A Phase I/II Study of Duvelisib and Venetoclax in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma or Patients With Richter's Syndrome
Phase: PHASE1
Conditions: Chronic Lymphocytic Leukemia, Richter Syndrome
Sponsor: Dana-Farber Cancer Institute

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NCI Protocol #: N/A
DF/HCC Protocol #: 18-089
Sponsor Protocol #:  IST-145-15 
TITLE:  A Phase I/II Study of Duvelisib and Venetoclax in Patients with Relapsed or 
Refractory Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, or Patients with 
Richters Syndrome
Coordinating Center:
Dana-Farber/Harvard Cancer Center 
Principal Investigator (PI):
Matthew S. Davids, MD, MMSc
Dana-Farber Cancer Institute
Matthew_Davids@dfci.harvard.edu
 
Other Investigators:
Jennifer Crombie, MD
Dana-Farber Cancer Institute
Jlcrombie@partners.org
Jennifer R. Brown, MD, PhD
Dana-Farber Cancer Institute
Jennifer_Brown@dfci.harvard.edu
Jacob Soumerai, MD
Massachusetts General Hospital 
Jsoumerai@mgh.harvard.edu
 
Responsible Research Nurse:
N/A
Responsible Project Manager: Celeste Carey
Dana-Farber Cancer Institute
Celeste_Carey@dfci.harvard.edu
NCI-Supplied Agent(s):  N/A
Other Agent(s):   Venetoclax (ABT-199/GDC-0199, commercial), Duvelisib (IPI-145, Secura 
Bio, Inc.)
IND #: 137998
IND Sponsor: Matthew S. Davids, MD, MMSc 

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Version # / Version Date: 8.0 / October 18, 2024
SCHEMA
Phase I Dose Escalation 
Phase II
CLL/SLL Cohort

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Stage I: Enroll 12 CLL/SLL patients
Stage II:  If at least 2 CLL/SLL patients achieve a complete response (CR) as defined by the 
IWCLL 2008 criteria after one year, an additional 23 patients will be enrolled in the second 
stage.
RS Cohort
Twenty patients with RS will be enrolled to a separate phase II cohort and treated with the same 
regimen as above for the phase II CLL/SLL Cohort.

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SYNOPSIS
Title of Study: A Phase I/II Study of Duvelisib and Venetoclax in Patients with Relapsed or 
Refractory Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, or patients 
with Richters Syndrome
Principal Investigator:  Matthew S. Davids, MD, MMSc
Study Center(s): This study will be conducted within the Dana-Farber/Harvard Cancer 
Center (Dana-Farber Cancer Institute and Massachusetts General Hospital. Collaborator 
includes Dr. Jacob Soumerai (MGH).
Rationale: 
Venetoclax, a potent, selective inhibitor of BCL-2, was approved by the U.S. Food and Drug 
Administration (FDA) in 2016 for the treatment of relapsed/refractory chronic lymphocytic 
leukemia (CLL) with deletion 17p (del(17p)). Venetoclax has since been established as an 
effective therapeutic option for patients with traditionally difficult to treat disease. While 
venetoclax has demonstrated impressive clinical results, complete response (CR) rates range 
from only 10-20% as monotherapy, and responses are not durable for many patients. In the 
initial phase I trial, 35% of patients progressed within 15 months of initiating therapy. Based 
on experience with chemoimmunotherapy, achieving a CR with minimal residual disease 
(MRD) negativity is highly beneficial both in terms of remission duration and overall 
survival (OS). Novel therapeutic strategies, especially those utilizing combination 
approaches, are urgently needed, as they have the potential to deepen responses and thus 
improve outcomes for patients with relapsed/refractory CLL. 
Duvelisib, an oral, reversible and selective small molecule dual inhibitor of PI3K- and 
PI3K-, has emerged as a promising therapeutic option for patients with CLL. Preclinical 
studies have shown that duvelisib inhibits B-cell receptor (BCR) signaling, reduces 
chemotaxis, and inhibits cytokine mediated CLL cell proliferation. PI3K- inhibition also 
inhibits the tumor-promoting effects of T-cells and myeloid cells in the microenvironment, 
providing the potential for enhanced anti-tumor effect as compared to PI3K- inhibition 
alone. At concentrations achieved at a dose of 25 mg BID, duvelisib results in near complete 
inhibition of PI3K- and fifty percent inhibition of PI3K-. Early phase clinical trials have 
shown overall response rates in relapsed/refractory CLL in the 80% range with a manageable 
toxicity profile at this dose, making this a suitable partner for combination studies.  Duvelisib 
was FDA-approved in 2018 for patients with relapsed/refractory CLL after 2 or more prior 
therapies.
As venetoclax and duvelisib target pathways fundamental to CLL biology and have distinct 
mechanisms of action, they offer great promise as a combination therapy for the treatment of 
patients with CLL. Preclinical data further supports this combination, as duvelisib therapy 
has been shown to upregulate BCL-2 transcript and protein expression levels and enhance the 
ability of venetoclax to induce apoptosis in ex vivo human CLL cells. BH3 profiling has also 

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previously shown that inhibition of PI3K enhances the apoptotic threshold of CLL cells and 
sensitivity to BCL-2 inhibition. 
Study Concept:  
In this phase I/II trial, we combine duvelisib and venetoclax in patients with 
relapsed/refractory CLL, small lymphocytic lymphoma (SLL), or Richters Syndrome (RS). 
We aim to determine the maximum tolerated dose (MTD) of venetoclax to be used in 
combination with duvelisib and the safety of combination therapy. We will also monitor for 
MRD. Patients achieving MRD negativity have the option to discontinue therapy after at 
least one year of treatment, which has the potential to reduce the toxicities associated with 
indefinite treatment, improve adherence to therapy, and significantly reduce costs. 
In correlative laboratory studies, we will utilize BH3 profiling, a functional assay that 
determines the apoptotic threshold of a cell, to determine whether duvelisib primes cells for 
death or enhances their reliance on BCL-2 for survival. This has the potential to predict 
response and identify patients likely to benefit from combination therapy. We can also use 
this tool to identify whether the dependence on other anti-apoptotic proteins, such as MCL-1 
or BCL-XL, confers resistance to therapy. Given the effects of PI3K inhibition on T-cells and 
myeloid cells in the microenvironment, we also plan to use cytometry by time-of-flight 
(CyTOF) to identify the effect of duvelisib on immune subsets and determine how this 
impacts response to therapy as well as toxicity. 
Primary Objectives: 
 Phase I:

Determine the dose limiting toxicities (DLTs), and the maximum tolerated dose 
(MTD) as well as the recommended phase II dose for this combination regimen of 
duvelisib plus venetoclax for patients with relapsed or refractory CLL/SLL 
Phase II: 

Determine the rate of complete response (CR) of duvelisib in combination with the 
MTD of venetoclax, as defined by the IWCLL 2008 criteria for CLL/SLL or Lugano 
2014 Criteria for RS
Secondary Objectives: 
Phase I:

Evaluate pharmacokinetics of both duvelisib and venetoclax in patients with 
CLL/SLL and with RS
Phase II:

Evaluate preliminary efficacy, including objective response rate (ORR), duration of 
response (DOR) among patients who have achieved a partial response (PR) or CR, 
progression free survival (PFS), and OS in patients treated with combined duvelisib 
and venetoclax 

Determine the rate of MRD negativity (MRD-negative CR) in the bone marrow after 
six months and one year of combination therapy

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
Determine the association of FISH abnormalities, TP53, NOTCH1, or 
SF3B1mutations, complex karyotype, and IGHV mutational status with ORR, CR 
rate, and PFS 

Evaluate pharmacokinetics of both duvelisib and venetoclax in patients with RS
Exploratory Objectives: 

Use both standard (performed prior to initiation of therapy and following one week of 
duvelisib monotherapy) and dynamic BH3 profiling to determine whether duvelisib 
therapy enhances mitochondrial priming and how this correlates with response 

Use BH3 profiling (performed prior to initiation of therapy, following one week of 
duvelisib monotherapy, and after three and six months of combination therapy) to 
determine whether dependency of anti-apoptotic proteins other than BCL-2 (i.e. 
MCL-1 and BCL-XL) predicts resistance to therapy 

Use CyTOF to identify how duvelisib monotherapy and duvelisib and venetoclax 
combination therapy impacts immune cell subtypes, in particular the ratio of 
regulatory to conventional T cells, and how this correlates with response and toxicity

Determine change in lymph node size following one week of duvelisib monotherapy 

Determine change in quality of life score using quality of life survey (appendix F) 
after one week of duvelisib monotherapy
Study Design: This is an open-label, multicenter, phase I/II study of duvelisib in 
combination with venetoclax for patients with relapsed/refractory CLL/SLL or patients with 
Richters Syndrome (RS) of any disease status
Phase I: 
In the phase I study, patients will start with 25 mg BID of duvelisib for seven days. A 
traditional 3 + 3 design will be used to accrue patients to one of three doses of venetoclax, 
which will start on day 8 and will be given in combination with duvelisib. The starting dose 
level of venetoclax will be 100 mg daily (dose level +1) with escalation to 200 mg daily 
(dose level +2) and to 400 mg daily (dose level +3). De-escalation to 50 mg daily (dose level 
-1) will be performed if unexpected toxicity is observed. 
At each dose level, patients will undergo a weekly dose ramp-up of venetoclax starting with a 
dose of 10 mg (given the potential for drug-drug interactions), and subsequently ramp-up to 
the eventual cohort dose. Patients in the initial dosing cohorts will stop at a lower dose of 
venetoclax than the approved dose of 400 mg. Patients will be admitted for each dose of 
venetoclax during the dose ramp-up for close monitoring for tumor lysis syndrome (TLS). 
Patients will continue combination therapy for up to one year. Once the MTD of venetoclax 
in combination with duvelisib is determined, patients assigned to lower dose levels in the 
phase I trial will also have the option to escalate their venetoclax dose to the MTD. 
Phase II: 
The phase II study will include two stages. We will start by enrolling 12 CLL/SLL patients 
who will receive 25 mg BID of duvelisib followed by venetoclax. If 2 CLL/SLL patients 

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achieve a CR after one year of therapy, an additional 23 CLL/SLL patients will be enrolled in 
the second stage.  A separate cohort of 20 patients with Richters Syndrome will be enrolled 
in parallel with the CLL/SLL cohort in a one stage design.
Since no TLS was observed with the 10 mg starting dose of venetoclax in phase I, patients in 
the phase II portion of the study start will have the option to start with 10 or 20 mg of 
venetoclax as per the standard of care and will follow a standard dose ramp-up to the MTD. 
Patients who are low- or medium risk for TLS and wish to be treated all in the outpatient 
setting will have to start at 10 mg and then the following week go up to 20 mg, and then 
complete the rest of the usual ramp-up to 50 mg, 100 mg, 200 mg, and 400 mg.
High risk patients will all be hospitalized for the initial dose ramp-ups, and will have the 
option to start at 10 or 20 mg.  If they start at 10 mg, they will need to be hospitalized for the 
first 3 dose ramp-ups (10 mg, 20 mg, and 50 mg), or first 2 dose ramp-ups (20 and 50mg) if 
they start at 20 mg. When venetoclax dosing is performed as an outpatient, TLS labs should 
be checked pre-dose, approximately 6-8 hours after first dose and approximately 24 
hours after treatment.
Accelerated ramp up for RS patients: Given the potential for rapidly progressive RS, these 
patients will also have the option to undergo an accelerated venetoclax ramp-up in the 
inpatient setting modeled after another study of venetoclax plus chemotherapy that was 
recently reported (Davids et al., ICML, 2019).  In that study, venetoclax was safely ramped 
up in a daily fashion for 20 RS patients, who were monitored closely in the inpatient setting, 
with no evidence of tumor lysis syndrome.  The venetoclax is dosed at 20mg for day 1, and if 
no TLS is observed on labs done 6-8 hours and 24 hours later, then the dose is ramped up to 
50mg on day 2, 100mg on day 3, 200mg on day 4, and 400mg on day 5 if the daily labs done 
6-8 hours and 24 hours later continue to show no TLS.  If laboratory TLS does occur, the 
next days dose will be held until there is improvement in the TLS, at which point escalation 
to the next dose may occur 
Study visits will occur weekly through cycles 1-2, once per cycle during cycles 3-7, every 2 
cycles from cycle 8-13, then every 3 cycles up to cycle 60, and then every 6 cycles thereafter 
until discontinuation of therapy. Patients will be treated with duvelisib plus venetoclax 
combination therapy for up to one year (12 cycles), followed by venetoclax monotherapy 
until the time of disease progression without clinical benefit, death, unacceptable toxicity, 
withdrawal of consent. 
Additionally, if after at least one year of combination treatment, a patient achieves a 
complete remission (CR) or complete remission with incomplete count recovery (CRi) with 
MRD-negativity in the bone marrow, they will have the option to discontinue therapy. Those 
that come off treatment for this reason will be monitored for disease recurrence with 
peripheral blood MRD testing by flow cytometry approximately every 3 months. Patients 
who have detectable recurrence (at minimum, confirmed by two successive peripheral blood 
MRD positive assessments) in the peripheral blood will have the option to restart venetoclax. 
If they do not achieve MRD negativity or have evidence of disease progression after reaching 

