectrometry 
LDH 
Lactate Dehydrogenase 
LFT 
Liver Function Test 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEOI 
Medical Events of interest 
MMRM 
Mixed Effect Repeated Measures 
MRD 
Minimal Residual Disease 
NCI 
National Cancer Institute 
NCS 
Abnormal but Not Clinically Significant 
NED 
No Evidence of Disease 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetics 
PP 
Per-Protocol 
PR 
Partial Response 
PRwL 
PR with Lymphocytosis 


IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
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Page 9 of 41 
Abbreviation 
Description 
PT 
Preferred Term 
QoL 
Quality of Life 
RBC 
Red Blood Cell 
RPSFT 
Rank Preserving Structural Failure Time 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SI 
Standard International System of Units 
SLL 
Small Lymphocytic Lymphoma 
SOC 
System Organ Class 
SPD 
Sum of Products 
TEAE 
Treatment Emergent Adverse Event 
TTR 
Time to Response 
UNK 
Unknown 
VAS 
Visual Analog Scale 
WHO 
World Health Organization 
WHO-DD 
World Health Organization Drug Dictionary 
 
 


IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Version 2.0 (24 Nov 2015) 
CONFIDENTIAL 
Page 10 of 41 
1 INTRODUCTION 
This is the statistical analysis plan (SAP) for study IPI-145-07, A phase 3 study of IPI-145 versus 
ofatumumab in subjects with relapsed or refractory chronic lymphocytic leukemia/small 
lymphocytic lymphoma. This SAP is prepared according to Amendment 2 of the protocol, dated  
02 March 2015. 
2 STUDY OBJECTIVES 
2.1 Primary Objective 
The primary objective of this trial is to examine the efficacy of duvelisib (IPI-145) monotherapy 
versus ofatumumab monotherapy in subjects with relapsed or refractory Chronic Lymphocytic 
Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). 
2.2 Secondary Objectives 
• To determine the safety of duvelisib in subjects with CLL or SLL 
• To evaluate the pharmacokinetics (PK) of duvelisib and, if applicable, its metabolite(s) 
2.3 Exploratory Objectives  
• To evaluate the health-related quality of life (QoL) of subjects 
• To evaluate pharmacodynamic biomarkers of duvelisib  
• To evaluate biomarkers that may predict duvelisib clinical activity and/or safety 
• To evaluate mechanisms of resistance in subjects who exhibit disease progression while 
being treated with duvelisib or ofatumumab 
• To evaluate genomic features of tumors predictive of response in subjects treated with 
duvelisib or ofatumumab 
 
 


IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Version 2.0 (24 Nov 2015) 
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3 STUDY DESIGN 
3.1 Overview 
Study IPI-145-07 is a two-arm, randomized (1:1 ratio), open-label, phase 3, superiority trial 
designed to evaluate the efficacy and safety of duvelisib compared to ofatumumab.  
Subjects who meet all the eligibility criteria at Screening will return to the clinic on Day 1 to 
receive their first dose of study drug (randomized to either duvelisib or ofatumumab). The first 
treatment cycle for each treatment arm will be 3 weeks (21±2 days). Subsequent treatment cycles 
will be 4 weeks (28±4 days). 
Subjects randomized to duvelisib will be given a starting dose of 25 mg duvelisib administered 
orally twice daily (BID) initially in a 21-day treatment cycle followed by 28-day treatment cycles 
for up to 18 cycles or until disease progression or unacceptable toxicity (whichever comes first). 
After completing approximately 18 cycles of treatment, subjects may receive additional cycles of 
duvelisib for up to 3 years (39 cycles of total treatment) if they have documented evidence of 
response and disease requiring continued treatment according to the modified IWCLL/revised 
IWG criteria. 
Subjects randomized to ofatumumab will receive treatment consistent with the approved product 
labeling: 8 weekly infusions, starting with an initial IV dose of 300 mg ofatumumab on Day 1 
followed by seven weekly doses of 2000 mg. Thereafter, subjects will receive 2000 mg 
ofatumumab once every month for four months or until disease progression or unacceptable 
toxicity (whichever comes first), as outlined in the schedule of assessments. Administration of 
ofatumumab will not exceed the 12 doses (within 7 cycles) as described in the prescribing 
information.  
Subjects will be followed for survival for up to 6 years (or other duration as specified by the 
protocol) from randomization or until death. Follow-up visits will occur every 6 months which 
can be conducted through a telephone interview.    
3.2 Sample Size Consideration 
This study employs a randomized, open-label, parallel design to assess the potential superiority 
of duvelisib treatment over ofatumumab treatment on progression-free survival (PFS) in CLL or 
SLL subjects. 
The sample size was determined to provide sufficient power to test the primary endpoint of PFS 
in a group sequential design with one planned interim analysis. 
Assuming an exponential distribution for PFS, a total of 185 PFS events (deaths or progressions) 
will provide approximately 93% power to detect a hazard ratio of 0.6 (median PFS of 9 months 
in the ofatumumab group versus 15 months in the duvelisib group) using a one-sided log-rank 
test at a 2.5% overall significance level (ie, alpha of 0.025). The study design employs the Lan-
DeMets spending function for O’Brien-Fleming boundary as the alpha spending function and the 
Hwang-Shih-DeCani gamma (-4) spending function as the beta spending function. A total of 300 


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subjects will be randomized in a 1:1 ratio to receive either ofatumumab or duvelisib. Assuming a 
peak accrual rate of 30 subjects per month with 11 months for accrual ramp-up and a 4% 
cumulative dropout rate per year, the enrollment would complete in 16 months, with the final 
analysis for PFS estimated to occur approximately 27.5 months from the randomization of the 
first subject. 
3.3 Randomization 
Once a subject has met all entry criteria, the Interactive Response Technology (IRT) will be used 
to generate a distinct subject identifier. If a subject discontinues from the study, the subject 
identifier will not be reused and the subject will not be allowed to re-enter the study.  
Eligible subjects will be randomized via IRT in a 1:1 ratio to one of two treatment arms:  
• Arm 1: duvelisib 25 mg BID  
• Arm 2: Ofatumumab  
In order to ensure subject balance between treatment groups, study subjects will be stratified by 
the following: 
• High risk cytogenetics (presence vs absence of del[17p]) 
• Refractory/early relapse to purine analog based treatment (progression <12 months after 
fludarabine/pentostatin: yes vs no)  
• Grade 4 cytopenia(s) (presence vs absence of neutropenia or thrombocytopenia at 
baseline)   
First dose is to occur within 7 days of randomization after all screening assessments have been 
completed. 
3.4 Blinding  
This study is open-label and Investigators, site staff, Sponsor and Sponsor designees will have 
access to treatment assignments for individual subjects. To reduce bias, a blinded independent 
central review of disease status will be conducted, which will be blinded to individual subject 
treatment assignments. Investigators, site staff, Sponsor and Sponsor designees will only have 
access to blinded (pooled) aggregate study data, except for a select number of Sponsor staff, who 
may review aggregate SAEs and Medical Events of Interest (MEOI) data by treatment groups. 
3.5 Planned Analyses 
Interim and final analyses are planned for PFS and OS. For an interim analysis, the actual p-
value boundaries will be calculated based on the actual number of PFS and OS events at the 
analysis. For the final analysis, the actual p-value boundary for efficacy will be calculated based 
on the actual number of PFS and OS events at the interim analysis (or analyses) and the final 
analysis. 


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The Independent Data Monitoring Committee (IDMC) will review PFS, OS and other efficacy 
data at the time of PFS interim analysis. The list of IDMC deliverables, including tables and 
listings, is included in the IDMC charter.  These deliverables will be based on the methods 
described in this SAP.  
3.5.1 Planned Analyses for PFS 
There will be two planned analyses for PFS, one interim analysis and one final analysis. After 
approximately 50% of the planned PFS events (ie, 93 PFS events) have been observed based on 
the blinded, independent, central review, an interim analysis of efficacy will be performed.  
At the interim analysis, PFS will be tested at the alpha level based on the Lan-DeMets alpha 
spending function for the O’Brien-Fleming boundary with the opportunity to stop the study 
(other than survival follow-up) for overwhelming evidence of efficacy. If the interim analysis 
occurs at exactly 50% of the planned events, the criterion of stopping for efficacy is one-sided p-
value of 0.0015 (corresponding approximately to a HR of 0.540). In the meantime, PFS will also 
be tested at the alpha level for futility based on the alpha and beta spending functions specified 
for the study design. If the interim analysis occurs at exactly 50% of the planned events, the 
criterion of stopping for futility is one-sided p-value of 0.4791 (corresponding approximately to a 
HR of 0.990). The futility boundary of this study is non-binding, meaning that the Type I error is 
properly controlled even if the study is continued after the futility boundary for PFS is crossed at 
the interim analysis.  Under the protocol design assumptions (eg, the study is fully enrolled in 16 
months), the interim analysis is expected to occur approximately 17 months after the first subject 
is randomized.  
If the study is not stopped at the interim analysis, the final analysis will be performed when 
approximately 185 PFS events have occurred in the study.  If the interim analysis and the final 
analysis occur at exactly 93 and 185 PFS events, the criterion of statistical significance (ie, 
boundary for efficacy) is one-sided p-value of 0.0245 (corresponding approximately to a HR of 
0.748).  
3.5.2 Planned Analyses for OS 
There will be three planned analyses for OS, two interim analyses and one final analysis. The 
first interim analysis of OS will be at the planned PFS interim analysis, which is to happen after 
93 PFS events have occurred. The second interim analysis of OS will be performed at the PFS 
final analysis, which is to happen after 185 PFS events have occurred. If the planned final 
analysis of PFS is not performed due to early stop for efficacy, then the second interim analysis 
of OS will be conducted approximately one year after the first interim analysis of OS. Since all 
subjects will be followed for survival for 6 years, the final analysis of OS will take place at the 
end of follow-up of all subjects, or approximately 6 years from the last subject being 
randomized. To control the overall one-sided type I error under 0.025, the cumulative alpha 
spending at the three analyses will be 0.0001, 0.0249, and 0.0250, respectively. As a result, the 
p-value stopping boundaries for the three analyses will be 0.0001, 0.0249 and 0.0003, 
respectively. The statistical significance of OS will be claimed as specified in Section 6.3.    


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4 ANALYSIS SETS 
4.1 Intent-To-Treat (ITT) Analysis Set 
The intent-to-treat (ITT) analysis set includes all subjects who are randomized, with treatment 
group designated according to randomization. 
This analysis set will serve as the primary analysis set for all efficacy endpoints and 
demographics.  
4.2 All-Treated (AT) Analysis Set 
The all-treated (AT) analysis set includes all subjects who receive any amount of study drug 
(duvelisib or ofatumumab), with treatment group designated according to actual study treatment 
received. The AT analysis set will be the primary analysis set for safety endpoints. 
4.3 Per-Protocol (PP) Analysis Set 
The per-protocol (PP) analysis set includes all subjects in the ITT analysis set who do not violate 
the terms of the protocol in a way that would significantly affect the study outcome, with 
treatment group designated according to randomization. Subjects who meet any of the following 
criteria may be excluded from this analysis set:  
• Do not have documented diagnosis of CLL or SLL  
• Do not have measurable nodal disease at baseline as determined by the IRC 
• ECOG performance status >2 
• History of Richter's transformation or prolymphocytic leukemia  
• Refractory to ofatumumab  (defined as progression or relapse <12 months of receiving 
ofatumumab monotherapy or <24 months of receiving an ofatumumab-containing 
regimen)   
• Prior exposure to a PI3K inhibitor 
• Receive concomitant prohibited anticancer therapy  
• Permanent discontinuation from study drug due to non-compliance 
The PP analysis set will be a secondary analysis set for selected efficacy analyses.  
 
 


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5 STUDY ENDPOINTS  
5.1 Primary Endpoint 
The primary efficacy endpoint PFS is defined as time from randomization to the first 
documentation of progressive disease (PD) as determined by independent review or death due to 
any cause.  
The censoring method of the primary endpoint can be found in Appendix A. The detailed 
algorithm will be specified in the Analysis Data Model (ADaM) specifications.  
5.2 Secondary Endpoints 
The secondary efficacy endpoints of the study are: 
• Overall Response Rate (ORR), with overall response (based on independent review) 
defined as best response of complete response/remission (CR), CR with incomplete 
marrow recovery (CRi), partial response/remission (PR), or PR with lymphocytosis 
(PRwL), according to the IWCLL or revised IWG Response Criteria, with modification 
for treatment-related lymphocytosis  
• Lymph node response rate, with lymph node response defined as ≥50% decrease in the 
SPD of target lymph nodes  
• Overall Survival (OS), defined as time from randomization to death 
• Hematologic improvement rate, defined as any of following hematologic improvement 
sustained for at least 60 days without transfusion or exogenous growth factors: 
o Neutrophil count >1,500/µL or an increase ≥50% from Baseline; or 
o Hemoglobin >11 g/dL or an increase ≥50% from Baseline; or  
o Platelet count >100,000/µL or an increase ≥50% from Baseline  
• Duration of Response (DOR), defined as time from the first documentation of response to 
first documentation of PD or death due to any cause.  
Other secondary endpoints of the study are: 
• TEAEs and changes in safety laboratory values  
• PK parameters derived from plasma duvelisib concentrations and, if applicable, its 
metabolite(s) 
5.3 Exploratory Endpoints 
The exploratory efficacy endpoints of the study are: 
• Improvement in disease-related symptoms of fatigue, weight loss, unexplained fevers and 
night sweats from Baseline 
• Minimal Residual Disease (MRD) in subjects with documented CR or CRi 
• Time to Response (TTR), defined as the time from randomization to the first 
documentation of response (CR, CRi, PR or PRwl)  


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The QoL endpoints of the study are: 
• Health-related QoL of subjects as assessed by the following subject-reported 
questionnaires:  
o EuroQol-5D (EQ-5D) 
o Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) 
The biomarkers of the study are: 
• Serum and tissue biomarkers and blood immunophenotype 
• Tumor genomic features (eg, DNA sequence variation, DNA copy number variation, 
and/or RNA expression) 
• Germline DNA sequence variations 
 
 
 


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6 GENERAL STATISTICAL METHODS AND DATA HANDLING 
6.1 General Methods 
Summary statistics will be presented by treatment group, unless stated otherwise.  
Unless otherwise specified, descriptive statistics for continuous data will include the number of 
subjects with data to be summarized (n), mean, standard deviation, 25% quartile, median, 75% 
quartile, and minimum and maximum. The same number of decimal places as in the raw data 
will be presented when reporting the minimum and maximum, one more decimal place than the 
raw data will be presented when reporting mean and median, and 2 more decimal places than the 
raw data will be presented when reporting standard deviation. 
Descriptive statistics for categorical/qualitative data will include frequency counts and 
percentages. The total number of subjects in the treatment group will be used as the denominator 
for percent calculations, unless stated otherwise. All percentages will be presented with one 
decimal, unless otherwise specified. Percentages equal to 100 will be presented as 100, and 
percentages will not be presented for zero frequencies. 
Descriptive statistics associated with time-to-event analyses will include the number of events, 
the number of subjects censored, 25% quartile, median, 75% quartile, and 95% confidence 
interval for median. These statistics will be presented for all time-to-event analyses, unless stated 
otherwise.  
Listings will be provided for selected endpoints. For listings broken down by center and 
treatment arm, site (center) number will be ordered by country. 
6.2 Handling of Missing Data 
In general, values for missing data will not be imputed unless methods for handling missing data 
are specified. 
6.2.1 Handling of Missing Dates/Months/Years for Adverse Events 
Adverse events (AEs) with incomplete onset dates will be handled as follows for the sole 
purpose of determining treatment emergence (TEAE is defined in Section 7.3.1): 
• If the start/end date of an AE is partially missing, the date will be compared as far as 
possible with the date of the start of administration of study drug and the date of last dose 
of study drug plus 30 days. The AE will be assumed to be treatment emergent if it cannot 
be definitively shown that the AE did not occur or worsen during the treatment-emergent 
period (worst case approach). The detailed algorithm will be specified in ADaM 
specifications.  
• If the start date is completely missing, an AE will be considered treatment-emergent 
unless the stop date is before study drug administration. 
• If the dose start date is missing for a subject at a data-cut, all AEs of the subject will be 
considered treatment-emergent.  


