A Phase II Study of Intermittent Duvelisib Dosing in Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)
Phase: PHASE2
Conditions: Recurrent Chronic Lymphocytic Leukemia, Recurrent Small Lymphocytic Lymphoma, Refractory Chronic Lymphocytic Leukemia, Refractory Small Lymphocytic Lymphoma
Sponsor: City of Hope Medical Center

IRB #: 19563 
Packet: 02 
10/14/2020 
CITY OF HOPE 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
DEPARTMENT OF HEMATOLOGY AND HEMATOPOIETIC CELL TRANSPLANTATION
TITLE: A Phase II study of intermittent duvelisib dosing in patients with chronic lymphocytic leukemia/small 
lymphocytic lymphoma (CLL/SLL) (19402) 
CITY OF HOPE PROTOCOL NUMBER/VERSION: IRB # 19563  
Protocol Date: 10/14/20 
 
Initial Submission  
 
Protocol dated 03/02/2020 
 
Version: 00 
COH Amendment 01   
Protocol dated 10/14/20 
Packet:   01 
COH Amendment 02   
Protocol dated 10/14/20(TP)  
Packet:   02 
SITE:  
Chronic Lymphocytic Leukemia (CLL)/ Small Lymphocytic 
Lymphoma (SLL)
STAGE (If applicable): 
MODALITY:
TYPE:
Phase II 
PRINCIPAL INVESTIGATOR: 
Alexey Danilov, M.D. 
PARTICIPATING CLINICIANS: 
Elizabeth Budde, M.D., Ph.D. 
Matthew Mei, M.D. 
Liana Nikolaenko, M.D. 
Leslie Popplewell, M.D. 
Steven Rosen, M.D. 
Geoffrey Shouse, D.O. 
Jasmine Zain, M.D. 
Tanya Siddiqi, M.D. 
Swetha Kambhampati, M.D. 
John Baird, M.D. 
BIOSTATISCIAN:
` 
Lu Chen, Ph.D. 

 
 
1 
 
Study Title: 
A Phase II study of intermittent duvelisib dosing in patients with 
chronic lymphocytic leukemia/small lymphocytic lymphoma 
(CLL/SLL) 
Protocol Number:  19563 
Investigational product: Duvelisib 
Version Number:  4.0 
Version Date: 14 Oct 2020 
Replaces: 3.0 dated 02 Mar 2020 
Principal Investigator: 
Alexey Danilov, MD PhD 
City of Hope National Medical Center 
Dept. of Hematology 
1500 E Duarte Rd,  
Duarte, CA 91010 
Phone: 626-218-2405 
Email: adanilov@coh.org 
 
Sub-Investigators at 
COH: 
Elizabeth Budde, MD PhD, Matthew Mei, MD, 
Liana Nikolaenko, MD, Leslie Popplewell, MD 
Steven Rosen, MD, Geoffrey Shouse, DO 
Jasmine Zain, MD. 
 
Co-Investigator at OHSU 
Stephen Spurgeon, MD PhD 
Center for Hematologic Malignancies 
Oregon Health & Science University 
3181 SW Sam Jackson Park Road, L592 
Portland, OR 97239 
Phone: 503-494-8969 
Email: spurgeos@ohsu.edu 
 
Co-Investigator at DFCI 
Jennifer R. Brown, MD PhD CLL Center 
Dana-Farber Cancer Institute 
450 Brookline Ave 
Boston, MA 02215 
Phone: 617-632-6246 
E-mail: Jennifer_Brown@dfci.harvard.edu 
 
Statistician: 
Lu Chen, PhD. 
Dept Computational and Quantitative Medicine 
City of Hope National Medical Center 
Phone: 626-218-6626 
Email: lchen@coh.org  
 
 
 
 

 
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SYNOPSIS 
 
Study Title A Phase II study of intermittent duvelisib dosing in patients with chronic 
lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) 
Protocol # 19563 
Study Center multicenter [U.S. only]   
Sites City of Hope (COH) and Dana Farber Cancer Institute (DFCI) 
Clinical Phase Phase II - Single Agent  
Investigational Component  Investigational Drug  
Interventional Study Type Single-arm 
Précis 
B-cell receptor (BCR)-targeting agents (e.g. ibrutinib, idelalisib) are an 
approved therapy for several B-cell malignancies. However, treatment 
with BCR inhibitors does not result in disease eradication, and the 
remaining cells may be a reservoir of treatment resistance.  Targeting 
phosphatidylinositol 3-kinase (PI3K) has emerged as a promising 
pathway for the treatment of CLL and NHL; however, toxicities of the 
PI3K inhibitors are anticipated to be an important concern limiting their 
use.  Duvelisib is a potent oral inhibitor of both the PI3K-δ and PI3K-γ 
isoforms that is now approved for treatment of relapsed/refractory 
CLL/SLL after at least two prior therapies. It is also approved for 
treatment of relapsed/refractory follicular lymphoma.  This study will 
assess if intermittent administration of duvelisib can result in optimal 
efficacy, but not be associated with severe adverse events.  
Specifically, participants will undergo a duvelisib treatment regimen 
consisting of an induction phase and a maintenance phase.  Whereas 
the induction phase is comprised of continuous dosing of duvelisib (25 
mg b.i.d PO), the maintenance phase will have participants receive 
intermittent dosing of duvelisib consisting of 2 days on-treatment at 75 
mg b.i.d. PO and 5 days off-treatment.  The rationale for this 2-day (i.e., 
4-dose) alternative treatment regimen is thought to facilitate a ‘steady-
state’ concentration of study drug for a significant period of time, which 
effectively mimics the concentrations achieved during continuous 
treatment. Meanwhile, weekly treatment holidays is thought to mitigate 
the adverse events. 
 
Primary Objectives 
To evaluate the efficacy of duvelisib (induction followed by maintenance 
[intermittent dosing]) in patients with relapsed or refractory CLL, as 
measured by the progression-free survival (PFS). 
Secondary Objectives 
1. To evaluate safety of duvelisib induction and maintenance (by 
intermittent dosing) in relapsed/refractory CLL 
2. To evaluate clinical benefits to duvelisib treatment 
Exploratory Objectives To evaluate T-cell populations in patients with CLL treated with 
duvelisib  
Primary Endpoints Proportion of PFS at 12 months  
Secondary Endpoints 
1. Objective Response Rate (including CR and PR rate) 
2. Median PFS 
3. Duration of response 
4. Incidence of toxicity [per CTCAE v5.0 and IWCLL 2018 guidelines] 
5. Duration of therapy 

 
A Phase II study of intermittent duvelisib dosing in patients with CLL/SLL 
COH #19563 
Version # 4.0 
Oct 14, 2020 
PI: Alexey Danilov, MD PhD 
 
 
 
 
 
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Exploratory Endpoints % of T-cell subsets in duvelisib-treated CLL patients  
 
Number of Participants A total of 30 participants are planned for enrollment to this study.  
Duration of Therapy Participants will continue on-study treatment with duvelisib until disease 
progression, or upon occurrence of predefined adverse events 
Duration of Follow Up Until death, next therapy or a minimum of 12 months end of treatment 
Key Inclusion Criteria 
1. Histologically or flow cytometry confirmed diagnosis of B-CLL/SLL  
2. Participant underwent ≥ 1 prior chemotherapy-based or 
immunotherapy-based regimen or targeted therapy (e.g., inhibitors 
of BTK, BCL2 etc.) administered for ≥2 cycles (i.e., ≥8 weeks for 
oral therapies), and have had either documented disease 
progression or no response (stable disease) to the most recent 
treatment regimen.  
i) 
Participants intolerant of ibrutinib therapy and those who 
progress on ibrutinib are eligible as long as they satisfy the 
above criteria.  
3. Patients must demonstrate active disease meeting at least 1 of the 
IWCLL 2008 criteria for requiring treatment: 
i) 
A minimum of any one of the following constitutional 
symptoms: 
• 
Unintentional weight loss >10% within the previous 6 
months prior to screening. 
• 
Extreme fatigue (unable to work or perform usual 
activities). 
• 
Fevers of greater than 100.5 F for ≥2 weeks without 
evidence of infection. 
• 
Night sweats without evidence of infection. 
ii) Evidence of progressive marrow failure as manifested by the 
development of, or worsening of anemia or thrombocytopenia. 
iii) Massive (i.e., >6 cm below the left costal margin), progressive 
or symptomatic splenomegaly. 
iv) Massive nodes or clusters (i.e., > 10 cm in longest diameter) or 
progressive lymphadenopathy. 
v) Progressive lymphocytosis with an increase of >50% over a 2-
month period, or an anticipated doubling time of less than 6 
months. 
vi) Autoimmune anemia or thrombocytopenia that is poorly 
responsive to corticosteroids. 
4. Patients must have ECOG performance status ≤2  
5. Patients must have organ function as defined below: 
i) 
total bilirubin ≤2 X institutional ULN (unless due to known 
Gilbert’s syndrome or compensated hemolysis directly 
attributable to CLL)  
ii) AST or ALT less than 2.5 X institutional ULN  
iii) estimated CrCL using the Cockroft-Gault equation ≥30 mL/min. 
iv) platelets ≥30,000/mm3 independent of transfusion support, with 
no active bleeding, and absolute neutrophil count (ANC) 
≥500/mm3, unless due to disease involvement in the bone 
marrow. 

 
A Phase II study of intermittent duvelisib dosing in patients with CLL/SLL 
COH #19563 
Version # 4.0 
Oct 14, 2020 
PI: Alexey Danilov, MD PhD 
 
 
 
 
 
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Key Exclusion Criteria 
1. Prior therapeutic intervention with any of the following: 
i) 
therapeutic anticancer antibodies within 4 weeks;  
ii) radio- or toxin-immunoconjugates within 10 weeks;  
iii) inhibitors 
of 
BTK 
(ibrutinib), 
BH3-mimetic 
venetoclax, 
lenalidomide and other “targeted” therapy – within 6 half-lives 
(i.e., 36 hours for ibrutinib) 
iv) all other chemotherapy, radiation therapy within 3 weeks prior to 
initiation of therapy. 
v) PI3K inhibitors (idelalisib, copanlisib or any investigational PI3K 
inhibitor including duvelisib and umbralisib) at any time 
2. Inadequate recovery from adverse events related to prior therapy 
to grade ≤1 (excluding Grade 2 alopecia and neuropathy). 
3. Chronic use of corticosteroids in excess of prednisone 30 mg/day 
or its equivalent. 
4. Allogeneic stem cell transplant within the past 12 months, or 
ongoing immunosuppressive therapy other than prednisone ≤ 10 
mg/day (or equivalent) 
5. Use of strong CYP3A4 inhibitors or inducers, in the one week prior 
to initiating study treatment or concomitant 
6. History of prior malignancy except:  
i) 
malignancy treated with curative intent and no known active 
disease present for ≥ 2 years prior to initiation of therapy on 
current study;  
ii) adequately treated non-melanoma skin cancer or lentigo 
maligna (melanoma in situ) without evidence of disease;  
iii) adequately treated in situ carcinomas (e.g., breast, cervical, 
esophageal, etc.) without evidence of disease;  
iv) asymptomatic prostate cancer managed with “watch and wait” 
strategy;  
7. Uncontrolled immune hemolysis or thrombocytopenia (positive 
direct antiglobulin test in absence of hemolysis or history of 
immune-mediated cytopenias are not exclusions). 
8. 
History of Human Immunodeficiency Virus (HIV) infection or active 
hepatitis B or C. 
9. 
Major surgery (requiring general anesthesia) within 2 weeks prior to 
initiation of therapy. 
10. Active uncontrolled infection 
 
Investigational Product Duvelisib 
 
Statistical Considerations 
A sample size of 27 patients produces a two-sided exact Clopper-
Pearson 95% confidence interval with a width equal to 0.39 (0.30-0.69) 
when the target proportion is 0.5. Anticipating a dropout rate of 10%, a 
total of 30 patients will need to be enrolled. 

 
A Phase II study of intermittent duvelisib dosing in patients with CLL/SLL 
COH #19563 
Version # 4.0 
Oct 14, 2020 
PI: Alexey Danilov, MD PhD 
 
 
 
 
 
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SCHEMATIC OF STUDY DESIGN  
 
 

 
A Phase II study of intermittent duvelisib dosing in patients with CLL/SLL 
COH #19563 
Version # 4.0 
Oct 14, 2020 
PI: Alexey Danilov, MD PhD 
 
 
 
 
 
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Contents 
SYNOPSIS ................................................................................................................................. 2 
SCHEMATIC OF STUDY DESIGN ............................................................................................. 5 
LIST OF TABLES ..................................................................................................................... 11 
LIST OF ABBREVIATIONS ...................................................................................................... 12 
1. BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ...................................... 14 
1.1 
Overview of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma ............ 14 
1.2 
B-cell antigen receptor (BCR) Signaling .................................................................... 14 
1.2.1 PI3K Therapeutic Targeting and Toxicity .............................................................. 14 
1.3 
Overview of Duvelisib ............................................................................................... 17 
1.4 
Rationale .................................................................................................................. 18 
1.5 
Potential Risks and Benefits ..................................................................................... 19 
1.5.1 Known Potential Risks .......................................................................................... 19 
1.5.2 Known Potential Benefits ..................................................................................... 19 
1.6 
Exploratory Studies ................................................................................................... 19 
2. OBJECTIVES ...................................................................................................................... 20 
2.1 
Primary Objectives .................................................................................................... 20 
2.2 
Secondary Objectives ............................................................................................... 20 
2.3 
Exploratory Objectives .............................................................................................. 20 
3. STUDY DESIGN AND ENDPOINTS .................................................................................... 21 
3.1 
Description of the Study Design ................................................................................ 21 
3.2 
Study Endpoints ........................................................................................................ 21 
3.2.1 Primary Endpoint .................................................................................................. 21 
3.2.2 Secondary Endpoints ........................................................................................... 21 
3.2.3 Exploratory Endpoints .......................................................................................... 22 
4. STUDY ENROLLMENT AND WITHDRAWAL ..................................................................... 23 
4.1 
Participant Inclusion Criteria ..................................................................................... 23 
4.2 
Participant Exclusion Criteria .................................................................................... 24 
4.3 
Strategies for Recruitment and Retention ................................................................. 25 
4.3.1 Accrual Estimates ................................................................................................ 26 
4.3.2 Inclusion of Children ............................................................................................. 26 
4.4 
Registration Procedures ........................................................................................... 26 
4.4.1 Registration .......................................................................................................... 26 

 
A Phase II study of intermittent duvelisib dosing in patients with CLL/SLL 
COH #19563 
Version # 4.0 
Oct 14, 2020 
PI: Alexey Danilov, MD PhD 
 
 
 
 
 
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4.4.2 Pre-Enrollment Informed Consent and Screening Procedures ............................. 26 
4.4.3 Participant Enrollment .......................................................................................... 26 
4.4.4 Screen Failures and Registered Participants Who Do Not begin Study 
Treatment ........................................................................................................ 28 
5. INVESTIGATIONAL PRODUCT .......................................................................................... 29 
5.1 
Duvelisib ................................................................................................................... 29 
5.1.1 Acquisition ............................................................................................................ 29 
5.1.2 Formulation, Appearance, Packaging and Labeling ............................................. 29 
5.1.3 Product Storage and Stability ............................................................................... 29 
5.1.4 Handling ............................................................................................................... 29 
5.1.5 Administration ...................................................................................................... 29 
5.1.6 Accountability ....................................................................................................... 29 
5.1.7 Destruction and Return ........................................................................................ 30 
6. TREATMENT PLAN............................................................................................................. 31 
6.1 
Dosage and Administration ....................................................................................... 31 
6.1.1 Duvelisib Induction Phase .................................................................................... 31 
6.1.2 Duvelisib Maintenance Phase .............................................................................. 31 
6.2 
Dosing Delays and management of Toxicities ........................................................... 32 
6.3 
Treatment Period and Maintenance .......................................................................... 35 
6.4 
Concomitant Medication and Supportive Care Guidelines ........................................ 35 
6.4.1 Infection Prophylaxis and treatment ..................................................................... 35 
6.4.2 Nausea/vomiting .................................................................................................. 36 
6.4.3 Diet ...................................................................................................................... 36 
6.4.4 Transfusion of platelets and red blood cells (RBC) ............................................... 36 
6.4.5 Anti-platelet agents and anticoagulants ................................................................ 36 
6.4.6 Growth factors ...................................................................................................... 36 
6.4.7 Skin Rashes ......................................................................................................... 36 
6.4.8 Tumor lysis syndrome .......................................................................................... 37 
6.4.9 Contraception ....................................................................................................... 37 
6.4.10 
Use in Pregnancy ............................................................................................ 38 
6.4.11 
Use in Nursing Women .................................................................................... 38 
6.5 
Precautionary Medications, Treatments, and Procedures ......................................... 38 
6.6 
Prohibited Medications, Treatments, and Procedures ............................................... 38 
7. STUDY PROCEDURES/EVALUATIONS AND SCHEDULE ................................................ 39 
7.1 
Study Specific Procedures ........................................................................................ 39 

 
A Phase II study of intermittent duvelisib dosing in patients with CLL/SLL 
COH #19563 
Version # 4.0 
Oct 14, 2020 
PI: Alexey Danilov, MD PhD 
 
 
 
 
 
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7.1.1 Medical history ..................................................................................................... 39 
7.1.2 Disease Assessment ............................................................................................ 39 
7.1.3 Medication history ................................................................................................ 39 
7.1.4 Physical examination ............................................................................................ 39 
7.1.5 Electrocardiogram (ECG) ..................................................................................... 40 
7.1.6 Radiographic or other imaging assessments ........................................................ 40 
7.1.7 Adverse event evaluation ..................................................................................... 40 
7.1.8 Assessment of study agent adherence ................................................................. 40 
7.2 
Laboratory Procedures and Evaluations ................................................................... 40 
7.2.1 Hematology .......................................................................................................... 41 
7.2.2 Biochemistry ........................................................................................................ 41 
7.2.3 Urinalysis ............................................................................................................. 41 
7.2.4 Coagulation panel ................................................................................................ 41 
7.2.5 Pregnancy test ..................................................................................................... 41 
7.2.6 Lymph node biopsy .............................................................................................. 41 
7.2.7 Bone Marrow Biopsy ............................................................................................ 41 
7.3 
Exploratory Studies ................................................................................................... 42 
7.4 
Screening Assessments ........................................................................................... 43 
7.5 
Assessments During Treatment ................................................................................ 43 
7.6 
End of Treatment or Early Termination Visit .............................................................. 44 
7.7 
Follow-up .................................................................................................................. 44 
7.8 
Unscheduled Visits ................................................................................................... 44 
7.9 
Schedule of Events ................................................................................................... 45 
8. EFFICACY MEASURES ...................................................................................................... 47 
8.1 
Disease Evaluation ................................................................................................... 47 
8.2 
Efficacy Criteria for Tumor Response ....................................................................... 47 
8.2.1 Progression-Free Survival .................................................................................... 48 
8.2.2 Objective Response Rate ..................................................................................... 48 
8.2.3 Duration of Response ........................................................................................... 48 
8.3 
Response Review ..................................................................................................... 48 
9. SAFETY ............................................................................................................................... 49 
9.1 
Specification Of Safety Parameters .......................................................................... 49 
9.2 
Definitions ................................................................................................................. 49 
9.2.1 Adverse Event (AE) .............................................................................................. 49 
9.2.2 Serious Adverse Event (SAE) .............................................................................. 49 

 
A Phase II study of intermittent duvelisib dosing in patients with CLL/SLL 
COH #19563 
Version # 4.0 
Oct 14, 2020 
PI: Alexey Danilov, MD PhD 
 
 
 
 
 
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9.3 
Assessment of Adverse Events................................................................................. 50 
9.3.1 Assessment of Adverse Event Name and Grade: ................................................. 50 
9.3.2 Assessment of Attribution ..................................................................................... 51 
9.3.3 Assessment of Expectedness .............................................................................. 51 
9.4 
Adverse Event List .................................................................................................... 52 
9.4.1 Adverse Event List for Duvelisib ........................................................................... 52 
9.5 
Unanticipated Problems (UP) .................................................................................... 52 
9.6 
Adverse Event Assessment and Follow-Up .............................................................. 53 
9.7 
Routine AE Collection and Reporting Guidelines ...................................................... 53 
9.6.1 Reporting of Adverse Events .................................................................................... 53 
9.6.2 Expediting Reporting Requirements of SAEs and UPs ............................................. 54 
9.8 
Reporting to the FDA ................................................................................................ 55 
9.9 
Reporting to Participating Investigators ..................................................................... 55 
9.10 Manufacturer Reporting Requirements ..................................................................... 55 
9.10.1 
Reporting Of Pregnancy .................................................................................. 56 
9.11 Study Stopping Rules ............................................................................................... 56 
10. STATISTICAL CONSIDERATIONS .................................................................................. 58 
10.1 Analysis Populations ................................................................................................. 58 
10.2 Description of Statistical Methods ............................................................................. 58 
10.2.1 
General Approach ........................................................................................... 58 
10.2.2 
Analysis of Primary Endpoint ........................................................................... 58 
10.2.3 
Analysis Of The Secondary Endpoint(S) .......................................................... 58 
10.2.4 
Analysis Of The Exploratory Endpoint(s) ......................................................... 58 
10.3 Sample Size, Power, Accrual Rate and Study Duration ............................................ 59 
10.3.1 
Sample size and Power ................................................................................... 59 
10.4 Handling of Missing Data .......................................................................................... 59 
10.5 Duration of study ....................................................................................................... 59 
11. DATA AND SAFETY MONITORING ................................................................................. 60 
11.1 Protocol deviations ................................................................................................... 60 
11.2 REPORTING OF DEVIATIONS AND PPDS ............................................................. 60 
11.3 All investigator responsibilities .................................................................................. 60 
11.4 Protocol Management team (PMT) ........................................................................... 61 
11.5 Monitoring ................................................................................................................. 61 
11.6 city of hope data and safety monitoring committee ................................................... 62 
12. DATA HANDLING AND MANAGEMENT RESPONSIBILITIES ........................................ 63 