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full dose venetoclax monotherapy, they will also have the option to add duvelisib and 
continue it until MRD negativity is achieved on two successive peripheral blood MRD 
assessments or indefinitely depending on tolerability.
CT scans (or PET/CT for Richters participants) will occur at C4, C7, C13.  After this first 
year, scans can be done every 6 cycles thereafter, or at the investigators discretion.  Bone 
marrow biopsies and aspirates will be mandatory at study entry (unless within screening 
window), at the C7D1, C13D1, and C25D1 re-staging visits and as clinically indicated 
thereafter. Patients will be evaluated for MRD negativity in the peripheral blood 
approximately every 3 months and with each bone marrow biopsy (other than the baseline 
biopsy). MRD testing will be performed by 4-color flow cytometry with a sensitivity of 10-4 
and when possible by next generation sequencing. 
Patients who achieve CR or best response and are candidates for allogeneic transplant can 
elect to go off study to undergo transplant. 
Baseline Labs: 

CBC with differential

Comprehensive metabolic panel

Amylase and lipase 

Testing to rule out active Hep B, Hep C, CMV and HIV infection

Serum pregnancy test (pre-menopausal female patients only)

FISH and karyotype cytogenetic analysis

IGHV and TP53 mutational status of all participants- Additional somatic mutation 
testing for NOTCH1 and, SF3B1 will be done for Dana-Farber CLL/SLL patients 
only.
Instrumental Tests: 

CT scans (or PET/CT scans for RS patients) prior to cycle 4, 7, and 13 and every 6 
cycles thereafter at the investigators discretion

Bone marrow biopsy and aspirate prior to cycle 7, 13 and 25 and as clinically 
indicated thereafter 

MRD testing in the bone marrow prior to cycle 7, 13 and 25 and any time a clinically 
indicated bone marrow biopsy is performed thereafter 

MRD testing in the peripheral blood will occur approximately every 3 cycles during 
treatment up to Cycle 60, and every 6 cycles thereafter- This will also be tested 
approximately every 3 months during active follow up for routine disease monitoring
Sample Size: 
We anticipate that approximately 12 CLL/SLL patients will be enrolled in the phase I study, 
using the traditional 3+3 design as described above. 

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For the phase II study, a Simons two-stage design will be employed with 12 CLL/SLL 
patients accrued to the first stage. All patients will be followed for up to one year. If at least 2 
patients achieve a CR then an additional 23 patients will be accrued to the second 
stage. Patients who receive the MTD of venetoclax in the phase I portion of the trial can also 
be counted in the analysis of the phase II portion of the trial. 
A separate cohort of 20 patients with Richters Syndrome will be enrolled in parallel with the 
CLL/SLL cohort in a one stage design.
Key Eligibility Criteria (please see protocol section 3 for complete list):
Inclusion Criteria:

Must have a confirmed diagnosis of chronic lymphocytic leukemia or small 
lymphocytic lymphoma requiring therapy, as per IW-CLL 2008 criteria OR biopsy 
confirmed Richters Syndrome (RS)

Disease that has progressed during or relapsed after at least one previous CLL/SLL 
therapy (CLL/SLL patients only)

ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)

Adequate hepatic function defined as:
o
Serum aspartate transaminase (AST) and alanine transaminase (ALT) 
≤ 3.0 x upper limit of normal (ULN), bilirubin ≤1.5 x ULN (unless bilirubin 
rise is due to Gilberts syndrome or of non-hepatic origin

Adequate renal function as defined by:
o
Serum creatinine ≤1.5 x ULN or creatinine clearance ≥ 50 mL/min using a 24-
hour urine collection 

Patients must meet the following hematologic criteria at screening, unless they have 
significant bone marrow involvement of CLL confirmed on biopsy:
o
Absolute neutrophil count ≥500 cells/mm3 (0.5 x 109/L).  Growth factor is 
allowed in order to achieve this
o
Platelet count ≥25,000 cells/mm3 (25 x 109/L) independent of transfusion 
within 7 days of screening 
Exclusion Criteria:

Previous treatment with venetoclax or duvelisib (prior venetoclax allowed for RS 
patients and for CLL/SLL patients if they have been off venetoclax therapy for at 
least one year prior to enrollment)