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The original partial or missing date will be shown in listings of AEs. 
6.2.2 Handling of Missing Dates/Months/Years for Concomitant Medications 
Prior or concomitant medications with incomplete start dates will be handled as follows for the 
sole purpose of determining whether a non-study medication is a concomitant medication: 
• If the start/stop date of a medication is partially missing, the date will be compared as far 
as possible with the date of the start of administration of study drug and the date of last 
dose of study drug plus 30 days. The medication will be assumed to be concomitant if it 
cannot be definitively shown that the stop date is before the start of administration of 
study drug, or the start date is more than 30 days after the last date of administration of 
study drug. The detailed algorithm will be specified in ADaM specifications.  
• If the start/stop dates are completely missing, a medication will be considered 
concomitant. 
• If the dose start date is missing for a subject at a data-cut, all non-study medications of 
the subject will be considered concomitant. 
The original partial or missing date will be shown in listings of all non-study medications. 
6.2.3 Handling of Missing Dates/Months/Years for Disease History and Prior Therapies 
For the purpose of calculating the duration from initial diagnosis, most recent relapse/refractory 
diagnosis or most recent prior therapy to randomization, partial/missing dates for diagnosis and 
last prior therapy completion will be imputed as follows:  
 
• If both date and month are missing and the year is prior to the year of screening, the 
imputed date and month will be 01 July.  
• If both date and month are missing and the year is the same as the year of screening, the 
imputed date will be the middle point between 01 Jan of the year and the screening date. 
If the middle point falls between two dates, the first of the two dates will be used.  
• If date is missing and the month and year are prior to the month and year of screening, 
the imputed date will be 15th day of the month.  
• If date is missing and the month and year are the same as the month and year of 
screening, the imputed date will be the middle point between the first date of the month 
and the screening date. If the middle point falls between two dates, the first of the two 
dates will be used.  
• No imputation will be performed if the year is missing.  
6.3 Multiple Comparisons/Multiplicity Adjustment 
Of the secondary endpoints, ORR, Lymph Node Response Rate, OS, and Hematologic 
Improvement Rate are designated as key secondary efficacy endpoints. The primary endpoint 
and key secondary endpoints will be tested at an overall one-sided alpha level of 0.025 based on 
a gatekeeping approach.  
If the primary endpoint is significant, the 4 secondary endpoints will be sequentially tested in the 
order listed above. ORR will be tested at the one-sided 0.025 level only if PFS is declared 


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statistically significant. Lymph Node Response Rate will be tested at the one-sided 0.025 level 
only if PFS and ORR are declared statistically significant. OS will be tested according to the 
planned alpha spending specified in Section 3.5.2 only if PFS, ORR and Lymph Node Response 
Rate are declared statistically significant. Hematologic Improvement Rate will be tested at the 
one-sided 0.025 level only if PFS, ORR, Lymph Node Response Rate and OS are declared 
statistically significant. If any null hypothesis is not rejected in this sequence of tests, formal 
sequential testing will be stopped.  
6.4 Adjustments for Covariates 
Adjustments for covariates will be considered for analysis of primary and key secondary 
endpoints, with details provided in Sections 7.2.1 and 7.2.2. 
6.5 Subgroups 
PFS, ORR and OS will be examined in the subgroups based on the following baseline 
characteristics or variables: 
• Stratification factors (1. captured from central lab; 2 and 3 captured on the eCRF): 
1 High-risk cytogenetics (presence vs absence of del[17p]) 
2 Refractory/early relapse to purine analog-based therapy (defined as progression 
<12 months after fludarabine/pentostatin: yes vs no)  
3 Grade 4 cytopenia(s) (presence vs absence of neutropenia or thrombocytopenia at 
baseline)   
• Diagnosis (CLL or SLL) 
• Gender (Male or Female) 
• Age group (<65 or ≥65) 
• Race (White or Non-White) 
• Previously treated with ofatumumab (yes vs no, if sample size allows the analysis) 
• Time from last dose of most recent prior anti-cancer therapy to randomization <12 
months: yes vs no  
If TP53 mutation status is available at the time of analyses, PFS, ORR and OS may also be 
examined in the subgroups based on the following variable:  
• del[17p] or TP53 mutation (either or both present vs neither present; del[17p] will be as 
captured from central lab) 
TEAEs (All Causalities) and TEAEs (Treatment-Related) will be examined in the following 
subgroups: 
• Gender (Male or Female) 
• Age group (<65 or ≥65) 
• Race (White or Non-White) 
• Baseline ECOG performance status (0 or 1 vs 2) 
More details will be specified in Sections 7.2.1, 7.2.2 and 7.3.1. 


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6.6 Visit Windows 
All data will be categorized based on the scheduled visit at which it was collected.  These visit 
designators are predefined values that appear as part of the visit tab in the eCRF.  There will be 
no additional analysis windowing done based on the assessment date. 
6.7 Unscheduled Visits 
Unscheduled visits will not be included in by-visit summary tables, unless otherwise specified.  
For laboratory tests, data from unscheduled visits will be included in listings and summaries of 
maximum changes from baseline, and the best or worst post-baseline values.  For endpoints 
based on disease status assessment, data from unscheduled assessments will be included in the 
derivation and analyses of the endpoints. 
6.8 Baseline Values  
Unless otherwise specified, the baseline value is defined as the value collected at the time closest 
to, and prior to, the start of study drug administration.  Values collected at unscheduled visits 
prior to the start of the study drug administration will be included in the calculation of baseline 
values.  
 
6.9 Computing and Coding Standards 
Activities will be performed using the following tools: 
Table, listing, and figure production 
SAS Version 9.2 or higher 
Coding 
 
 
Adverse Events 
MedDRA Version 16.1 or higher 
 
Medical Histories 
MedDRA Version 16.1 or higher 
 
Prior and Concomitant Medications 
WHODrug Version September 2013 
Grading 
 
 
AEs 
CTCAE Version 4.03 
 
Labs 
CTCAE Version 4.03 
 
 
 
 
 
 
 


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7 STATISTICAL ANALYSES 
7.1 Study Subjects 
7.1.1 Disposition of Subjects 
The disposition of subjects will include the number and percentage of subjects for the following 
categories: the number randomized, the number and percentage randomized but not dosed, the 
number and percentage dosed. These categories will be summarized for each treatment arm and 
for the two treatment arms combined (total).  The percentages will be based on all randomized 
subjects (ITT analysis set).   
An end-of-treatment disposition (still on treatment vs discontinued from treatment) will be 
provided for each treatment arm and for the two treatment arms combined (total) based on the 
AT analysis set. The primary reason for treatment discontinuation will be included in the table. A 
listing of these subjects will also be provided, broken down by center and treatment arm. 
An end-of-study disposition (still on study vs discontinued from study) will also be provided for 
each treatment arm and for the two treatment arms combined (total) based on the ITT analysis 
set. The primary reason for study discontinuation will be included in the table. A listing of these 
subjects will also be provided, broken down by center and treatment arm. 
A summary of strata as captured in IRT will be presented by treatment arm and for the two 
treatment arms combined (total) based on the ITT analysis set.  A summary table and a listing of 
the discrepancies in data for stratification factors between those captured in the IRT and those 
reported on the eCRF will be presented. 
7.1.2 Protocol Deviations 
Protocol deviations will be categorized as major or minor prior to data release for the interim or 
final analysis of the primary endpoint. A summary table of the major protocol deviations will be 
provided by treatment arm and for two arms combined (total) for the ITT analysis set. A listing 
of major protocol deviations will be provided, broken down by center and treatment arm. 
7.1.3 Demographic and Other Baseline Characteristics 
Demographic and other baseline variables will be summarized for each treatment arm based on 
all randomized subjects (ITT analysis set) and for the two treatment arms combined (total). The 
variables will include age, age group (<65 versus >=65), sex, race, ethnicity, height, weight and 
the following biomarkers: 
• del[17p] (captured from central lab, presence vs absence vs indeterminate) 
• del[17p] (captured from local lab, presence vs absence vs indeterminate) 
• IgHV status (mutated vs unmutated vs indeterminate) 
• CD38 (Positive (≥30%) vs Negative (<30%) vs indeterminate) 
• ZAP70 (Positive (>19%) vs Negative (≤19%) vs indeterminate) 


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A separate table will be provided to compare del[17p] values captured from central lab and local 
lab. Demographic and other baseline variables will also be summarized based on the PP analysis 
set.  
TP53 mutation status (biomaker) may be summarized as a baseline characteristic as described 
above, if data are availble at the time of analyses.  TP53 may be summarized alone and/or in 
association with del[17p]: 
• del[17p] and/or TP53 mutation (either or both present vs neither present vs indeterminate; 
del[17p] will be as captured from central lab) 
• TP53 mutation (presence vs absence vs indeterminate) 
 
7.1.4 Disease History 
Disease history will be summarized for each treatment arm and for the two treatment arms 
combined (total) based on the ITT analysis set. The variables will include diagnosis (CLL or 
SLL), risk factors used for randomization that are reported on eCRF (high risk cytogenetics [17p 
deletion: presence vs absence], refractory/early relapse to purine analog based treatment [yes vs 
no], grade 4 cytopenia(s) [presence vs absence]), years from initial diagnosis to randomization, 
months from most recent relapse/refractory diagnosis to randomization, Binet/Rai stage at initial 
diagnosis, type of prior treatment, Binet/Rai stage at baseline, and baseline lymphocyte count.  
The durations to be summarized are defined as follows: 
• Years from initial diagnosis to randomization will be calculated as (date of randomization 
– date of initial diagnosis + 1)/365.25.  
• Months from most recent relapse/refractory diagnosis to randomization will be calculated 
as (date of randomization – date of most recent relapse/refractory diagnosis + 1)/ 
(365.25/12).  
The imputation of partial/missing dates is described in Section 6.2.3. 
7.1.5 Prior Therapies 
Prior therapies will be summarized for each treatment arm and for the two treatment arms 
combined (total) based on the ITT analysis set. The variables will include number of prior 
systemic therapies (summarized as a continuous variable and as a categorical variable) and 
months from most recent prior systemic therapy to randomization. 
The duration to be summarized is defined as follows.  
• Months from most recent prior systemic therapy to randomization will be calculated as 
(date of randomization – stop date of most recent systemic therapy +1)/ (365.25/12).  
The imputation of partial/missing dates is described in Section 6.2.3.  


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7.1.6 Medical History 
Medical history will be summarized for each treatment arm and for the two treatment arms 
combined (total) based on the AT analysis set. 
Medical history will be summarized by system organ class (SOC) and preferred term (PT) using 
the number and percentage of subjects who had at least one occurrence of an SOC or PT. The 
summary will be sorted alphabetically in SOC and by decreasing frequency of PT in the 
duvelisib arm within an SOC. 
7.1.7 Prior and Concomitant Medications  
Medications will be considered as prior if they stopped before the date of first dose of study 
drug.  
Medications will be considered concomitant if they were taken at any time between the date of 
first dose of study drug and 30 days after the date of last dose of study drug, inclusive.  If the 
start date or end date of a medication is completely or partially missing, refer to Section 6.2.2 for 
the algorithm to determine whether a medication is concomitant. 
Prior medications and concomitant medications will be summarized separately. Both summaries 
will be based on the AT analysis set. 
Medications will be summarized by ATC level 1, ATC level 2, and preferred drug name for each 
treatment arm. The summary will be sorted by decreasing frequency in ATC level 1, ATC level 2 
and preferred drug name in the duvelisib arm. A subject taking the same drug multiple times will 
only be counted once. 
A listing will be provided for all non-study medications taken on the study. An identifier will be 
provided to show if a medication is prior or concomitant. Medications that started more than 30 
days after the last dose of study drug will be identified as post-treatment.  
7.1.8 Exposure to Study Drug 
Extent of exposure will be summarized for each treatment arm based on the AT analysis set.  
Extent of exposure will be summarized for the following variables: 
• Duration (weeks): (date of last dose – date of first dose + 1) divided by 7 
• Number of cycles started (continuous and categorical) 
• Ofatumumab arm only: For each infusion (1-12), number and percent of subjects 
receiving the infusion 
• Relative dose intensity, defined as 100% x (total dose received)/ (planned 
cumulative dose for the duration of treatment) 
• Number and percentage of subjects with a dose reduction  
• duvelisib arm only: Number and percentage of subjects with a dose increase  
• Number and percentage of subjects with a dose interruption   


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• Number and percentage of subjects with study drug discontinued  
A by-subject listing will be presented for exposure to study drug. 
7.2 Efficacy Analyses 
For PFS, ORR, lymph node response rate, DOR and other endpoints derived from progression 
and/or response status, the primary analyses will be based on the endpoints derived from 
independent central review by Independent Review Committee (IRC). The endpoints derived 
from investigator assessment will be used in sensitivity analyses. 
All efficacy analyses will be based on the ITT analysis set unless stated otherwise.  If analyses 
are performed on more than one analysis set, the analyses on the ITT analysis set will be 
considered primary.   
For stratified analysis of any efficacy endpoint, the following algorithm will be used to pool 
strata if there is insufficient information in any stratum (ie, there are <6 subjects, or there is no 
event for a time-to-event endpoint, or all subject have the same outcome for a binary endpoint in 
a stratum). (1) Strata will be ranked from the smallest to the largest based on the number of 
subjects, and if there is a tie, based on the number of events or responses. If there is still a tie, 
based on the reverse order of strata as determined by the stratification factors and levels (see 
Section 3.3). (2) The smallest stratum will be compared with the criteria of insufficient 
information. (3) If there is insufficient information in the smallest stratum, that stratum will be 
pooled with the smallest of the adjacent strata, which are defined as strata having 2 of the 3 
stratification factors being at the same level as the smallest stratum. At the end of the three steps, 
the pooled stratum will replace the original two contributing strata.  If there is still insufficient 
information in any stratum, the three steps will be repeated with the last pooled stratum assuming 
the stratum label of the larger of the two contributing strata for the purpose of additional pooling. 
The resulting pooled strata will be the strata used for the stratified analysis described in this 
section. 
Listings of all efficacy endpoints will be provided.  
7.2.1 Analyses of Primary Endpoint 
7.2.1.1 Primary Analyses of PFS  
The primary analyses of PFS will use PFS based on IRC assessment in the ITT analysis set. 
Number of subjects with events, types of events (progression or death before progression), 
number of subjects censored, number of subjects for each reason of censoring, estimates and 
95% confidence intervals for the 25th percentile, median, and 75th percentile for PFS will be 
presented by treatment group. Probabilities of event free at selected time points may also be 
presented. 
A stratified log-rank test (one-sided) will be used to compare PFS of the duvelisib arm against 
PFS of the ofatumumab arm at the interim and final analyses with the overall one-sided 
significance level controlled at 0.025. The nominal p-value required for statistical significance at 