 
A Phase II study of intermittent duvelisib dosing in patients with CLL/SLL 
COH #19563 
Version # 4.0 
Oct 14, 2020 
PI: Alexey Danilov, MD PhD 
 
 
 
 
 
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12.1 Source Data/Documents ........................................................................................... 63 
12.2 Participant & Data Confidentiality .............................................................................. 63 
12.3 Data Collection & Storage: Privacy, Confidentiality & Security .................................. 63 
12.3.1 
Future Use of Stored Specimens ..................................................................... 64 
12.4 Maintenance of Records ........................................................................................... 64 
12.5 Multicenter Guidelines .............................................................................................. 64 
12.6 Publication and Data Sharing Policy ......................................................................... 65 
12.7 Delivery of Progress Reports to Study Funder .......................................................... 65 
13. ETHICS/PROTECTION OF HUMAN PARTICIPANTS ...................................................... 66 
13.1 Ethical Standard ....................................................................................................... 66 
13.2 Regulatory Compliance ............................................................................................. 66 
13.3 Institutional Review Board......................................................................................... 66 
13.4 Informed Consent ..................................................................................................... 67 
13.5 Protocol Review ........................................................................................................ 67 
13.6 Changes to Protocol ................................................................................................. 67 
14. REFERENCES .................................................................................................................. 68 
APPENDIX A: PERFORMANCE STATUS ............................................................................... 71 
APPENDIX B: CONTRACEPTION ........................................................................................... 72 
APPENDIX C: CYTOCHROME INHIBITORS, INDUCERS, AND SUBSTRATES .................... 73 
APPENDIX D: MEDICATION DIARY ....................................................................................... 74 
APPENDIX E: DUVELISIB DRUG ORDER .............................................................................. 78 
APPENDIX F: REGISTRATION COVERSHEET ...................................................................... 79 
APPENDIX G: EXPEDITED REPORTING COVERSHEET ...................................................... 80 
APPENDIX H: CORRELATIVE BLOOD COLLECTION FORM FOR NON-COH SITES ONLY
 
81 
APPENDIX I: BLOOD SHIPPING GUIDELINES TO CITY OF HOPE ...................................... 82 
 
 
 
 
 

 
A Phase II study of intermittent duvelisib dosing in patients with CLL/SLL 
COH #19563 
Version # 4.0 
Oct 14, 2020 
PI: Alexey Danilov, MD PhD 
 
 
 
 
 
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LIST OF TABLES 
 
Table 1. PI3K Inhibitors in clinical development ........................................................................15 
Table 2. Population Demographics and Projected Accruals for Oregon ..... Error! Bookmark not 
defined. 
Table 3. Population Demographics and Projected Accruals for Massachusetts Error! Bookmark 
not defined. 
Table 4. Recommended Duvelisib Dose Modifications for Non-hematologic Adverse Reactions
 .................................................................................................................................................32 
Table 5. Recommended Duvelisib Dose Modifications for Hematologic Adverse Reactions* ....34 
Table 6. Duvelisib Dose Modifications .......................................................................................35 
Table 7. Recommended Management by Toxicity Grade – Skin rash .......................................36 
Table 8. Response Definition for CLL/SLL .................................. Error! Bookmark not defined. 
Table 9. Summary of most frequent TEAEs – All Disease Groups ............................................52 
Table 10. Summary of most frequent TEAEs – R/R CLL/SLL ....................................................52 
Table 11. Sample size estimate ................................................................................................59 
 
 
 
 

 
A Phase II study of intermittent duvelisib dosing in patients with CLL/SLL 
COH #19563 
Version # 4.0 
Oct 14, 2020 
PI: Alexey Danilov, MD PhD 
 
 
 
 
 
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LIST OF ABBREVIATIONS 
 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical (Classification System) 
AUC 
Area under the curve 
BCR 
B-cell antigen receptor 
BUN 
Blood urea nitrogen 
CBC 
Complete blood cell (count) 
CFR 
United States Code of Federal Regulations  
CoC 
National Institutes of Health (NIH) Certificate of Confidentiality 
CLL 
Chronic lymphocytic leukemia 
CR 
Complete remission 
CRC 
Clinical Research Coordinator 
CRMS 
Clinical research management system 
CRQA 
Clinical Research Quality & Administration 
CRRC 
Clinical Research Review Committee (OHSU) 
CRF 
Case report form 
CT 
Computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMC 
Data and Safety Monitoring Committee 
DSMP 
Data and Safety Monitoring Plan 
ECG, EKG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
eCRIS 
Electronic Clinical Research Information System 
EDC 
Electronic data capture 
FDA 
United States Food and Drug Administration 
FL 
Follicular lymphoma 
GCP 
Good Clinical Practice 
HBeAg 
Hepatitis B “e” antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIPPA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IND 
Investigational new drug application 
IGHV 
Immunoglobulin heavy chain variable region 
IRB 
Institutional Review Board 
iwCLL 
International Workshop on Chronic Lymphocytic Leukemia 
LDH 
Lactate dehydrogenase 
LFT 
Liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
NHL 
Non-Hodgkin’s lymphoma 
OHRP 
Office for Human Research Protections 
OHSU 
Oregon Health & Science University 

 
A Phase II study of intermittent duvelisib dosing in patients with CLL/SLL 
COH #19563 
Version # 4.0 
Oct 14, 2020 
PI: Alexey Danilov, MD PhD 
 
 
 
 
 
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ORR 
Objective response rate 
PD 
Progressive Disease 
PET 
Positron emission tomography 
PFS 
Progression free survival 
PI 
Principle Investigator 
PI3K 
Phosphatidyl-inositol 3 kinase 
PK 
Pharmacokinetics 
PO 
Per os (by mouth, orally) 
PR 
Partial remission 
RBC 
Red blood cell (count) 
RNI 
Reportable new information 
SAE 
Serious adverse event 
SLL 
Small lymphocytic leukemia 
TCL 
T-cell lymphoma 
T-reg 
T regulatory 
ULN 
Upper limit of normal 
UP 
Unanticipated problem 
WBC 
White blood cell (count) 
 

 
A Phase II study of intermittent duvelisib dosing in patients with CLL/SLL 
COH #19563 
Version # 4.0 
Oct 14, 2020 
PI: Alexey Danilov, MD PhD 
 
 
 
 
 
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1. BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
 
1.1 
OVERVIEW OF CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC 
LYMPHOMA 
 
Chronic lymphocytic leukemia (CLL) accounts for nearly 34% of all new leukemia cases and 
1.2% of all new cancer cases in the United States.1  The majority (>70%) of patients with CLL 
are aged >65 years, with males affected nearly 2-times more often than females.  In the United 
States, approximately 20,940 new cases of CLL and 4,510 deaths are expected in 2018.  The 
disease is characterized by the clonal proliferation and accumulation of mature and typically 
CD5+ B-cells within the blood, bone marrow, lymph nodes, and spleen.  In the absence of 
peripheral clonal lymphocytes, the presence of clonal B-cell populations within enlarged lymph 
nodes is termed small lymphocytic lymphoma (SLL), and is considered a clinical variant of the 
same histopathologic disease.  
 
1.2 
B-CELL ANTIGEN RECEPTOR (BCR) SIGNALING 
 
Constitutive activation of the B-cell antigen receptor (BCR) appears to be a key driver of CLL, 
whereby BCR activation elicits activation of Src family kinases SYK and LYN that in turn 
activates Bruton’s tyrosine kinase (BTK) and phospholipase C (PLC)-γ2 molecules.2  Likewise, 
BCR signaling also elicits activation of the phosphatidylinositol 3 kinase (PI3K) δ subunit, which 
further elicits AKT-mediated activation of multiple downstream effectors that promote 
proliferation and survival.3,4  Both BTK and PI3K-δ activation are intrinsically higher in CLL, and 
their identification as important mediators of BCR signaling has resulted in the development of 
several targeted therapies that have entered the clinic (e.g., ibrutinib and idelalisib, 
respectively).5 
 
Ibrutinib is an oral selective and irreversible inhibitor of BTK that prevents kinase activity and 
blocks downstream signaling pathways.  Approved for the therapy of any CLL patient in any line 
of therapy, ibrutinib is associated with durable clinical responses in relapsed/refractory (R/R) 
CLL patients, as well as those that have high-risk (17p deletion) cytogenetic abnormalities.  
Treatment with ibrutinib in patients with relapsed/refractory CLL yields an overall response rate 
(ORR) of 70–90%, but complete remission is only achieved in a relative minority of patients.6-8  
A pooled analysis of the PCYC-1102 and PCYC-1112 studies, in which CLL patients received 
single agent ibrutinib, revealed that 32 of 327 patients (9.8%) achieved a complete response 
(CR), where the median time to CR was 14.7 months.9  Although the precise incidence is 
unknown, resistance to ibrutinib emerges early in up to 13% of patients with all R/R CLL, and in 
up to 43% of high-risk patients.10  Regardless, for those patients that develop resistance to 
ibrutinib, the outcome is extremely poor, with ~3 months of median survival following 
discontinuation.11  For such patients treatment options are limited and commonly include a PI3K 
inhibitor (e.g., idelalisib in combination with rituximab), a BH3-mimetic venetoclax, 
chemotherapy, or investigational agents.5  
 
1.2.1 PI3K THERAPEUTIC TARGETING AND TOXICITY 
 
The PI3K heterodimer is comprised of a catalytic and regulatory subunit, with the p110 catalytic 
subunit of PI3K existing as four possible isotypes: alpha, beta, gamma, and delta.  Whereas 
p110-α and p110-β subunits are ubiquitously expressed in mammalian tissue, the expression of 
p110-δ and p110-γ subunits is predominantly found in leukocytes and are shown to contribute to 
a variety of hematological malignancies.12,13 In CLL patients with leukemic clones having 
minimal (< 2% difference from germline) or no mutation in the immunoglobulin heavy chain 
variable region (IGHV) gene (unmutated CLL [U-CLL]) the prognosis is worse than those with 
IGHV-mutated CLL (M-CLL).14,15  Notably, PI3K-mediated signaling is constitutively activated in 

 
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CLL, where U-CLL patients have significantly greater PI3K expression compared to those with 
M-CLL.16,17  Likewise, the elevated activation of PI3K-AKT signaling in ibrutinib-resistant 
lymphomas has provided further rationale for subsequent targeting of the PI3K-AKT pathway as 
means to overcome ibrutinib resistance.18   
 
There are several PI3K inhibitors in different stages of clinical development (Table 1); however, 
notable toxicities such as increased incidences of colitis, hepatitis, pneumonitis, and infectious 
complications, have limited their use in widespread clinical practice. It has been proposed that 
these treatment-emergent adverse events (TEAEs) are immune-mediated, and, in general, may 
be attributed to an overall PI3K inhibitor class effect. Moreover, these TEAEs appear more 
frequently in patients with an intact immune system not previously treated; a phenomenon that 
is possibly associated with multiple rounds of prior therapy having further compromised their 
immune system.19  
 
Table 1. PI3K Inhibitors in clinical development 
Drug 
PI3K 
Specificity 
Cancers 
Clinical 
Trial 
Phase 
Clinical Trial 
Status 
Idelalisib 
Δ 
R/R CLL, lymphoma 
I-III 
FDA-
approved 
Duvelisib 
γ/δ 
R/R CLL, lymphoma 
I-III 
FDA-
approved 
TGR-1202 
Δ 
CLL, lymphoma 
I-III 
Ongoing 
AMG319 
Δ 
B-cell malignancies, HNSCC 
I 
Discontinued 
Acalisib 
β/δ 
Lymphoid malignancies 
I 
Ongoing 
Copanlisib 
Pan 
MCL, iNHL, breast cancer, HNSCC 
I-III 
FDA-
approved 
Pilaralisib 
Pan 
CLL, lymphoma, solid malignancies 
I and II 
Completed 
Buparlisib 
Pan 
CLL, glioblastoma, breast cancer, 
lung cancer 
I 
Ongoing 
SAR260301 
Β 
Various 
I 
Ongoing 
GSK263677
1 
Β 
Lymphoma, prostate cancer, gastric 
cancer 
I 
Ongoing 
PX-866 
Pan 
NSCLC, prostate cancer, 
glioblastoma 
I and II 
Ongoing 
Alpelisib 
Α 
Metastatic breast cancer 
I-III 
Ongoing 
Pictilisib 
α/δ 
Breast cancer, NSCLC 
I 
Ongoing 
AZD8186 
β/δ 
NSCLC, prostate cancer, TNBC 
I 
Ongoing 
ZSTK474 
Pan 
Solid malignancies 
I 
Ongoing 
Table adapted from Vangapandu et al20 
 
Idelalisib is a potent and selective inhibitor of p110-δ, which is FDA-approved for use in 
relapsed/refractory CLL, follicular lymphoma (FL), and small lymphocytic lymphoma (SLL).21  
Preferential inhibition of p110-δ by idelalisib inhibits pro-survival pathways, and the combination 
of idelalisib and rituximab is associated with producing an overall response rate (ORR) of 77% 
and a 12-month PFS of 66% in R/R CLL.22  Although efficacious, idelalisib administration is also 
associated with several toxicities; particularly, the occurrence of autoimmune and infectious 
toxicities, including grade ≥ 3 transaminitis, hypotension, rash, sepsis, and pulmonary 
infiltrates.23-26  Additionally, idelalisib is also associated with late-onset induced diarrhea, where 
many patients who are treated with idelalisib for ≥3 months and develop colitis exhibit findings 
intestinal inflammation with intra-epithelial lymphocytosis, crypt cell apoptosis, and neutrophilic 

 
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infiltration of crypt epithelium.27,28  The delayed onset of idelalisib-induced diarrhea is thought to 
be a symptom of autoimmune-mediated colitis.27 
 
Duvelisib is a potent oral inhibitor of both the p110-δ and p110-γ isoforms. The FDA granted 
approval for use of duvelisib in adult patients with relapsed or refractory CLL/SLL or follicular 
lymphoma (FL) who have received at least two prior therapies. Clinical investigators who 
participated in a phase I study reported on the safety and efficacy of duvelisib given to 210 
patients with advanced hematological malignancies.29  Patients were administered duvelisib 
twice daily in continuous 28 day cycles (dose range = 8-100 mg) for a median treatment 
duration of 16 weeks across all doses. The authors observed clinical responses across several 
disease subtypes with the ORR in patients with iNHL (n=31), R/R CLL (n = 55), peripheral T-cell 
lymphoma (TCL; n = 16), and cutaneous TCL (n=19) reported as 58%, 56%, 50%, 32%, 
respectively.  The median time to response was approximately 1.8 months.  Specifically, among 
the 55 patients with R/R CLL, the authors reported 1 complete response (CR), 30 partial 
response (PR), and a median PFS of 15.7 months.  Similar to results from patients treated with 
idelalisib, severe (grade ≥3) adverse events occurred in 84% of patients administered duvelisib, 
including: neutropenia (32%), alanine transaminase (ALT) increase (20%), aspartate 
transaminase (AST) increase (15%), anemia and thrombocytopenia (each 14%), diarrhea 
(11%), and pneumonia (10%). Severe diarrhea had a late onset of 5 to 6 months from start of 
treatment.29   
 
Copanlisib is a pan-class I PI3K inhibitor, with predominant activity against the p110-α and 
p110-δ isoforms. U.S. Food and Drug Administration granted accelerated approval to copanlisib 
(ALIQOPA, Bayer HealthCare Pharmaceuticals Inc.) for the treatment of adult patients with 
relapsed FL who have received at least two prior systemic therapies. Dreyling et al30 carried out 
a phase 2 study to evaluate the clinical efficacy of administering copanlisib to 84 patients with 
either indolent lymphoma (n = 33) or aggressive lymphoma (n = 51).  Patients in this study were 
given copanlisib intravenously (0.8 mg/kg) on days 1, 8, and 15 of a 28 day cycle. The authors 
reported an objective response rate of 44% and 27% in the indolent and aggressive disease 
cohorts, respectively. The median PFS across the indolent and aggressive disease cohorts was 
294 days and 70 days, respectively. Serious grade ≥ 3 treatment emergent adverse events 
(TEAEs) occurring in two or more patients included: grade 3 lung infection (10.7%), grade 3 
diarrhea (3.6%), and grade 3 febrile neutropenia (3.6%).  Additional severe toxicities observed 
included grade 4 decreased neutrophil count, grade 3 hyperglycemia, grade 3 pneumonitis, 
grade 3 pancreatitis, grade 3 cardiac disorders—other, and grade 3 infection/infestations (2.4% 
each).30   
 
In contrast to reports of adverse effects of idelalisib and duvelisib, onset of copanlisib-induced 
diarrhea was reported in 40.5% of patients, of which only 4.8% had diarrhea grade ≥3, and there 
were no reports of colitis.30  Moreover, results of several idelalisib studies have reported a 48% 
to 60% incidence of all-grade elevations in aminotransferases, with an 8% to 13% incidence of 
grade ≥3 elevations.23,25,26  Likewise, duvelisib was associated with 38% incidence of all-grade 
elevations in aminotransferases, with a 15% to 19.5% incidence of grade ≥ 3 elevations.29 In 
contrast, Dreyling et al30 reported that the incidence of ALT and AST elevations associated with 
intermittent copanlisib treatment were grade 1 events (23.2% and 24.4%, respectively), with 
only a small proportion of patients experiencing grade 3 ALT and AST elevations (3.7% and 
2.4%, respectively).  
 
1.2.1.1 PI3K inhibition in T-cells and autoimmune toxicity 
 
The p110-δ and p110-γ isoforms appear to be important in the functioning of regulatory T-
cells.31  Though the exact mechanism is unknown, in vivo mouse modeling of single point 
mutation in p110-δ resulted in its inactivation, and was associated with the mice developing 

 
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inflammatory bowel disease in the large intestine.32  Similar to B-cell targeting of p110-δ and 
p110-γ isoforms, emerging evidence suggests that PI3K inhibitors also inactivate these isoforms 
in T-cells, and this may be associated with autoimmune toxicity.  
 
O’Brien et al33 observed the presence of T-cell infiltrates in the colonoscopic biopsies of patients 
with diarrhea after receiving idelalisib.  In another study, Matos et al34 observed that patients 
who received idelalisib had decreased number of T regulatory (Treg) cells that resulted in a 
comparatively higher ratio of conventional CD4 and CD8 T-cells to Tregs, respectively. Though 
there was no difference observed in these ratios between patients who did or did not experience 
autoimmune toxicities, the authors noted that in patients who developed autoimmunity, baseline 
Tregs had higher expression of PD-1 and lower expression of certain other markers, such as 
GITR, Tbet, CXCR3, PDL-1, granzyme-β and TIM-3. 
 
1.3 
OVERVIEW OF DUVELISIB 
 
Duvelisib’s affinity for targeted inhibition of both p110-δ and p110-γ isoforms is being exploited 
as a potential therapeutic for a variety of hematologic malignancies.  In addition to perturbing 
BCR and cytokine-dependent survival signaling, the combined inhibition of p110-δ and p110-γ 
also impacts the functional microenvironment supporting CLL tumor cells.  For example, 
duvelisib inhibition of p110-γ can prevent the migration of T-cells, which in turn play a role in 
supporting CLL tumor cell survival by way of producing cytokines and cell-to-cell contact.35   
 
Over 20 completed or ongoing clinical studies have been implemented to assess the safety and 
efficacy of duvelisib in the treatment of hematological malignancies, asthma, and rheumatoid 
arthritis.  Oral administration of duvelisib is characterized by rapid absorption, with peak 
concentrations occurring approximately 0.5 to 2 hours after dosing.  The mean half-life of 
duvelisib ranges from 2.6 to 7.5 hours, with steady state concentrations reached within 48 to 72 
hours.36  Results of study IPI-145-02, a phase 1, open-label, dose escalation study established 
the maximum tolerated dose (MTD) of duvelisib as being 75 mg b.i.d.. In this study, 124 patients 
were treated with 75 mg p.o. bid, with a median time on therapy of 4 months.  The adverse 
event profile and efficacy were similar between the two doses (25 mg po, b.i.d and 75 mg po 
b.i.d).  Administration of duvelisib at 25 mg b.i.d provided clinically meaningful activity (i.e., rapid 
and sustained reductions in p-AKT and Ki67 expression) and was selected as the 
recommended dose in CLL and B-cell lymphoma.29  Meanwhile, duvelisib is used at 75 mg po 
b.i.d in combination studies in T-cell lymphoma, as it is anticipated that additional PI3K-γ 
isoform inhibition will be achieved at this dose level. Refer to investigator brochure for additional 
details regarding pharmacokinetics, pharmacodynamics, as wells safety and efficacy results.36   
 
Flinn et al37 reported on IPI-145-07 (DUO, NCT02004522), a 2-arm, randomized, open label, 
phase III trial designed to compare the efficacy and safety of duvelisib to ofatumumab in 
patients with R/R CLL/SLL.  Three-hundred and nineteen (319) patients with R/R CLL/SLL were 
randomized 1:1 to receive either duvelisib (25 mg b.i.d) or ofatumumab.  The authors observed 
a median progression free survival (mPFS) of 13.3 months among those treated with duvelisib 
compared to 9.9 months for those receiving ofatumumab; representing a 48% reduction in the 
risk of progression or death.  The ORR was significantly greater among those receiving 
duvelisib over ofatumumab (73.8% vs 45.3%, respectively; p<0.0001), with reduced lymph node 
burden >50% among duvelisib-treated patients versus those in the ofatumumab treatment arm 
(85% vs 16%).  Overall Survival (OS) was similar for those randomized to either duvelisib or 
ofatumumab.  In an extension to this study, Kuss et al38 further showed that among 89 patients 
that had disease progression with ofatumumab that were allowed to crossover to the duvelisib 
treatment arm, achieved an ORR of 73%, with a mPFS of 15 months.  Moreover, 83% of 
evaluable patients had >50% reduction in target nodal lesions.  
 