Patients receiving cancer therapy (i.e., chemotherapy, radiation therapy, 
immunotherapy, biologic therapy, surgery) within 2 weeks of Cycle 1/Day 1 with the 
following exceptions:
o
For patients on targeted therapies, a washout of at least five half-lives is 
required
o
Patients who experience clinical deterioration may start therapy after a shorter 

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washout period with prior approval by the PI
o
Corticosteroid therapy (prednisone or equivalent <20 mg daily) is allowed 

Confirmed central nervous system involvement 

Allogeneic hematologic stem cell transplant within 6 months of starting study or 
active graft vs. host disease (GVHD) requiring treatment or prophylaxis 

Active malignancy other than CLL/SLL or Richters Syndrome requiring ongoing 
therapy, with the exception of hormonal therapy 

Any active systemic infection requiring IV antibiotics or other uncontrolled, active 
infections 

Unable to receive prophylactic treatment for pneumocystis, herpes simplex virus 
(HSV), or herpes zoster (VZV) at screening

Administration of live or live attenuated vaccine within 6 weeks of initiation of 
therapy

Human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus 
(HBV) 

Major surgery within 4 weeks of first dose of study drug 

Currently active gastrointestinal disease, including colitis, inflammatory bowel 
disease and diarrhea requiring therapy 

Currently active, clinically significant cardiovascular disease, such as uncontrolled 
arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart 
Association Functional Classification; or a history of myocardial infarction, unstable 
angina,  acute coronary syndrome, stroke, or sustained ventricular arrhythmia within 
6 months prior to initiation of therapy

Any life-threatening illness, medical condition, or organ system dysfunction that, in 
the investigators opinion, could compromise the subjects safety 

Use of Coumadin for anticoagulation (other anticoagulants permitted)

Concurrent administration of medications or foods that are strong inhibitors or 
inducers of CYP3A (see Appendix D)

Ongoing treatment with chronic immunosuppressants (e.g., cyclosporine)

History of chronic liver disease or veno-occlusive disease/sinusoidal obstruction 
syndrome  

History or concurrent condition of interstitial lung disease of any severity and/or 
severely impaired lung function

Active abuse of alcohol or illicit drugs
Intervention and Mode of Delivery: 
Duvelisib, 25 mg BID, oral 
Venetoclax, up to 400 mg daily, oral 
Regulatory and Feasibility Issues: Patients must have access to commercially available 
venetoclax. Secura Bio, Inc. will provide duvelisib at no cost to the participant.

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TABLE OF CONTENTS
SCHEMA.........................................................................................................................................2
1.
OBJECTIVES....................................................................................................................15
1.1
Study Design..........................................................................................................15
1.2
Primary Objectives.................................................................................................15
1.3
Secondary Objectives.............................................................................................16
2.
BACKGROUND: ..............................................................................................................17
2.1
Chronic Lymphocytic Leukemia ...........................................................................17
2.2
Richters Syndrome ...............................................................................................17
2.3
Venetoclax .............................................................................................................18
2.4
Duvelisib................................................................................................................20
2.5
Rationale for Duvelisib and Venetoclax Combination Therapy............................21
2.6
Rationale for inclusion of Richters Syndrome patients........................................22
2.7
Correlative Studies Background ............................................................................23
3.
PARTICIPANT SELECTION...........................................................................................24
3.1
Eligibility Criteria..................................................................................................24
3.2
Exclusion Criteria ..................................................................................................26
3.3
Inclusion of Women and Minorities ......................................................................28
4.
REGISTRATION  PROCEDURES ..................................................................................29
4.1
General Guidelines for DF/HCC Institutions ........................................................29
4.2
Registration Process for DF/HCC Institutions.......................................................29
4.3
General Guidelines for Other Investigative Sites ..................................................29
4.4
Registration Process for Other Investigative Sites.................................................29
5.
TREATMENT PLAN........................................................................................................31
5.1
Treatment Regimen................................................................................................34
5.2
Pre-Treatment Criteria ...........................................................................................38
5.3
Definition of Dose-Limiting Toxicity (DLT) ........................................................39
5.4
General Concomitant Medication and Supportive Care Guidelines......................40
5.5
Criteria for Taking a Participant Off Protocol Therapy.........................................42
5.6
Duration of Follow Up and Active Disease Monitoring........................................44
5.7
Resuming Treatment after Discontinuation...........................................................45
5.8
Criteria for Taking a Participant Off Study (No longer being followed for 
Survival).................................................................................................................46
6.
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................47
6.1
Duvelisib:...............................................................................................................47
6.2
Venetoclax: ............................................................................................................50

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7.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................53
7.1
Definitions: ............................................................................................................53
7.2
Serious Adverse Event:..........................................................................................54
7.3
Adverse Event List for Venetoclax:.......................................................................54
7.4
Adverse Event List for Duvelisib: .........................................................................57
7.5
Expedited Adverse Event Reporting......................................................................59
7.6
Reporting to the Food and Drug Administration (FDA) .......................................61
7.7
Routine Adverse Event Reporting .........................................................................61
7.8 Expedited Reporting to Hospital Risk Management ...................................................61
8.
PHARMACEUTICAL INFORMATION..........................................................................61
8.1
Duvelisib................................................................................................................61
8.2
Venetoclax .............................................................................................................64
9.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................67
9.1
BH3 Profiling:........................................................................................................67
9.2
Cytometry by Time of Flight (CyTOF):................................................................68
9.3
Minimal Residual Disease (MRD): .......................................................................68
9.4
Exome sequencing of tumor cells..........................................................................70
9.5
Pharmacokinetic (PK) Testing (Phase I) : .............................................................71
9.6
Jennifer Brown Lab Sample Collection and Shipping Instructions.......................72
10.
STUDY CALENDAR .......................................................................................................74
11.
MEASUREMENT OF EFFECT .......................................................................................81
11.1
Definitions: ............................................................................................................81
11.2
Methods for Evaluation of Measurable Disease:...................................................81
11.3
Response Criteria...................................................................................................82
12.
DATA REPORTING / REGULATORY REQUIREMENTS...........................................89
12.1
Data Reporting.......................................................................................................89
12.2
Data Safety Monitoring..........................................................................................89
12.3
Multicenter Guidelines: .........................................................................................90
12.4
Collaborative Agreements Language: N/A............................................................90
13.
STATISTICAL CONSIDERATIONS...............................................................................91
13.1
Study Design/Endpoints ........................................................................................91
13.2
Sample Size, Accrual Rate and Study Duration ....................................................94
13.3
Analysis of Secondary Endpoints..........................................................................94
13.4
Reporting and Exclusions ......................................................................................96
14.
PUBLICATION PLAN .....................................................................................................96
APPENDIX A: PERFORMANCE STATUS CRITERIA...........................................................101