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an analysis will be calculated based on the numbers of PFS events at all preceding and current 
analyses. The HR (duvelisib/ofatumumab) and the corresponding 2-sided 95% CI will be 
estimated using a stratified Cox proportional hazards model. For both the stratified log-rank test 
and the stratified Cox model, the strata will be those used for stratified randomization, with 
potential pooling of strata specified earlier in Section 7.2.   
PFS will be plotted for each treatment group using the Kaplan-Meier method. The plot will 
include the number of subjects at risk for each treatment group over time. 
7.2.1.2 Sensitivity Analyses of PFS 
The following sensitivity analyses will be performed: 
• PFS based on investigator assessment: This endpoint will be analyzed using the same 
methods as the primary analyses described for PFS based on IRC assessment. In 
addition, the differences between investigator assessment and IRC assessment will be 
summarized. 
• Worst-case sensitivity analysis: Subjects who are alive and have not had documented 
progression by data cutoff and who are “lost to follow-up” (missing at least one 
disease assessment right before data cut off) will be treated as censored at their last 
adequate disease assessment if they are on the control arm (ofatumumab) and treated 
as having a PFS event at the time of the next scheduled assessment following the last 
adequate disease assessment if they are on the experimental arm (duvelisib). PFS 
based on IRC assessment with the above worst-case censoring/event rule will be 
analyzed using the same methods as the primary analyses for PFS. 
• Event-free survival (EFS): This is defined as time from randomization to the first 
documentation of PD as determined by IRC, start of new anticancer treatment or 
procedure, or death due to any cause.  The event/censoring method is presented in 
Appendix B. EFS will be analyzed using the same methods as the primary analyses 
for PFS except that the summary of types of events will include a category of new 
anticancer treatment or procedure. 
• Analysis using the PP analysis set. 
• Analysis using the AT analysis set. 
• Unstratified analyses: An unstratified log-rank test (one-sided) will be used to 
compare the two trreatment arms. An unstratified Cox regression (one-sided) will be 
used to estimate the hazard ratio (duvelisib/ofatumumab) with its 95% confidence 
interval. Other aspects of the analyses will be the same as the primary analyses of 
PFS. 
• Cox regression with baseline covariates: A stratified Cox regression will be used to 
test treatment effect on PFS, adjusting for demographic and other baseline 
characteristics. The strata will be those used for stratified randomization, with 
potential pooling of strata specified earlier in Section 7.2. A stepwise variable 
selection will be performed to choose the variables in the Cox regression. Candidate 
variables are age, gender, race, disease diagnosis (CLL or SLL), years from initial 


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diagnosis, months from most recent relapse/refractory diagnosis, stage at diagnosis, 
stage at baseline, and number of prior systemic therapies. PFS based on IRC 
assessment will be used for this analysis. 
7.2.1.3 Subgroup analyses of PFS 
Subgroup analyses for PFS will be performed using the subgroups specified in Section 6.5. The 
HR (duvelisib/ofatumumab) with its 95% CI will be calculated based on an unstratified Cox 
regression model for each subgroup. The hazard ratios and their 95% confidence intervals will be 
displayed for all subgroups graphically in a forest plot. 
7.2.2 Analyses of Secondary Efficacy Endpoints 
Of the secondary endpoints, ORR, Lymph Node Response Rate, OS, and Hematologic 
Improvement Rate are designated as key secondary efficacy endpoints. These endpoints will be 
tested for statistical significance under an overall one-sided significance level of 0.025 if and 
only if the primary endpoint is significant. Details of multiplicity adjustment are provided in 
Section 6.3. 
The analysis of another secondary efficacy endpoint, Duration of Response (DOR), will be 
descriptive only. No hypothesis testing will be performed.   
7.2.2.1 Overall Response Rate (ORR) 
The primary analyses of ORR will use ORR based on IRC assessment in the ITT analysis set. 
ORR will be derived from best overall response (BOR), which is defined as the best time point 
response that a subject achieves during the course of the study, with the response ranked 
according to the following order (from best to worst): CR>CRi>PR>PRwL>SD>PD  (CRi 
applies to CLL only).  In addition, the IRC may assign a timepoint response of unknown (UNK) 
due to missing, incomplete, or inadequate data; at baseline, the IRC may assign a timepoint 
response of no evidence of disease (NED) if both radiological and clinical data indicate no 
disease involvement; for a post-baseline timepoint, the IRC may also assign a timepoint response 
of not evaluable (NE) if no target lesions were identified at baseline and the radiological and 
clinical data at the post-baseline timepoint do not support the disease response of PD or UNK; 
these categories will be classified as OTHER in the summary.    
The estimated ORR (percent of subjects with a BOR of CR, CRi, PR or PRwL) and a 2-sided 
95% CI will be provided for each treatment arm.  Number and percent of subjects with BOR in 
each of the response categories (CR, CRi, PR, PRwL, SD, PD, OTHER) will also be presented 
by treatment arm.  All subjects in the analysis set will be included in the denominator in the 
calculation of the percentage for each response category or ORR.  
ORR will be analyzed using the Cochran-Mantel-Haenszel (CMH) test (one-sided, see Appendix 
C) to compare the two treatment groups. The strata for the test will be those used for stratified 
randomization, with potential pooling of strata specified earlier in Section 7.2. The odds ratio 
and its 95% CI will be estimated. 


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The following sensitivity analyses will be performed: 
• ORR based on investigator assessment 
• Overall Confirmed Response Rate (OCRR), with overall confirmed response (based on 
independent review) defined as best confirmed response (time between response and 
confirmation must be ≥8 weeks in duration) of CR, CRi, PR, or PRwL, according to the 
IWCLL or revised IWG Response Criteria, with modification for treatment-related 
lymphocytosis 
• Overall Response Rate without PRwL: with overall response (based on independent 
review) defined as best response of complete response/remission (CR), CR with 
incomplete marrow recovery (CRi), partial response/remission (PR) 
• Overall Confirmed Response Rate without PRwL 
• Overall Response Rate in subset of subjects with baseline assessment other than UNK 
and NED. This analysis will be performed if there are at least 5% subjects with baseline 
assessment of UNK or NED 
• Overall Response Rate in subset of subjects who are on treatment for 60 days or longer 
• Analysis using the PP analysis set 
• Analysis using the AT analysis set 
Subgroup analyses will be performed for ORR using the subgroups specified in Section 6.5.  
The odds ratio (duvelisib/ofatumumab) with its 95% CI will be calculated for each subgroup 
based on unstratified test. The odds ratios and their 95% confidence intervals will be displayed 
for all subgroups graphically in a forest plot. 
7.2.2.2 Lymph Node Response Rate 
The primary analyses of lymph node response rate will be based on IRC assessment in the ITT 
analysis set. The number of subjects with lymph node response, estimated lymph node response 
rate, and a 2-sided 95% CI will be provided for each treatment arm. 
Lymph node response rate will be analyzed using the CMH test (one-sided) to compare the two 
treatment groups. The strata for the test will be those used for stratified randomization, with 
potential pooling of strata specified earlier in Section 7.2. 
A sensitivity analysis will be performed using lymph node response rate based on investigator 
measurements. 
7.2.2.3 Overall Survival (OS) 
The primary analyses of OS will be based on the ITT analysis set.  
Subjects without documentation of death at the time of the data cutoff for analysis will be 
censored at the date the subject was last known to be alive, or the data cutoff date, whichever is 
earlier.  A stratified one-sided log-rank test will be used to compare OS between the 2 treatment 
groups.  The HR along with the 95% CI will be estimated using a stratified Cox model. For both 
the stratified log-rank test and the stratified Cox model, the strata will be those used for stratified 


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randomization, with potential pooling of strata specified earlier in Section 7.2. A Kaplan-Meier 
plot for OS will be presented by treatment group. Estimates and 95% confidence intervals for the 
25th percentile, median, and 75th percentile for OS will be presented by treatment group (if 
estimable).  Probabilities of survival at selected time points may also be presented. 
A majority of subjects can be expected to take subsequent anticancer therapy, especially after 
disease progression. To adjust for the effects of subsequent therapy, the following sensitivity 
analysis may be performed: 
1. Primary analyses except additional censoring at the start date of subsequent 
therapy 
2. Rank preserving structural failure time (RPSFT) analysis 
3. Inverse probability of censoring weighted (IPCW) analysis 
The following sensitivity analyses will be performed: 
• Analysis using the PP analysis set. 
• Analysis using the AT analysis set.  
• Unstratified analyses: An unstratified log-rank test (one-sided) will be used to 
compare the two treatment arms. An unstratified Cox regression (one-sided) will be 
used to estimate the hazard ratio (duvelisib /ofatumumab) with its 95% confidence 
interval.  
Subgroup analyses for OS will be performed using the subgroups specified in section 6.5. The 
HR (duvelisib /ofatumumab) with its 95% CI will be calculated based on an unstratified Cox 
regression model for each subgroup. The HRs and their 95% CIs will be displayed for all 
subgroups graphically in a forest plot. 
OS follow-up time, defined as time from randomization to the date of last procedure or 
assessment (including telephone interview), will be summarized by treatment arm and for the 
two treatment arms combined (total) using the reverse Kaplan-Meier method, which applies 
Kaplan-Meier method to the OS data with the same event/censoring time as the primary OS 
analyses while reversing event/censoring indicator. The 25th percentile, median, and 75th 
percentile ofOS follow-up time will be presented.   
7.2.2.4 Hematologic Improvement Rate 
A subject with a hematologic improvement is one who consistently met the criteria of an 
improvement in neutrophil count, hemoglobin or platelet count for a period of at least 60 days 
during which the subject did not have a transfusion or exogenous cytokines. Missing data or 
missing scheduled assessments during a potential 60-day hematologic improvement episode will 
result in categorization of not having a hematologic improvement.  
The number of subjects with hematologic improvement, estimated hematologic improvement 
rate, and a 2-sided 95% CI will be provided for each treatment arm. 


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Hematologic improvement rate will be compared between treatment groups using one-sided 
CMH test. The strata for the test will be those used for stratified randomization, with potential 
pooling of strata specified earlier in Section 7.2.  
7.2.2.5 Duration of Response (DOR) 
DOR will be presented using the Kaplan-Meier method for each treatment arm based on all 
randomized subjects with a documentation of response (i.e., CR, CRi, PR, or PRwL) as 
determined by IRC assessment. The censoring method will be the same as that for the primary 
endpoint (see Appendix A).  The Kaplan-Meier plot for DOR will be presented by treatment 
group. Estimates and 95% confidence intervals for the 25th percentile, median, and 75th 
percentile for DOR will be presented by treatment group (if estimable). No treatment comparison 
will be performed.  
7.2.3 Analyses of Exploratory Efficacy Endpoints 
7.2.3.1 Improvement in Disease-Related Symptoms 
Disease-related symptoms of fever, weight loss, and drenching night sweats will be assessed as 
present or absent at each timepoint. Improvement in each of the three disease-related symptoms 
from baseline will be analyzed separately.  The summary will display by treatment arm the 
proportion of subjects with an improvement while on treatment. Descriptive analysis of 
improvement in these disease-related symptoms will also be presented over the course of the 
study (eg, for each scheduled assessment) by treatment arm.  
The disease-related symptom of fatigue will be measured by the ECOG performance status. 
Summary statistics will be provided by treatment arm for the ECOG score and the change from 
baseline at each timepoint.  
7.2.3.2 Minimal Residual Disease  
MRD status for subjects with a response of CR or CRi will be determined using flow cytometry 
from a central lab. MRD will be classified as positive or negative. The estimated rates of subjects 
with negative MRD and their 95% confidence intervals in subjects with a response of CR or CRi 
will be provided for each treatment arm.  
7.2.3.3 Time To Response (TTR) 
TTR will be presented for each treatment arm based on all randomized subjects with a 
documentation of response (i.e., CR, CRi, PR, or PRwL). Summary statistics and a 2-sided 
confidence interval for median TTR will be provided by treatment arm. No treatment comparison 
will be performed.  
7.3 Safety Analyses 
All safety analyses will be performed using the AT analysis set. 


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7.3.1 Adverse Events  
Adverse events will be coded using MedDRA Version 16.1 or higher. The Grade of the AE will 
be assessed according to the NCI-CTCAE Version 4.03. If an AE is not included in the NCI-
CTCAE Version 4.03, the Grade of the AE will be assessed according to the protocol, Section 
8.2.1.2. 
The summary of AEs will be focused on treatment-emergent AEs. A treatment-emergent AE 
(TEAE) is defined as any AE that emerges or worsens in the period from the first dose of study 
treatment to 30 days after the last dose of study treatment.  The onset date of an AE will be 
compared to the first dose date and the last dose date plus 30 days to determine whether the AE 
is treatment-emergent or not.  If the onset date of an AE is completely or partially missing, refer 
to Section 6.2.1 for the algorithm to determine whether an AE is treatment emergent. 
TEAEs will be summarized for each treatment arm by MedDRA system organ class (SOC) and 
preferred term (PT), or PT only.  For summary tables by SOC and PT, SOC will be sorted 
alphabetically and PT will be sorted by decreasing frequency in the duvelisib arm within each 
SOC.  For summary tables by PT only, PT will be sorted by decreasing frequency in the 
duvelisib arm.   
If multiple TEAEs of the same PT occur within a subject, only the maximum grade observed for 
this PT will be used in summary of TEAEs by grade, the subject will be counted only once in the 
number of subjects for this PT and only once for the number of subjects for the SOC to which 
this PT belongs.  
An overview TEAE summary table will be provided, which will include the number of subjects 
with AEs in selected categories. In addition, TEAEs will be summarized for the following 
categories, and will be tabulated by SOC and PT, unless otherwise specified.  
• 
Treatment-emergent AEs (All Causalities) 
• 
Treatment-emergent AEs (Treatment-Related) 
• 
Treatment-emergent AEs (All Causalities, by maximum grade) 
• 
Treatment-emergent AEs (Treatment-Related, by maximum grade) 
• 
Grade 3 or higher treatment-emergent AEs (All Causalities) 
• 
Grade 3 or higher treatment-emergent AEs (Treatment-Related) 
• 
Treatment-emergent SAE (All Causalities) 
• 
Treatment-emergent SAE (Treatment-Related) 
• 
Treatment-emergent AEs resulting in discontinuation of study drug (All Causalities) 
• 
Treatment-emergent AEs resulting in dose hold (All Causalities) 
• 
Treatment-emergent AEs resulting in dose reduction (All Causalities) 
• 
Treatment-emergent AEs resulting in dose hold or reduction (All Causalities) 


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• 
Treatment-emergent AEs resulting in discontinuation of study drug (Treatment-
Related) 
• 
Treatment-emergent AEs resulting in death (All Causalities) 
• 
Treatment-emergent AEs resulting in death (Treatment-Related) 
• 
Treatment-emergent AEs by PT (All Causalities) 
• 
Treatment-emergent AEs by PT (AEs with onset date within 24 weeks after the first 
dose of study treatment; All Causalities) 
• 
Grade 3 or higher treatment-emergent AEs by PT (All Causalities) 
• 
Grade 3 or higher treatment-emergent AEs by PT (AEs with onset date within 24 
weeks after the first dose of study treatment; All Causalities) 
• 
Treatment-emergent SAEs by PT (All Causalities) 
• 
Treatment-emergent SAEs by PT (Treatment-Related) 
• 
Treatment-emergent AEs reported in ≥5% of subjects and occurred at ≥2% higher 
incidence in subjects receiving duvelisib (All Causalities) 
A by-subject listing of the following AE categories will be presented.  
• 
All AEs (TEAEs will be flagged) 
• 
All SAEs (TEAEs will be flagged) 
• 
Treatment-emergent AEs resulting in dose hold  
• 
Treatment-emergent AEs resulting in dose reduction 
• 
Treatment-emergent AEs resulting in discontinuation of study drug 
• 
Treatment-emergent AEs resulting in death 
Treatment-emergent AEs (All Causalities) and Treatment-emergent AEs (Treatment-Related) 
will also be tabulated in each subgroup specified in Section 6.5.  
 
 
7.3.2 Laboratory Data 
Laboratory tests will be reported separately for hematology and blood chemistry. 
For the purposes of presentation in both tables and listings, the following laboratory test results 
will be converted to the International System of Units (SI) before presentation: sodium, 
potassium, chloride, bicarbonate (or CO2), albumin, total protein, creatinine, uric acid, calcium, 
phosphorus, magnesium, glucose, total and direct bilirubin, and alkaline phosphatase, red blood 
cell (RBC) count, hemoglobin, hematocrit, platelets, white blood cell count with 5-part 
differential performed manually or by flow cytometry (lymphocytes, neutrophils, monocytes, 
basophils, and eosinophils), etc.  


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Lab tests performed after the start of the first dose of study treatment, up to 30 days from the last 
dose, will be considered treatment-emergent. Only treatment-emegent lab tests will be included 
in the analyses in this section. 
 