 
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1.4 
RATIONALE 
 
Therapy with both idelalisib and duvelisib has been associated with delayed severe adverse 
events, including diarrhea/colitis and pneumonitis.  Increased levels of liver transaminases are 
also commonly observed among patients receiving either idelalisib or duvelisib.  Moreover, the 
risk of those adverse events is highest in patients who have not received prior therapy and 
younger patients.19  As CLL therapy moves toward targeted agents such as ibrutinib, and many 
patients are never exposed to chemotherapy, toxicities of the PI3K inhibitors are anticipated to 
be an important concern limiting their widespread use. 
 
In contrast to both idelalisib and duvelisib, copanlisib, is associated with very low frequency of 
autoimmune events.19,29,30  While p110-δ inhibition is known to down-modulate suppressive T-
regs39, targeted inhibition of p110-α has limited effect on T-cell function.40  Rather, one 
explanation for reduced autoimmune toxicity observed with copanlisib may be related to 
interrupted dosing.  Specifically, Dreyling et al30 reported that copanlisib was administered 
intravenously on days 1, 8, and 15 of a 28 day cycle.  Given the half-life of copanlisib (t1/2 = 39.1 
hours [range: range: 14.6 to 82.4 hours]), weekly IV administration results in strong fluctuations 
in plasma drug concentration, it is possible that intermittent saturation of the target is sufficient 
to induce durable anti-tumor responses.  This study is founded on the hypothesis that similar, 
intermittent administration of duvelisib will result in optimal efficacy, but will not be associated 
with severe adverse events.   
 
This study is intended to assess whether intermittent dosing of duvelisib can achieve clinical 
efficacy while reducing unwanted treatment-related toxicities.  Specifically, participants will 
receive a duvelisib treatment regimen consisting of an induction phase and a maintenance 
phase.  Whereas the induction phase is comprised of continuous dosing of duvelisib (25 mg 
b.i.d PO), the maintenance phase will have participants receive intermittent dosing of duvelisib 
75 mg b.i.d PO consisting of 2 days on-treatment and 5-days off-treatment.  The rationale for 
this 2-day (i.e., 4-dose) intermittent treatment regimen is thought to facilitate a ‘steady-state’ 
concentration of study drug, which effectively mimics the concentrations achieved during 
continuous treatment, for a short period of time. In general, the approximate maximal 
concentration (Cmax) of duvelisib following 25 mg b.i.d administration is 3 µM.  Given that the 
mean t1/2 of duvelisib ranges from 2.6 to 7.5 hours following multiple dose administrations, 
steady state concentrations are expected to be reached within 48-72 hours.  
 
During the maintenance phase of the study, we will use duvelisib 75 mg PO b.i.d., rather than 
25 mg po b.i.d. for 2 out of 7 days. While duvelisib 25 mg po b.i.d achieves nearly complete 
inhibition of PI3K-δ isoform, this dose only reaches ~50% of PI3K-γ isoform. It is hoped that 
higher dose of duvelisib will help reach improved coverage of the PI3K-γ isoform and thus 
modulation of the microenvironment.  In the Phase I study (IPI-145-02), 124 patients were 
treated with 75 mg PO b.i.d, with a median time on therapy of 4 months.  Of those patients, 22 
patients had relapsed/refractory CLL.  While not directly compared, the adverse event profile 
and efficacy were similar between the two doses.  The respective frequency of AEs in patients 
treated with 75 mg PO b.i.d or 25 mg PO b.i.d., corresponded as follows: febrile neutropenia -
11.3% and 6%, gastrointestinal AEs – 17.7% and 18.2%, colitis 4% and 6.1%, and infections – 
29.8% and 24.2% Currently, duvelisib is used at 75 mg po b.i.d in combination studies in T-cell 
lymphoma. 
 
This study is focused on examining intermittent therapy in R/R CLL/SLL patients.  As such, it is 
anticipated that patients who progress on ibrutinib or venetoclax will likely be enrolled on to this 

 
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study.  Results of a prior study show that patients that progress on ibrutinib and receive 
subsequent treatment with idelalisib have a PFS of approximately 9 months; however, nearly 
half of these patients discontinue idelalisib due to toxicity.41  Thus, with the goal of reducing 
TEAEs via intermittent duvelisib dosing, this study anticipates a lower discontinuation rate and 
expects the PFS to be similar to that reported with continuous therapy.  As such, the primary 
endpoint of this study is to evaluate a target PFS of 50% at 12 months.  
 
1.5 
POTENTIAL RISKS AND BENEFITS 
 
1.5.1 KNOWN POTENTIAL RISKS  
 
Frequent treatment-emergent severe adverse events (TESAE); i.e., occurring in ≥ 5% of 
patients) across hematologic oncology studies include febrile neutropenia, pneumonia, diarrhea, 
disease progression, and pyrexia.36  Refer to investigator’s brochure and Section 9.4 for 
additional information.  
 
1.5.2 KNOWN POTENTIAL BENEFITS 
 
Intermittent dosing may alleviate TEAEs associated with PI3K inhibitors and may provide 
access to a new treatment approach not previously available.  It cannot, however, be 
guaranteed that participants in this study will directly benefit from treatment during participation, 
as the clinical trial is designed to provide information about the safety and effectiveness of the 
investigational approach. 
 
1.6 
EXPLORATORY STUDIES 
 
Limited data exist regarding the functional outcomes of in vivo targeting of different PI-3K 
isoforms in T-cells. In preclinical studies, selective targeting PI3Kδ with a tumor-specific vaccine 
down-modulated suppressive Treg cells and increased numbers of vaccine-induced CD8 T-cells 
within the tumor microenvironment, eliciting potent antitumor efficacy 39. Therefore, targeting 
PI3Kγ/δ is expected to result in enhanced expression of T-cell activation markers, and down-
modulation of Treg cells, an increase in Th17 cells with increased T-cell mediated cytotoxicity. 
However, we anticipate that intermittent dosing of duvelisib may result in attenuated effects on 
the immune system.  In this setting, it is possible that we will observe recovery of Treg cells 
following completion of duvelisib induction.  We will use this hypothesis as a rationale for 
detailed evaluation of T-cell repertoire and the T-cell activation markers following induction and 
maintenance therapy with duvelisib. 
 

 
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2. OBJECTIVES 
 
2.1 
PRIMARY OBJECTIVES 
 
To evaluate the efficacy of duvelisib (induction followed by maintenance [intermittent dosing]) in 
patients with relapsed or refractory CLL, as measured by the PFS. 
 
2.2 
SECONDARY OBJECTIVES 
 
1. To evaluate safety of duvelisib induction and maintenance (by intermittent dosing) in 
relapsed/refractory CLL 
2. To evaluate clinical benefits to duvelisib treatment 
 
2.3 
EXPLORATORY OBJECTIVES 
 
To evaluate T-cell populations in patients with CLL treated with duvelisib. 

 
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3. STUDY DESIGN AND ENDPOINTS 
 
3.1 
DESCRIPTION OF THE STUDY DESIGN 
 
Refer to Section 10, Statistical Considerations, for additional information regarding statistical 
methods used in this study. 
 
This is a phase II, single-arm, open label study to assess the efficacy and safety of intermittent 
maintenance dosing of duvelisib in patients with R/R CLL/SLL.  Participants must meet the 
inclusion criteria, have none of the exclusion criteria, and have provided written informed 
consent before the conduct of any screening tests not performed routinely in their treatment. 
 
In this study, eligible participants with R/R CLL/SLL will receive duvelisib treatment in two 
phases: induction and maintenance.  In the induction phase, duvelisib (25 mg b.i.d, PO) will 
be administered to participants in a continuous fashion for 12 weeks (i.e., three 4-week cycles). 
Participants that experience predefined adverse toxicities during the 12 week induction period 
(see Section 6.1.1) may switch early to the maintenance phase of treatment regimen (i.e., 
before the end of 12 week induction period).  Participants entering the maintenance phase of 
the treatment regimen will receive duvelisib (75 mg b.i.d, PO) for 2 consecutive days (i.e., 4 
doses) followed by a 5-day break in treatment.  This intermittent dosing schedule will continue 
until participants experience prohibitive adverse events, or undergo disease progression.  
 
Primary and secondary endpoints in this study will evaluate the clinical efficacy and safety 
associated with duvelisib induction and intermittent maintenance dosing.  This study plans on 
enrolling 30 participants with R/R CLL/SLL.   
 
3.2 
STUDY ENDPOINTS 
 
3.2.1 PRIMARY ENDPOINT 
 
Endpoint 
Start  
End  
Proportion of PFS at 12 months  
First 
dose of 
duvelisib 
Death, time of progression, start of new 
therapy, or 12 months from start of therapy, 
whichever occurs first  
 
3.2.2 SECONDARY ENDPOINTS 
 
Endpoint 
Start  
End  
1. Objective Response Rate (ORR) 
First 
dose of 
duvelisib 
At designated time points 
2. Median PFS 
Death, time of progression, or start of new 
therapy, whichever occurs first 
3. Duration of response 
Time of 
ORR 
Death, time of progression, start of new 
therapy, or end of follow-up, whichever 
occurs first 
4. Incidence of toxicity  
 
First 
dose of 
duvelisib 
3 months post-discontinuation of duvelisib 
5. Duration of therapy  
Time of duvelisib discontinuation 
 

 
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3.2.3 EXPLORATORY ENDPOINTS 
 
Endpoint 
Start  
End  
Percent distribution of circulating T-cells 
within duvelisib-treated CLL patients 
First dose 
of duvelisib 
After 3 (end of induction), 6 and 12 
cycles of therapy 
 

 
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4. STUDY ENROLLMENT AND WITHDRAWAL 
 
Patient MRN (COH Only) 
Patient Initials (F, M, L): 
Institution:     
 
4.1 
PARTICIPANT INCLUSION CRITERIA 
 
To be eligible to participate in this study, an individual must meet all of the following criteria: 
 
1. Ability to understand and the willingness to sign a written informed consent document. 
2. Participants are ≥ 18 years old at time of informed consent. 
3. Histologically or flow cytometry confirmed diagnosis of B-CLL/SLL according to NCI-WG 
1996 guidelines. Patients who lack CD23 expression on their leukemia cells should be 
examined for (and found NOT to have) either t(11;14) or cyclin D1 overexpression, to rule 
out mantle cell lymphoma. 
4. Participants have undergone ≥ 1 prior chemotherapy-based or immunotherapy-based 
regimen or targeted therapy (e.g., inhibitors of BTK [e.g., ibrutinib], or BCL2 [e.g., 
venetoclax]) administered for ≥2 cycles (≥8 weeks for oral therapies), and have had either 
documented disease progression or no response (i.e., stable disease [SD]) to the most 
recent treatment regimen.  
Note: Individuals intolerant to ibrutinib therapy and those who progress on ibrutinib are 
eligible as long as they satisfy the above criteria.  
5. Patients with CLL/SLL must demonstrate active disease meeting at least 1 of the IWCLL 
2018 criteria for requiring treatment: 
i) A minimum of any one of the following constitutional symptoms: 
• Unintentional weight loss >10% within the previous 6 months prior to screening. 
• Extreme fatigue (unable to work or perform usual activities). 
• Fevers of greater than 100.5°F for ≥2 weeks without evidence of infection. 
• Night sweats without evidence of infection. 
ii) Evidence of progressive marrow failure as manifested by the development of, or 
worsening of anemia or thrombocytopenia. 
iii) Massive (i.e., >6 cm below the left costal margin), progressive or symptomatic 
splenomegaly.  
iv) Massive nodes or clusters (i.e., > 10 cm in longest diameter) or progressive 
lymphadenopathy. 
v) Progressive lymphocytosis with an increase of >50% over a 2-month period, or an 
anticipated doubling time of less than 6 months. 
vi) Autoimmune anemia or thrombocytopenia that is poorly responsive to corticosteroids. 
vii) Symptomatic or functional extranodal involvement (eg, skin, kidney, lung, spine) 
6. Patients must have ECOG performance status ≤ 2 (Appendix A). 
7. Prior to starting study agent, participant must have organ function as defined below: 

 
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i) Total bilirubin ≤2 X institutional upper limit of normal (ULN); unless due to known 
Gilbert’s syndrome or compensated hemolysis directly attributable to CLL 
ii) AST or ALT less than 2.5 X institutional ULN  
iii) Estimated CrCL using the Cockroft-Gault equation (or an alternative equation, per 
institutional standard) ≥30 mL/min.   
iv) Platelets ≥30,000/mm3 independent of transfusion support, with no active bleeding, 
and absolute neutrophil count (ANC) ≥500/mm3, unless due to disease involvement in 
the bone marrow. 
8. Participant must be able to swallow tablets or capsules.  A participant with any 
gastrointestinal disease that would impair ability to swallow, retain, or absorb drug is not 
eligible. 
9. Female participants of childbearing potential (defined as a sexually mature woman who has 
not undergone surgical sterilization or who has not been naturally postmenopausal for at 
least 12 consecutive months for women >55 years of age) must have a negative urine or 
serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If 
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be 
required.   
10. Female participants of childbearing potential must agree to use adequate methods of 
contraception (Appendix B) starting with the first dose of study therapy through 60 days 
after the last dose of study therapy.   
Participants of childbearing potential are those who have not been surgically sterilized or 
have not been free from menses for >1 year without an alternative medical cause.  
11. Male participants must agree to use an adequate method of contraception (Appendix B) 
starting with the first dose of study therapy through 60 days after the last dose of study 
therapy.  
 
4.2 
PARTICIPANT EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
 
1. Prior therapeutic intervention with any of the following: 
i) Therapeutic anticancer antibodies within 4 weeks; 
ii) Radio- or toxin-immunoconjugates within 10 weeks;  
iii) Inhibitors of BTK (e.g., ibrutinib), BH3-mimetic venetoclax, lenalidomide and other 
“targeted” therapy – within 6 half-lives (i.e., 36 hours for ibrutinib) 
iv) All other chemotherapy, radiation therapy within 3 weeks prior to initiation of therapy.  
v) PI3K inhibitors (idelalisib, copanlisib or any investigational PI3K inhibitor including 
duvelisib and umbralisib) at any time 
2. Any adverse event related to prior therapy that has not recovered to grade ≤ 1 
3. Chronic use of corticosteroids in excess of prednisone 30 mg/day or its equivalent. 
4. Allogeneic stem cell transplant within the past 12 months, or ongoing immunosuppressive 
therapy other than prednisone ≤ 10 mg/day (or equivalent) 

 
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5. Use of strong CYP3A4 inhibitors or inducers, in the one week prior to initiating study 
treatment or concomitant.  
6. Unable to receive prophylactic treatment for pneumocystis, herpes simplex virus (HSV), or 
herpes zoster (VZV) at screening 
7. History of prior malignancy except:  
i) Malignancy treated with curative intent and no known active disease present for ≥ 2 
years prior to initiation of therapy on current study;  
ii) Adequately treated non-melanoma skin cancer or lentigo maligna (melanoma in situ) 
without evidence of disease;  
iii) Adequately treated in situ carcinomas (e.g., breast, cervical, esophageal, etc.) without 
evidence of disease;  
iv) Asymptomatic prostate cancer managed with “watch and wait” strategy 
8. Uncontrolled immune hemolysis or thrombocytopenia (positive direct antiglobulin test in 
absence of hemolysis or history of immune-mediated cytopenias are not exclusions). 
9. History of Human Immunodeficiency Virus (HIV) infection or active hepatitis B or C. 
10. History of chronic liver disease 
11. Major surgery (requiring general anesthesia) within 2 weeks prior to initiation of therapy. 
12. Patients with clinically significant medical condition of malabsorption, inflammatory bowel 
disease, chronic conditions which manifest with diarrhea, refractory nausea, vomiting or any 
other condition that will interfere significantly with drug absorption.  
13. History of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring 
medication or a pacemaker within the last 6 months prior to screening 
14. Baseline QT interval corrected with Fridericia’s method (QTcF) >500 ms 
 [NOTE: criterion does not apply to subjects with a right or left bundle branch block BBB] 
15. Active uncontrolled infection 
16. Psychiatric illness/social situations that would limit compliance with study requirements 
17. Participant is pregnant or breastfeeding, or expecting to conceive or father children within 
the projected duration of the trial, starting with the screening visit through 120 days after the 
last dose of trial treatment. 
 
Eligibility Confirmed* by 
(Choose as applicable): 
Print Name 
Signature 
Date 
 Site PI 
 
 
 
 Authorized study MD 
 
 
 
 Study Nurse 
 
 
 
 Study CRA/ CRC 
 
 
 
Other:______________ 
 
 
 
*Eligibility should be confirmed per institutional policies. 
 
4.3 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Participants for this study will primarily be recruited from hematology and oncology practices 

 
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within City of Hope (PI: Alexey V. Danilov) and the subsites: Dana-Farber Cancer Institute 
(DFCI) CLL center (co-PI: Jennifer R. Brown) and Oregon Health and Science University (PI: 
Stephen Spurgeon). Participants may be identified and referred to this study by their primary 
treating physician from within COH or the subsite, or from the outside community.  Participants 
may be identified by a member of the patient’s treatment team, the PI, research team, or 
medical and surgical oncology clinics part of COH or the subsite.  As a member of the treatment 
team, the investigator(s) will screen their patient’s medical records for suitable research study 
participants and discuss the study and their potential for enrolling in the research study. Referral 
of potential participants to investigator(s) of this study is made as part of standard of care, with 
the referring physician seeking advice on the diagnosis, evaluation, and/or treatment of the 
patient’s malignancy.   
 
The investigators(s) may also screen the medical records of potential participants with whom 
the investigator does not have a treatment relationship.  This will be done for the limited purpose 
of identifying patients who would be eligible to enroll in the study and to record appropriate 
contact information in order to approach these potential individuals regarding the possibility of 
participating in the study.  Participants may also initiate contact with the investigator through 
information of this study posted on the clinicaltrials.gov website. 
 
4.3.1 ACCRUAL ESTIMATES 
 
An estimated 30 participants (12 at COH, 12 at DFCI and 6 at OHSU) will be recruited over a 24 
month period.  
 
4.3.2 INCLUSION OF CHILDREN 
 
This protocol does not include children as the number of children with this type of cancer is 
limited. 
 
4.4 
REGISTRATION PROCEDURES 
 
4.4.1 REGISTRATION 
 
Participants will be required to give written informed consent to participate in the study before 
any screening tests or evaluations are conducted that are not part of standard care. 
 
 
4.4.2 PRE-ENROLLMENT INFORMED CONSENT AND SCREENING PROCEDURES 
 
Diagnostic or laboratory studies performed exclusively to determine eligibility will be done only 
after obtaining written informed consent. Studies or procedures that are performed for clinical 
indications (not exclusively to determine study eligibility) may be used for baseline values and/or 
to determine pre-eligibility, even if the studies were done before informed consent was obtained. 
The informed consent process is to be fully documented, and the prospective participant must 
receive a copy of the signed informed consent document. Screening procedures are listed in 
Section 7.9 (Study Calendar). 
 
4.4.3 PARTICIPANT ENROLLMENT 
 
4.4.3.1 COH DCC Availability and Contact Information 
 

 
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Eligible participants will be registered on the study centrally by the Data Coordinating Center 
(DCC) at City of Hope.   
 
DCC staff are available between the hours of 8.00 am and 5.00 pm PST, Monday through 
Friday (except holidays).  
o E-mail: DCC@coh.org 
 
4.4.3.2 Slot verification and reservation 
A designated study team member should email the DCC to verify current slot availability, and to 
reserve a slot for a specific prospective subject (provide DCC with subject initials), including a 
tentative treatment date. Slots can only be held for a limited time, at the discretion of the study 
PI. 
 
The DCC should be notified of cancellations of prospective participants holding slots as soon as 
possible.   
 
4.4.3.3 Registration Process  
 
Allow up to 24 hours for the DCC to review eligibility. To register a participant the subsequent 
procedure is to be followed: 
 
1. The study team should contact the DCC via email to provide notification regarding the 
pending registration and communicate desired timeline of the registration, especially if it 
must be completed promptly to meet the registration window.  
 
2. The study team will email a Complete Eligibility Packet to the DCC, which consists of a 
copy of the following documents: 
o Registration Cover Sheet (Appendix E) 
o Completed eligibility checklist (printed from Section 4.0 of the protocol) with 
required signature(s) 
o Source documents that support all eligibility criteria listed in the eligibility checklist 
o Signed Informed Consent  
o Signed HIPAA authorization form (if separate from informed consent) 
o Signed subject’s bill of Rights (California only) 
 
3. When all source documents are received, the DCC will review to verify eligibility, working 
with the study team to resolve any missing required source elements. Any missing 
documents may delay review and registration.  A participant failing to meet all protocol 
eligibility requirements will not be registered and the study team will be immediately 
notified. 
 
4. Once eligibility is confirmed, the DCC will send a Confirmation of Registration Form and 
signed Eligibility Checklist, including the Subject Study Number and cohort assignment to:  
o The study team: Site Lead Investigator, treating physician/ sub-investigator, 
protocol nurse, CRC and pharmacy (as needed). 

 
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o The COH Study PI and COH study team designees (including but not limited to 
study monitor(s) and statistician(s)). 
 
5. Upon receipt of the Confirmation of Registration Form, COH study team will register the 
patient in OnCore. The DCC will register non-COH patients in OnCore. 
 
4.4.4 SCREEN FAILURES AND REGISTERED PARTICIPANTS WHO DO NOT BEGIN 
STUDY TREATMENT 
Notify the DCC immediately if the participant screen fails after registration or if the participant 
does not start treatment. 
For non-COH sites, the reason for screen failure will be documented in the registration coversheet 
(Appendix E) and submitted to the DCC. 
Issues that would cause treatment delays should be discussed with the Study Principal 
Investigator. 

 
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5. INVESTIGATIONAL PRODUCT 
 
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 9.4, Adverse Events List. 
 