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APPENDIX B: CAIRO BISHOP DEFINITIONS OF LABORATORY AND CLINICAL 
TUMOR LYSIS SYNDROME .......................................................................................102
APPENDIX C:  MANAGEMENT OF TUMOR LYSIS SYNDROME.....................................103
APPENDIX D: LIST OF EXCLUDED OR CAUTIONARY MEDICATIONS:.......................105
APPENDIX E: PATIENT WALLET CARD..............................................................................106
APPENDIX F: DRUG DIARY ...................................................................................................107
Appendix G: Quality of Life Questionnaire ................................................................................110
APPENDIX H: Grading scale for hematologic toxicity in CLL studies .....................................111
APPENDIX I: DF/HCC Multicenter Data Safety and Monitoring PLan....................................112
15.
INTRODUCTION ...........................................................................................................116
15.1
Purpose.................................................................................................................116
15.2
Multi-Center Data and Safety Monitoring Plan Definitions................................116
16.
GENERAL ROLES AND RESPONSIBILITIES ...........................................................117
16.1
DF/HCC Sponsor.................................................................................................117
16.2
Coordinating Center.............................................................................................118
16.3
Participating Institution........................................................................................119
17.
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS ...........................119
17.1
Protocol Distribution............................................................................................119
17.2
Protocol Revisions and Closures .........................................................................119
17.3
Informed Consent Requirements .........................................................................120
17.4
IRB Documentation .............................................................................................120
17.5
IRB Re-Approval.................................................................................................121
17.6
Participant Confidentiality and Authorization Statement....................................121
17.7
DF/HCC Multi-Center Protocol Registration Policy...........................................121
17.8
DF/HCC Protocol Case Number..........................................................................122
17.9
Safety Assessments and Toxicity Monitoring .....................................................123
17.10 Data Management................................................................................................124
18.
REQUISITIONING INVESTIGATIONAL DRUG........................................................125
19.
MONITORING: QUALITY CONTROL........................................................................125
19.1
Ongoing Monitoring of Protocol Compliance.....................................................125
19.2
Monitoring Reports..............................................................................................126
19.3
Accrual Monitoring..............................................................................................126
20.
AUDITING: QUALITY ASSURANCE .........................................................................126

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20.1
DF/HCC Internal Audits......................................................................................126
20.2
Audit Notifications...............................................................................................126
20.3
Audit Reports.......................................................................................................126
20.4
Participating Institution Performance ..................................................................127

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1. OBJECTIVES
1.1
Study Design
This is an open-label, multicenter, phase I/II study of duvelisib in combination with venetoclax 
for patients with relapsed/refractory CLL or SLL or Richters Syndrome.
Phase I 
The phase I portion of the trial will determine the dose, schedule, safety and tolerability of 
duvelisib in combination with venetoclax. Patients will start with 25 mg BID of duvelisib for 
seven days. A traditional 3 + 3 design will be used to accrue patients to one of three doses of 
venetoclax, which will start on day 8. The starting dose level of venetoclax will be 100 mg daily 
(dose level +1) with escalation to 200 mg daily (dose level +2) and to 400 mg daily (dose level 
+3). De-escalation to 50 mg daily (dose level -1) will be performed if unexpected toxicity is 
observed. At each dose level, patients start with 10 mg of venetoclax followed by a weekly dose 
ramp-up, with patients in the initial dosing cohorts stopping at a lower dose of venetoclax than 
the approved dose of 400 mg. 
Phase II 
The phase II study will occur in two stages in order to determine the rate of complete response 
(CR) of duvelisib in combination with the MTD of venetoclax. Patients will be treated with 
duvelisib plus venetoclax for up to one year followed by venetoclax monotherapy until the time 
of disease progression without clinical benefit, death, unacceptable toxicity, or withdrawal of 
consent. 
Additionally, if after at least one year of treatment, a patient achieves a complete remission (CR) 
or complete remission with incomplete count recovery (CRi) with MRD-negativity in the bone 
marrow, they will have the option to discontinue therapy. Those that come off treatment for this 
reason will be monitored for disease recurrence with peripheral blood MRD testing by flow 
cytometry approximately every 3 months. Patients who have detectable recurrence (at minimum, 
confirmed by two successive peripheral blood MRD positive assessments) in the peripheral 
blood will have the option to restart venetoclax. If they do not achieve MRD negativity or have 
disease progression with venetoclax monotherapy after reaching full dose venetoclax, they have 
the option to add duvelisib and continue it until MRD negativity is achieved on two successive 
peripheral blood MRD assessments or indefinitely depending on tolerability. 
Patients will be regularly monitored for minimal residual disease (MRD) throughout the trial. 
1.2
Primary Objectives
Phase I

Determine the dose limiting toxicities (DLT), maximum tolerated dose (MTD) as well as 
the recommended phase II dose and safety profile for this combination regimen of 
duvelisib plus venetoclax for patients with relapsed or refractory CLL/SLL 

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Phase II: 

Determine the best rate of complete response (CR) or complete response with incomplete 
count recovery (CRi) of duvelisib in combination with the MTD of venetoclax as defined 
by the IWCLL 2008 criteria for CLL/SLL or Lugano 2014 criteria for RS.
1.3
Secondary Objectives
Phase 1