If a laboratory test value is reported using a non-numeric qualifier (e.g., less than [<] a certain 
value, or greater than [>] a certain value), the given numeric value will be used in the summary 
statistics, ignoring the non-numeric qualifier. 
For laboratory tests with NCI-CTCAE grades, a shift table from baseline grade to the maximum 
post-baseline grade will be provided. Laboratory tests with bi-directional grades (e.g., 
Hyperglycemia and Hypoglycemia) will be presented separately for each direction within the 
shift table.  
Listings will be provided for all laboratory test results and for laboratory test results grade 3 and 
higher.  A listing of subjects with ALT or AST >3xULN with simultaneous total bilirubin 
>2xULN will be presented, where ULN stands for upper limit of normal. The elevations of 
ALT/AST and total bilirubin must occur within 2 days of each other. 
7.3.3 Vital Signs 
The actual values of vital sign parameters, including temperature, heart rate, weight and systolic 
and diastolic blood pressure, will be presented in a by-subject listing.  
7.3.4 Electrocardiogram (ECG) 
A by-subject listing will be presented for baseline ECGs and post-baseline unscheduled ECGs (if 
any).  
7.3.5 Concomitant Medications and Procedures 
Please refer to Section 7.1.7 for the definition and summary of concomitant medications. 
Concomitant procedures will not be summarized. A by-subject listing will be presented. 
 
7.3.6 Deaths 
On-treatment deaths are defined as deaths that occur within 30 days of the last dose of duvelisib. 
Deaths on treatment and causes for deaths occurring on-treatment, and deaths during follow-up 
will be summarized.  
A by-subject listing of deaths on study will be presented. 
7.4 Quality of Life Instruments 
Analyses of the QoL instruments (EQ-5D and FACIT-F) will be performed on the ITT analysis 
set. Additional analyses may be considered as needed.  


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7.4.1 EQ-5D 
The EQ-5D contains a descriptive system with one response for each of 5 dimensions (Mobility, 
Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression). The first response is 
coded as 1 (indicating no problems), the second response is coded as a 2 (indicating some 
problems), and the third response is coded as a 3 (indicating extreme problems). Ambiguous 
responses (eg, more than one response in a dimension) are treated as missing values. The EQ-5D 
also contains a Visual Analog Scale (VAS) for health state ranging from 0 to 100, where 0 
represents worst imaginable health state and 100 represents the best imaginable health state.  
For each dimension of the descriptive system, the number and percentage of subjects with no 
problems, some problems, and extreme problems will be reported at each visit.  
Summary statistics for the VAS of health state and the change from baseline will be reported for 
each visit.   
7.4.2 FACIT-F 
The FACIT-F contains 5 subscales, Physical Well-Being, Social/Family Well-Being, Emotional 
Well-Being, Functional Well-Being, and Fatigue (Additional Concerns on eCRF). Each subscale 
contains multiple items, and each item has a response of 0 to 4. Scores will be computed for each 
subscale, as well as for the FACIT-F Trial Outcome Index, FACT-G total score, and the FACIT-
F total score.  
The Physical Well-Being subscale contains 7 items. To compute the subscale score, compute the 
item score by subtracting each item response from 4 (item score = 4 – item response), sum the 
item scores, multiply the sum by 7 and divide by the number of items answered. At least 4 
questions must be answered. If fewer than 4 questions are answered, then the subscale score will 
be missing. The Physical Well-Being score ranges from 0 to 28 with higher scores representing 
better quality of life. 
The Social/Family Well-Being score contains 7 questions. To compute the subscale score, sum 
the item responses, multiply the sum by 7 and divide by the number of items answered. At least 4 
questions must be answered. If fewer than 4 questions are answered, then the subscale score will 
be missing. The Social/Family Well-Being score ranges from 0 to 28 with higher scores 
representing better quality of life. 
The Emotional Well-Being subscale contains 6 items. To compute the subscale score, compute 
the item score first. For items 1, 3, 4, 5, and 6, subtract each item response from 4 (item score = 4 
– item response). For item 2, the item score is the same as the item response (no subtraction is 
needed). Sum the item scores, multiply the sum by 6 and divide by the number of items 
answered to compute the subscale score. At least 3 questions must be answered. If fewer than 3 
questions are answered, then the subscale score will be missing. The Emotional Well-Being 
score ranges from 0 to 24 with higher scores representing better quality of life. 
The Functional Well-Being score contains 7 questions. To compute the subscale score, sum the 
item responses, multiply the sum by 7 and divide by the number of items answered. At least 4 
questions must be answered. If fewer than 4 questions are answered, then the subscale score will 


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be missing. The Functional Well-Being score ranges from 0 to 28 with higher scores 
representing better quality of life. 
The Fatigue subscale contains 13 items. To compute the subscale score, compute the item score 
first. For all items except An5 and An7, subtract each item response from 4 (item score = 4 – 
item response). For items An5 and An7, the item score is the same as the item response (no 
subtraction is needed). Sum the item scores, multiply the sum by 13 and divide by the number of 
items answered to compute the subscale score. At least 7 questions must be answered. If fewer 
than 7 questions are answered, then the subscale score will be missing. The Fatigue score ranges 
from 0 to 52 with higher scores representing better quality of life. 
To derive the FACIT-F Trial Outcome Index, sum the subscale scores for Physical Well-Being, 
Functional Well-Being, and Fatigue. If any of these subscale scores is missing, the score for the 
FACIT-F Trial Outcome Index will be missing. The score ranges from 0 to 108.  
To derive the FACT-G score, sum the subscale scores for Physical Well-Being, Social/Family 
Well-Being, Emotional Well-Being, and Functional Well-Being. If any of these subscale scores 
is missing, the FACT-G score will be missing. The score ranges from 0 to 108. 
To derive the FACIT-F total score, sum all 5 subscale scores. If any subscale score is missing, 
the FACIT-F total score will be missing. The score ranges from 0 to 160. 
For each of the five subscale scores and for each of the FACIT-F Trial Outcome Index, the 
FACT-G score, and the FACIT-F total score, summary statistics for the actual values and 
changes from Baseline will be reported at each visit.  
7.5 Pharmacokinetic Analyses 
Plasma samples will be analyzed for duvelisib and IPI-656 (metabolite) concentrations using a 
validated high performance liquid chromatography-tandem mass spectrometry (LC/MS/MS) 
method.  A listing of the duvelisib and IPI-656 concentrations will be provided; the sample 
collection date and time, and the date, time and amount of the preceding duvelisib dose 
administration will be included in the listing. 
The PK data collected will be analyzed by standard population PK methods, using appropriate 
software. Analysis of exposure-response relationships for efficacy and safety endpoints will be 
conducted. If there is only a limited amount of plasma concentration data from this study, the 
data may be pooled with the results of other studies to perform the population PK and exposure-
response analyses.  Further details on these analyses will be outlined in a separate analysis plan. 
Results of the population PK and exposure-response analysis will be summarized in a separate 
technical report. 
7.6 Biomarker Analyses 
The following exploratory analyses may or may not be presented formally. If presented, they will 
be limited to biomarkers for which data from a sufficient number of subjects are available. 


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Further details on these analyses may be outlined in a separate analysis plan, and results may be 
summarized in a separate techinical report. 
7.6.1 Pharmacodynamic and Potentially Predictive Biomakers 
The relationship between tumor genomics, gene expression, protein expression, and clinical 
endpoints may be explored as follows: 
• 
Evaluation of serum biomarkers,blood immunophenotype and tumor biomarkers for 
relationships with duvelisib clinical activity and safety 
• 
Evaluation of tumor genomic features (eg, cytogenetics, FISH, DNA sequence 
variation, DNA copy number variation, and/or RNA expression) for relationships 
with duvelisib clinical activity 
• 
Evaluation of the relationship between serum and/or tumor biomarkers and disease 
progression of duvelisib and ofatumumab 
7.6.2 Pharmacogenomics 
DNA may be extracted from the pharmacogenomics sample in order to evaluate a subject’s 
germline DNA.  This sample may be used to explore the following: 
• Evaluate the relationship between germline DNA sequence variations and PK of 
duvelisib 
• Evaluate germline DNA as a control to verify that tumor sequence variations are 
somatic mutations 
 
 
 


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8 CHANGES IN PLANNED ANALYSES  
8.1 Changes in Planned Analyses from Protocol Amendment 1 to SAP V1.0  
There are no changes from Protocol Amendment 1. More details are provided in the SAP. 
8.2 Changes in Planned Analyses from SAP V1.0 to SAP V2.0 
The main changes from SAP V1.0 to SAP V2.0 are described below. 
1. Section 3.5.2 Clarification 
Old (V1.0): The second analysis of OS will be performed at the PFS final analysis, which is 
expected to happen after 185 PFS events have occurred, or approximately 27.5 months after 
the first subject is randomized. 
New (V2.0): The second interim analysis of OS will be performed at the PFS final 
analysis, which is to happen after 185 PFS events have occurred. If the planned final 
analysis of PFS is not performed due to early stop for efficacy, then the second interim 
analysis of OS will be conducted approximately one year after the first interim analysis of 
OS. 
2. New censoring method for event-free survival were specified.  
3. Prior irradiation and prior surgery were removed from prior therapy summary. 
The following additional analyses/summaries have been added to this version of the SAP: 
1. Analysis of ORR of subjects who are on treatment for 60 days or longer 
2. Median time to OS follow up  
3. Time to response 
4. Treatment-emergent AEs reported in ≥5% of CLL/SLL subjects and occurred at ≥2% 
higher incidence in subjects receiving duvelisib (All Causalities) 
5. Grade 3 or higher treatment-emergent AEs reported in ≥5% of CLL/SLL subjects and 
occurred at ≥2% higher incidence in subjects receiving duvelisib (All Causalities) 
6. Treatment-emergent AEs by PT (All Causalities, AE onset date within 24 weeks after 
the first dose of study treatment) 
7. Treatment-emergent AEs resulting in discontinuation of study drug (Treatment-
Related) 
8. Treatment-emergent AEs resulting in death (Treatment-Related) 
9. Treatment-emergent SAEs by PT (All Causalities). 
10. Treatment-emergent SAEs by PT (Treatment-Related) 
11. Deaths on treatment 
12. Deaths during follow-up 
13. A by-subject listing of treatment-emergent AEs resulting in dose hold  


IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
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14. A by-subject listing of treatment-emergent AEs resulting in dose reduction 
15. A by-subject listing of deaths on study 
16. A summary table and a listing of the discrepancies in data for stratification factors 
between those captured in the IRT and those reported on the eCRF  
17. Comparision of del[17p] values captured from central lab and local lab. 
18. The following biomarkers will be summarized as baseline characteristics:  
• del[17p] (captured from central lab, presence vs absence vs indeterminate) 
• del[17p] (captured from local lab, presence vs absence vs indeterminate) 
• del[17p] and/or TP53 mutation (del[17p] and/or TP53 mutation, del[17p] 
captured from central lab, either or both present vs neither present vs 
indeterminate) 
• del[17p] and TP53 mutation (del[17p] and TP53 mutation,del[17p] 
captured from central lab, both present vs either vs neither present vs 
indeterminate) 
• TP53 mutation (presence vs absence vs indeterminate) 
• IgHV status (mutated vs unmutated vs indeterminate) 
• CD38 (Positive (≥30%) vs Negative vs indeterminate) 
• ZAP70 (Positive (>19%) vs Negative (<=19%) vs indeterminate) 
19. Subgroup analyses of PFS, OS and ORR based on the following factors: 
• Time from last dose of most recent prior anti-cancer therapy to 
randomization <12 months: yes vs no  
• del[17p] (captured from central lab) or TP53 mutation (either or both 
present vs neither present ) 
 
 
 
 


IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
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CONFIDENTIAL 
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9 REFERENCES 
1 O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 
1979; 35:549-556. 
 
2 Robins JM. Information recovery and bias adjustment in proportional hazard 
regression analysis of randomized trials using surrogate markers. Proceedings of the 
Biopharmaceutical Section, American Statistical Association 1993; pp. 24-33.  
 
3 Robins JM, Finkelstein D.  Correcting for Non-compliance and dependent censoring 
in an AIDS clinical trial with inverse probability of censoring weighted (IPCW) log-
rank tests. Biometrics, 2000; 56(3):779-788. 
 
4 Robins JM, Tsiatis, AA. Correcting for noncompliance in randomized trials using 
rank preserving structural failure time models. Communications in Statistics, 1991; 
20, 2609-2631. 
 
 
 


IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Version 2.0 (24 Nov 2015) 
CONFIDENTIAL 
Page 39 of 41 
10 APPENDICES 
10.1 Appendix A: Primary PFS Event/Censoring Method 
Censoring of PFS will be performed as detailed in the table below.  
 
Situation 
Date of Event or 
Censoring 
Outcome 
No adequate baseline disease status assessment  Date of randomization 
Censored 
No adequate post-baseline disease status 
assessment unless death occurs prior to first 
post-baseline assessment 
Date of randomization + 1 
Censored 
No documented progression or death before 
data cutoff 
Date of last adequate 
disease status assessment 
Censored 
Documented progression with ≤1 missing 
scheduled disease status assessment before 
progression 
Date of the earliest 
assessment that results in a 
finding of unequivocal 
progression 
Event 
Death before progression being documented 
with ≤1 missing scheduled disease status 
assessment before death 
Date of death 
Event 
Documented progression or death following a 
long gap between adequate disease status 
assessments (eg, 2 or more consecutive missed 
scheduled disease status assessments)  
Date of last adequate 
disease status assessment 
before the gap 
Censored 
New anticancer treatment or procedure started 
before documented progression 
Date of last adequate 
disease status assessment 
Censored 
Note: Disease status assessment includes CT scans (chest, abdomen and pelvis), bone marrow aspirate and/or biopsy 
(may not be required of all subjects at all scheduled disease status assessments), CBC and differential count, focused 
physical examination, disease related constitutional symptoms for disease assessment, and ECOG performance 
status. An adequate baseline disease status assessment is any baseline disease status assessment that include WBC 
counts and CT scans. An adequate post-baseline disease status assessment is any disease status assessment for which 
a disease status (eg, CR, CRi, PR, PRwL, SD, and PD) is arrived per protocol-defined criteria by the IRC (for IRC 
assessment) or investigator (for investigator assessment).   


IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
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10.2 Appendix B: Event-Free Survival (EFS) Event/Censoring Method 
Situation 
Date of Event or 
Censoring 
Outcome 
No adequate baseline disease status assessment  Date of randomization 
Censored 
No adequate post-baseline disease status 
assessment unless death or new anticancer 
treatment/procedure occurs prior to first post-
baseline assessment 
Date of randomization + 1 
Censored 
No documented progression, death or new 
anticancer treatment/procedure started before 
data cutoff 
Date of last adequate 
disease status assessment 
Censored 
Documented progression with ≤1 missing 
scheduled disease status assessment before 
progression, and no new anticancer treatment/ 
procedure started before documented 
progression 
Date of the earliest 
assessment that results in a 
finding of unequivocal 
progression 
Event 
Death before progression being documented 
with ≤1 missing scheduled disease status 
assessment before death, and no new 
anticancer treatment/procedure started before 
death 
Date of death 
Event 
Documented progression, death or new 
anticancer treatment/procedure following a 
long gap between adequate disease status 
assessments (eg, 2 or more consecutive missed 
scheduled disease status assessments)  
Date of last adequate 
disease status assessment 
before the gap 
Censored 
New anticancer treatment/procedure started 
before documented progression with ≤1 
missing scheduled disease status assessment 
prior to new anticancer treatment/procedure 
Start date of new anticancer 
treatment/procedure 
Event 
 
 
 
 
 


IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
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10.3 Appendix C: One-Sided Cochran–Mantel–Haenszel (CMH) Test 
 
The Cochran–Mantel–Haenszel (CMH) test compares binary responses of two 
treatment groups, adjusting for stratification factors. In the CMH test, the data are 
arranged in a series of associated 2 × 2 contingency tables, the null hypothesis is that the 
observed response is independent of the treatment used in any 2 × 2 contingency table. 
 