5.1 
DUVELISIB 
 
Duvelisib (VS-0145 [IPI-145]) is an orally active, dual inhibitor of p110-δ and p110-γ.  The 
following information is derived from the IB, please refer to the IB for additional details.36   
 
5.1.1 ACQUISITION 
 
Duvelisib will be supplied by the manufacturer, Verastem Inc., and prepared by the research 
pharmacy at each institution per manufacturer instructions.   
 
Both COH and study subsites will request drug directly from Verastem by completing and 
emailing the drug request form provided in Appendix E. 
 
 
5.1.2 FORMULATION, APPEARANCE, PACKAGING AND LABELING  
 
Duvelisib is characterized as a freebase, hydrate (hydration can vary with humidity), white-to-
off-white solid, and is made available in 2 different capsule strengths (15 mg and 25 mg) for oral 
delivery.  Duvelisib capsules are packaged in opaque high-density polyethylene bottles with 
induction sealed child resistant caps, or thermoform blister strips with push-through lidding 
packaged into wallets (dose pack). 
 
5.1.3 PRODUCT STORAGE AND STABILITY 
 
Duvelisib is chemically stable under the recommended storage condition of 20°C to 25°C 
(excursions permitted between 15°C to 30°C). 
 
5.1.4 HANDLING 
 
National Institute for Occupational Safety and Health (NIOSH) recommends the use of single 
gloves by anyone handling intact tablets or capsules or administering from a unit-dose package. 
 
Manufacturer urges caution when handling duvelisib, including avoidance of eye or skin contact 
with the drug product.  If there is exposure to the drug product, the individual should be treated 
for physical exposure (skin washing) or inhalation (move to fresh air, as necessary), and, if 
needed, seek medical advice. 
 
5.1.5 ADMINISTRATION 
 
Duvelisib (25 mg or 75 mg during the maintenance phase) is to be administered orally, with or 
without a meal.  
 
5.1.6 ACCOUNTABILITY 
 
The Investigator, or a responsible party designated by the Investigator, must maintain a careful 
record of the inventory and disposition of the study agent. (See the NCI Investigator’s Handbook 
for Procedures for Drug Accountability and Storage).   

 
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Responsibility for drug accountability at the study site rests with the Investigator; however, the 
Investigator may assign some of the drug accountability duties to an appropriate pharmacist or 
designee. Inventory and accountability records must be maintained and readily available for 
inspection by the study monitor and are open to inspection at any time by any applicable 
regulatory authorities or other oversight bodies. 
 
The Investigator or designee will collect and retain all used, unused, and partially used 
containers of study medication until full accounting has been completed. The Investigator or 
designee must maintain records that document: 
• Investigational product delivery to the study site. 
• The inventory at the study site. 
• Use by each participant including pill/unit counts from each supply dispensed. 
• Return of investigational product to the Investigator or designee. 
• Destruction or return of investigational product for final disposal. 
 
These records should include dates, quantities, batch/serial numbers (if available), and the 
unique code numbers (if available) assigned to the investigational product and study 
participants. 
 
The investigational product must be used only in accordance with the protocol. The Investigator 
will also maintain records adequately documenting that the participants were provided the 
correct study medication specified. 
 
Completed accountability records will be archived by the site. At the completion of the study, the 
Investigator or designee will oversee shipment of any remaining study drug back to Verastem 
Inc. for destruction according to institutional standard operating procedures. If local procedures 
mandate site destruction of investigational supply, prior written approval must be obtained from 
Verastem Inc. 
 
5.1.7 DESTRUCTION AND RETURN 
 
At the end of the study, or earlier upon approval from study management, unused supplies of 
duvelisib should be destroyed according to institutional policies.  Drug supplies will be counted 
and reconciled in full at the site with all monitoring procedures complete before destruction.  
Destruction will be documented in the Drug Accountability Record Form. 

 
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6. TREATMENT PLAN 
 
6.1 
DOSAGE AND ADMINISTRATION 
 
Treatment will be administered on an out-patient basis (in-patient administration is allowed if 
deemed necessary by the Investigator), with 28 consecutive days (4 weeks) defined as a 
treatment cycle.  Reported adverse events and potential risks are described in Section 9.4, 
Adverse Event List.  Appropriate dose modifications or delays are described in Section 6.2.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the participant's malignancy. 
 
 
6.1.1 DUVELISIB INDUCTION PHASE 
 
Duvelisib will be dosed continuously at 25 mg PO b.i.d, with induction lasting for 12 weeks.  
Participants may, however, enter into maintenance phase of treatment regimen earlier than 12 
weeks if they experience any one of the following toxicities: 
• 
All Grade ≥ 4 hematological toxicities persisting for > 14 days, 
• 
Febrile neutropenia 
• 
Clinical CMV infection or viremia 
• 
All Grade ≥ 3 non-hematological toxicities (except for tumor lysis or alopecia, or Grade 3 
nausea, vomiting, or uncomplicated electrolyte abnormalities that resolve within 48 hours 
with medical intervention), 
• 
Any toxicity requiring a second dose reduction 
• 
Any of the following hepatic toxicities:  
o ALT/AST > 8 X ULN, or  
o ALT/AST > 5 X and ≤ 8 X ULN, that fails to return to Grade 0-1 within 2 weeks despite 
medical intervention, or  
o Total bilirubin > 5 ULN, or   
o ALT/AST > 3 X ULN and concurrent total bilirubin > 2 X ULN, or 
o Recurrence of ALT/AST > 3 X ULN after re-challenge following initial hepatotoxicity 
 
Maintenance will be initiated at a planned dose of 75 mg PO b.i.d as described in Section 6.1.2. 
 
6.1.2 DUVELISIB MAINTENANCE PHASE 
 
The maintenance portion of this study will include intermittent duvelisib dosing administered at 
75 mg PO b.i.d for 2 days (preferably to occur on Saturday and Sunday), followed by 5-days of 
being off-treatment (e.g., Monday through Friday).  Maintenance therapy using this intermittent 
dosing schedule should continue until disease progression, treatment intolerance, participant 
withdrawal, or death.   
Duvelisib Regimen Description 
Agent 
Dose 
Route Schedule 
Cycle 
Length 
Duvelisib –induction 
25 mg b.i.d 
PO 
Continuous dosing for 12 weeks  
(3 cycles) 
28 days 
Duvelisib -maintenance 75 mg b.i.d 
Repeated intermittent dosing:  
2 days on-treatment,  
5 days off-treatment 

 
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6.2 
DOSING DELAYS AND MANAGEMENT OF TOXICITIES 
 
Any toxicity observed during the course of the study could be managed by an interruption of the 
study drug treatment.  Repeat dose interruptions are allowed as required, for a maximum of 4 
weeks on each occasion. 
 
In general, dosing interruptions are permitted in the case of medical / surgical events or 
logistical reasons (i.e., elective surgery, unrelated medical events) not related to study therapy.  
Participants should be placed back on study therapy within 2 weeks of the scheduled 
interruption, unless otherwise discussed with the investigator.  The reason for interruption 
should be documented in the participant's study record. 
 
If vomiting occurs shortly after the duvelisib tablets are swallowed, the dose should only be 
replaced if all of the intact tablets can be seen and counted.  Should a participant miss a 
scheduled dose for whatever reason (e.g., forgot to take the tablets, or vomiting), the participant 
will be allowed to take the scheduled dose up to a maximum of 2 hours after that scheduled 
dose time.  If greater than 2 hours after the scheduled dose time, the missed dose is not to be 
taken and the participant should take their allotted dose at the next scheduled time. 
 
Please see Duvelisib Prescribing Information for details. General guidelines are in Table 2 and 
Table 3. 
 
Table 2. Recommended Duvelisib Dose Modifications for Non-hematologic Adverse 
Reactions  
Toxicity 
Adverse Reaction Grade 
Recommended Management  
Non-infectious 
Diarrhea / 
Colitis 
Grade 1-2 (defined as an 
increase of up to 6 stools/day 
over baseline); 
• 
Responsive to anti-diarrheal 
agents 
• 
No dose interruption 
• 
Use supportive care with 
antidiarrheal agents as appropriate 
• 
Monitor weekly until resolved 
Grade 1-2 (defined as an 
increase of up to 6 stools/day 
over baseline); 
• 
Unresponsive to anti-
diarrheal agents 
• 
Interrupt duvelisib 
• 
Monitor weekly until resolved 
• 
Resume at reduced dose (see Table 
4) 
Grade 3 (defined as ≥ 7 
stools/day over baseline or 
hospitalization due to diarrhea)  
OR 
• 
radiologically or 
histologically confirmed 
colitis 
• 
Interrupt duvelisib 
• 
Monitor weekly until resolved 
• 
If occurs during induction phase: 
start maintenance dosing 
• 
If occurs during maintenance phase: 
Resume at reduced dose (see Table 
4) 
• 
Grade 4 (defined as life 
threatening diarrhea) 
• 
Permanently withhold duvelisib 

 
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Table 2. Recommended Duvelisib Dose Modifications for Non-hematologic Adverse 
Reactions  
Toxicity 
Adverse Reaction Grade 
Recommended Management  
Recommended management using antidiarrheal agents:  
• ≤ Grade 1:  Treat with loperamide 
• Grade 2:  Consider treatment with loperamide. If the diarrhea does not resolve within 24 
hours, consider treatment budesonide or prednisolone at 1mg/kg with a taper. 
• Grade 3:  Treat with budesonide, and consider prednisolone at 1 mg/kg with a quick taper. 
• Grade 4:  Treat with budesonide or prednisolone at 1 mg/kg with a taper. 
Transaminitis 
• 
Grade 2 (defined as 
ALT/AST >3x ULN – 5x 
ULN) 
• 
Continue at current dose.  Monitor 
LFT levels weekly until return to < 3 
X ULN 
• 
Grade 3 (defined as 
ALT/AST > 5-20 x ULN) 
• 
Interrupt duvelisib 
• 
Monitor LFT levels weekly until 
return to < 3 X ULN 
• 
If occurs during induction phase: see 
Section 6.1.1 for guidelines to switch 
to maintenance phase 
• 
If occurs during maintenance phase 
or induction phase and a switch to 
maintenance phase is not indicated: 
Resume duvelisib at same dose (first 
occurrence) or reduced dose for 
subsequent occurrences (see Table 
4) 
• 
Grade 4 (defined as > 20 x 
ULN) 
• 
Interrupt duvelisib 
• 
Monitor weekly until return to < 3 X 
ULN 
• 
Induction phase: switch to 
maintenance phase  
• 
Maintenance Phase: Permanently 
discontinue duvelisib 
Pneumonitis 
• 
Moderate (Grade 2) 
symptomatic pneumonitis 
• 
Interrupt duvelisib until resolved 
• 
Induction phase: switch to 
maintenance phase 
• 
Maintenance phase: resume 
duvelisib at reduced dose 
• Discontinue duvelisib if pneumonitis 
recurs 
• 
Severe (Grade 3) 
pneumonitis that is 
radiologically or 
histologically confirmed 
Discontinue duvelisib 
Infections 
• 
Clinical CMV infection or 
viremia (positive PCR or 
antigen test) 
• 
Interrupt duvelisib until infection or 
viremia has resolved  
• 
Induction phase: switch to 
maintenance  

 
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Table 2. Recommended Duvelisib Dose Modifications for Non-hematologic Adverse 
Reactions  
Toxicity 
Adverse Reaction Grade 
Recommended Management  
• 
Maintenance phase: discontinue 
duvelisib 
• 
Confirmed Pneumocystis 
jiroveci pneumonia (PJP) 
Discontinue duvelisib 
• 
Grade 3 infections 
• 
Interrupt duvelisib until resolved 
• 
Induction phase: see Section 6.1.1  
• 
Maintenance phase: resume at same 
(first occurrence) or reduced dose for 
subsequent occurrences (see Table 
4) 
 
Table 3. Recommended Duvelisib Dose Modifications for Hematologic Adverse 
Reactions* 
Toxicity 
Adverse Reaction Grade 
Management 
Neutropenia 
ANC < 1,000 /µL (Grade 3-4) 
without fever 
Monitor ANC at least weekly 
Febrile neutropenia  
• 
Interrupt duvelisib 
• 
Monitor ANC until > 500 /µL and 
resolution of febrile neutropenia  
• 
Induction phase: switch to 
maintenance phase 
• 
Maintenance phase: Resume 
duvelisib at same dose (first 
occurrence) or reduce dose for 
subsequent occurrences (see 
Table 4) 
Thrombocytopenia 
Platelet count decreased by 
50-74% from baseline value 
(Grade 3) without clinically 
significant bleeding 
Monitor platelet counts at least 
weekly 
Platelet count decreased by 
50-74% from baseline value 
(Grade 3) with clinically 
significant bleeding  
or  
Platelet count decreased by 
≥75% from baseline (Grade 
4) 
• 
Interrupt duvelisib 
• 
Monitor platelet counts until > 
25% of baseline value and 
resolution of bleeding (if 
applicable) 
• 
Resume duvelisib at same dose 
(first occurrence) or reduce dose 
for subsequent occurrences 
(Table 4) 
*Growth factors allowed per investigator discretion 
 

 
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Table 4. Duvelisib Dose Modifications 
Dose Level 
Dose 
Induction Phase 
Initial Dose (Induction Phase) 
25 mg twice daily 
First Dose Reduction 
15 mg twice daily 
Second Dose Reduction 
Switch to maintenance phase 
Maintenance Phase 
Initial Dose (Maintenance Phase) 
75 mg twice daily 
First Dose Reduction 
25 mg twice daily 
Second Dose Reduction 
15 mg twice daily 
Subsequent Dose Modification 
Discontinue duvelisib 
 
6.3 
TREATMENT PERIOD AND MAINTENANCE 
 
Following a maximum of 12 weeks of continuous duvelisib therapy during the induction phase, 
participants will initiate intermittent maintenance dosing of duvelisib.  This intermittent 
maintenance dosing will continue until disease progression, treatment intolerance, participant 
withdrawal, or death.   
 
6.4 
CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES 
 
Medications required to treat AEs, manage cancer symptoms, concurrent diseases and 
supportive care agents, such as pain medications, anti-emetics and anti-diarrheals are allowed 
in general.  The participant must be told to notify the investigational site about any new 
medications begun after the start of the study treatment.  All medications or nutritional/herbal 
supplements known to interact with study agent should be excluded.  If the medication or 
supplement cannot be discontinued or replaced, the subject should be excluded from this study.  
Each participant’s medication and supplement profile should be reviewed by investigator and/or 
an oncology trained pharmacist to ensure compliance with this aspect of care.  All medications 
(other than investigational products) and significant non-drug therapies (including vitamins, 
herbal medications, physical therapy and blood transfusions) administered during the study 
must be listed on the CRF. 
 
6.4.1 INFECTION PROPHYLAXIS AND TREATMENT 
 
Patients receiving duvelisib are at risk for infection, including pneumocystis, herpes, aspergillus, 
cytomegalovirus (CMV), and respiratory syncytial virus (RSV), as well as various bacterial 
infections.  Please consult Duvelisib Prescribing Information for guidance. Some suggestions 
also follow below. 
 
Pneumocystis (PJP): Participants receiving duvelisib should receive pneumocystis prophylaxis 
in accordance with institutional standards.  Examples include Bactrim DS 1 pills by mouth three 
times per week; pentamidine 300 mg IV every 4 weeks etc. For participants who are intolerant 
of pneumocystis prophylaxis, an alternative regimen should be considered. If patients are 
unable or unwilling to receive PJP prophylaxis, their care should be discussed with the Principal 
Investigator (Alexey V. Danilov, MD), to determine if they are able to continue on study therapy. 
 
Herpes and CMV infections: Peripheral blood analysis for CMV DNA is recommended at least 
every 4 weeks during induction phase, and at least every 8 weeks during maintenance phase of 
therapy. Additional prophylaxis for herpes and CMV viral infections may be used per institutional 
standards for the duration that they receive duvelisib.  

 
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In general, participants with documented infectious complication should receive oral or IV 
antibiotics or other anti-infective agents as considered appropriate by the Investigator for a 
given infectious condition, according to standard institutional practice.   
 
Pneumonia: Participants that develop new pulmonary symptoms (e.g., cough, shortness of 
breath, dyspnea on exertion) or new radiographic findings suggestive of pulmonary infection 
should have duvelisib held as specified in the protocols, and receive antibiotics or other anti-
infective agents as considered appropriate by the Investigator. Duvelisib should be held and 
subsequently restarted after complete resolution of symptoms. Non-infectious pneumonitis 
should be considered on the differential diagnosis. 
 
6.4.2 NAUSEA/VOMITING 
 
No routine prophylactic anti-emetic treatment is required at the start of treatment; however, 
participants should receive appropriate anti-emetic treatment at the first onset of nausea or 
vomiting and as required thereafter per institutional guidelines.  
 
6.4.3 DIET 
 
Participants should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
 
6.4.4 TRANSFUSION OF PLATELETS AND RED BLOOD CELLS (RBC) 
 
Platelet transfusion are permitted as medically necessary per institutional guidelines (e.g., for 
platelets <10,000/μL in the absence of clinical bleeding).  Red blood cell transfusion should be 
considered for all patients with anemia, especially those with hemoglobin values ≤7 g/dL, or per 
institutional guidelines. 
 
6.4.5 ANTI-PLATELET AGENTS AND ANTICOAGULANTS 
 
May be used in patients who have controlled coagulopathy at baseline, as well as those who 
develop a coagulopathy on study. Patients who develop a requirement for therapeutic 
anticoagulation while on study (e.g., new atrial fibrillation, or venous thrombosis) may stay on 
study, and will be carefully monitored for bleeding risks. 
 
6.4.6 GROWTH FACTORS 
 
Allowed at the discretion of the Investigator 
 
6.4.7 SKIN RASHES 
 
Suggests regarding management of rashes are noted in Table 5.  
 
Table 5. Recommended Management by Toxicity Grade – Skin rash 
Grade 
Management of Duvelisib 
Grade 1 
Continue duvelisib.  
• Consider symptomatic treatment, including oral antipruritics (e.g., 
diphenhydramine or hydroxyzine) and topical therapy (e.g., urea cream) per 
institutional guidelines 

 
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6.4.8 TUMOR LYSIS SYNDROME 
 
Tumor lysis syndrome should be monitored (e.g., uric acid) and appropriate hydration measure 
and therapy with anti-hyperuricemic (e.g., allopurinol) should be performed as clinically 
indicated per institutional guidelines.  There were no cases of tumor lysis syndrome observed in 
patients with CLL treated with duvelisib in prior clinical trials. 
 
6.4.9 CONTRACEPTION 
 
The study agent described within this protocol may have adverse effects on a fetus in utero.  
Non-pregnant, non-breast-feeding women may be enrolled if they are willing to use adequate 
methods of birth control (Refer to Appendix B) or are considered highly unlikely to conceive.  
 
Highly unlikely to conceive women are defined as:  
 
1. Surgically sterilized, or  
2. Women will be considered post-menopausal if they have been amenorrheic for 12 months 
without an alternative medical cause. The following age-specific requirements apply: 
a. Women <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in 
the post-menopausal range for the institution or underwent surgical sterilization (bilateral 
oophorectomy or hysterectomy).  
b. Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced menopause with last menses >1 year ago, had 
chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical 
sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy). 
3. Not heterosexually active for the duration of the study.  
Table 5. Recommended Management by Toxicity Grade – Skin rash 
Grade 
Management of Duvelisib 
Grade 2 
For persistent (>1 to 2 weeks) Grade 2 events, hold scheduled study drug until 
resolution to Grade ≤1 or baseline.  
• If toxicity worsens, then treat as Grade 3 
• If toxicity improves to Grade ≤1 or baseline, then resume drug/study 
regimen after completion of steroid taper. 
Grade 3 
Hold duvelisib until resolution to Grade ≤1 or baseline.  If temporarily holding 
duvelisib does not provide improvement of the Grade 3 skin rash to Grade ≤1 
or baseline within 28 days, then permanently discontinue study drug/study 
regimen. 
• Consult dermatology as needed. 
• Promptly initiate empiric IV methylprednisolone (1 to 2 mg/kg/day) or 
equivalent per institutional guidelines  
o Gradually taper steroids over ≥28 days once improvement in symptoms is 
observed. Consider prophylactic antibiotics, antifungals, and anti-PCP 
treatment per institutional guidelines. 
Grade 4 
Permanently discontinue duvelisib 

 
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Participants should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in 
the study individuals must adhere to the contraception requirement (described above) for the 
duration of the study and during the follow-up period defined in Section 9.7.  If there is any 
question that a participant will not reliably comply with the requirements for contraception, they 
should not be entered into the study. 
 
6.4.10 USE IN PREGNANCY 
 
If a participant inadvertently becomes pregnant while on treatment with study agent, the 
participant will immediately be removed from the study.  The site will contact the participant at 
least monthly and document the participant’s status until the pregnancy has been completed or 
terminated.  The pregnancy will be recorded on the CRF and reported by the Investigator to the 
IRB (refer to Section 9.10.1). 
 
6.4.11 USE IN NURSING WOMEN 
 
It is unknown whether duvelisib is excreted in human milk.  Since many drugs are excreted in 
human milk, and because of the potential for serious adverse reactions in the nursing infant, 
participants who are breast-feeding are not eligible for enrollment. 
 
6.5 
PRECAUTIONARY MEDICATIONS, TREATMENTS, AND PROCEDURES 
 
Duvelisib and its major metabolite, IPI-656, have the potential to inhibit CYP3A4. When 
midazolam, a sensitive CYP3A4 substrate, was co-administered with duvelisib, a moderate 
increase in AUC∞ (4.3-fold) was observed. Use caution when co-administering duvelisib with 
CYP3A4 substrates. Refer to Appendix C for examples. 
 