Evaluate pharmacokinetics of both duvelisib and venetoclax in CLL/SLL and RS
Phase II 

Evaluate preliminary efficacy, including the best objective response rate (ORR), duration 
of response (DOR) among patients who have achieved a partial response (PR) or CR, 
progression free survival (PFS), and overall survival (OS) in patients treated with 
combined duvelisib and venetoclax 

Determine the rate of minimal residual disease (MRD-negative CR) in the bone marrow 
at six months, one year and two years, and rate of best MRD-negative CR/CRi in the 
bone marrow

Determine the association of FISH abnormalities, TP53, NOTCH1, or SF3B1 mutations, 
and IGHV mutational status with ORR and CR rate 
Exploratory Objectives: 

Use both standard (performed prior to initiation of therapy and following one week of 
duvelisib monotherapy) and dynamic BH3 profiling to determine whether duvelisib 
therapy enhances mitochondrial priming and how this correlates with response

Use BH3 profiling (performed prior to initiation of therapy, following one week of 
duvelisib monotherapy, and after three and six months of combination therapy) to 
determine whether BCL-2 dependency predicts response to therapy or risk of tumor lysis 
syndrome. Alternatively, we will determine whether dependency of anti-apoptotic 
proteins other than BCL-2 (i.e., MCL-1 and BCL-XL) predicts resistance to therapy 

Use Cytometry by Time of Flight (CyTOF) to identify how duvelisib monotherapy and 
duvelisib and venetoclax combination therapy impacts immune cell subtypes, in 
particular the ratio of regulatory to conventional T cells 

Determine change in lymph node size following one week of duvelisib monotherapy 

Determine change in quality of life score using quality of life survey (appendix F) after 
one week of duvelisib monotherapy

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2. BACKGROUND:
2.1
Chronic Lymphocytic Leukemia 
Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia in the western 
world, with approximately 19,000 new cases diagnosed in the United States each year.1 Although 
a subset of patients will have an indolent disease course, some patients experience more rapidly 
progressive disease despite multiple lines of therapy, and few patients are cured. Over the past 
few decades, a deeper insight into the molecular and genetic underpinnings of CLL have helped 
to elucidate these differences in outcomes and have paved the way for a pharmacologic 
revolution, with the development of a variety of highly effective and well-tolerated novel 
targeted agents. Although this has led to an expansion in therapeutic options for patients unable 
to tolerate traditional chemoimmunotherapy (CIT) and for patients with relapsed/refractory 
disease or high-risk biology, complete response (CR) rates remain low and responses are not 
durable in a large subset of patients on novel agent monotherapy. Novel therapeutic combination 
strategies are urgently needed to deepen responses and improve outcomes. 
Among the novel targeted agents available for patients with relapsed/refractory disease 
and high-risk biology are Brutons tyrosine kinase inhibitors, such as ibrutinib. Ibrutinib is an 
oral, covalent inhibitor of BTK, a key component in B-cell signaling. The first phase Ib-II trial of 
ibrutinib for patients with relapsed/refractory CLL and symptomatic older patients with 
treatment naïve CLL demonstrated high response rates and an acceptable safety profile.2,3 
Patients with relapsed/refractory CLL showed an 86% overall response rate (ORR) and 10% CR 
rate with a median progression free survival (PFS) of 52 months. While patients with deletion 
17p (del(17p)) had high response rates, responses were less durable, with a median PFS of 26 
months. The confirmatory phase III trial, RESONATE, also demonstrated an improvement in 
ORR, PFS, and overall survival (OS) of ibrutinib monotherapy compared to ofatumumab in 
patients with relapsed CLL, leading to full FDA approval of ibrutinib for this population.4,5 
Although patients have demonstrated excellent responses to ibrutinib, the effects are not 
durable for many patients, especially for those with high-risk features such as del(17p). For 
patients who relapse after ibrutinib, the survival is poor, with median overall survival ranging 
from 3 months to 23 months in one study.6 Other patients are not able to tolerate ibrutinib given 
associated side effects such as atrial fibrillation and bleeding risk.7,8 Novel therapeutic options 
for these patients are urgently needed. 
2.2
Richters Syndrome 
Although the course for most CLL patients is at least initially an indolent one, it is
estimated that between 1% to 11% CLL patients transform to an aggressive lymphoma.9 The 
most common transformation event, known as Richters syndrome (RS), involves CLL 
transforming into diffuse large B cell lymphoma (DLBCL).10 
Overall, the prognosis for patients with RS is poor, though response to therapy depends on