Let 
hij
O
 be the observed frequency of treatment i (i=1 or 2) with outcome j (j= 1 or 2) in 
stratum h and 
hij
E
be the expected frequency of treatment i (i=1 or 2) with outcome j (j= 
1 or 2) in stratum h, where 
 
22
21
12
11
2
1
2
1
)
(
)
(
h
h
h
h
j
h
j
h
hi
hi
hij
O
O
O
O
O
O
O
O
E
+
+
+
+
⋅
+
=
 
 
Also, let 
hij
P
be the probability of outcome being j given treatment being i (i=1 or 2, j= 1 
or 2) in stratum h. To test the following hypothesis, 
 
  
 
21
11
0 :
h
h
P
P
H
=
 for all ℎ∈{1, … , 𝐻𝐻}   
versus   
21
11
1 :
h
h
P
P
H
>
 for at least one ℎ∈{1, … , 𝐻𝐻} 
 
The one-sided Cochran-Mantel-Haenszel Test Statistics is constructed as: 
 
Z
V
E
O
Z
H
h
h
h
CMH
~
)
(
11
1
11
11
∑
=
−
=
 
 
Where 
 
 
∑
∑
=
=
−
+
+
+
•
=
−
=
H
h
h
h
h
h
h
h
H
h
h
h
O
O
O
O
E
E
E
O
Var
V
1
22
21
12
11
22
11
1
11
11
11
1
))
(
(
 
 
The test statistic 
CMH
Z
  will be compared with standard normal distribution to 
obtain p-value of the CMH test. 


IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
 
STATISTICAL ANALYSIS PLAN 
 
Protocol IPI-145-07 
A Phase 3 Study of IPI-145 versus Ofatumumab in Subjects with Relapsed or 
Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma 
 
 
 
 
 
 
 
 
 
 
 
This statistical analysis plan contains confidential information and is the proprietary 
property of Infinity Pharmaceuticals, Inc. This document may not be copied or 
made available for review by an unauthorized person or firm without the prior 
written authorization of Infinity Pharmaceuticals, Inc. 
 
 
Protocol Version: 
Amendment 1 
 
Type of Analysis 
Plan: 
Interim and Final Analysis 
 
Version: 
1.0 
 
Date: 
2 Oct 2014 
 
Author: 
Shijie Tang, PhD 
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Page 1 of 37 




IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
 
 
DOCUMENT HISTORY 
 
Version 
Date 
Author(s) 
Brief Summary of Changes 
1.0 
2 Oct 2014 
Shijie Tang 
Original 
 
 
 
 
 
 
 
 
 
 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
 
Table of Contents 
 
LIST OF ABBREIVATIONS ......................................................................................................... 7 
1 
INTRODUCTION ................................................................................................................ 10 
2 
STUDY OBJECTIVES ......................................................................................................... 10 
2.1 
Primary Objective .......................................................................................................... 10 
2.2 
Secondary Objectives ..................................................................................................... 10 
2.3 
Exploratory Objectives ................................................................................................... 10 
3 
STUDY DESIGN.................................................................................................................. 11 
3.1 
Overview ........................................................................................................................ 11 
3.2 
Sample Size Consideration............................................................................................. 11 
3.3 
Randomization ............................................................................................................... 12 
3.4 
Blinding .......................................................................................................................... 12 
3.5 
Planned Analyses ........................................................................................................... 12 
3.5.1 
Planned Analyses for PFS ....................................................................................... 13 
3.5.2 
Planned Analyses for OS ........................................................................................ 13 
4 
ANALYSIS SETS ................................................................................................................ 14 
4.1 
Intent-To-Treat (ITT) Analysis Set ................................................................................ 14 
4.2 
All-Treated (AT) Analysis Set ....................................................................................... 14 
4.3 
Per-Protocol (PP) Analysis Set ...................................................................................... 14 
5 
STUDY ENDPOINTS .......................................................................................................... 15 
5.1 
Primary Endpoint ........................................................................................................... 15 
5.2 
Secondary Endpoints ...................................................................................................... 15 
5.3 
Exploratory Endpoints.................................................................................................... 15 
6 
GENERAL STATISTICAL METHODS AND DATA HANDLING ................................. 17 
6.1 
General Methods ............................................................................................................ 17 
6.2 
Handling of Missing Data .............................................................................................. 17 
6.2.1 
Handling of Missing Dates/Months/Years for Adverse Events .............................. 17 
6.2.2 
Handling of Missing Dates/Months/Years for Concomitant Medications ............. 18 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
6.2.3 
Handling of Missing Dates/Months/Years for Disease History and Prior Therapies
 
18 
6.3 
Multiple Comparisons/Multiplicity Adjustment ............................................................ 18 
6.4 
Adjustments for Covariates ............................................................................................ 19 
6.5 
Subgroups ....................................................................................................................... 19 
6.6 
Visit Windows ................................................................................................................ 19 
6.7 
Unscheduled Visits ......................................................................................................... 19 
6.8 
Baseline Values .............................................................................................................. 20 
6.9 
Computing and Coding Standards ................................................................................. 20 
7 
STATISTICAL ANALYSES ............................................................................................... 21 
7.1 
Study Subjects ................................................................................................................ 21 
7.1.1 
Disposition of Subjects ........................................................................................... 21 
7.1.2 
Protocol Deviations ................................................................................................. 21 
7.1.3 
Demographic and Other Baseline Characteristics .................................................. 21 
7.1.4 
Disease History ....................................................................................................... 21 
7.1.5 
Prior Therapies ........................................................................................................ 22 
7.1.6 
Medical History ...................................................................................................... 22 
7.1.7 
Prior and Concomitant Medications ....................................................................... 22 
7.1.8 
Exposure to Study Drug .......................................................................................... 23 
7.2 
Efficacy Analyses ........................................................................................................... 23 
7.2.1 
Analyses of Primary Endpoint ................................................................................ 24 
7.2.2 
Analyses of Secondary Efficacy Endpoints ............................................................ 25 
7.2.3 
Analyses of Exploratory Efficacy Endpoints .......................................................... 28 
7.3 
Safety Analyses .............................................................................................................. 29 
7.3.1 
Adverse Events ....................................................................................................... 29 
7.3.2 
Laboratory Data ...................................................................................................... 30 
7.3.3 
Vital Signs ............................................................................................................... 31 
7.3.4 
Electrocardiogram (ECG) ....................................................................................... 31 
7.3.5 
Concomitant Medications and Procedures.............................................................. 31 
7.4 
Quality of Life Instruments ............................................................................................ 31 
7.4.1 
EQ-5D ..................................................................................................................... 31 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
7.4.2 
FACIT-F ................................................................................................................. 31 
7.5 
Pharmacokinetic Analyses ............................................................................................. 33 
7.6 
Biomarker Analyses ....................................................................................................... 33 
7.6.1 
Pharmacodynamic and Potentially Predictive Biomakers ...................................... 33 
7.6.2 
Pharmacogenomics ................................................................................................. 33 
8 
CHANGES IN PLANNED ANALYSES FROM PROTOCOL .......................................... 34 
9 
REFERENCES ..................................................................................................................... 35 
10 APPENDICES ...................................................................................................................... 36 
 
 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
LIST OF ABBREIVATIONS 
Abbreviation 
Description 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
AT 
All-Treated  
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BID 
Twice a day 
BOR 
Best Overall Response 
BUN 
Blood Urea Nitrogen 
CI 
Confidence Interval 
CLL 
Chronic Lymphocytic Leukemia 
CMH 
Cochran–Mantel–Haenszel 
CO2 
Bicarbonate 
CR 
Complete Response 
CRi 
Complete Response with Incomplete Marrow Recovery 
CS 
Abnormal and Clinically Significant 
CTCAE 
Common Terminology Criteria for Adverse Events 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
Electronic Case Report Form 
eDISH 
Evaluation of Drug Induced Serious Hepatotoxicity 
EQ-5D 
European Quality of Life-5 Dimensions 
FACIT-F 
Functional Assessment of Chronic Illness Therapy-Fatigue 
FACT-G 
The Functional Assessment of Cancer Therapy - General 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Abbreviation 
Description 
HR 
Hazard Ratio 
IDMC 
Independent Data Monitoring Committee 
IPI-145 
(S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-
phenylisoquinolin-1(2H)-one 
IPCW 
Inverse Probability of Censoring Weighted 
IRC 
Independent Central Review 
IRT 
Interactive Response Technology 
ITT 
Intent-To-Treat 
IV 
Intravenous 
IWCLL 
International Workshop on Chronic Lymphocytic Leukemia 
IWG 
International Working Group 
LC/MS/MS 
Liquid Chromatography-tandem Mass Spectrometry 
LDH 
Lactate Dehydrogenase 
LFT 
Liver Function Test 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEOI 
Medical Events of interest 
MMRM 
Mixed Effect Repeated Measures 
MRD 
Minimal Residual Disease 
NCI 
National Cancer Institute 
NCS 
Abnormal but Not Clinically Significant 
NED 
No Evidence of Disease 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetics 
PP 
Per-Protocol 
PR 
Partial Response 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Abbreviation 
Description 
PRwL 
PR with Lymphocytosis 
PT 
Preferred Term 
QoL 
Quality of Life 
RBC 
Red Blood Cell 
RPSFT 
Rank Preserving Structural Failure Time 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SI 
Standard International System of Units 
SLL 
Small Lymphocytic Lymphoma 
SOC 
System Organ Class 
SPD 
Sum of Products 
TEAE 
Treatment Emergent Adverse Event 
UNK 
Unknown 
VAS 
Visual Analog Scale 
WHO 
World Health Organization 
WHO-DD 
World Health Organization Drug Dictionary 
 
 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
1 INTRODUCTION 
This is the statistical analysis plan (SAP) for study IPI-145-07, A phase 3 study of IPI-145 versus 
ofatumumab in subjects with relapsed or refractory chronic lymphocytic leukemia/small 
lymphocytic lymphoma. This SAP is prepared according to Amendment 1 of the protocol, dated 
02 April 2014. 
2 STUDY OBJECTIVES 
2.1 Primary Objective 
The primary objective of this trial is to examine the efficacy of IPI-145 monotherapy versus 
ofatumumab monotherapy in subjects with relapsed or refractory Chronic Lymphocytic (CLL) or 
Small Lymphocytic Lymphoma (SLL). 
2.2 Secondary Objectives 
• To determine the safety of IPI-145 in subjects with CLL or SLL 
• To evaluate the pharmacokinetics (PK) of IPI-145 and, if applicable, its metabolite(s) 
2.3 Exploratory Objectives  
• To evaluate the health-related quality of life (QoL) of subjects 
• To evaluate pharmacodynamic biomarkers of IPI-145  
• To evaluate biomarkers that may predict IPI-145 clinical activity and/or safety 
• To evaluate mechanisms of resistance in subjects who exhibit disease progression while 
being treated with IPI-145 or ofatumumab 
• To evaluate genomic features of tumors predictive of response in subjects treated with 
IPI-145 or ofatumumab 
 
 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
3 STUDY DESIGN 
3.1 Overview 
Study IPI-145-07 is a two-arm, randomized (1:1 ratio), open-label, phase 3, superiority trial 
designed to evaluate the efficacy and safety of IPI-145 compared to ofatumumab.  
Subjects who meet all the eligibility criteria at Screening will return to the clinic on Day 1 to 
receive their first dose of study drug (randomized to either IPI-145 or ofatumumab). The first 
treatment cycle for each treatment arm will be 3 weeks (21±2 days). Subsequent treatment cycles 
will be 4 weeks (28±4 days). 
Subjects randomized to IPI-145 will be given a starting dose of 25 mg IPI-145 administered 
orally twice daily (BID) initially in a 21-day treatment cycle followed by 28-day treatment cycles 
for up to 18 cycles or until disease progression or unacceptable toxicity (whichever comes first). 
After 18 complete cycles of treatment, subjects may receive additional cycles of IPI-145 for up 
to 3 years (36 cycles of total treatment) if they have documented evidence of response and 
disease requiring continued treatment according to the modified IWCLL/revised IWG criteria. 
Subjects randomized to ofatumumab will receive treatment consistent with the approved product 
labeling: 8 weekly infusions, starting with an initial IV dose of 300 mg ofatumumab on Day 1 
followed by seven weekly doses of 2000 mg. Thereafter, subjects will receive 2000 mg 
ofatumumab once every month for four months or until disease progression or unacceptable 
toxicity (whichever comes first), as outlined in the schedule of assessments. Administration of 
ofatumumab will not exceed the 12 doses (within 7 cycles) as described in the prescribing 
information.  
Subjects will be followed for survival for up to 3 years (or other duration as specified by the 
protocol) from randomization or until death. Follow-up visits will occur every 6 months which 
can be conducted through a telephone interview.    
3.2 Sample Size Consideration 
This study employs a randomized, open-label, parallel design to assess the potential superiority 
of IPI-145 treatment over ofatumumab treatment on PFS in CLL or SLL subjects. 
The sample size was determined to provide sufficient power to test the primary endpoint of PFS 
in a group sequential design with one planned interim analysis. 
Assuming an exponential distribution for PFS, a total of 185 PFS events (deaths or progressions) 
will provide approximately 93% power to detect a hazard ratio of 0.6 (median PFS of 9 months 
in the ofatumumab group versus 15 months in the IPI-145 group) using a 1-sided log-rank test at 
a 2.5% overall significance level (ie, alpha of 0.025). The study design employs the Lan-DeMets 
spending function for O’Brien-Fleming boundary as the alpha spending function and the Hwang-
Shih-DeCani gamma (-4) spending function as the beta spending function. A total of 300 
subjects will be randomized in a 1:1 ratio to receive either ofatumumab or IPI-145. Assuming a 
peak accrual rate of 30 subjects per month with 11 months for accrual ramp-up and a 4% 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
cumulative dropout rate per year, the enrollment would complete in 16 months, with the final 
analysis for PFS estimated to occur approximately 27.5 months from the randomization of the 
first subject. 
3.3 Randomization 
Once a subject has met all entry criteria, the Interactive Response Technology (IRT) will be used 
to generate a distinct subject identifier. If a subject discontinues from the study, the subject 
identifier will not be reused and the subject will not be allowed to re-enter the study.  
Eligible subjects will be randomized via IRT in a 1:1 ratio to one of two treatment arms:  
• Arm 1: IPI-145 25 mg BID  
• Arm 2: Ofatumumab  
In order to ensure subject balance between treatment groups, study subjects will be stratified by 
the following: 
• High risk cytogenetics (presence vs absence of del[17p]) 
• Refractory/early relapse to purine analog based treatment (progression <12 months after 
fludarabine/pentostatin: yes vs no)  
• Grade 4 cytopenia(s) (presence vs absence of neutropenia or thrombocytopenia at 
baseline)   
Randomization is to occur within 7 days of first dose after all screening assessments have been 
completed. 
3.4 Blinding  
This study is open-label and Investigators, site staff, Sponsor and Sponsor designees will have 
access to treatment assignments for individual subjects. To reduce bias, a blinded independent 
central review of disease status will be conducted, which will be blinded to individual subject 
treatment assignments. Investigators, site staff, Sponsor and Sponsor designees will only have 
access to blinded (pooled) aggregate study data, except for a select number of Sponsor staff, who 
may review aggregate SAEs and Medical Events of Interest (MEOI) data by treatment groups. 
3.5 Planned Analyses 
For the interim analysis, the actual p-value boundaries will be calculated based on the actual 
number of PFS and OS events at the analysis. For the final analysis, the actual p-value boundary 
for efficacy will be calculated based on the actual number of PFS and OS events at both the 
interim analysis and the final analysis. 
The Independent Data Monitoring Committee (IDMC) will review PFS, OS and other efficacy 
data at the time of PFS interim analysis. The list of IDMC deliverables, including tables and 
listings, is included in the IDMC charter.  These deliverables will be based on the methods 
described in this SAP.  
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
3.5.1 Planned Analyses for PFS 
After approximately 50% of the planned PFS events (ie, 93 PFS events) have been observed 
based on the blinded, independent, central review, an interim analysis of efficacy will be 
performed.  
At the interim analysis, PFS will be tested at the alpha level based on the Lan-DeMets alpha 
spending function for the O’Brien-Fleming boundary with the opportunity to stop the study 
(other than survival follow-up) for overwhelming evidence of efficacy. If the interim analysis 
occurs at exactly 50% of the planned events, the criterion of stopping for efficacy is 1-sided p-
value of 0.0015 (corresponding approximately to a HR of 0.540). In the meantime, PFS will also 
be tested at the alpha level for futility based on the alpha and beta spending functions specified 
for the study design. If the interim analysis occurs at exactly 50% of the planned events, the 
criterion of stopping for futility is 1-sided p-value of 0.4791 (corresponding approximately to a 
HR of 0.990). The futility boundary of this study is non-binding, meaning that the Type I error is 
properly controlled even if the study is continued after the futility boundary for PFS is crossed at 
the interim analysis.  Under the protocol design assumptions (ie, the study is fully enrolled in 16 
months), the interim analysis is expected to occur approximately 17 months after the first subject 
is randomized.  
If the study is not stopped at the interim analysis, the final analysis will be performed when 
approximately 185 PFS events have occurred in the study.  The criterion of statistical 
significance (ie, boundary for efficacy) is 1-sided p-value of 0.0245 (corresponding 
approximately to a HR of 0.748).  
 