6.6 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES  
 
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial: 
 
• 
Duvelisib is primarily metabolized by CYP3A4, and inhibition of this enzyme results in 
increased duvelisib levels. Likewise, use of CYP3A inducers greatly decrease duvelisib 
levels.36  As such, concomitant use of drugs or foods that are strong inhibitors or inducers of 
CYP3A are not allowed during treatment with duvelisib.  Refer to Appendix C for examples.  
Minimal changes in exposure are expected in the presence of mild or moderate CYP3A4 
inhibitors and therefore, no dose adjustment is recommended. 
• 
Any anti-cancer systemic chemotherapy, biological therapy, or radiation therapy while 
receiving duvelisib 
• 
Use of herbal and dietary supplements is discouraged. Their use should be approved by the 
Investigator and clearly documented. Use of supplements which may interfere with CYP3A4 
is strongly discouraged. 
Participants who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management may be removed from the trial. Participants 
may receive other medications that the investigator deems to be medically necessary.   
Participant exclusion criteria (Section 4.2) describes other medications prohibited in this trial. 

 
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7. STUDY PROCEDURES/EVALUATIONS AND SCHEDULE 
 
7.1 
STUDY SPECIFIC PROCEDURES 
 
7.1.1 MEDICAL HISTORY  
 
A medical history will be obtained by the investigator or qualified designee. In addition to 
collecting information on demographics, the medical history will include all active conditions, and 
any condition diagnosed within the prior 10 years that are considered to be clinically significant 
by the Investigator.  Details regarding the participant’s CLL/SLL will be recorded separately and 
not listed as medical history. 
 
7.1.2 DISEASE ASSESSMENT 
 
The Investigator or qualified designee will obtain prior and current details regarding the 
participant’s CLL/SLL. 
 
7.1.3 MEDICATION HISTORY  
 
A complete medication history will be acquired concurrent with medical history.  
 
7.1.4 PHYSICAL EXAMINATION  
 
Physical exams must be performed by a medically qualified individual such as a licensed 
physician, Physician’s Assistant or advanced Registered Nurse Practitioner as local law permits. 
The physical exam at baseline should include a complete physical exam per institutional 
standards.  All other physical exams after baseline will include an evaluation of any AEs, or any 
previously reported symptoms, or prior physical examination findings. 
 
A physical examination may include evaluating: weight, general appearance, head, ears, eyes, 
nose, throat, neck, skin, cardiovascular system, respiratory system, gastrointestinal system, and 
nervous system.  Physical examination will also include assessment of number of sites and 
sizes of lymphadenopathies, hepatomegaly and splenomegaly.  More extensive physical exams 
will be performed if guided by the development of new symptoms.  
 
As part of screening visit, physical examination is to be conducted within 30 days prior to start of 
treatment.  All physical examinations will also include: 
 
7.1.4.1 Vital signs  
 
Vitals to be collected include BP, HR, temperature, and oxygen saturation by pulse oximetry.  
Vitals will be obtained during each study visit.  
 
Significant findings that were present prior to the signature of the informed consent must be 
included in the Medical History CRF page.  Significant new findings that begin or worsen after 
beginning study treatment must be recorded on the Adverse Event CRF page.  
 
7.1.4.2 Height and weight  
 
Weight is collected as part of physical examination. Height is only required as part of screening.  
 

 
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7.1.4.3 Performance status  
 
Refer to Appendix A for performance criteria. 
 
7.1.5 ELECTROCARDIOGRAM (ECG)  
 
Resting 12-lead ECGs will be recorded at screening, and as clinically indicated throughout the 
study (refer to schedule in Section 7.9).   
 
7.1.6 RADIOGRAPHIC OR OTHER IMAGING ASSESSMENTS  
 
Computed tomography (CT) scan of neck, chest, abdomen and pelvis per institutional 
guidelines (with intravenous contrast, wherever possible), should be performed at screening, 
then at the end of 3 (induction phase), 6 and 12 cycles of therapy.  Positron emission 
topography with CT (PET-CT) and/or magnetic resonance imaging studies will be performed as 
clinically indicated, per institutional guidelines, and is acceptable in place of CTs, if performed.  
For example, PET-CT may be performed if disease transformation is suspected. 
 
7.1.7 ADVERSE EVENT EVALUATION  
 
Toxicities and adverse experiences will be assessed at each visit using the CTCAE v5.0.  
Hematologic toxicities will be assessed per IWCLL 2018 guidelines 42. Safety will be monitored 
by assessing physical examination, vital signs, body height and weight, performance status, 
hematology, chemistry, coagulation, urinalysis, thyroid function, pregnancy, ECG, cytokine 
testing, as well as collecting of the AEs at every visit after initiation of therapy. 
 
The AE reporting period begins from the time the patient starts treatment through and including 
30 calendar days after the last study drug dose. All treatment-related AEs/SAEs should be 
followed until resolution or stabilization. Any SAE occurring after the reporting period must be 
promptly reported if a causal relationship to the investigational drug is suspected. If the patient 
begins a new anticancer therapy, the safety reporting period ends at the time the new treatment 
is started, however, death must always be reported if it occurs during the AE reporting period 
irrespective of intervening treatment. 
 
Participants will be instructed to report all AEs during the study and will be assessed for the 
occurrence of AEs throughout the study. All AEs (serious and non-serious) must be recorded on 
the source documents and CRFs regardless of the assumption of a causal relationship with the 
study drug, except for the following: (specify any AEs and/or grades that are excluded from this 
requirement).  Refer to Section 9 for details on AE collection and reporting. 
 
7.1.8 ASSESSMENT OF STUDY AGENT ADHERENCE 
 
Participants will self-administer oral study agent, duvelisib, and are required to maintain a 
medication diary to assess compliance (refer to Appendix D).  Participants will receive 
instruction on how to administer study drug from a physician, clinical research nurse, or other 
designated, qualified research team member such as study coordinators..  Participants will be 
provided with a medical diary and are required to record the date, dose, and the time of the 
ingestion. 
 
7.2 
LABORATORY PROCEDURES AND EVALUATIONS 
 

 
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Refer to Section 7.9 for a schedule of all laboratory test and procedures.  Additional laboratory 
tests and procedures may be performed as clinically indicated.  
 
7.2.1 HEMATOLOGY 
 
Complete Blood Count (CBC) with differential, including: RBC, hematocrit, hemoglobin, platelet, 
WBC, and WBC Differential. 
 
Reticulocyte count is required at screening, and may be performed thereafter as clinically 
indicated.  
 
7.2.2 BIOCHEMISTRY  
 
Comprehensive metabolic panel (CMP), including: Na, K, Cl, CO2, BUN, Creatinine, Ca, Glu, 
Albumin, Alkaline Phosphatase, total bilirubin, AST, ALT, total protein, lactate dehydrogenase 
(LDH), uric acid.  
 
Beta-2-microglobulin will be evaluated at screening only. 
 
HIV test is not required. History of HIV is sufficient.  Hepatitis B (e.g., HBsAg) and Hepatitis C 
(e.g., HCV Ab) status are required at screening only.  Prior results from within 12 months from 
time to first dose of study treatment are acceptable.  
 
Direct Coomb’s test is required at screening, and may be performed thereafter as clinically 
indicated.  
 
Serum immunoglobulins, IgG, IgM, and IgA are required at screening and at end of treatment.  
 
7.2.3 URINALYSIS  
 
Urinalysis will be collected at screening. 
 
7.2.4 COAGULATION PANEL 
 
Activated Partial Thromboplastin Time (aPTT) and pro-thrombin time (INR) are only required at 
screening 
 
7.2.5 PREGNANCY TEST  
 
A serum pregnancy test will be done at screening.  A serum or urine pregnancy test will be done 
on Day 1 of each cycle for women of childbearing potential.  If the urine pregnancy test is 
positive, a serum pregnancy test must be performed per institutional standards.  
 
7.2.6 LYMPH NODE BIOPSY 
 
A lymph node biopsy not required for this study, but may be requested at the discretion of the 
investigator or treating physician to establish the diagnosis of a transformation into an 
aggressive lymphoma (e.g., Richter syndrome), if suspected. 
 
7.2.7 BONE MARROW BIOPSY 
 
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required for the study at screening and is performed at the discretion of the Investigator. Results 
of molecular and genetic assays (listed below) derived from a bone marrow biopsy performed 
within 6 months prior to the first dose of study treatment are acceptable.   
 
An additional on-study bone marrow biopsy should be performed in participants who are 
suspected of achieving CR within 4 weeks. 
 
7.2.7.1 Molecular and genetic assays 
 
Testing results are not required to proceed with study enrollment.  Cellular and molecular 
assays will be performed according to institutional standards, at screening.  
The following assays will be planned as per standard of care:  
- 
CLL FISH Panel (as per institutional standards) 
- 
immunoglobulin heavy chain (IGVH) mutational status 
- 
prognostic gene panel (e.g., HopeSeq panel performed at COH). 
 
7.3 
EXPLORATORY STUDIES 
 
The exploratory objectives of this study are to evaluate the T-cell repertoire in participants with 
CLL that receive duvelisib.  The effects of duvelisib treatment on T-cell repertoire will be 
evaluated by flow cytometry.   
 
i) Collection of Specimen(s) 
 
Peripheral blood for research purposes will be collected at specified time points as outlined 
under “Research blood draw” in the Schedule of Events Section 7.9.. Four green-top sodium 
heparin tubes (15-20 mL of peripheral blood in total) will be collected prior to first dose of 
study drug (at C1D1 visit), after three cycles (at C4D1 visit – except if maintenance starts 
early – see below), after six cycles (at C7D1) and after twelve (at C13D1) cycles of therapy. 
 
If a study participant switches to maintenance therapy prior to C4D1, a research blood draw 
will occur at that time (i.e., at the beginning of the corresponding first Maintenance cycle), 
rather than on C4D1. 
 
 
ii) Handling of Specimens at Investigators’ Laboratories (COH and DFCI) 
 
Peripheral blood samples will be diluted 1:1 with phosphate buffered saline (PBS) before 
separation of peripheral blood mononuclear cells (PBMCs) by density gradient 
centrifugation.  Cells will be washed in RPMI1640 supplemented with 10% fetal calf serum 
and 25 mg of gentamicin, and either used immediately or frozen and stored in liquid 
nitrogen.  Flow cytometry will be used to evaluate leukocyte subpopulations (e.g., CD3, 
CD4, CD45, TCRγδ, CD14, CD16, CD56). Additional surface markers will be used to 
discriminate different maturation stages of effector cells (CD28, CD27, CD45RA, CD3, CD8, 
CCR7, CD4, CD45): naive T cells, central memory, effector memory and CD45RA 
expressing effector memory cells; Tregs (CD4+CD25+FoxP3+CD127low); Th17 (IL-
17positive).  
 
iii) Shipping of Specimens 
 
Freshly isolated samples will be transported in a closed container from clinic to City of Hope 
(Danilov) or DFCI (Brown) research laboratories, respectively, for processing as described 

 
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above.  
 
For shipping from OHSU to City of Hope Danilov lab, please see Appendix H and Appendix I 
for forms and instructions. 
 
For COH- & OHSU-derived specimens: 
 
Samples will be transported to Dr. Danilov's laboratory: 
 
Alexey Danilov MD, PhD 
Kaplan Clinical Research Building 1st floor, 158-1022 
City of Hope National Medical Center 
1500 E Duarte Rd, Duarte, CA 
 
For DFCI-derived specimens: 
 
Samples will be transported to Dr. Jennifer Brown's laboratory: 
 
Stacey Fernandes 
CLL Center, J. Brown Lab 
1 Jimmy Fund Way 
JF426  
Boston MA 02115 
617-632-5828 
 
iv) Site Performing Correlative Study 
 
Flow cytometry for research purposes will be performed in investigators’ laboratories.  
 
7.4 
SCREENING ASSESSMENTS 
 
A screening (consultation) visit may occur as part of standard of care. If a participant is eligible 
for the study after review of key inclusion/exclusion criteria, additional screening visits will be 
scheduled while staff members are requesting insurance authorization to participate in a clinical 
trial. 
 
The following will be reviewed at screening visit:  
• 
Clinical history and physical exam (per standard of care) 
• 
Informed consent obtained and documented 
 
Toxicities which occur prior to the start of treatment will not be subject to analysis.  Consent 
must be obtained before initiation of any clinical screening procedure that are performed solely 
for the purpose of determining eligibility for this research study.  Evaluations performed as part 
of routine care before informed consent can be utilized as screening evaluations if done within 
the defined time period.  
 
7.5 
ASSESSMENTS DURING TREATMENT 
 
Specific on-study assessments are listed in the Section 7.9, Schedule of Events.  Visits should 
occur on Day 1 of every cycle. Under certain circumstances (e.g., clinic holiday, inclement 
weather) scheduled visits may be delayed by no more than 3 days, or may occur earlier than 

 
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scheduled by no more than 3 days during each treatment cycle cycles (induction phase). For 
maintenance phase, 7-day window is permitted.   
 
During induction phase, clinical visits, including laboratory testing, should occur every 2 weeks 
for the first 12 weeks (i.e., during induction phase). During maintenance phase, visits will occur 
every 4 weeks until cycle 13, and then every 8 weeks thereafter.  When physical exam is not 
required, laboratory studies may be performed locally.  
 
7.6 
END OF TREATMENT OR EARLY TERMINATION VISIT 
 
Any participant that discontinues treatment must be evaluated within 30 days after termination 
or prior to the initiation of any other off-study interventional therapy, if not performed within the 
last 30 days.  End of treatment assessments are listed in the Section 7.9, Schedule of Events.   
 
If participants do not reach the end of treatment due to transition to hospice or death, an end of 
treatment visit will not be conducted.  At the discretion of the investigator, participants may have 
the option to continue on study drug; particularly if there is a documented clinical benefit. 
 
7.7 
FOLLOW-UP 
 
Participants removed from protocol therapy for unacceptable AE(s) will be followed until 
resolution or stabilization of the AE.  Participants will be followed every 3 months after removal 
from protocol therapy until 12 months after end of treatment, introduction of next treatment, or 
death, whichever occurs first (see Section 7.9, Schedule of Events).   
 
7.8 
UNSCHEDULED VISITS 
 
Unscheduled study visits may occur at any time if medically warranted. 

 
45 
 
7.9 
SCHEDULE OF EVENTS 
 
 
Screen 
(30-day 
window) 
INDUCTION  
(cycle 1-3) 
MAINTENANCE  
(cycle 4-12) 
MAINTENANCE  
(cycles 13 - ) 
End of treatment 
Follow-up † 
Day 1 
(±3 days) 
Day 14 
(±3 days) 
Day 1  
(±7 days) 
Day 1 (±7 days) 
EVERY 8 weeks 
Every 3 months 
(±2 weeks) 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
Medical history 
X 
X 
 
X 
X 
X 
X 
Medication historyA 
X 
X 
 
X 
X 
X 
X 
Physical ExaminationB 
X 
X 
 
X 
X 
X 
X 
CT ImagingC 
X 
 
 
X (C4D1, C7D1) 
X (C13D1) 
 
 
12-lead ECGD 
X 
 
 
 
 
 
 
HematologyE 
X 
X 
X 
X 
X 
X 
X 
Reticulocyte CountE 
X 
 
 
 
 
 
 
CMPF 
X 
X 
X 
X 
X 
X 
X 
Hepatitis B & C StatusG 
X 
 
 
 
 
 
 
Serum IgG, IgA, IgM 
X 
 
 
 
 
X 
 
Beta-2-Microglobulin 
X 
 
 
 
 
 
 
Direct Coomb’s testH 
X 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
Coagulation 
X 
 
 
 
 
 
 
Pregnancy testI 
X 
X 
 
X 
X 
 
 
Molecular+genetic testsJ 
X 
 
 
 
 
 
 
Bone Marrow ExamK 
X 
 
 
 
 
 
 
Research blood draw 
 
X(C1D1) 
 
X (C4D1M, C7D1) 
X (C13D1) 
 
 
AE assessmentL 
 
X 
 
X 
X 
X 
X 
Treatment cycles are 28 days. During induction, duvelisib is administered as continuous dosing (25 mg b.i.d) for 12 weeks (3 cycles). During maintenance, duvelisib is administered 
as repeated intermittent dosing consisting of 2 days on-treatment, followed by 5 days off-treatment. 
† Follow-up should occur every 3 months after removal from protocol therapy until 12 months after end of treatment, introduction of next treatment, or death, whichever occurs first. 
 A For concomitant medications – enter new medications started during the trial through the end of treatment visit. Record all medications taken for grade 3 and 4 SAEs (see Section 
9.7). 
B All physical exams will include assessing weight, vital signs, and ECOG performance status.  
C Imaging should be performed at the end of induction (C4D1), and after 6 and 12 cycles. ORR assessment will co-occur with CTs 
D 12-lead ECG will be checked at screening and may be performed thereafter as clinically indicated. 

 
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EComplete Blood Count (CBC) with differential, including: RBC, hematocrit, hemoglobin, platelet, WBC, and WBC Differential. Reticulocyte count is required at screening, and may be 
performed thereafter as clinically indicated.  
F CMP (Na, K, Cl, CO2, BUN, Creatinine, Ca, Glu, Albumin, Alkaline Phosphatase, total bilirubin, AST, ALT, total protein, lactate dehydrogenase (LDH), uric acid. Beta-2-
microglobulin at screening only. History of HIV is sufficient. Hepatitis B (e.g., HBsAg) and Hepatitis C (e.g., HCV Ab) status are required at screening only.  Prior results from within 12 
months from time to first dose of study treatment are acceptable.  
G Hepatitis B and C status are required at screening. Prior results from within 12 months from time to first dose of study treatment are acceptable.   
H Direct Coomb’s required only at screening and may be performed thereafter as clinically indicated 
I For women of reproductive potential: Serum pregnancy test at screening, and urine pregnancy test should be performed on Day 1 of every cycle beginning with C2 during first 12 
cycles, and then every 8 weeks. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test is required. 
J CLL FISH (as per institutional standards), immunoglobulin heavy chain (IGVH) mutational status, prognostic gene panel. 
K Bone marrow biopsy to be performed as per Investigator discretion at screening, and in patient who are suspected having achieved CR 
L AEs and laboratory safety measurements will be graded per NCI CTCAE version 5.0. Hematologic toxicities will be assessed per IWCLL 2018 guidelines.  All AEs, whether 
gradable by CTCAE or not, will also be evaluated for seriousness.. Report grade 3 and 4 hematological and non-hematological SAEs (related and unrelated to trial treatment) 
occurring up until 30 days after the last dose of trial treatment, or the start of new anti-cancer treatment, whichever comes first. Afterwards, report only SAEs that are related to trial 
treatment 
MIf maintenance starts earlier than cycle 4, research blood draw should occur at the time point corresponding to the first Maintenance cycle visit. 
 

 
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8. EFFICACY MEASURES 
 
8.1 
DISEASE EVALUATION 
 
Physical examination – physical exams will focus on documenting a change in the number of 
sites and sizes of lymphadenopathies, hepatomegaly and splenomegaly at schedule time points 
defined in Section 7.9.  More extensive physical exams will be performed if guided by the 
development of new symptoms.  
 
CBC – white blood cell count, hemoglobin and hematocrit, platelet count, and differential count, 
including both percent and absolute number of lymphocytes. CBC with differential should be 
assessed at schedule time points defined in Section 7.9.  
 
CT scan of neck, chest, abdomen and pelvis with contrast, will be performed at schedule time 
points defined in Section 7.9.   
 
8.2 
EFFICACY CRITERIA FOR TUMOR RESPONSE 
 
Treatment response will be determined per the investigators’ assessment, according to IWCLL 
2018 guidelines as in Hallek et al42. All participants who receive at least one dose of study 
medication will be evaluable for efficacy. 
 
Table 8. Response Definition for CLL/SLL 
 
 
 
 
 
 
 
 
 
*Sum of the products of 6 or fewer lymph nodes (as evaluated by CT scans and physical examination) 
**Patients not meeting the PR criterion for circulating lymphocyte count, but meeting all PR criteria 
otherwise, should be regarded as  having PR-L.  Presence of lymphocytosis for these patients will be 
documented. 
CR, complete remission (all of the criteria have to be met); PD, progressive disease (at least 1 of the 
criteria of group A or group B has to be met); PR, partial remission (for a PR, at least 2 of the 
parameters of group A and 1 parameter of group B need to improve if previously abnormal; if only 1 
parameter of both groups A and B is abnormal before therapy, only 1 needs to improve); SD, stable 
disease (all of the criteria have to be met; constitutional symptoms alone do not define PD). 
NOTE: PD based on circulating lymphocyte count is determined as increase ≥50% over nadir. 
However, duvelisib may initially cause redistribution lymphocytosis. Please refer to Section 5.3 of 
Hallek et al, 2018 (ref 42) and contact the Sponsor-Investigator if clarification is required. 

 
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8.2.1 PROGRESSION-FREE SURVIVAL 
 
PFS will be estimated from start of duvelisib treatment until death, time of progression, start of 
new therapy, or end of follow-up, whichever occurs first.  PFS will be censored at the start of 
new therapy or end of follow-up, whichever occurs first.  
Proportion of PFS at 12 months is the primary endpoint in this study.  In addition, median PFS 
will be estimated. 
 
8.2.2 OBJECTIVE RESPONSE RATE 
 
The rate of response will be measured as the proportion of participants who have a CR or PR 
(including PR-L) at the pre-specified time-points, to coincide with CT measurements at the end 
of Cycles 3, 6 and 12 of study intervention (refer to Section 7.9, Schedule of Events). 
 
8.2.3 DURATION OF RESPONSE 
 
Duration of response (DOR), for participants who responded to the study intervention, should be 
measured from the time of first documented objective response (i.e., CR or PR/PR-L) until 
evidence of progressive disease, start of new therapy, death, or end of follow-up.  DOR will be 
censored at the start of new therapy or end of follow-up, whichever occurs first. 
 
8.3 
RESPONSE REVIEW 
 
Response assessment will be determined by the investigator. 
 

 
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9. SAFETY 
 
9.1 
SPECIFICATION OF SAFETY PARAMETERS 
 
The Investigator is responsible for monitoring the safety of participants who have enrolled in the 
study.  Safety assessments will be based on medical review of adverse events and the results 
of safety evaluations at specified time points as described in Section 7.9, Schedule of Events. 
Any clinically significant adverse events persisting at the end of treatment visit will be followed 
by the Investigator until resolution/stabilization or death, whichever comes first. 
 