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whether the disease is clonally related to the antecedent CLL. Patients with clonally unrelated
RS have a median survival estimated at 62 months11; however, about 80% of patients have 
clonally-related Richters, and the median overall survival for these patients ranges from 8 to 14 
months depending on the study.9   
Based largely on extrapolation of data from de novo DLBCL, the approach to RS treatment has
historically been to use anthracycline containing chemotherapy, most commonly the rituximab,
cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen. The efficacy
of this approach has been evaluated in small phase 2 studies such as the German CLL2G trial,
which included 15 patients with RS, and the CR rate was only 7%.14 Recently, data were 
published by the CLL group at Ohio State University on the use of a dose adjusted infusional 
regimen of rituximab, etoposide, cyclophosphamide, doxorubicin, vincristine, and prednisone 
(da-R-EPOCH) in 46 patients with RS.15 The CR rate of 20% was modest, and the durability of 
response was short.  As such, novel approaches to treating Richters Syndrome are urgently 
needed. 
2.3
Venetoclax
Venetoclax is an oral, potent, selective inhibitor of BCL-2, a key mediator of the intrinsic 
pathway of apoptosis. BCL-2 inhibits cell death by binding to pro-death, BCL-2 family proteins 
that activate apoptosis at the level of the mitochondria.19 CLL cells express high levels of BCL-2 
and are dependent on it for their survival, making BCL-2 an attractive therapeutic target.20,21 
Preclinical studies have demonstrated that venetoclax selectively binds BCL-2 with 
subnanomolar affinity (Ki<0.01 nM) and rapidly induces apoptosis in human CLL cells.22  
Venetoclax also has a lower affinity for other anti-apoptotic BCL-2 family proteins, like BCL-
XL and BCL-w (> 4,000-fold and > 2,000- to > 20,000-fold lower affinity than to BCL-2, 
respectively) and therefore has a different safety profile than prior dual BCL-2/BCL-XL 
inhibitors, which led to dose-limiting thrombocytopenia due to inhibition of BCL-XL. 
Venetoclax yields an improved therapeutic index by maintaining efficacy against tumor cells 
while avoiding dose-limiting thrombocytopenia.
In the first-in-human, phase I trial in CLL, venetoclax was well-tolerated and active at all 
doses studied.16 There were a total of 116 patients enrolled in the study, which was divided into a 
dose escalation cohort (n=56), treated with doses ranging from 150 to 1,200 mg, and a dose 
expansion cohort (n=60), treated with a dose of 400 mg. The most prominent toxicity observed 
early in the study was tumor lysis syndrome (TLS).  The three initial patients treated with 
venetoclax (with initial dosing at 100 mg or 200 mg) experienced laboratory TLS after the first 
dose. Despite further reduction in the starting dose to 50 mg and weekly ramp-up to a target dose 
for each cohort, two patients experienced clinical TLS, with one patient requiring hemodialysis 
and one fatality due to presumed cardiac dysrhythmia. The risk of TLS was subsequently 
mitigated with a reduction of the initial dose to 20 mg, extended ramp-up of dosing with weekly 
increases to 50 mg, 100 mg, and 200 mg per day to the target dose of 400 mg, as well as close 
monitoring of and prophylaxis against TLS. With these modifications, only one of sixty patients 

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in the expansion cohort had laboratory findings of tumor lysis and none had clinical sequelae. 
Other toxicities associated with venetoclax, such as neutropenia and gastrointestinal adverse 
events, were manageable.  
In the initial phase I trial, the ORR, including both the dose-escalation and expansion 
cohorts, was 79%, with a 20% CR rate. Overall, 5% of patients achieved minimal residual 
disease (MRD) negativity by 4-color flow cytometry in the peripheral blood, though analysis was 
not uniformly available. Of note, response rates among patients with del(17p) were similar to the 
overall cohort, with a 71% ORR and 16% CR rate. Patients with other high-risk features, 
including unmutated IGHV, refractoriness to fludarabine, and bulky disease similarly had 
excellent responses to venetoclax. 
The follow-up landmark, phase II study included 107 patients with del(17p) CLL.17 An 
ORR of 79.4% was achieved, with a CR rate of 10%. In a subset of 45 patients evaluated for 
MRD in peripheral blood, 18 had no evidence of detectable disease. At the time of the analysis, 
the median duration of overall response, event free survival, time to progression, PFS and OS 
had not been reached. The estimated 12-month PFS and OS were 72% and 86.7%, respectively. 
The results of this study led to accelerated approval of venetoclax by the FDA for relapsed or 
refractory del(17p) CLL. More recently venetoclax has also been tested in patients who relapsed 
after or were refractory to ibrutinib or idelalisib, a group recently appreciated to have a 
particularly poor prognosis. Although the sample size in this study is small, there was a less than 
5% CR rate.23
Venetoclax has since been studied in combination with rituximab. The initial phase Ib 
trial demonstrated that this combination was well tolerated, efficacious, and associated with a 
high degree of MRD negativity.24 This prompted the phase III MURANO trial, a randomized 
trial of venetoclax plus rituximab versus BR for patients with relapsed/refractory CLL, which 
demonstrated a 2-year PFS of 84.9% with venetoclax plus rituximab as compared to 36.3% with 
BR, leading to FDA approval in 2018 of venetoclax in combination with rituximab in CLL 
patients after one prior line of therapy, independent of del(17p) status.25 
While the results of venetoclax monotherapy are promising, CR rates range from only 5-
20%, and a large subset of patients did not have durable responses, especially those with 
complex karyotype and/or del(17p).16,26 In the phase I study, 35% of patients progressed with 15 
months of initiating therapy.16 Similarly, a phase II trial of patients who were refractory to or 
relapsed after ibrutinib therapy, showed a median PFS of 22 months.23 Based on experience with 
chemoimmunotherapy, achieving CR with MRD negativity is highly beneficial both in terms of 
remission duration and OS. The use of combination therapy has the potential to deepen responses 
for this difficult to treat population and thus improve outcomes for patients for 
relapsed/refractory or high-risk CLL. 
For additional information regarding the pharmacology, metabolism, toxicology, and 
pharmacokinetics, please refer to the venetoclax package insert.