3.5.2 Planned Analyses for OS 
There will be three planned OS analyses. The first one will be at the planned PFS interim 
analysis, which is expected to happen after 93 PFS events have occurred, or approximately 17 
months after the first subject is randomized. The second analysis of OS will be performed at the 
PFS final analysis, which is expected to happen after 185 PFS events have occurred, or 
approximately 27.5 months after the first subject is randomized. Since all subjects will be 
followed for survival for 6 years, the final analysis of OS will take place at the end of follow-up 
of all subjects, which is approximately 88 months after the first subject is randomized, or 6 years 
from last subject is randomized. To control the overall 1-sided type I error under 0.025, the 
cumulative alpha spending at the three analyses will be 0.0001, 0.0249, and 0.0250, respectively. 
As a result, the p-value stopping boundaries for the three analyses will be 0.0001, 0.0249 and 
0.0003, respectively. The statistical significance of OS will not be claimed unless the PFS 
reaches statistical significance.    
 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
4 ANALYSIS SETS 
4.1 Intent-To-Treat (ITT) Analysis Set 
The intent-to-treat (ITT) analysis set includes all subjects who are randomized, with treatment 
group designated according to randomization. 
This analysis set will be used in the analyses of subject characteristics and efficacy endpoints.  
4.2 All-Treated (AT) Analysis Set 
The all-treated (AT) analysis set includes all subjects who receive any amount of study drug 
(IPI-145 or ofatumumab), with treatment group designated according to actual study treatment 
received. The AT analysis set will be the primary analysis set for safety endpoints. 
4.3 Per-Protocol (PP) Analysis Set 
The per-protocol (PP) analysis set includes all subjects in the ITT analysis set who do not violate 
the terms of the protocol in a way that would significantly affect the study outcome, with 
treatment group designated according to randomization. Subjects who meet any of the following 
criteria may be excluded from this analysis set:  
• Do not have documented diagnosis of CLL or SLL within medical records  
• Do not have measurable nodal disease at baseline as determined by the IRC 
• ECOG performance status >2 
• History of Richter's transformation or prolymphocytic leukemia  
• Refractory to ofatumumab  (defined as progression or relapse <12 months of receiving 
ofatumumab monotherapy or <24 months of receiving an ofatumumab-containing 
regimen)   
• Prior exposure to a PI3K inhibitor or a BTK inhibitor 
• Receive concomitant prohibited anticancer therapy  
• Permanent discontinuation from study drug due to non-compliance 
The PP analysis set will be a secondary analysis set for selected efficacy analyses.  
 
 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
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5 STUDY ENDPOINTS  
5.1 Primary Endpoint 
The primary efficacy endpoint PFS is defined as time from randomization to the first 
documentation of progressive disease (PD) as determined by independent review or death due to 
any cause.  
The censoring rule of the primary endpoint can be found in Appendix A. The detailed algorithm 
will be specified in the Analysis Data Model (ADaM) specifications.  
5.2 Secondary Endpoints 
The secondary efficacy endpoints of the study are: 
• Overall Response Rate (ORR), with overall response (based on independent review) 
defined as best response of complete response/remission (CR), CR with incomplete 
marrow recovery (CRi), partial response/remission (PR), or PR with lymphocytosis 
(PRwL), according to the IWCLL or revised IWG Response Criteria, with modification 
for treatment-related lymphocytosis  
• Lymph node response rate, with lymph node response defined as ≥50% decrease in the 
SPD of target lymph nodes  
• Overall Survival (OS), defined as time from randomization to death 
• Hematologic improvement rate, defined as any of following hematologic improvement 
sustained for at least 60 days without transfusion or exogenous growth factors: 
o Neutrophil count >1,500/µL or an increase ≥50% from Baseline; or 
o Hemoglobin >11 g/dL or an increase ≥50% from Baseline; or  
o Platelet count >100,000/µL or an increase ≥50% from Baseline  
• Duration of Response (DOR), defined as time from the first documentation of response to 
first documentation of PD or death due to any cause.  
Other secondary endpoints of the study are: 
• TEAEs and changes in safety laboratory values  
• PK parameters derived from plasma IPI-145 concentrations and, if applicable, its 
metabolite(s) 
5.3 Exploratory Endpoints 
The exploratory efficacy endpoints of the study are: 
• Improvement in disease-related symptoms of fatigue, weight loss, unexplained fevers and 
night sweats from Baseline 
• Minimal Residual Disease (MRD) in subjects with documented CR or CRi 
The QoL endpoints of the study are: 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
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• Health-related QoL of subjects as assessed by the following subject-reported 
questionnaires:  
o EuroQol-5D (EQ-5D) 
o Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) 
The biomarkers of the study are: 
• Serum and tissue biomarkers and blood immunophenotype 
• Tumor genomic features (eg, DNA sequence variation, DNA copy number variation, 
and/or RNA expression) 
• Germline DNA sequence variations 
 
 
 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
6 GENERAL STATISTICAL METHODS AND DATA HANDLING 
6.1 General Methods 
Summary statistics will be presented by treatment group, unless stated otherwise.  
Unless otherwise specified, descriptive statistics for continuous data will include the number of 
subjects with data to be summarized (n), mean, standard deviation, median, and minimum and 
maximum. The same number of decimal places as in the raw data will be presented when 
reporting the minimum and maximum, one more decimal place than the raw data will be 
presented when reporting mean and median, and 2 more decimal places than the raw data will be 
presented when reporting standard deviation. 
Descriptive statistics for categorical/qualitative data will include frequency counts and 
percentages. The total number of subjects in the treatment group will be used as the denominator 
for percent calculations, unless stated otherwise. All percentages will be presented with one 
decimal, unless otherwise specified. Percentages equal to 100 will be presented as 100, and 
percentages will not be presented for zero frequencies. 
Descriptive statistics associated with time-to-event analyses will include the number of events, 
the number of subjects censored, 25% quartile, median, 75% quartile, and corresponding 95% 
confidence interval for median. These statistics will be presented for all time-to-event analyses, 
unless stated otherwise. 
For listings broken down by center and treatment arm, site (center) number will be ordered by 
country. 
6.2 Handling of Missing Data 
In general, values for missing data will not be imputed unless methods for handling missing data 
are specified. 
6.2.1 Handling of Missing Dates/Months/Years for Adverse Events 
Adverse events (AEs) with incomplete onset dates will be handled as follows for the sole 
purpose of determining treatment emergence (TEAE is defined in Section 7.3.1): 
• If the start/end date of an AE is partially missing, the date will be compared as far as 
possible with the date of the start of administration of study drug and the date of last dose 
of study drug plus 30 days. The AE will be assumed to be treatment emergent if it cannot 
be definitively shown that the AE did not occur or worsen during the treatment-emergent 
period (worst case approach). The detailed algorithm will be specified in ADaM 
specifications.  
• If the start date is completely missing, an AE will be considered treatment-emergent 
unless the stop date is before study drug administration. 
• If the dose start date is missing for a subject at a data-cut, all AEs of the subject will be 
considered treatment-emergent.  
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
The original partial or missing date will be shown in all listings of AEs. 
6.2.2 Handling of Missing Dates/Months/Years for Concomitant Medications 
Prior or concomitant medications with incomplete start dates will be handled as follows for the 
sole purpose of determining whether a non-study medication is a concomitant medication: 
• If the start/stop date of a medication is partially missing, the date will be compared as far 
as possible with the date of the start of administration of study drug and the date of last 
dose of study drug plus 30 days. The medication will be assumed to be concomitant if it 
cannot be definitively shown that the stop date is before the start of administration of 
study drug, or the start date is more than 30 days after the last date of administration of 
study drug. The detailed algorithm will be specified in ADaM specifications.  
• If the start/stop dates are completely missing, a medication will be considered 
concomitant. 
• If the dose start date is missing for a subject at a data-cut, all non-study medications of 
the subject will be considered concomitant. 
The original partial or missing date will be shown in listings of all non-study medications. 
6.2.3 Handling of Missing Dates/Months/Years for Disease History and Prior Therapies 
For the purpose of calculating the duration from initial diagnosis, most recent relapse/refractory 
diagnosis or most recent prior therapy to randomization, partial/missing dates for diagnosis and 
last prior therapy completion will be imputed as follows:  
 
• If both date and month are missing and the year is prior to the year of screening, the 
imputed date and month will be 01 July.  
• If both date and month are missing and the year is the same as the year of screening, the 
imputed date will be the middle point between 01 Jan of the year and the screening date. 
If the middle point falls between two dates, the first of the two dates will be used.  
• If date is missing and the month and year are prior to the month and year of screening, 
the imputed date will be 15th day of the month.  
• If date is missing and the month and year are the same as the month and year of 
screening, the imputed date will be the middle point between the first date of the month 
and the screening date. If the middle point falls between two dates, the first of the two 
dates will be used.  
• No imputation will be performed if the year is missing.  
6.3 Multiple Comparisons/Multiplicity Adjustment 
Of the secondary endpoints, ORR, Lymph Node Response Rate, OS, and Hematologic 
Improvement Rate are designated as key secondary efficacy endpoints. The primary endpoint 
and key secondary endpoints will be tested at an overall 1-sided alpha level of 0.025 based on a 
gatekeeping approach.  
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
If the primary endpoint is significant, the 4 secondary endpoints will be sequentially tested at the 
1-sided 0.025 significance level in the order listed above. If a null hypothesis is not rejected, 
formal sequential testing will be stopped. 
6.4 Adjustments for Covariates 
Adjustments for covariates will be considered for analysis of primary and key secondary 
endpoints, with details provided in Sections 7.2.1 and 7.2.2. 
6.5 Subgroups 
PFS, ORR and OS will be examined in the following subgroups: 
• Stratification factors (captured on the eCRF): 
1 High-risk cytogenetics (presence vs absence of del[17p]) 
2 Refractory/early relapse to purine analog-based therapy (defined as progression 
<12 months after fludarabine/pentostatin: yes vs no)  
3 Grade 4 cytopenia(s) (presence vs absence of neutropenia or thrombocytopenia at 
baseline)   
• Diagnosis (CLL or SLL) 
• Gender (Male or Female) 
• Age group (<65 or ≥65) 
• Race (White or Non-White) 
• Previously treated with ofatumumab (yes vs no, if sample size allows the analysis) 
• Most recent prior anti-cancer therapy to randomization <12 months: yes vs no  
TEAEs (All Causalities) and TEAEs (Treatment-Related) will be examined in the following 
subgroups: 
• Gender (Male or Female) 
• Age group (<65 or ≥65) 
• Race (White or Non-White) 
• Baseline ECOG performance status (0 or 1 versus 2) 
More details will be specified in Sections 7.2.1, 7.2.2 and 7.3.1. 
6.6 Visit Windows 
All data will be categorized based on the scheduled visit at which it was collected.  These visit 
designators are predefined values that appear as part of the visit tab in the eCRF.  There will be 
no additional analysis windowing done based on the assessment date. 
6.7 Unscheduled Visits 
Unscheduled visits will not be included in by-visit summary tables, unless otherwise specified.  
For laboratory tests, data from unscheduled visits will be included in listings and summaries of 
maximum changes from baseline, and the best or worst post-baseline values.  For endpoints 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
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based on disease status assessment, data from unscheduled assessments will be included in the 
derivation and analyses of the endpoints. 
6.8 Baseline Values  
Unless otherwise specified, the baseline value is defined as the value collected at the time closest 
to, and prior to, the start of study drug administration.  Values collected at unscheduled visits 
prior to the start of the study drug administration will be included in the calculation of baseline 
values.  
6.9 Computing and Coding Standards 
Activities will be performed using the following tools: 
Table, listing, and figure production 
SAS Version 9.2 or higher 
Coding 
 
 
Adverse Events 
MedDRA Version 16.1 or higher 
 
Medical Histories 
MedDRA Version 16.1 or higher 
 
Prior and Concomitant Medications 
WHODrug Version September 2013 
Grading 
 
 
AEs 
CTCAE Version 4.03 
 
Labs 
CTCAE Version 4.03 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
7 STATISTICAL ANALYSES 
7.1 Study Subjects 
7.1.1 Disposition of Subjects 
The disposition of subjects will include the number and percentage of subjects for the following 
categories: the number randomized, the number and percentage randomized but not dosed, the 
number and percentage dosed. These categories will be summarized for each treatment arm and 
for the two treatment arms combined (total).  The percentages will be based on all randomized 
subjects (ITT analysis set).   
An end-of-treatment disposition (still on treatment vs discontinued from treatment) will be 
provided for each treatment arm and for the two treatment arms combined (total) based on the 
AT analysis set. The primary reason for treatment discontinuation will be included in the table. A 
listing of these subjects will also be provided, broken down by center and treatment arm. 
An end-of-study disposition (still on study vs discontinued from study) will also be provided for 
each treatment arm and for the two treatment arms combined (total) based on the ITT analysis 
set. The primary reason for study discontinuation will be included in the table. A listing of these 
subjects will also be provided, broken down by center and treatment arm. 
A summary of strata as captured in IRT will be presented by treatment arm and for the two 
treatment arms combined (total) based on the ITT analysis set.  A listing of the discrepancies in 
data for stratification factors between those captured in the IRT and those reported on the eCRF 
will be presented. 
7.1.2 Protocol Deviations 
Protocol deviations will be assessed during monitoring visits and by data review.  At minimum, 
the following categories of study conduct or data will be assessed for potential protocol 
deviations: entry criteria, concomitant medications, dosing records, laboratory results, visit 
schedule and procedures. Protocol deviations will be categorized as major or minor prior to data 
release for the final analysis of the primary endpoint. A summary table of the protocol deviations 
will be provided by treatment arm and for two arms combined (total) for the ITT analysis set. A 
listing of all protocol deviations will be provided, broken down by center and treatment arm. 
7.1.3 Demographic and Other Baseline Characteristics 
Demographic variables will be summarized for each treatment arm based on all randomized 
subjects (ITT analysis set) and for the two treatment arms combined (total). The variables will 
include age, age group (<65 versus >=65), sex, race, ethnicity, height, and weight.  
Demographic variables will also be summarized based on the PP analysis set.  
7.1.4 Disease History 
Disease history will be summarized for each treatment arm and for the two treatment arms 
combined (total) based on the ITT analysis set. The variables will include diagnosis (CLL or 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
SLL), risk factors used for randomization that are reported on eCRF (high risk cytogenetics [17p 
deletion: presence vs absence], refractory/early relapse to purine analog based treatment [yes vs 
no], grade 4 cytopenia(s) [presence vs absence]), years from initial diagnosis to randomization, 
months from most recent relapse/refractory diagnosis to randomization, stage at initial diagnosis, 
type of prior treatment, current stage, Binet/Rai stage, and baseline lymphocytes.  
The durations to be summarized are defined as follows: 
• Years from initial diagnosis to randomization will be calculated as (date of randomization 
– date of initial diagnosis + 1)/365.25.  
• Months from most recent relapse/refractory diagnosis to randomization will be calculated 
as (date of randomization – date of most recent relapse/refractory diagnosis + 1)/ 
(365.25/12).  
The imputation of partial/missing dates is described in Section 6.2.3. 
7.1.5 Prior Therapies 
Prior therapies will be summarized for each treatment arm and for the two treatment arms 
combined (total) based on the ITT analysis set. The variables will include number of prior 
systemic therapies (summarized as a continuous variable and as a categorical variable), months 
from most recent prior therapy to randomization, number and percentage of subjects with prior 
radiotherapy, and number and percentage of subjects with prior surgery related to primary 
diagnosis. 
The durations to be summarized are defined as follows.  
• Months from most recent prior therapy to randomization will be calculated as (date of 
randomization – stop date of most recent systemic therapy, prior irradiation or prior 
surgery +1)/ (365.25/12).  
The imputation of partial/missing dates is described in Section 6.2.3. A by-subject listing will be 
presented for prior systemic therapy. 
 