9.2 
DEFINITIONS 
 
9.2.1 ADVERSE EVENT (AE) 
 
An adverse event is defined as any undesirable physical, psychological or behavioral effect 
experienced by a participant during their participation in an investigational study, in conjunction 
with the use of the investigational product, whether or not considered intervention-related (21 
CFR 312.32 (a)). In general, this includes signs or symptoms experienced by the participant 
from the time of the first dose of study drug to completion of the study.   
 
AEs may include, but are not limited to: 
• 
Subjective or objective symptoms spontaneously offered by the participant and/or observed 
by the Investigator or medical staff.  
• 
Clinically significant laboratory abnormalities.  
• 
A significant worsening of the participant’s condition from study entry.  
• 
Disease signs and symptoms and/or laboratory abnormalities existing prior to the use of the 
study treatment that resolve but then recur after treatment.  
• 
Disease signs and symptoms and/or laboratory abnormalities existing prior to the use of the 
study treatment which increase in frequency, intensity, or a change in quality after treatment.  
 
For laboratory abnormalities, the criteria for determining whether an abnormal test finding 
should be reported as an adverse event are as follows: 
 
• 
Test result is associated with accompanying symptoms, and/or 
• 
Test result requires additional diagnostic testing or medical/surgical intervention, and/or 
• 
Test result leads to a change in study dosing outside of protocol-stipulated dose 
adjustments or discontinuation from the study, significant additional concomitant drug 
treatment, or therapy, and/or 
• 
Test result is considered to be an adverse event by the Investigator 
 
9.2.2 SERIOUS ADVERSE EVENT (SAE) 
 
An AE or suspected adverse reaction is considered "serious" if, in the view of either the 
Investigator, it results in any of the following outcomes: 
  
• 
Death,  
• 
A life-threatening adverse event,  
• 
In-patient hospitalization or prolongation of existing hospitalization,  
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions, or 
• 
A congenital anomaly/birth defect 

 
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• 
Secondary malignancy*  
• 
Any other adverse event that, based upon appropriate medical judgment, may jeopardize 
the subject’s health and may require medical or surgical intervention to prevent one of the 
outcomes listed above (examples of such events include allergic bronchospasm requiring 
intensive treatment in the 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). 
 
*Modified from 21 CFR 312.32 
 
9.3 
ASSESSMENT OF ADVERSE EVENTS 
 
The Study PI/ site Investigator will be responsible for determining the event name, assessing 
the severity (i.e., grade), expectedness, and attribution of all adverse events. 
9.3.1 ASSESSMENT OF ADVERSE EVENT NAME AND GRADE: 
Adverse events will be characterized, when applicable, using the descriptions and grading 
scales found in the current version of the CTCAE v5.0. Hematologic toxicities will be graded per 
IWCLL 2018 guidelines. In the event of an AE for which no grading scale exists, the Investigator 
will classify the AE as defined below:  
 
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 activity 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: a semi-colon indicates ‘or’ within the description of the grade. 
 
iwCLL Guidelines42 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Grades: 1, mild; 2, moderate; 3, severe; 4, life-threatening; 5, fatal. Death occurring as a result 
of toxicity at any level of decrease from baseline will be recorded as grade 5. 
 

 
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†Platelet counts must be below normal levels for grades 1-4. If, at any level of decrease the 
platelet count is <20 × 109/L, this will be considered grade 4 toxicity unless a severe or life-
threatening decrease in the initial platelet count (eg, 20 × 109/L) was present at baseline, in which 
case the patient is not evaluable for toxicity referable to platelet counts. 
 
‡Hb levels must be below normal levels for grades 1-4. Baseline and subsequent Hb 
determinations must be performed before any given transfusions. The use of erythropoietin is 
irrelevant for the grading of toxicity, but should be documented. 
 
§If the absolute neutrophil count (ANC) reaches <1 × 109/L, it should be judged to be grade 3 
toxicity. Other decreases in the white blood cell count or in circulating granulocytes are not to be 
considered because a decrease in the white blood cell count is a desired therapeutic end point. A 
gradual decrease in granulocytes is not a reliable index in CLL for stepwise grading of toxicity. 
If the ANC was <1 × 109/L before therapy, the patient is not evaluable for toxicity referable to 
the ANC. The use of G-CSF is irrelevant for the grading of toxicity, but should be documented 
 
9.3.2 ASSESSMENT OF ATTRIBUTION 
 
For all collected AEs, the clinician who examines and evaluates the participant will determine 
the AE’s causality based on temporal relationship and his/her clinical judgment. The degree of 
certainty about causality will be graded using the categories below. 
 
• 
Unrelated – The event is clearly related to other factors such as the participant’s clinical 
state, other therapeutic interventions, or concomitant medications administered to the 
participant. 
• 
Unlikely – The event is doubtfully related to the investigational agent(s). The event was 
most likely related to other factors such as the participant’s clinical state, other therapeutic 
interventions, or concomitant drugs. 
• 
Possible – The event follows a reasonable temporal sequence from the time of drug 
administration, but could have been produced by other factors such as the participant’s 
clinical state, other therapeutic interventions, or concomitant drugs.  
• 
Probable – The event follows a reasonable temporal sequence from the time of drug 
administration, and follows a known response pattern to the study drug. The event cannot 
be reasonably explained by other factors such as the participant’s clinical state, 
therapeutic interventions, or concomitant drugs.  
• 
Definite – The event follows a reasonable temporal sequence from the time of drug 
administration, follows a known response pattern to the study drug, cannot be reasonably 
explained by other factors such as the participant’s condition, therapeutic interventions, or 
concomitant drugs, AND occurs immediately following study drug administration, improves 
upon stopping the drug, or reappears on re-exposure.  
 
9.3.3 ASSESSMENT OF EXPECTEDNESS 
 
The following definitions will be used to determine the expectedness of the event: 
Unexpected Adverse Event - [Modified from 21 CFR 312.32 (a)] An adverse event is 
unexpected if it is not listed in the investigator’s brochure and/or package insert; is not listed at 

 
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the specificity or severity that has been observed; is not consistent with the risk information 
described in the protocol and/or consent; is not an expected natural progression of any 
underlying disease, disorder, condition, or predisposed risk factor of the research participant 
experiencing the adverse event. 
Expected Adverse Event - An adverse event is expected if it does not meet the criteria for an 
unexpected event, OR is an expected natural progression of any underlying disease, disorder, 
condition, or predisposed risk factor of the research participant experiencing the adverse event. 
 
9.4 
ADVERSE EVENT LIST  
 
9.4.1 ADVERSE EVENT LIST FOR DUVELISIB 
 
In studies to treat hematological malignancies, use of duvelisib has been related to 19 deaths, 
of which 14 participant deaths were associated with a serious infection. Across all hematologic 
oncology studies (n= 443), the most common SAE associated with duvelisib includes:, 
pneumonia (10.84%), diarrhea (10.16%), pyrexia (3.61%), febrile neutropenia (5.87%), 
pneumonitis (3.39%), and rash (1.35%).  The most frequent (≥ 10%) TEAEs among all 
participants with any hematological malignancy studied and those specifically with CLL/SLL are 
summarized in Table 6 and Table 7.36  Refer to investigator’s brochure for additional details.36  
 
Table 6. Summary of most frequent TEAEs – All Disease Groups  
 
Frequency (n = 588) 
Diarrhea  
49.0% 
Neutropenia  
34.7% 
Rash 
34.7% 
Fatigue 
33.2% 
Cough 
26.7% 
Upper respiratory tract infection 
22.3% 
Transaminase Elevation 
22.8% 
Musculoskeletal Pain 
22.6% 
Edema peripheral 
16.7% 
Headache 
13.8% 
Renal insufficiency 
11.7% 
 
Table 7. Summary of most frequent TEAEs – R/R CLL/SLL 
 
Frequency (n = 331) 
Diarrhea 
52.9% 
Neutropenia 
36.6% 
Rash 
32.9% 
Fatigue 
27.8% 
Pneumonia 
26.9% 
Upper respiratory tract infection 
25.7% 
Cough 
23.6% 
Musculoskeletal Pain 
17.2% 
Transaminase Elevation 
14.5% 
 
9.5 
UNANTICIPATED PROBLEMS (UP) 
 

 
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Unanticipated Problem (UP) - An unanticipated problem is any incident, experience, or 
outcome that meets all three of the following criteria: 
 
1. Unexpected in terms of nature, severity, or frequency given (a) the research procedures that 
are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document, or Investigator Brochure (IB); and (b) the 
characteristics of the participant population being studied; AND 
2. Related or possibly related to participation in the research (“possibly related” means there is 
a reasonable possibility that the incident, experience, or outcome may have been caused by 
the procedures involved in the research); AND 
3. Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than previously known or recognized. 
 
9.6 
ADVERSE EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an UP, AE or SAE may come to the attention of study personnel during study 
visits and interviews of a study participant presenting for medical care, or upon review by a 
study monitor. All AEs including local and systemic reactions not meeting the criteria for SAEs 
will be captured on the appropriate CRF.  Information to be collected includes event description, 
time of onset, clinician’s assessment of severity, seriousness, expectedness, relationship to 
study product (assessed only by those with the training and authority to make a diagnosis), and 
date of resolution/stabilization of the event. All AEs occurring while on study must be 
documented appropriately regardless of relationship.  All AEs will be followed to adequate 
resolution (until grade 1, or until per Investigator’s opinion, AEs stabilized and further resolution 
is unlikely). 
 
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE.  However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of 
the event at each level of severity to be performed. 
 
At each study visit, the Investigator will inquire about the occurrence of AE/SAEs since the last 
visit.  Events will be followed for outcome information until resolution (to at least grade 1) or 
stabilization.  
 
Any SAE that occurs after 30 days of last active treatment will be reported only if the 
Investigator or current treating physician has assessed the SAE as related to the study 
treatment. Adverse events will be evaluated using the current version of the CTCAE v5.0. 
Hematologic toxicities will be evaluated per IWCLL 2018 guidelines. 
  
9.7 
ROUTINE AE COLLECTION AND REPORTING GUIDELINES 
 
9.6.1 
REPORTING OF ADVERSE EVENTS 
Routine Reporting of Non-Serious Adverse Events by Site Investigators  
Routine AE recording will occur via data entry into the study eCRF. Adverse events will be 
monitored by the Protocol Management Team (PMT). Adverse events that do not meet the 
criteria of serious OR are not unanticipated problems do not require expedited reporting.  AEs 

 
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reported through expedited processes (i.e. reported to the IRB, DSMC, FDA, etc.) must also be 
reported in routine study data submissions.  
 
9.6.2 
EXPEDITED REPORTING REQUIREMENTS OF SAES AND UPS  
Criteria for Reporting SAEs/UPs 
Adverse events that require expedited reporting include: 
• 
AEs or SAEs that meet the definition of an unanticipated problem 
• 
All serious adverse events (Grades 1-5) that occur within 30 days of active treatment 
• 
All serious adverse events occurring after 30 days of active treatment/therapy that are 
considered possibly, probably, or definitely related to the study agent or procedure  
 
Note: Follow-up reports must be submitted for all events that require expedited reporting when 
the status of the event changes and until the resolution or stabilization of the event. 
 
Reportable serious adverse events must be followed until the event is resolved, stabilized, or 
determined to be irreversible by the participating investigator; for ongoing reportable adverse 
events that are unrelated to study agent, the follow-up period may end at the 30-days post 
study-drug assessment. The Coordinating Center should be consulted prior to ending the follow-
up of events that have stabilized. 
 
Non-COH Sites: Procedure for Reporting SAEs/UPs to the COH Data Coordinating Center  
All events that meet the criteria will be reported to the DCC and Study PI within 24 hours 
of notification that the event met the expedited reporting criteria. 
1. Document/describe the AE/UP on each of the following: 
a. MedWatch 3500A or local IRB submission document* 
MedWatch 3500A is downloadable form at 
http://www.fda.gov/medwatch/getforms.htm 
*The local IRB submission document may be used if the document template is 
approved by the DCC 
b. Expedited Reporting Coversheet. The Expedited Reporting Coversheet is found in 
Appendix F. A modifiable Microsoft Word document is also available from the DCC. 
An electronic signature on the document will be accepted. 
2. Scan and email above documents to DCC@coh.org with the subject title as “[Verastem] 
SAE COH IRB #19563”.  
a. All expedited reports received at this account are immediately forwarded to the Study 
PI, and to DCC personnel.  
b. While not required, if available and applicable, please also include the local IRB 
submission for this event in the submission.  
3. If an email receipt from DCC personnel is not received within one working day, please call 
(626)-218-7904 and/or email DCC@coh.org. 
 
Reporting to COH IRB and DSMC 

 
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The study PI (or designee) will report to COH IRB and DSMC via iRIS all reportable serious 
adverse events that occur at COH and non-COH sites and meet COH IRB and DSMC expedited 
reporting criteria according to City of Hope’s Institutional policy.  The study PI will also submit a 
Protocol Management Team (PMT) report to the COH DSMC at the frequency outlined in 
Section 11.6. This report will include a review of aggregate adverse event data.   
 
Email the following information to DCC@coh.org and the Study PI: Participant ID, date the 
event met criteria for reporting, whether the event meets the definition of serious, whether the 
event is an unanticipated problem, grade of event, attribution of event, whether the event is a 
known expected toxicity to study agent. 
 
9.8 
REPORTING TO THE FDA  
The study PI (or designee) will be responsible for contacting the Office of IND Development and 
Regulatory Affairs (OIDRA) at COH to ensure prompt reporting of safety reports to the FDA.  
OIDRA will assist the PI with the preparation of the report and submit the report to the FDA in 
accordance with the approved City of Hope’s Institutional policy.  
 
Serious Adverse Events meeting the requirements for expedited reporting to the Food and Drug 
Administration (FDA), as defined in 21 CFR 312.32, will be reported as an IND safety report 
using the MedWatch Form FDA 3500A for Mandatory Reporting. 
 
The criteria that require reporting using the Medwatch 3500A are: 
• 
Any unexpected fatal or life threatening adverse experience associated with use of 
the drug must be reported to the FDA no later than 7 calendar days after initial 
receipt of the information [21 CFR 312.32(c)(2)] 
• 
Any adverse experience associated with use of the drug that is both serious and 
unexpected must be submitted no later than 15 calendar days after initial receipt of 
the information [21 CFR 312.32(c)(1)] 
• 
Any follow-up information to a study report shall be reported as soon as the relevant 
information becomes available. [21 CFR 312.32(d)(3)] 
 
In addition, the study PI will submit annually within 60 days (via COH OIDRA) of the anniversary 
date of when the IND went into effect, an annual report to the FDA which is to include a 
narrative summary and analysis of the information of all FDA reports within the reporting 
interval, a summary report of adverse drug experiences, and history of actions taken since the 
last report because of adverse drug experiences. 
 
9.9 
REPORTING TO PARTICIPATING INVESTIGATORS 
The study PI (or designee) will report all reportable serious adverse events to participating 
investigators as an IND Safety Report occurring within 30 calendar days of receipt of sponsor 
(lead site) notification, and indicate whether or not a protocol and/or consent form change is 
required.  A cover letter will indicate the protocol title, the IND#, whether the FDA was informed, 
and, for non-COH sites, a statement that the report should be submitted to their local IRB for 
review as an IND safety report if applicable per local IRB policy. 
 
9.10 
MANUFACTURER REPORTING REQUIREMENTS 
 
All initial and follow-up SAEs and Safety Information will be reported to Verastem, Inc. Safety 
and Pharmacovigilance within 24 hours of knowledge of the event. Reports should be submitted 

 
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in English via the Sponsor-Investigator internal AE form, MedWatch or CIOMS forms.  SAE and 
Safety Information reports must contain the following minimum information: 
• 
At least one identifiable reporter 
• 
One single identifiable patient 
• 
At least one suspect adverse reaction or Safety Information 
• 
At least one suspect medicinal product 
• 
The Sponsor-investigator’s assessment of causality for the event 
 
Copies of any correspondence or telephone conversation logs with the applicable Regulatory 
Authorities regarding all SAE(s), irrespective of association with the Study Drug(s), within a 
reasonable time frame must be provided to Verastem, Inc. Safety and Pharmacovigilance using 
the following contact information:  
 
Via email: PVSafety@Verastem.com   
 
Vial mail: COH shall send via a certified overnight service with a signature required and all 
fees prepaid to: 
Verastem, Inc. Safety and Pharmacovigilance 
117 Kendrick Street, Suite 500 
Needham, MA 02494 USA 
 
9.10.1 REPORTING OF PREGNANCY 
 
To ensure participant safety, each pregnancy in a participant on study treatment must be 
reported within 24 hours of learning of its occurrence.  The pregnancy should be followed to 
determine outcome, including spontaneous or voluntary termination, details of the birth, and the 
presence or absence of any birth defects, congenital abnormalities, or any pregnancy- or 
childbirth-related and/or newborn complications. 
 
The pregnancy should be recorded on a CRF and reported by the Investigator to the Verastem 
Inc.  Pregnancy follow-up should be reported using the same form. Any SAE experienced during 
pregnancy must be reported. 
  
If while on study treatment a participant’s sexual partner becomes pregnant, the pregnancy and 
pregnancy outcomes must also be reported as described above.  Consent to report information 
regarding the pregnancy should be obtained from the pregnant individual. 
 
9.11 
STUDY STOPPING RULES 
 
The accrual to this study will be temporarily suspended until a full review performed by the study 
PI’s (COH PI: Dr. Alexey Danilov, DFCI PI Dr. Jennifer Brown; OHSU PI Dr. Stephen Spurgeon) 
and the DSMC if the following events occur: 
• 
Life-threatening grade 4 toxicity attributable to protocol therapy that is unexpected. 
• 
Death suspected to be related to duvelisib 
 
 
In addition, the following toxicities will result in temporary suspension of study accrual and a 
full review by study PI’s and the DSMC if one of them occurs in ≥2 patients and is 
attributable to protocol therapy: 

 
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o Grade 4 suspected or biopsy-proved colitis which persists for > 7 days despite adequate 
therapy (including IV steroids) and results in prolonged hospital stay 
o Grade 4 hepatic failure 
o Grade 4 pneumonitis 
 
Since duvelisib is FDA approved in treatment of relapsed/refractory CLL/SLL, it is not 
anticipated that the study will need to be stopped. However, this decision will remain at the 
discretion of study PI’s and DSMC. Furthermore, dose de-escalation during maintenance phase 
(to 25 mg po bid 2 days out of 7) will be considered if the above toxicities occur during 
maintenance phase of the study. 
 
With 30 patients, the probabilities of having at least one incidence of the specific events (as 
defined above) that will trigger the stopping rule at the first occurrence, as well as the 
probabilities of having at least two incidences of the specific events (as defined above) that will 
trigger the stopping rule at the second occurrence, are shown in the table below.  
 
True toxicity 
incidence 
Probability of having at least 1 
incidence of the toxicity in 30 patients 
Probability of having at least 2 
incidences of the toxicity in 30 
patients 
1% 
26% 
4% 
2% 
45% 
12% 
3% 
60% 
23% 
4% 
71% 
34% 
5% 
79% 
45% 
6% 
84% 
54% 
7% 
89% 
63% 
8% 
92% 
70% 
9% 
94% 
77% 
10% 
96% 
82% 
 
   

 
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10. STATISTICAL CONSIDERATIONS 
 
Refer to Section 3.1, Description of the Study Design for a detailed description of the study 
design and endpoints.   
 
10.1 
ANALYSIS POPULATIONS  
 
The safety analysis set includes all enrolled participants that receive at least one dose of study 
medications.  
 
The efficacy analysis set includes all participants who receive at least one dose of duvelisib.  
 
10.2 
DESCRIPTION OF STATISTICAL METHODS 
 
10.2.1 GENERAL APPROACH 
 
This is a phase II, single arm, open label study to assess the efficacy and safety of duvelisib in 
patients with R/R CLL/SLL.  For continuous variables, descriptive statistics will include the 
mean, standard deviation (or standard error), median, range, and interquartile range.  For 
categorical variables, descriptive statistics will include the number and percent. 
 
10.2.2 ANALYSIS OF PRIMARY ENDPOINT 
 
Using efficacy analysis set, the proportion of subjects achieving 12 month PFS will be estimated 
along with a two-sided exact Clopper-Pearson 95% confidence interval. 
 
10.2.3 ANALYSIS OF THE SECONDARY ENDPOINT(S)  
 
Using efficacy analysis set, the probability of having ORR will be measured and reported (if 
available) with 95% exact confidence interval.  The descriptive statistics of DOR including mean, 
median, minimum, maximum, standard deviation, and 95% confidence interval will be reported.  
 
The incidence of having Grade 3+ acute toxicity will be determined for participants with CLL/SLL 
that received at least one dose of duvelisib. The 95% confidence interval will be reported with 
the point estimate of toxicity rate. 
 
Using efficacy analysis set, the estimated distribution of the PFS will be plotted using Kaplan 
Meier curves and reported with median PFS and 95% confidence intervals if available. 
 
Using the safety analysis set, estimate the duration of therapy from the first dose of study drug 
until therapy is discontinued for any reason.  The proportion of subjects completing the induction 
phase will be reported including 95% confidence interval. Proportion who move prematurely to 
maintenance phase will be reported. 
 
10.2.4 ANALYSIS OF THE EXPLORATORY ENDPOINT(S)  
 
Flow cytometry will be used to assess T-cell repertoire and evaluate changes associated with 
duvelisib.  The distribution of T-cell subtypes distribution will be described by mean, standard 
deviation (SD), minimal, and maximal values.  .  
 

 
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10.3 
SAMPLE SIZE, POWER, ACCRUAL RATE AND STUDY DURATION 
 
10.3.1 SAMPLE SIZE AND POWER 
 
A sample size of 27 patients produces a two-sided exact Clopper-Pearson 95% confidence 
interval with a width equal to 0.394 (0.303-0.697) when the target 12 month PFS rate is 0.5 (see 
Table 8). Anticipating a dropout rate of 10%, a total of 30 patients will need to be enrolled. 
 
Table 8. Sample size estimate 
Confidence Level 
Size (N) Proportion (P) Lower Limit Upper Limit 
Width if 
Target P = 0.5 
0.95 
17 
0.5 
0.254 
0.746 
0.493 
0.95 
18 
0.5 
0.260 
0.740 
0.480 
0.95 
19 
0.5 
0.266 
0.734 
0.467 
0.95 
20 
0.5 
0.272 
0.728 
0.456 
0.95 
27 
0.5 
0.303 
0.697 
0.394 
0.95 
28 
0.5 
0.306 
0.694 
0.387 
0.95 
29 
0.5 
0.310 
0.690 
0.380 
0.95 
30 
0.5 
0.313 
0.687 
0.374 
 
10.4 
HANDLING OF MISSING DATA 
 
Every attempt will be made to obtain data at the defined time points as described in the primary 
and secondary endpoints.  For time points that have no data, we will evaluate whether or not the 
other time points can be used to fulfill the primary and secondary data.  If the data are not 
sufficient to analyze specific endpoints, the participant’s data may be excluded entirely or 
partially, depending on the specific endpoints in question and in consultation with the 
biostatistician.  No missing data will be imputed.  Whenever possible, all available data will be 
included in the analysis.  A sample size for each analysis will be clearly stated along with the 
reason for exclusion, if any participant is excluded from the analysis due to missing data. 
 
10.5 
DURATION OF STUDY 
 
The duration of study will be 4 to 6 years (e.g., accrual 2 years + treatment 1-3 years + follow-up 
1 year). 
 

 
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11. DATA AND SAFETY MONITORING 
 
11.1 
PROTOCOL DEVIATIONS 
It is understood that deviations from the protocol should be avoided, except when necessary to 
eliminate an immediate hazard to a research participant. As a result of deviations, corrective 
actions are to be developed by the study staff and implemented promptly. An investigator is 
responsible for ensuring that an investigation is conducted according to the signed investigator 
statement, the investigational plan, and applicable regulations; for protecting the rights, safety, 
and welfare of subjects under the investigator's care; and for the control of drugs under 
investigation.  
 
Deviation 
Any change, divergence, or departure from the study design or procedures of a research 
protocol. 
 
Planned Protocol Deviation (PPD) 
Any anticipated change, divergence, or departure from the study design or procedures of a 
research protocol that receives prospective IRB approval prior to implementation. 
 
11.2 
REPORTING OF DEVIATIONS AND PPDS 
 
Reporting Deviations 
Deviations from the protocol will be reported to the COH DSMC and IRB within 5 calendar days 
of notification of its occurrence via iRIS in accordance with the Clinical Research Protocol 
Deviation policy. A list of deviations from all participating sites will be submitted along with the 
Protocol Management Team (PMT) progress report to the COH DSMC. 
 
For non-COH sites: 
The local IRB and/or DSMC must be notified according to local institutional policies. The study 
Principal Investigator must be notified as soon as practical (within 24 hours of notification of the 
event). 
 
Reporting Planned Protocol Deviations 
The PPD must be submitted via iRIS in accordance with IRB guidelines and the Clinical 
Research Protocol Deviation policy. An IRB approved PPD does not need to be submitted as a 
deviation to the DSMC. 
 
For non-COH sites: 
The local IRB and/or DSMC must be notified according to local institutional policies. All non-
emergency planned deviations from the protocol must have prior approval by the Study 
Principal Investigator, the Site Principal Investigator, COH IRB, and when applicable, the local 
IRB. In addition, if contractually obligated, the sponsor must also approve the deviation. 
 
 
11.3 
ALL INVESTIGATOR RESPONSIBILITIES 
 
An investigator is responsible for ensuring that an investigation is conducted according to the 
signed investigator statement, the investigational plan, and applicable regulations; for protecting 
the rights, safety, and welfare of subjects under the investigator's care; and for the control of 

 
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drugs under investigation.  
 
All Investigators agree to: 
• 
Conduct the study in accordance with the protocol and only make changes after notifying 
the Sponsor (or designee), except when necessary to protect the safety, rights or welfare 
of subjects. 
• 
Personally conduct or supervise the study (or investigation).  
• 
Ensure that the requirements relating to obtaining informed consent and IRB review and 
approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56.  
• 
Report to the Sponsor or designee any AEs that occur in the course of the study, in 
accordance with §21 CFR 312.64.  
• 
Ensure that all associates, colleagues and employees assisting in the conduct of the study 
are informed about their obligations in meeting the above commitments.  
• 
Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to make 
those records available for inspection with the Sponsor (or designee).  
• 
Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be 
responsible for initial and continuing review and approval of the clinical study.  
• 
Promptly report to the IRB and the Sponsor all changes in the research activity and all 
unanticipated problems involving risks to subjects or others (to include amendments and 
IND safety reports).  
• 
Seek IRB and Sponsor approval before any changes are made in the research study, 
except when necessary to eliminate hazards to the patients/subjects.  
• 
Comply with all other requirements regarding the obligations of clinical investigators and 
all other pertinent requirements listed in § 21 CFR part 312. 
 
11.4 
PROTOCOL MANAGEMENT TEAM (PMT) 
 
The Protocol Management Team (PMT), minimally consisting of the study PI, site investigators, 
collaborating investigators, research nurse, clinical research associate/coordinator, and the 
study biostatistician, is responsible for ongoing monitoring of the data and safety of this study, 
including implementation of the stopping rules for safety/toxicity. 
 
The PMT is recommended to meet (in person or via teleconference) at least monthly to review 
study status. This review will include, but not be limited to, reportable AEs and UPs, and an 
update of the ongoing study summary that describes study progress in terms of the study 
schema. The meeting will be a forum to discuss study related issues including accrual, 
SAE/AEs experienced, study response, deviations/violations and study management issues. 
The appropriateness of further subject enrollment and the specific intervention for subsequent 
subject enrollment are addressed. It is recommended that minutes of these discussions be 
taken to document the date of these meetings, attendees and the issues that were discussed (in 
a general format).   
 
11.5 
MONITORING 
 
Clinical site monitoring is conducted to ensure that the rights of human subjects are protected, 
that the study is implemented in accordance with the protocol and regulatory requirements, and 
that the quality and integrity of study data and data collection methods are maintained. 
Monitoring for this study will be performed by the City of Hope Office of Clinical Trials Auditing 
and Monitoring (OCTAM). 

 
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The site Investigator/Institution will permit the study monitors and appropriate regulatory 
authorities direct access to the study data and to the corresponding source data and documents 
to verify the accuracy of this data. The Investigator will allocate adequate time for such 
monitoring activities. The Investigator will also ensure that the monitor or other compliance or 
quality assurance reviewer is given access to all the above noted study-related documents and 
study related facilities (e.g. pharmacy, diagnostic laboratory, etc.), and has adequate space to 
conduct the monitoring visit. Documentation of monitoring activities and findings will be provided 
to the site study team, the site PI, study PI, and the COH DSMC.  
 
11.6 
CITY OF HOPE DATA AND SAFETY MONITORING COMMITTEE 
 
This is a risk level 4 study as defined in the City of Hope Institutional Data and Safety Monitoring 
Plan. This determination was made because the study involves a COH held IND. 
 
The DSMC is a multidisciplinary committee charged with overseeing the monitoring of safety of 
participants in clinical trials, and the conduct, progress, validity, and integrity of the data for all 
clinical trials that are sponsored by City of Hope. The committee is composed of clinical 
specialists with experience in oncology and who have no direct relationship with the study. The 
committee reviews the progress and safety of all active research protocols that are not 
monitored by another safety and data monitoring committee or board.  
 
The Study Principal Investigator is required to submit periodic status reports (the PMT report) 
according to the guidelines and frequency outlined in the City of Hope Institutional Data and 
Safety Monitoring Plan.  
 
The COH Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity and 
accrual data from this trial. The DSMC will review up-to-date participant accrual; summary of all 
adverse events captured via routine and expedited reporting; a summary of deviations; any 
response information; monitoring reports, and summary comments provided by the study team. 
Other information (e.g. scans, laboratory values) will be provided upon request. The DSMC will 
monitor data and safety for dose escalation. A review of outcome results (response, toxicity and 
adverse events) and factors external to the study (such as scientific or therapeutic 
developments) is discussed, and the Committee votes on the status of each study. Information 
that raises any questions about participant safety will be addressed with the Principal 
Investigator, statistician and study team. The PMT report and DSMC recommendations will be 
circulated to all participating sites for submission to their IRBs, in accordance with NIH 
guidance. 
 
 

 
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12. DATA HANDLING AND MANAGEMENT RESPONSIBILITIES 
 
12.1 
SOURCE DATA/DOCUMENTS 
 
The Investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported.  All source documents should be completed in a neat, legible 
manner to ensure accurate interpretation of data.  The Investigator will maintain adequate case 
histories of study participants, including accurate case report forms (CRFs), and source 
documentation. 
 
12.2 
PARTICIPANT & DATA CONFIDENTIALITY 
 
The information obtained during the conduct of this clinical study is confidential, and unless 
otherwise noted, disclosure to third parties is prohibited. Information contained within this study 
will be maintained in accordance with applicable laws protecting participant privacy, including 
the provisions of the Health Insurance Portability and Accountability Act (HIPAA). 
 
Participant confidentiality is strictly held in trust by the participating Investigator(s) and study 
team. This confidentiality is extended to cover testing of biological samples and genetic tests in 
addition to the clinical information relating to participants. Therefore, the study protocol, 
documentation, data, and all other information generated will be held in strict confidence. No 
information concerning the study or the data will be released to any unauthorized third party 
without prior written approval of the sponsor. 
 
 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB 
or manufacturer supplying study product may inspect all documents and records required to be 
maintained by the Investigator, including but not limited to, medical records (office, clinic, or 
hospital) and pharmacy records for the participants in this study. The clinical study site will 
permit access to such records.  
 
Upon enrollment, participants will be assigned a code that will be used instead of their name, 
medical record number or other personally identifying information. Electronic files or data 
analysis will contain only the participant code. Codes will not contain any part of the 18 HIPAA 
identifiers (e.g., initials, DOB, MRN). The key associating the codes and the participants’ 
personally identifying information will be restricted to the Investigator and study staff. Electronic 
case report forms, participant, and study information will be kept in an electronic password 
protected database indefinitely. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by local IRB and institutional guidelines. No 
records will be destroyed without the written consent of the sponsor-investigator. It is the 
responsibility of the sponsor to inform the Investigator when these documents no longer need to 
be retained.  
 
 
12.3 
DATA COLLECTION & STORAGE: PRIVACY, CONFIDENTIALITY & SECURITY  
 
Data for this trial will be collected using Medidata RAVE, City of Hope’s electronic capture 
system. Medidata RAVE is a web-based, password-protected system that is fully compliant with 
global regulatory requirements, including 21CRF Part 11 compliant. 
 

 
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Study personnel will enter data from source documents corresponding to a subject’s visit into 
the protocol-specific electronic Case Report Form (eCRF). 
 
The investigator is responsible for all information collected on subjects enrolled in this study. All 
data collected during the course of this study must be reviewed and verified for completeness 
and accuracy by the investigator. All case report forms must be completed by designated study 
personnel. The completed case report forms must be reviewed, signed, and dated by the 
Investigator or designee in a timely fashion. 
 
This research will be conducted in compliance with federal and state of California requirements 
relating to protected health information (PHI). When results of this study are reported in medical 
journals or at meetings, identification of those taking part will not be disclosed. Medical records 
of subjects will be securely maintained in the strictest confidence, according to current legal 
requirements. They will be made available for review, as required by the FDA, HHS, or other 
authorized users such as the NCI, under the guidelines established by the Federal Privacy Act 
and rules for the protection of human subjects. 
 
12.3.1 FUTURE USE OF STORED SPECIMENS 
 
Each participant who signs consent will be assigned a unique coded identifier consisting of 
numbers. This identifier will be associated with the participant throughout the duration of their 
participation in the trial. The coded identifier will be used to identify any participant specific 
samples. Biological samples collected for the purposes of this protocol will be stored in Dr. 
Danilov’s laboratory at City of Hope in the event that additional analysis is required. Tissue and 
blood samples derived from participants enrolled at DFCI will be stored in Dr. Brown’s 
laboratory, and samples derived from participants enrolled at OHSU will be transferred to Dr. 
Danilov’s laboratory at City of Hope in the event that additional analysis is required. All 
participants will be made aware of the sample storage conditions during the consent and 
enrollment process. 
 
12.4 
MAINTENANCE OF RECORDS 
 
Records and documents pertaining to the conduct of this study, source documents, consent 
forms, laboratory test results and medication inventory records, must be retained by the 
Investigator for a period of 2 years following the date a marketing application is approved for the 
drug for the indication for which it is being investigated; or, if no application is to be filed or if the 
application is not approved for such indicate, until 2 years after the investigation is discontinued 
and FDA is notified.   
 
If the Investigator relocates or for any reason withdraws from the study, the study records must 
be transferred to an agreed upon designee, such as another institution or another investigator at 
COH. Records must be maintained according to institutional or FDA requirements.  
 
12.5 
MULTICENTER GUIDELINES 
 
COH Coordinating Center will manage trial data in the following ways:  
a. Confirm that all sites have received and are using the most recent version of the protocol. 
Documentation of the version that was sent to the site must be kept in the regulatory 
binders.  
b. Confirm that the protocol and informed consent form have local IRB approval at each site 

 
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prior to registration of the first participant. Documentation of IRB approval from other sites 
for continuing review must be submitted and kept in the binder.  
c. Provide centralized participant registration in the clinical research management system. 
d. . 
e. Maintain documentation for all SAE reports and submit regular summaries of all AEs, SAEs 
and UPs from all sites to the DSMC per DSMC requirements. 
f. Ensure that relevant IRB correspondence and study status changes are communicated to all 
participating sites. Any changes that affect participant safety of study enrollments will be 
communicated immediately. 
g. Participating sites must submit regulatory documents including, but not limited to the 
following:  
• 
Current CV (signed and dated) for each Investigator. 
• 
Current medical license number for physician investigators. 
• 
Current signed FDA Form 1572.  
• 
Certificate of completion of institution-required human participant training course, the 
NIH online training in the protection of human research participants or other appropriate 
training. 
• 
Documentation of institutional Conflict of Interest. 
h. IRB approved site-specific ICF (must be reviewed and approved by the subsite’s 
Investigator and study team prior to submission to the local IRB. 
i. 
All IRB approved documents and approval memos. 
j. 
Delegation log. 
k. . 
l. 
Completed CRFs (data entry) within 10 business days of study visit. 
 
12.6 
PUBLICATION AND DATA SHARING POLICY 
 
This study will adhere to the requirements set forth by the ICMJE and FDAAA that requires all 
clinical trials to be registered in a public trials registry (e.g., ClinicalTrials.gov) prior to participant 
enrollment.  
 
12.7 
DELIVERY OF PROGRESS REPORTS TO STUDY FUNDER 
 
Upon the request of Verastem Inc., the Institution will submit oral or written reports on the 
progress of the Study as provided by this protocol.  Within one hundred twenty (120) days 
following the completion or termination of the study, Institution will furnish Verastem Inc. with a 
final report detailing the results of the Study. 
 

 
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13. ETHICS/PROTECTION OF HUMAN PARTICIPANTS 
 
13.1 
ETHICAL STANDARD 
 
The Investigator will ensure that this study is conducted in full conformity with Regulations for 
the Protection of Human Participants of Research codified in 45 CFR Part 46, 21 CFR Part 50, 
21 CFR Part 56, 21 CFR Part 312 (if applicable), and/or the ICH E6. 
 
13.2 
REGULATORY COMPLIANCE 
This study is to be conducted in compliance with the IRB approved protocol and according to 
the following considerations: 
o US Code of Federal Regulations (CFR) governing clinical study conduct 
 
Title 21 Part 11 – Electronic Records; Electronic Signatures  
 
Title 21 Part 50 – Protection of Human Subjects  
 
Title 21 Part 54 – Financial Disclosure by Clinical Investigators  
 
Title 21 Part 56 – Institutional Review Boards  
 
Title 21 Part 58 – Good Laboratory Practice for Nonclinical Laboratory Studies  
 
Title 21 Part 312 – Investigational New Drug Application 
 
Title 45 Part 46 – Protection of Human Subjects  
o US Federal legislation, including but not limited to 
 
Health Insurance Portability and Accountability Act of 1996  
 
Section 801 of the Food and Drug Administration Amendments Act   
o Applicable state and local laws. For research occurring in California, this includes but is 
not limited to State of California Health and Safety Code, Title 17 
o Applicable NIH policies and procedures 
o Applicable institutional research policies and procedures 
 
13.3 
INSTITUTIONAL REVIEW BOARD 
An Institutional Review Board (IRB) that complies with the federal regulations at 45 CFR 46 and 
21 CFR 50, 56 and State of California Health and Safety code, Title 17, must review and 
approve this protocol, informed consent form and any additional documents that the IRB may 
need to fulfill its responsibilities (Investigator’s Brochure, information concerning patient 
recruitment, payment or compensation procedures, or other pertinent information) prior to 
initiation of the study. Revisions to approved documents will require review and approval by the 
IRB before the changes are implemented in the study. All institutional, NCI, Federal, and State 
of California regulations must be fulfilled. 
Each participating non-COH institution must provide for the review and approval of this protocol 
and the associated informed consent documents by an appropriate IRB holding a current US 
Federal wide Assurance issued by and registered with the Office for Human Research 
Protections (OHRP). The protocol and consent will be reviewed and approved by the COH IRB 
before submission to a participating site IRB. 
The IRB’s written unconditional approval of the study protocol and the informed consent 
document must be in the possession of the investigator, and, for external sites, the possession 
of the DCC, before the study is initiated. 
The IRB will be informed of serious unexpected, unanticipated adverse experiences, and 
unanticipated problems occurring during the study, and any additional adverse experiences in 
accordance with the standard operating procedures and policies of the IRB; new information 
that may affect adversely the safety of the patients of the conduct of the study; an annual 
update and/or request for re-approval; and when the study has been completed. 

 
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13.4 
INFORMED CONSENT 
Each participating non-COH institution will be provided with a model informed consent form. 
Each institution may revise or add information to comply with local and/or institutional 
requirements, but may not remove procedural or risk content from the model consent form. 
Furthermore, prior to submission to the site’s IRB (initial submission and amendments), the 
consent and accompanying HIPAA form, if separate to the consent, must be reviewed and 
approved by the DCC. 
The Principal Investigator or IRB approved named designee will explain the nature, duration, 
purpose of the study, potential risks, alternatives and potential benefits, and all other information 
contained in the informed consent document. In addition, they will review the experimental 
subject’s bill of rights if applicable, and the HIPAA research authorization form. Prospective 
participants will be informed that they may withdraw from the study at any time and for any 
reason without prejudice, including as applicable, their current or future care or employment at 
City of Hope or participating institution or any relationship they have with City of Hope. 
Prospective participants will be afforded sufficient time to consider whether or not to participate 
in the research. 
After the study has been fully explained, written informed consent will be obtained from either 
the prospective participant or his/her guardian or legal representative before study participation. 
The method of obtaining and documenting the informed consent and the contents of the 
consent must comply with the ICH-GCP and all applicable regulatory requirements. 
A copy of the signed informed consent will be given to the participant or his/her legally 
authorized representative. The original signed consent must be maintained by the investigator 
and available for inspection by sponsor designated representatives, or regulatory authority at 
any time. 
Informed consent is a process that is initiated prior to the individual agreeing to participate in the 
study and continues throughout study participation. 
13.5 
PROTOCOL REVIEW 
 
The protocol and informed consent form for this study must be reviewed and approved in writing 
by the COH Cancer Protocol Review and Monitoring Committee (CPRMC) and the appropriate 
IRB prior to any participant being consented on this study.   
 
13.6 
CHANGES TO PROTOCOL  
 
Any modification of this protocol must be documented in the form of a protocol revision or 
amendment submitted by the Investigator and approved by the CPRMC (if applicable) and IRB, 
before the revision or amendment may be implemented.  The only circumstance in which the 
amendment may be initiated without regulatory approval is for a change necessary to eliminate 
an apparent and immediate hazard to the participant.  In that event, the Investigator must notify 
the local IRB (and other regulatory authorities, if applicable) within 5 business days after the 
implementation.  An Investigator who holds an IND application must also notify the FDA of 
changes to the protocol per 21 CFR 312.  