7.1.6 Medical History 
Medical history will be summarized for each treatment arm and for the two treatment arms 
combined (total) based on the AT analysis set. 
Medical history will be summarized by system organ class (SOC) and preferred term (PT) using 
the number and percentage of subjects who had at least one occurrence of an SOC or PT. The 
summary will be sorted alphabetically in SOC and by decreasing frequency of PT in the IPI-145 
arm within an SOC. 
7.1.7 Prior and Concomitant Medications  
Medications will be considered as prior if they stopped before the date of first dose of study 
drug.  
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Medications will be considered concomitant if they were taken at any time between the date of 
first dose of study drug and 30 days after the date of last dose of study drug, inclusive.  If the 
start date or end date of a medication is completely or partially missing, refer to Section 6.2.2 for 
the algorithm to determine whether a medication is concomitant. 
Prior medications and concomitant medications will be summarized separately. Both summaries 
will be based on the AT analysis set. 
Medications will be summarized by ATC level 1, ATC level 2, and preferred drug name for each 
treatment arm. The summary will be sorted by decreasing frequency in ATC level 1, ATC level 2 
and preferred drug name in the IPI-145 arm. A subject taking the same drug multiple times will 
only be counted once. 
A listing will be provided for all non-study medications taken on the study. An identifier will be 
provided to show if a medication is prior or concomitant. Medications that started more than 30 
days after the last dose of study drug will be identified as post-treatment.  
7.1.8 Exposure to Study Drug 
Extent of exposure will be summarized for each treatment arm based on the AT analysis set.  
Extent of exposure will be summarized for the following variables: 
• Duration (weeks): (date of last dose – date of first dose + 1) divided by 7 
• Number of cycles started (continuous and categorical) 
• Ofatumumab arm only: For each infusion (1-12), number and percent of subjects 
receiving the infusion 
• Relative dose intensity, defined as 100% x (total dose received)/ (planned 
cumulative dose for the duration of treatment) 
• Number and percentage of subjects with a dose reduction  
• IPI-145 arm only: Number and percentage of subjects with a dose increase  
• Number and percentage of subjects with a dose interruption   
• Number and percentage of subjects with study drug discontinued  
7.2 Efficacy Analyses 
For PFS, ORR, lymph node response rate, DOR and other endpoints derived from progression 
and/or response status, the primary analyses will be based on the endpoints derived from 
independent central review (IRC). The endpoints derived from investigator assessment will be 
used in sensitivity analyses. 
All efficacy analyses will be based on the ITT analysis set unless stated otherwise.  If analyses 
are performed on more than one analysis set, the analyses on the ITT analysis set will be 
considered primary.   
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
For stratified analysis of any efficacy endpoint, the following algorithm will be used to pool 
strata if there is insufficient information in any stratum (ie, there are <6 subjects, or there is no 
event for a time-to-event endpoint, or all subject have the same outcome for a binary endpoint in 
a stratum). (1) Strata will be ranked from the smallest to the largest based on the number of 
subjects, and if there is a tie, based on the number of events or responses. If there is still a tie, 
based on the reverse order of strata as determined by the stratification factors and levels (see 
Section 3.3). (2) The smallest stratum will be compared with the criteria of insufficient 
information. (3) If there is insufficient information in the smallest stratum, that stratum will be 
pooled with the smallest of the adjacent strata, which are defined as strata having 2 of the 3 
stratification factors being at the same level as the smallest stratum. At the end of the three steps, 
the pooled stratum will replace the original two contributing strata.  If there is still insufficient 
information in any stratum, the three steps will be repeated with the last pooled stratum assuming 
the stratum label of the larger of the two contributing strata for the purpose of additional pooling. 
The resulting pooled strata will be the strata used for the stratified analysis described in this 
section. 
7.2.1 Analyses of Primary Endpoint 
7.2.1.1 Primary analyses of PFS  
Number of subjects with events, types of events (progression or death before progression), 
number of subjects censored, number of subjects for each reason of censoring, estimates and 
95% confidence intervals for the 25th percentile, median, and 75th percentile for PFS will be 
presented by treatment group. Probabilities of event free at selected time points may also be 
presented. 
A stratified log-rank test (1-sided) will be used to compare PFS of the IPI-145 arm against PFS 
of the ofatumumab arm at the interim and final analyses with the overall 1-sided significance 
level controlled at 0.025. The nominal p-value required for statistical significance at an analysis 
will be calculated based on the numbers of PFS events at all preceding and current analyses. The 
HR (IPI-145/ofatumumab) and the corresponding 2-sided 95% CI will be estimated using a 
stratified Cox proportional hazards model. For both the stratified log-rank test and the stratified 
Cox model, the strata will be those used for stratified randomization, with potential pooling of 
strata specified earlier in Section 7.2.   
PFS will be plotted for each treatment group using the Kaplan-Meier method. The plot will 
include the number of subjects at risk for each treatment group over time. 
7.2.1.2 Sensitivity analyses of PFS 
The following sensitivity analyses will be performed: 
• PFS based on investigator assessment: This endpoint will be analyzed using the same 
methods as the primary analyses described for PFS based on IRC assessment. In 
addition, the differences between investigator assessment and IRC assessment will be 
summarized. 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
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• Worst-case sensitivity analysis: Subjects who are alive and have not had documented 
progression by data cutoff and who are “lost to follow-up” (missing at least one 
disease assessment right before data cut off) will be treated as censored at their last 
adequate disease assessment if they are on the control arm (ofatumumab) and treated 
as having a PFS event at the time of the next scheduled assessment following the last 
adequate disease assessment if they are on the experimental arm (IPI-145). PFS based 
on IRC assessment with the above worst-case censoring/event rule will be analyzed 
using the same methods as the primary analyses for PFS. 
• Event-free survival (EFS): This is defined as time from randomization to the first 
documentation of PD as determined by IRC, start of new anticancer treatment or 
procedure, or death due to any cause.  The event/censoring rule in Appendix A, which 
is used for the primary endpoint, will be used except that start of new anticancer 
treatment or procedure will be considered an event. EFS will be analyzed using the 
same methods as the primary analyses for PFS except that the summary of types of 
events will include a category of new anticancer treatment or procedure. 
• Analysis using the PP analysis set. 
• Analysis using the AT analysis set. 
• Unstratified analyses: An unstratified log-rank test (1-sided) will be used to compare 
the two trreatment arms. An unstratified Cox regression (1-sided) will be used to 
estimate the hazard ratio (IPI-145/ofatumumab) with its 95% confidence interval. 
Other aspects of the analyses will be the same as the primary analysis of PFS. 
• Cox regression with baseline covariates: A stratified Cox regression will be used to 
test treatment effect on PFS, adjusting for demographic and baseline characteristics. 
The strata will be those used for stratified randomization, with potential pooling of 
strata specified earlier in Section 7.2. A stepwise variable selection will be performed 
to choose the variables in the Cox regression. Candidate variables are age, gender, 
race, disease diagnosis (CLL or SLL), years from initial diagnosis, months from most 
recent relapse/refractory diagnosis, stage at diagnosis, current stage, and number of 
prior systemic therapies. PFS based on IRC assessment will be used for this analysis. 
7.2.1.3 Subgroup analyses of PFS 
Subgroup analyses for PFS will be performed using the subgroups specified in Section 6.5. The 
HR (IPI-145/ofatumumab) with its 95% CI will be calculated based on an unstratified Cox 
regression model for each subgroup. The hazard ratio and their 95% confidence intervals will be 
displayed for all subgroups graphically in a forest plot. 
7.2.2 Analyses of Secondary Efficacy Endpoints 
Of the secondary endpoints, ORR, Lymph Node Response Rate, OS, and Hematologic 
Improvement Rate are designated as key secondary efficacy endpoints. These endpoints will be 
tested for statistical significance under an overall 1-sided significance level of 0.025 if and only 
if the primary endpoint is significant. Details of multiplicity adjustment are provided in Section 
6.3. 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
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The analysis of another secondary efficacy endpoint, Duration of Response (DOR), will be 
descriptive only. No hypothesis testing will be performed.   
7.2.2.1 Overall Response Rate 
The primary analyses of ORR will use ORR based on IRC assessment in the ITT analysis set. 
ORR will be derived from best overall response (BOR), which is defined as the best time point 
response that a subject achieves during the course of the study, with the response ranked 
according to the following order (from best to worst): CR>CRi>PR>PRwL>SD>PD  (CRi 
applies to CLL only).  In addition, the IRC may assign a timepoint response of unknown (UNK) 
due to missing, incomplete, or inadequate data, or a timepoint response of no evidence of disease 
(NED) if both radiological and clinical data indicate no disease involvement; for a post-baseline 
timepoint, the IRC may also assign a timepoint response of not evaluable (NE) if no target 
lesions were identified at baseline and the radiological and clinical data at the post-baseline 
timepoint do not support the disease response of PD or UNK; these categories will be classified 
as OTHER.    
The estimated ORR (percent of subjects with a BOR of CR, CRi, PR or PRwL) and a 2-sided 
95% CI will be provided for each treatment arm.  Number and percent of subjects with BOR in 
each of the response categories (CR, CRi, PR, PRwL, SD, PD, OTHER) will also be presented 
by treatment arm.  All subjects in the analysis set will be included in the denominator in the 
calculation of the percentage for each response category or ORR.  
ORR will be analyzed using the Cochran-Mantel-Haenszel test (1-sided) to compare the two 
treatment groups. The strata for the test will be those used for stratified randomization, with 
potential pooling of strata specified earlier in Section 7.2. The odds ratio and its 95% CI will be 
estimated. 
The following sensitivity analyses will be performed: 
• ORR based on investigator assessment 
• Overall Confirmed Response Rate (OCRR), with overall confirmed response (based on 
independent review) defined as best confirmed response (≥8 weeks in duration) of CR, 
CRi, PR, or PRwL, according to the IWCLL or revised IWG Response Criteria, with 
modification for treatment-related lymphocytosis 
• Overall Response Rate without PRwL: with overall response (based on independent 
review) defined as best response of complete response/remission (CR), CR with 
incomplete marrow recovery (CRi), partial response/remission (PR) 
• Overall Confirmed Response Rate without PRwL 
• Overall Response Rate in subset of subjects with baseline assessment other than UNK 
and NED. This analysis will be performed if there are at least 5% subjects with baseline 
assessment of UNK or NED. 
• Analysis using the PP analysis set. 
• Analysis using the AT analysis set. 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Subgroup analyses will be performed for ORR using the subgroups specified in Section 6.5. 
ORR will be analyzed using the (unstratified) Chi-Square test to compare the two treatment 
groups in each subgroup. A forest plot of estimated odds ratios and their 95% confidence 
intervals will be presented.  An estimated ORR and its 95% confidence interval in each subgroup 
will also be provided.  
 
7.2.2.2 Lymph Node Response Rate 
The primary analyses of lymph node response rate will be based on IRC assessment in the ITT 
analysis set. The number of subjects with lymph node response, estimated lymph node response 
rate, and a 2-sided 95% CI will be provided for each treatment arm. 
Lymph node response rate will be analyzed using the Cochran-Mantel-Haenszel test (1-sided) to 
compare the two treatment groups. The strata for the test will be those used for stratified 
randomization, with potential pooling of strata specified earlier in Section 7.2. 
A sensitivity analysis will be performed using lymph node response rate based on investigator 
measurements. 
7.2.2.3 Overall Survival 
The primary analyses of OS will be based on the ITT analysis set. Subjects without 
documentation of death at the time of the data cutoff for analysis will be censored at the date the 
subject was last known to be alive, or the data cutoff date, whichever is earlier.  A stratified 1-
sided log-rank test will be used to compare OS between the 2 treatment groups.  The HR along 
with the 95% CI will be estimated using a stratified Cox model. For both the stratified log-rank 
test and the stratified Cox model, the strata will be those used for stratified randomization, with 
potential pooling of strata specified earlier in Section 7.2. The Kaplan-Meier estimates of 
survival curves and 95% confidence intervals for the 25th percentile, median, and 75th percentile 
for OS will be presented by treatment group (if estimable).  Probabilities of survival at selected 
time points may also be presented. 
A majority of subjects can be expected to take subsequent anticancer therapy, especially after 
disease progression. To adjust for the effects of subsequent therapy, the following sensitivity 
analysis may be performed: 
1. Primary analyses except additional censoring at the start day of subsequent 
therapy 
2. Rank preserving structural failure time (RPSFT) analysis 
3. Inverse probability of censoring weighted (IPCW) analysis 
The following sensitivity analyses will be performed: 
• Analysis using the PP analysis set. 
• Analysis using the AT analysis set.  
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
• Unstratified analyses: An unstratified log-rank test (1-sided) will be used to compare 
the two treatment arms. An unstratified Cox regression (1-sided) will be used to 
estimate the hazard ratio (IPI-145/ofatumumab) with its 95% confidence interval.  
Subgroup analyses for OS will be performed using the subgroups specified in section 6.5. The 
HR (IPI-145/ofatumumab) with its 95% CI will be calculated based on an unstratified Cox 
regression model for each subgroup. The HRs and their 95% CIs will be displayed for all 
subgroups graphically in a forest plot. 
7.2.2.4 Hematologic Improvement Rate 
A subject with a hematologic improvement is one who consistently met the criteria of an 
improvement in neutrophil count, hemoglobin or platelet count for a period of at least 60 days 
during which the subject did not have a transfusion or exogenous cytokines. Missing data or 
missing scheduled assessments during a potential 60-day hematologic improvement episode will 
result in categorization of not having a hematologic improvement.  
The number of subjects with hematologic improvement, estimated hematologic improvement 
rate, and a 2-sided 95% CI will be provided for each treatment arm. 
Hematologic improvement rate will be compared between treatment groups using 1-sided 
Cochran–Mantel–Haenszel (CMH) test. The strata for the test will be those used for stratified 
randomization, with potential pooling of strata specified earlier in Section 7.2.  
7.2.2.5 Duration of Response (DOR) 
DOR will be presented using the Kaplan-Meier method for each treatment arm based on all 
randomized subjects with a documentation of response (i.e., CR, CRi, PR, or PRwL) as 
determined by IRC assessment. The censoring rule will be the same as that for the primary 
endpoint (see Appendix A).  The Kaplan-Meier estimates of survival curves and 95% confidence 
intervals for the 25th percentile, median, and 75th percentile for DOR will be presented by 
treatment group (if estimable). No treatment comparison will be performed.  
7.2.3 Analyses of Exploratory Efficacy Endpoints 
7.2.3.1 Improvement in Disease-Related Symptoms 
Disease-related symptoms of fever, weight loss, and drenching night sweats will be assessed as 
present or absent at each timepoint. Improvement in each of the three disease-related symptoms 
from baseline will be analyzed separately.  The summary will display the proportion of subjects 
with an improvement while on treatment. Descriptive analysis of improvement in these disease-
related symptoms will also be presented over the course of the study (eg, for each scheduled 
assessment).  
The disease-related symptom of fatigue will be measured by the ECOG performance status. 
Summary statistics will be provided for the ECOG score and the change from baseline at each 
timepoint.  
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
7.2.3.2 Minimal Residual Disease  
MRD status for subjects with a response of CR or CRi will be determined using flow cytometry 
from a central lab. MRD will be classified as positive or negative. The estimated rates of subjects 
with negative MRD and their 95% confidence intervals in subjects with a response of CR or CRi 
will be provided for each treatment arm.  
7.3 Safety Analyses 
All safety analyses will be performed using the AT analysis set. 
7.3.1 Adverse Events  
Adverse events will be coded using MedDRA Version 16.1 or higher. The Grade of the AE will 
be assessed according to the NCI-CTCAE Version 4.03. If an AE is not included in the NCI-
CTCAE Version 4.03, the Grade of the AE will be assessed according to the protocol, Section 
8.2.1.2. 
AEs will be summarized for each treatment arm by MedDRA system organ class (SOC) and 
preferred term (PT), or PT only.  For summary tables by SOC and PT, SOC will be sorted 
alphabetically and PT will be sorted by decreasing frequency in the IPI-145 arm within each 
SOC.  For summary tables by PT only, PT will be sorted by decreasing frequency in the IPI-145 
arm.   
If multiple AEs of the same PT occur within a subject, only the maximum grade observed for 
this PT will be used in summary of AEs by grade, the subject will be counted only once in the 
number of subjects for this PT and only once for the number of subjects for the SOC to which 
this PT belongs.  
A treatment-emergent AE (TEAE) is defined as any AE that emerges or worsens in the period 
from the first dose of study treatment to 30 days after the last dose of study treatment.  The onset 
date of an AE will be compared to the first dose date and the last dose date plus 30 days to 
determine whether the AE is treatment-emergent or not.  If the onset date of an AE is completely 
or partially missing, refer to Section 6.2.1 for the algorithm to determine whether an AE is 
treatment emergent. 
An overview TEAE summary table will be provided, which will include the number of AEs and 
the number of subjects with AEs in selected categories. In addition, TEAEs will be summarized 
for the following categories, and will be tabulated by SOC and PT, unless otherwise specified.  
• 
Treatment-emergent AEs (All Causalities) 
• 
Treatment-emergent AEs (Treatment-Related) 
• 
Treatment-emergent AEs (All Causalities, by maximum grade) 
• 
Treatment-emergent AEs (Treatment-Related, by maximum grade) 
• 
Grade 3 or higher treatment-emergent AEs (All Causalities) 
• 
Grade 3 or higher treatment-emergent AEs (Treatment-Related) 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
• 
Treatment-emergent SAE (All Causalities) 
• 
Treatment-emergent SAE (Treatment-Related) 
• 
Treatment-Emergent AEs Resulting in Discontinuation of Study Drug 
• 
Treatment-Emergent AEs Resulting in dose hold or reduction (number of subjects 
with hold, reduction, hold or reduction will be displayed) 
• 
Treatment-Emergent AEs Resulting in Death 
• 
Treatment-Emergent AEs by PT (All Causalities) 
• 
Grade 3 or higher treatment-emergent AEs by PT (All Causalities) 
A by-subject listing of the following AE categories will be presented.  
• 
All AEs (TEAEs will be flagged) 
• 
All SAEs (TEAEs will be flagged) 
• 
Treatment-Emergent AEs Resulting in Discontinuation of Study Drug 
• 
Treatment-Emergent AEs Resulting in Death 
Treatment-emergent AEs (All Causalities) and Treatment-emergent AEs (Treatment-Related) 
will also be tabulated in each subgroup specified in Section 6.5.  
7.3.2 Laboratory Data 
Laboratory tests will be reported separately for hematology/coagulation, blood chemistry, and 
urinalysis. 
For the purposes of presentation in both tables and listings, the following laboratory test results 
will be converted to the International System of Units (SI) before presentation: sodium, 
potassium, chloride, bicarbonate (or CO2), albumin, total protein, creatinine, uric acid, calcium, 
phosphorus, magnesium, glucose, total and direct bilirubin, and alkaline phosphatase, red blood 
cell (RBC) count, hemoglobin, hematocrit, platelets, white blood cell count with 5-part 
differential performed manually or by flow cytometry (for an absolute neutrophil count [ANC], 
lymphocyte count, neutrophils, monocytes, basophils, and eosinophils), etc. 
If a laboratory test value is reported using a non-numeric qualifier (e.g., less than [<] a certain 
value, or greater than [>] a certain value), the given numeric value will be used in the summary 
statistics, ignoring the non-numeric qualifier. 
For laboratory tests with NCI-CTCAE grades, a shift table from baseline grade to the maximum 
post-baseline grade will be provided. Laboratory tests with bi-directional grades (e.g., 
Hyperglycemia and Hypoglycemia) will be presented separately for each direction within the 
shift table.  
Listings will be provided for all laboratory test results and for laboratory test results grade 3 and 
higher.  A listing of subjects with ALT or AST >3xULN with simultaneous total bilirubin 
>2xULN will be presented, where ULN stands for upper limit of normal.  
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
7.3.3 Vital Signs 
The actual values of vital sign parameters, including temperature, heart rate, weight and systolic 
and diastolic blood pressure, will be presented in a by-subject listing.  
 
7.3.4 Electrocardiogram (ECG) 
The ECG categories will be summarized for each treatment arm for baseline and for each visit. 
The categories include normal, abnormal, NCS (abnormal but not clinically significant) and 
abnormal CS (abnormal and clinically significant). 
7.3.5 Concomitant Medications and Procedures 
Please refer to Section 7.1.6 for the definition and summary of concomitant medications. 
Concomitant procedures will not be summarized. A by-subject listing will be presented. 
7.4 Quality of Life Instruments 
Analyses of the QoL instruments (EQ-5D and FACIT-F) will be performed on the ITT analysis 
set. Additional analyses may be considered as needed.  
7.4.1 EQ-5D 
The EQ-5D contains a descriptive system with one response for each of 5 dimensions (Mobility, 
Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression). The first response is 
coded as 1 (indicating no problems), the second response is coded as a 2 (indicating some 
problems), and the third response is coded as a 3 (indicating extreme problems). Ambiguous 
responses (eg, more than one response in a dimension) are treated as missing values. The EQ-5D 
also contains a Visual Analog Scale (VAS) for health state ranging from 0 to 100, where 0 
represents worst imaginable health state and 100 represents the best imaginable health state.  
For each dimension of the descriptive system, the number and percentage of subjects with no 
problems, some problems, and extreme problems will be reported at each visit.  
Summary statistics for the VAS of health state and the change from baseline will be reported for 
each visit.   
 
7.4.2 FACIT-F 
The FACIT-F contains 5 subscales, Physical Well-Being, Social/Family Well-Being, Emotional 
Well-Being, Functional Well-Being, and Fatigue (Additional Concerns on eCRF). Each subscale 
contains multiple items, and each item has a response of 0 to 4. Scores will be computed for each 
subscale, as well as for the FACIT-F Trial Outcome Index, FACT-G total score, and the FACIT-
F total score.  
The Physical Well-Being subscale contains 7 items. To compute the subscale score, compute the 
item score by subtracting each item response from 4 (item score = 4 – item response), sum the 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
item scores, multiply the sum by 7 and divide by the number of items answered. At least 4 
questions must be answered. If fewer than 4 questions are answered, then the subscale score will 
be missing. The Physical Well-Being score ranges from 0 to 28 with higher scores representing 
better quality of life. 
The Social/Family Well-Being score contains 7 questions. To compute the subscale score, sum 
the item responses, multiply the sum by 7 and divide by the number of items answered. At least 4 
questions must be answered. If fewer than 4 questions are answered, then the subscale score will 
be missing. The Social/Family Well-Being score ranges from 0 to 28 with higher scores 
representing better quality of life. 
The Emotional Well-Being subscale contains 6 items. To compute the subscale score, compute 
the item score first. For items 1, 3, 4, 5, and 6, subtract each item response from 4 (item score = 4 
– item response). For item 2, the item score is the same as the item response (no subtraction is 
needed). Sum the item scores, multiply the sum by 6 and divide by the number of items 
answered to compute the subscale score. At least 3 questions must be answered. If fewer than 3 
questions are answered, then the subscale score will be missing. The Emotional Well-Being 
score ranges from 0 to 24 with higher scores representing better quality of life. 
The Functional Well-Being score contains 7 questions. To compute the subscale score, sum the 
item responses, multiply the sum by 7 and divide by the number of items answered. At least 4 
questions must be answered. If fewer than 4 questions are answered, then the subscale score will 
be missing. The Functional Well-Being score ranges from 0 to 28 with higher scores 
representing better quality of life. 
The Fatigue subscale contains 13 items. To compute the subscale score, compute the item score 
first. For all items except An5 and An7, subtract each item response from 4 (item score = 4 – 
item response). For items An5 and An7, the item score is the same as the item response (no 
subtraction is needed). Sum the item scores, multiply the sum by 13 and divide by the number of 
items answered to compute the subscale score. At least 7 questions must be answered. If fewer 
than 7 questions are answered, then the subscale score will be missing. The Fatigue score ranges 
from 0 to 52 with higher scores representing better quality of life. 
To derive the FACIT-F Trial Outcome Index, sum the subscale scores for Physical Well-Being, 
Functional Well-Being, and Fatigue. If any of these subscale scores is missing, the score for the 
FACIT-F Trial Outcome Index will be missing. The score ranges from 0 to 108.  
To derive the FACT-G score, sum the subscale scores for Physical Well-Being, Social/Family 
Well-Being, Emotional Well-Being, and Functional Well-Being. If any of these subscale scores 
is missing, the FACT-G score will be missing. The score ranges from 0 to 108. 
To derive the FACIT-F total score, sum all 5 subscale scores. If any subscale score is missing, 
the FACIT-F total score will be missing. The score ranges from 0 to 160. 
For each of the five subscale scores and for each of the FACIT-F Trial Outcome Index, the 
FACT-G score, and the FACIT-F total score, summary statistics for the actual values and 
changes from Baseline will be reported at each visit.  
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
7.5 Pharmacokinetic Analyses 
Plasma samples will be analyzed for IPI-145 and IPI-656 (metabolite) concentrations using a 
validated high performance liquid chromatography-tandem mass spectrometry (LC/MS/MS) 
method. The PK data collected will be analyzed by standard population PK methods, using 
appropriate software. Analysis of exposure-response relationships for efficacy and safety 
endpoints will be conducted. If there is only a limited amount of plasma concentration data from 
this study, the data may be pooled with the results of other studies to perform the population PK 
and exposure-response analyses.  Further details on these analyses will be outlined in a separate 
analysis plan. Results of the population PK and exposure-response analysis will be summarized 
in a separate technical report. 
7.6 Biomarker Analyses 
The following exploratory analyses may or may not be presented formally. If presented, they will 
be limited to biomarkers for which data from a sufficient number of subjects are available. 
7.6.1 Pharmacodynamic and Potentially Predictive Biomakers 
The relationship between tumor genomics, gene expression, protein expression, and clinical 
endpoints will be explored as follows: 
• 
Evaluation of serum biomarkers and blood immunophenotype and disease 
biomarkers for pharmacodynamic and predictive diagnostic relationships with IPI-
145 clinical activity and safety 
• 
Evaluation of tumor genomic features (eg, cytogenetics, FISH, DNA sequence 
variation, DNA copy number variation, and/or RNA expression) for 
pharmacodynamic and predictive diagnostic relationships with IPI-145 clinical 
activity 
• 
Evaluation of the relationship between serum and/or tumor biomarkers and disease 
progression of IPI-145 and ofatumumab 
7.6.2 Pharmacogenomics 
DNA may be extracted from the pharmacogenomics sample in order to evaluate a subject’s 
germline DNA.  This sample may be used to explore the following: 
• Evaluate the relationship between germline DNA sequence variations and PK of IPI-
145 
• Evaluate germline DNA as a control to verify that tumor sequence variations are 
somatic mutations 
 
 
 
 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
8 CHANGES IN PLANNED ANALYSES FROM PROTOCOL 
None. 
 
 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
9 REFERENCES 
1 O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 
1979; 35:549-556. 
 
2 Robins JM. Information recovery and bias adjustment in proportional hazard 
regression analysis of randomized trials using surrogate markers. Proceedings of the 
Biopharmaceutical Section, American Statistical Association 1993; pp. 24-33.  
 
3 Robins JM, Finkelstein D.  Correcting for Non-compliance and dependent censoring 
in an AIDS clinical trial with inverse probability of censoring weighted (IPCW) log-
rank tests. Biometrics, 2000; 56(3):779-788. 
 
4 Robins JM, Tsiatis, AA. Correcting for noncompliance in randomized trials using 
rank preserving structural failure time models. Communications in Statistics, 1991; 
20, 2609-2631. 
 
 
 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
10 APPENDICES 
A. PFS censoring rule 
Censoring of PFS will be performed as detailed in the table below.  
 
Primary PFS Censoring / Event Methodology 
Situation 
Date of Event or 
Censoring 
Outcome 
No adequate baseline disease status assessment  Date of randomization 
Censored 
No adequate post-baseline disease status 
assessment unless death occurs prior to first 
post-baseline assessment 
Date of randomization + 1 
Censored 
No documented progression or death before 
data cutoff 
Date of last adequate 
disease status assessment 
Censored 
Documented progression with ≤1 missing 
scheduled disease status assessment before 
progression 
Date of the earliest 
assessment that results in a 
finding of unequivocal 
progression 
Event 
Death before progression being documented 
with ≤1 missing scheduled disease status 
assessment before death 
Date of death 
Event 
Documented progression or death following a 
long gap between adequate disease status 
assessments (eg, 2 or more consecutive missed 
scheduled disease status assessments)  
Date of last adequate 
disease status assessment 
before the gap 
Censored 
New anticancer treatment or procedure started 
before documented progression 
Date of last adequate 
disease status assessment 
Censored 
Note: Disease status assessment includes CT scans (chest, abdomen and pelvis), bone marrow aspirate and/or biopsy 
(may not be required of all subjects at all scheduled disease status assessments), CBC and differential count, focused 
physical examination, disease related constitutional symptoms for disease assessment, and ECOG performance 
status. An adequate disease status assessment is any disease status assessment for which the blinded independent 
central review is able to arrive at a disease status (eg, CR, CRi, PR, PRwL, SD, and PD) per protocol-defined 
criteria.   
 
 
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IPI-145-07                                                                                                                         Infinity Pharmaceuticals, Inc. 
Statistical Analysis Plan 
B. Cochran–Mantel–Haenszel (CMH) test 
 
The Cochran–Mantel–Haenszel (CMH) test compares binary responses of two 
treatment groups, adjusting for stratification factors. In the CMH test, the data are 
arranged in a series of associated 2 × 2 contingency tables, the null hypothesis is that the 
observed response is independent of the treatment used in any 2 × 2 contingency table. 
 
Let 
hij
O
 be the observed frequency of treatment i (i=1 or 2) with outcome j (j= 1 or 2) in 
stratum h and 
hij
E
be the expected frequency of treatment i (i=1 or 2) with outcome j (j= 
1 or 2) in stratum h, where 
 
22
21
12
11
2
1
2
1
)
(
)
(
h
h
h
h
j
h
j
h
hi
hi
hij
O
O
O
O
O
O
O
O
E
+
+
+
+
⋅
+
=
 
 
Also, let 
hij
P
be the probability of outcome being j given treatment being i (i=1 or 2, j= 1 
or 2) in stratum h. To test the following hypothesis, 
 
  
 
21
11
0 :
h
h
P
P
H
=
 for all ℎ∈{1, … , 𝐻𝐻}   
versus   
21
11
1 :
h
h
P
P
H
>
 for at least one ℎ∈{1, … , 𝐻𝐻} 
 
The 1-sided Cochran-Mantel-Haenszel Test Statistics is constructed as: 
 
Z
V
E
O
Z
H
h
h
h
CMH
~
)
(
11
1
11
11
∑
=
−
=
 
 
Where 
 
 
∑
∑
=
=
−
+
+
+
•
=
−
=
H
h
h
h
h
h
h
h
H
h
h
h
O
O
O
O
E
E
E
O
Var
V
1
22
21
12
11
22
11
1
11
11
11
1
))
(
(
 
 
The test statistic 
CMH
Z
  will be compared with standard normal distribution to 
obtain p-value of the CMH test. 
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