 
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14. REFERENCES 
 
1. 
Noone AM, Howlader N, Krapcho M, et al. SEER Cancer Stat Facts: Chronic 
Lymphocytic Leukemia. SEER Cancer Statistics Review. 
2018;https://seer.cancer.gov/statfacts/html/clyl.html. 
2. 
Avalos AM, Meyer-Wentrup F, Ploegh HL. Chapter One - B-Cell Receptor Signaling in 
Lymphoid Malignancies and Autoimmunity. In: Ploegh HL, ed. Advances in Immunology. 
Vol 123: Academic Press; 2014:1-49. 
3. 
Herzog S, Reth M, Jumaa H. Regulation of B-cell proliferation and differentiation by pre-
B-cell receptor signalling. Nature Reviews Immunology. 2009;9:195. 
4. 
Manning BD, Cantley LC. AKT/PKB Signaling: Navigating Downstream. Cell. 
2007;129(7):1261-1274. 
5. 
Woyach JA. How I manage ibrutinib-refractory chronic lymphocytic leukemia. Blood. 
2017;129(10):1270-1274. 
6. 
Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with Ibrutinib in Relapsed Chronic 
Lymphocytic Leukemia. The New England journal of medicine. 2013;369(1):32-42. 
7. 
Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus Ofatumumab in Previously Treated 
Chronic Lymphoid Leukemia. The New England journal of medicine. 2014;371(3):213-
223. 
8. 
Byrd JC, Furman RR, Coutre SE, et al. Three-year follow-up of treatment-naïve and 
previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 
2015;125(16):2497-2506. 
9. 
O’Brien SM, Jaglowski S, Byrd JC, et al. Prognostic Factors for Complete Response to 
Ibrutinib in Patients With Chronic Lymphocytic Leukemia: A Pooled Analysis of 2 Clinical 
Trials. JAMA oncology. 2018:e175604. 
10. 
Zhang Shuang Q, Smith Sonali M, Zhang Shuang Y, Lynn Wang Y. Mechanisms of 
ibrutinib resistance in chronic lymphocytic leukaemia and non‐Hodgkin lymphoma. 
British Journal of Haematology. 2015;170(4):445-456. 
11. 
Jain P, Keating M, Wierda W, et al. Outcomes of patients with chronic lymphocytic 
leukemia after discontinuing ibrutinib. Blood. 2015;125(13):2062-2067. 
12. 
Hawkins PT, Anderson KE, Davidson K, Stephens LR. Signalling through Class I PI3Ks 
in mammalian cells. Biochemical Society Transactions. 2006;34(5):647-662. 
13. 
Castillo JJ, Iyengar M, Kuritzky B, Bishop KD. Isotype-specific inhibition of the 
phosphatidylinositol-3-kinase pathway in hematologic malignancies. OncoTargets and 
therapy. 2014;7:333-342. 
14. 
Damle RN, Wasil T, Fais F, et al. Ig V Gene Mutation Status and CD38 Expression As 
Novel Prognostic Indicators in Chronic Lymphocytic Leukemia. <span 
class="subtitle">Presented in part at the 40<sup>th</sup> Annual Meeting of The 
American Society of Hematology, held in Miami Beach, FL, December 4-8, 
1998</span>. 1999;94(6):1840-1847. 
15. 
Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig 
V<sub>H</sub> Genes Are Associated With a More Aggressive Form of Chronic 
Lymphocytic Leukemia. Blood. 1999;94(6):1848-1854. 
16. 
Herman SEM, Gordon AL, Wagner AJ, et al. Phosphatidylinositol 3-kinase-δ inhibitor 
CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by 
antagonizing intrinsic and extrinsic cellular survival signals. Blood. 2010;116(12):2078-
2088. 
17. 
Kienle D, Benner A, Kröber A, et al. Distinct gene expression patterns in chronic 
lymphocytic leukemia defined by usage of specific <em>VH</em> genes. Blood. 

 
A Phase II study of intermittent duvelisib dosing in patients with CLL/SLL 
COH #19563 
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2006;107(5):2090-2093. 
18. 
Chiron D, Di Liberto M, Martin P, et al. Cell Cycle Reprogramming for PI3K Inhibition 
Overrides Relapse-Specific C481S BTK Mutation Revealed by Longitudinal Functional 
Genomics in Mantle Cell Lymphoma. Cancer discovery. 2014;4(9):1022-1035. 
19. 
Lampson BL, Kasar SN, Matos TR, et al. Idelalisib given front-line for treatment of 
chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity. Blood. 
2016;128(2):195-203. 
20. 
Vangapandu HV, Jain N, Gandhi V. Duvelisib: A Phosphoinositide-3 Kinase δ/γ Inhibitor 
for Chronic Lymphocytic Leukemia. Expert opinion on investigational drugs. 
2017;26(5):625-632. 
21. 
Cheah CY, Fowler NH. Idelalisib in the management of lymphoma. Blood. 
2016;128(3):331-336. 
22. 
Sharman JP, Coutre SE, Furman RR, et al. Second Interim Analysis of a Phase 3 Study 
of Idelalisib (ZYDELIG<sup>®</sup>) Plus Rituximab (R) for Relapsed Chronic 
Lymphocytic Leukemia (CLL): Efficacy Analysis in Patient Subpopulations with Del(17p) 
and Other Adverse Prognostic Factors. Blood. 2014;124(21):330-330. 
23. 
Flinn IW, Kahl BS, Leonard JP, et al. Idelalisib, a selective inhibitor of 
phosphatidylinositol 3-kinase-delta, as therapy for previously treated indolent non-
Hodgkin lymphoma. Blood. 2014;123(22):3406-3413. 
24. 
Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and Rituximab in Relapsed Chronic 
Lymphocytic Leukemia. New England Journal of Medicine. 2014;370(11):997-1007. 
25. 
Gopal AK, Kahl BS, de Vos S, et al. PI3Kdelta inhibition by idelalisib in patients with 
relapsed indolent lymphoma. N Engl J Med. 2014;370(11):1008-1018. 
26. 
Kahl BS, Spurgeon SE, Furman RR, et al. A phase 1 study of the PI3Kdelta inhibitor 
idelalisib in patients with relapsed/refractory mantle cell lymphoma (MCL). Blood. 
2014;123(22):3398-3405. 
27. 
Coutré SE, Barrientos JC, Brown JR, et al. Management of adverse events associated 
with idelalisib treatment: expert panel opinion. Leukemia & Lymphoma. 
2015;56(10):2779-2786. 
28. 
Weidner A-S, Panarelli NC, Geyer JT, et al. Idelalisib-associated Colitis: Histologic 
Findings in 14 Patients. The American Journal of Surgical Pathology. 2015;39(12):1661-
1667. 
29. 
Flinn IW, O’Brien S, Kahl B, et al. Duvelisib, a novel oral dual inhibitor of PI3K-δ,γ, is 
clinically active in advanced hematologic malignancies. Blood. 2018;131(8):877-887. 
30. 
Dreyling M, Morschhauser F, Bouabdallah K, et al. Phase II study of copanlisib, a PI3K 
inhibitor, in relapsed or refractory, indolent or aggressive lymphoma. Annals of 
Oncology. 2017;28(9):2169-2178. 
31. 
Maharaj K, Sahakian E, Pinilla-Ibarz J. Emerging role of BCR signaling inhibitors in 
immunomodulation of chronic lymphocytic leukemia. Blood Advances. 2017;1(21):1867-
1875. 
32. 
Okkenhaug K, Bilancio A, Farjot G, et al. Impaired B and T Cell Antigen Receptor 
Signaling in p110δ PI 3-Kinase Mutant Mice. Science. 2002;297(5583):1031-1034. 
33. 
O'Brien SM, Lamanna N, Kipps TJ, et al. A phase 2 study of idelalisib plus rituximab in 
treatment-naïve older patients with chronic lymphocytic leukemia. Blood. 
2015;126(25):2686-2694. 
34. 
Matos TR, Lampson BL, Hirakawa M, et al. Altered Expression of Functional Proteins in 
CD4 Regulatory T Cells during Therapy with Idelalisib. Blood. 2015;126(23):1735-1735. 
35. 
Peluso M, Faia K, Winkler D, et al. Duvelisib (IPI-145) Inhibits Malignant B-Cell 
Proliferation and Disrupts Signaling from the Tumor Microenvironment through 

 
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Mechanisms That Are Dependent on PI3K-δ and PI3K-γ. Blood. 2014;124(21):328-328. 
36. 
Verastem Inc. Duvelisib Investigator's Brochure version s8.0. 2019. 
37. 
Flinn IW, Hillmen P, Montillo M, et al. Results from the Phase 3 DUO<sup>TM</sup> 
Trial: A Randomized Comparison of Duvelisib Vs Ofatumumab in Patients with 
Relapsed/Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma. 
Blood. 2017;130(Suppl 1):493-493. 
38. 
Kuss B, Davids MS, Hillmen P, et al. The efficacy of duvelisib monotherapy following 
disease progression on ofatumumab monotherapy in patients with relapsed/refractory 
CLL or SLL in the DUO crossover extension study. American Society of Clinical 
Oncology; 2018. 
39. 
Ahmad S, Abu-Eid R, Shrimali R, et al. Differential PI3Kdelta Signaling in CD4(+) T-cell 
Subsets Enables Selective Targeting of T Regulatory Cells to Enhance Cancer 
Immunotherapy. Cancer Res. 2017;77(8):1892-1904. 
40. 
So L, Yea SS, Oak JS, et al. Selective inhibition of phosphoinositide 3-kinase p110alpha 
preserves lymphocyte function. The Journal of biological chemistry. 2013;288(8):5718-
5731. 
41. 
Mato AR, Hill BT, Lamanna N, et al. Optimal sequencing of ibrutinib, idelalisib, and 
venetoclax in chronic lymphocytic leukemia: results from a multicenter study of 683 
patients. Annals of oncology : official journal of the European Society for Medical 
Oncology. 2017;28(5):1050-1056. 
42. 
Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for 
treatment, response assessment, and supportive management of CLL. Blood. 
2018;131(25):2745-2760. 
43. 
Cheson BD, Byrd JC, Rai KR, et al. Novel Targeted Agents and the Need to Refine 
Clinical End Points in Chronic Lymphocytic Leukemia. Journal of Clinical Oncology. 
2012;30(23):2820-2822. 
 
 

 
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APPENDIX A: PERFORMANCE STATUS 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able to 
carry on all pre-disease performance 
without restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or sedentary 
nature (e.g., light housework, office 
work). 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  Ambulatory 
and capable of all self-care, but 
unable to carry out any work 
activities.  Up and about more than 
50% of waking hours. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable of 
only limited self-care, confined to bed 
or chair more than 50% of waking 
hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any self-
care.  Totally confined to bed or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead. 

 
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APPENDIX B: CONTRACEPTION 
 
Females of childbearing potential who are sexually active with a non-sterilized male partner or 
partners of male participant must use 2 highly effective method of contraception. These include: 
levonorgestrel-releasing intrauterine system (e.g., Mirena®), copper intrauterine device, and 
hormonal methods. Appropriate hormonal contraceptives include:  Etonogestrel-releasing 
implants (e.g. Implanon® or Norplant®), ethinylestradiol/etonogestrel-releasing intravaginal 
devices (e.g. NuvaRing®), medroxyprogesterone injection (e.g., Depo-Provera®), normal and 
low dose combined oral contraceptive pill, norelgestromin/ethinylestradiol-releasing transdermal 
system (e.g. Ortho Evra®), progesterone based oral contraceptive pill using desogestrel (NB, 
Cerazette® is currently the only highly effective progesterone-based)  
 
Non-sterilized male participants, or partners of female participant, must use male condom plus 
spermicide throughout this period.  Cessation of birth control after this point should be 
discussed with a responsible physician.  Abstaining from sexual activity for the total duration of 
the drug treatment and the drug washout period is an acceptable practice for both female and 
male participants; however, periodic abstinence, the rhythm method, and the withdrawal method 
are not acceptable methods of birth control. Female participant should also refrain from 
breastfeeding throughout this period. 
 

 
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APPENDIX C: CYTOCHROME INHIBITORS, INDUCERS, AND SUBSTRATES 
 
This is not an exhaustive list, investigators should review all concomitant medications for 
potential as CYP3A4 inhibitors or inducers, as well as those that are CYP3A4 or CYP2C8 
substrates.  
 
Strong CYP3A4 inhibitors   
boceprevir, cobicistat, conivaptan, danoprevir, ritonavir, elvitegravir, grapefruit juice, indinavir, 
itraconazole, ketoconazole, lopinavir, paritaprevir, posaconazole, telaprevir(h), 
troleandomycin, voriconazole 
Strong CYP3A4 inducers   
carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John’s wort 
CYP3A4 Substrates   
alfentanil, avanafil, buspirone, conivaptan, darifenacin, darunavir, ebastine, everolimus, 
ibrutinib, lomitapide, lovastatin, midazolam, naloxegol, nisoldipine, saquinavir, simvastatin, 
sirolimus, tacrolimus, tipranavir, triazolam, vardenafil, budesonide, dasatinib, dronedarone, 
eletriptan, eplerenone, felodipine, indinavir, lurasidone, maraviroc, quetiapine, sildenafil, 
ticagrelor, tolvaptan, alprazolam, aprepitant, atorvastatin, colchicine, eliglustat, pimozide, 
rilpivirine, rivaroxaban, tadalafil 
 

 
74 
 
APPENDIX D: MEDICATION DIARY 
 
Study Name: A Phase II study of intermittent duvelisib dosing in patients with CLL/SLL – INDUCTION PHASE 
 
Participant Initials__________________ 
Participant Study ID#  ___________________ 
 
 
 
Instructions: Take medication with a large glass of water (~250ml) at the same 
time each day. Swallow medication whole, not to chew, crush or open them. 
 
 
 
Duvelisib 25 mg twice a day 
Day 
Date 
Time 
morning 
dose 
Dose/ # 
caplets 
taken 
Time  
evening 
dose 
Dose/ # 
caplets 
taken 
 
If dose missed, please 
provide reason: 
1 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
8 
 
 
 
 
 
 
 
9 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
13 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
15 
 
 
 
 
 
 
 
16 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
18 
 
 
 
 
 
 
 
19 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
22 
 
 
 
 
 
 
 

 
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Instructions: Take medication with a large glass of water (~250ml) at the same 
time each day. Swallow medication whole, not to chew, crush or open them. 
 
 
 
Duvelisib 25 mg twice a day 
Day 
Date 
Time 
morning 
dose 
Dose/ # 
caplets 
taken 
Time  
evening 
dose 
Dose/ # 
caplets 
taken 
 
If dose missed, please 
provide reason: 
23 
 
 
 
 
 
 
 
24 
 
 
 
 
 
 
 
25 
 
 
 
 
 
 
 
26 
 
 
 
 
 
 
 
27 
 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
Study 
personnel only:  
 
Drug compliance:(# taken _____ / # expected 
_____) x 100 = _____ %                    Study 
personnel initials/date: ____________________ 
 
 
Participant signature ______________________________________________ 
Date __________________________ 
 
 
Should you miss a dose for whatever reason (e.g., forgot to take the tablets, or vomiting), you will be allowed to take the dose up to 2 
hours late of your usual dose time.  If greater than 2 hours after the usual dose time, the missed dose is not to be taken and you 
should take your dose at the next scheduled time. 
 
 

 
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Study Name: A Phase II study of intermittent duvelisib dosing in patients with CLL/SLL – MAINTENANCE PHASE 
 
Participant Initials__________________ 
Participant Study ID#  ___________________ 
 
 
 
Instructions: Take medication with a large glass of water (~250ml) at the same 
time each day. Swallow medication whole, not to chew, crush or open them. 
 
 
 
Duvelisib 75 mg twice a day– Dose 
only on Days 1, 2, 8, 9, 15, 16, 22 and 
23 
Day 
Date 
Time 
morning 
dose 
Dose/ # 
caplets 
taken 
Time  
evening 
dose 
Dose/ # 
caplets 
taken 
 
If dose missed, please 
provide reason: 
1 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
8 
 
 
 
 
 
 
 
9 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
13 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
15 
 
 
 
 
 
 
 
16 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
18 
 
 
 
 
 
 
 
19 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 

 
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Instructions: Take medication with a large glass of water (~250ml) at the same 
time each day. Swallow medication whole, not to chew, crush or open them. 
 
 
 
Duvelisib 75 mg twice a day– Dose 
only on Days 1, 2, 8, 9, 15, 16, 22 and 
23 
Day 
Date 
Time 
morning 
dose 
Dose/ # 
caplets 
taken 
Time  
evening 
dose 
Dose/ # 
caplets 
taken 
 
If dose missed, please 
provide reason: 
22 
 
 
 
 
 
 
 
23 
 
 
 
 
 
 
 
24 
 
 
 
 
 
 
 
25 
 
 
 
 
 
 
 
26 
 
 
 
 
 
 
 
27 
 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
Study 
personnel only:  
 
Drug compliance:(# taken _____ / # expected 
_____) x 100 = _____ %                    Study 
personnel initials/date: ____________________ 
 
Participant signature ______________________________________________ 
Date __________________________ 
 
 
 
Should you miss a dose for whatever reason (e.g., forgot to take the tablets, or vomiting), you will be allowed to take the dose up to 2 
hours late of your usual dose time.  If greater than 2 hours after the usual dose time, the missed dose is not to be taken and you 
should take your dose at the next scheduled time. 
 

 
78 
 
APPENDIX E: DUVELISIB DRUG ORDER 

 
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APPENDIX F: REGISTRATION COVERSHEET  
COH IRB# 19563: A Phase II Study of Intermittent Duvelisib Dosing in Patients with Relapsed or 
Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) 
Data Coordinating Center:   
City of Hope 
1500 Duarte Road 
Duarte, CA 91010  
Email:  DCC@coh.org (use #secure# in subject line) 
Site Principal Investigator  
Name: 
 
CRA/Study Coordinator:     
Contact Number:   
Patient’s Initials: (F M L): 
Institution: 
PI/ Sub-Investigator: 
Patient’s DOB: 
IRB approval valid until (date): 
Sex: 
______Male 
______Female 
Date Informed Consent Signed: 
Projected start date of treatment: 
Race 
Ethnicity 
Method of 
Payment:_______________________ 
 
Black 
 Hispanic 
Codes: 
 
Caucasian 
 Non-Hispanic 
01 Private 
06 Military or Veterans 
Adm. sponsored 
 
Asian 
 Other_______________
__ 
02 Medicare 
07 Self-pay (no 
insurance) 
 
American Indian 
 
03 Medicare 
& private ins. 
08 No means of 
payment (no 
insurance) 
 
Native 
Hawaiian/Pacific 
Islander 
04 Medicaid 
09 Unknown 
 
Other_____________
__________________
____ 
05 Medicaid & Medicare 
Reason for Screen Failure: 
 
Reason for Failing to Initiate Protocol Therapy: 
 

 
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APPENDIX G: EXPEDITED REPORTING COVERSHEET 
NOTIFICATION OF UNANTICIPATED PROBLEM/SERIOUS ADVERSE EVENT 
For Use by Participating Institutions Only 
THIS FORM ALONG WITH A COPY OF THE MEDWATCH 3500 OR IRB REPORTING FORM MUST BE EMAILED TO 
DCC@COH.ORG WITHIN 24 HOURS OF KNOWLEDGE OF ONSET OF SERIOUS ADVERSE EVENT OR UNANCTICIPATED 
PROBLEM  
COH IRB #19563_- Participating Site IRB # ___________ 
 
From: 
Date: 
Phone No.: 
Email: 
Reporting Investigator: 
Event:  
Participant ID: 
Institution: 
Date Event Met Reporting Criteria (as defined in protocol):   
 
Type of Report: 
 Initial    Follow-up 
CTCAE Grade:   
 G1/mild    G2/moderate     G3/severe    G4/life threatening   
 G5 
Attribution to duvelisib: 
 Not Applicable*   Unrelated   Unlikely   Possible    Probable   
Definite 
Historical/Known Correlation 
to duvelisib: 
 Expected    Unexpected 
Meets Definition of Serious 
AE:   
   Serious      Non-serious 
Meets Definition of 
Unanticipated Problem: 
   UP      Not a UP 
Has the event been reported 
to the following institution’s 
IRB? 
   No      Yes; Date:_____/____/_____ 
* Not Applicable should only be used if subject has not received this agent. 
Authorized Investigator Signature:   
Date:____/____/____ 
 

 
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APPENDIX H: CORRELATIVE BLOOD COLLECTION FORM FOR NON-COH SITES 
ONLY 
Subject ID (issued by DCC):   
Participant Initials (F, M, L) (if applicable): 
Institution: 
 
To be used by non-COH sites for the following blood samples being sent to COH Danilov 
Laboratory: 
 
Sample # 
Time point of 
Collection * 
Expected 
Volume 
Tube Type 
Used 
Collected 
Volume 
Time of Collection 
Date of 
Collection 
1. 
 
Cycle 1, Day 1 
Pre-dose 
20 mL 
Green-top 
_____ mL 
____:____ AM/ PM 
 
____/____/____ 
 
2. 
 
Cycle 4, Day 1 
Pre-dose 
20 mL 
Green-top 
_____ mL 
____:____ AM/ PM 
 
____/____/____ 
 
3. 
 
Cycle 7, Day 1 
Pre-dose 
20 mL 
Green-top 
_____ mL 
____:____ AM/ PM 
 
____/____/____ 
 
4. 
 
Cycle 13, Day 1 
Pre-dose 
20 mL 
Green-top 
_____ mL 
____:____ AM/ PM 
 
____/____/____ 
 
5. 
 
*Cycle ___, Day 1 
Pre-dose 
20 mL 
Green-top 
_____ mL 
____:____ AM/ PM 
 
____/____/____ 
 
 
* Use if a study participant switches to maintenance therapy prior to C4D1. Indicate Cycle in the space provided. 
 
A copy of this form should accompany the sample shipments to COH APCF. Refer to the blood shipping guidelines 
for shipping instructions (Appendix I). 
 
CRA/Study Coordinator/ Nurse:   
Contact Number: 
CRA/Study Coordinator/ Nurse Signature:   
Date: 
 

 
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APPENDIX I: BLOOD SHIPPING GUIDELINES TO CITY OF HOPE 
These guidelines apply to non-COH sites only. 
All biological material must be shipped according to applicable government and International Air 
Transport Association (IATA) regulations.  
Shipping guidelines can also be found on the FedEx website. 
 
1. Aim to ship samples on a Monday through Thursday. If this is not feasible, advance arrangements 
should be made with Danilov lab (DL-danilovlab@coh.org) or designee. 
1. Blood samples in green-top tubes will be sent overnight at around +4oC with a refrigerated cool 
pack in an appropriate container via FedEx. 
2. On the day of shipment, email Danilov lab (DL-danilovlab@coh.org) or designee the FedEx 
shipment tracking#. 
3. Ship samples with a copy of the correlative blood collection form (Appendix H)and a copy of the 
latest CBC results (with differential) and the date of the test to: 
 
The Danilov Laboratory  
Kaplan Clinical Research Bldg [(KCRB) Building 158], Room #1022 
City of Hope, 1500 East Duarte Rd, Duarte CA 91010 
DL-danilovlab@coh.org 
626-218-1959