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2.4
Duvelisib 
Another key target in CLL is phosphatidylinositol-3-kinase (PI3K). PI3K is a 
heterodimeric lipid kinase composed of both a regulatory and catalytic subunit, that serves as a 
key component of B-cell receptor (BCR) signaling, which is constituently activated in CLL.27-29 
Of the four PI3K isoforms, PI3K- and PI3K-, are preferentially expressed in normal and 
malignant cells of hematopoietic lineage and have distinct and complementary roles in leukocyte 
signaling, differentiation, activation and chemotaxis.29,30 Inhibition of the PI3K- isoform with 
idelalisib, for example, is able to de-adhere CLL from the stroma and increase their susceptibility 
to apoptosis.31,32 Idelalisib has also shown clinical activity in patients with CLL, with an ORR of 
72% and a median PFS of 15.8 months, and is FDA-approved in combination with rituximab for 
relapsed/refractory CLL.33 
Duvelisib, an oral, reversible and selective small molecule dual inhibitor of PI3K- (Kd= 
23pM) and PI3K- (Kd=243 pM), has also emerged as a promising therapy for patients with 
CLL. Preclinical studies have shown that duvelisib inhibits BCR signaling, reduces chemotaxis, 
and inhibits cytokine mediated proliferation.34 PI3K- inhibition also inhibits the tumor-
promoting effects of T-cell and myeloid cells in the microenvironment, providing the potential 
for enhanced anti-tumor effect as compared to PI3K- inhibition alone.35 
The initial phase I study for duvelisib monotherapy enrolled patients with a variety of 
hematologic malignancies, including those with CLL.36,37  In 55 patients with CLL,  the most 
common adverse events were cytopenias (neutropenia 31%, thrombocytopenia 11%), febrile 
neutropenia (15%), and pneumonia (11%).38 Grade 3 ALT/AST increase occurred in 5% of 
patients and no grade 4 elevations were seen.37 There were initial concerns regarding infection 
risk, thus prompting the addition of mandatory infection prophylaxis. This trial demonstrated a 
maximum tolerated dose of 75 mg twice per day, though patients with CLL responded to lower 
doses of 25 mg twice per day, thus this lower dose was chosen for the follow-up phase II trial.36 
Even at 25 mg, there was complete suppression of PI3K- (>1C90) and partial inhibition of PI3K-
 (IC50). Of patients with baseline CT scans, 83% had a >50% in adenopathy. The best ORR by 
IW-CLL criteria for patients with CLL was 55%. Patients with del(17p) had similar response 
rates. 
A follow-up phase II trial, DYNAMO, included patients with follicular lymphoma (FL), 
small lymphocytic leukemia (SLL) and marginal zone lymphoma (MZL). The ORR in the SLL 
cohort was 68%. The phase III randomized trial of duvelisib vs. ofatumumab (DUO) was 
designed to seek regulatory approval for duvelisib. The study is currently being analyzed but top-
line data reported an improvement in PFS of duvelisib as compared to ofatumumab in patients 
with R/R CLL, with rates of 13.3 and 9.9 months, respectively, leading to recent FDA approval 
in September 2018.39
For additional information regarding the pharmacology, metabolism, toxicology, and 
pharmacokinetics, please refer to the duvelisib investigator brochure.

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2.5
Rationale for Duvelisib and Venetoclax Combination Therapy 
As venetoclax and duvelisib target pathways fundamental to CLL biology and have distinct 
mechanisms of action, they offer promise as a combination therapy for the treatment of patients 
with CLL and RS. Preclinical data further support this combination, as duvelisib therapy has 
been shown to upregulate BCL-2 transcript levels and protein expression levels and enhance the 
ability of venetoclax to induce apoptosis in ex vivo human CLL cells.35 BH3 profiling has also 
previously shown that inhibition of PI3K enhances the apoptotic threshold of CLL cells and 
sensitivity to BCL-2 inhibition.32 As PI3K inhibition results in decreased CLL cell adhesion, it 
has the potential to decrease the protective effects of stromal cells and increases the CLL cells 
susceptibility to apoptosis. Although duvelisib had minimal activity in aggressive non-Hodgkin 
lymphomas in the phase I study, there may be synergy when used in combination with 
venetoclax in this population.40 In DLBCL, it has also been shown that PI3K inhibition is 
synergistic with venetoclax in subtypes of DLBCL.41 
This trial provides the unique opportunity to combine agents with known activity in CLL 
with the goal of inducing higher rates of MRD-negative CR. Patients who achieve MRD 
negativity can discontinue therapy after a minimum of one year of treatment with close 
monitoring of recurrent disease, thus providing the opportunity to avoid the toxicities associated 
with indefinite treatment and significantly reduce costs. This strategy has already been employed 
in other studies.  For example, in a phase II trial of venetoclax plus rituximab, 13 patients who 
had responded to therapy discontinued all treatment.17 Among the 11 patients with MRD-
negative CR, all remained progression free off treatment, with some patients off therapy for 
greater than one year.17 Numerous ongoing trials in CLL are using MRD status as a decision 
point to guide treatment duration. 
While duvelisib and venetoclax have distinct mechanisms of action, they have potential 
for significant drug-drug interactions, given their simultaneous effects on CYP3A4. We will 
therefore initially add venetoclax to duvelisib at a lower dose than used in the initial phase I 
clinical trials and monitor closely for toxicity. 
Figure 1. (A) Treatment with a PI3K inhibitor (PI3K) demonstrates an ability to kill CLL cells even in the presence 
of stroma.  (B)  PI3K inhibition increases cytochrome release in response to the Bad peptide, suggesting increased 
BCL-2 dependency following PI3K inhibition (Davids et al., 2012).

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2.6
Rationale for inclusion of Richters Syndrome patients
In addition to the studies in CLL, venetoclax monotherapy has also been studied in a 
small number of patients with RS, where 3/7 patients (43%) achieved a partial response, 
including one patient who remains in remission on treatment now for over 18 months.18 
Venetoclax generally had a favorable toxicity profile in these RS patients that looked similar to 
its toxicity profile in CLL/SLL.  Direct evidence for the efficacy of PI3K-inhibitors such as 
duvelisib in RS remains anecdotal.  However, an interesting line of indirect evidence for the 
utility of the PI3Ki in RS comes from the large, randomized phase 3 trials of duvelisib and an 
older PI3Ki idelalisib, where a very low incidence of RS was observed (Flinn et al., Blood, 2018 
and Furman et al., NEJM, 2015).  It has been hypothesized that the immune-stimulating 
properties of PI3K inhibition may enhance anti-tumor immune surveillance, thereby eliminating 
early Richters clones that may emerge on treatment.  Additional prospective clinical studies of 
PI3Ki as a component of RS therapy are warranted, and given the known single agent activity of 
venetoclax in RS and the potential for synergy with duvelisib based on the preclinical data of this 
combination in CLL, we now plan to explore this combination in a separate exploratory cohort in 
this trial. 

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2.7
Correlative Studies Background
BH3 Profiling: 
This study will incorporate a laboratory technique known as BH3 profiling, which is a 
functional assay that uses synthetic peptides that mimic the BH3 domains of pro-apoptotic BCL-
2 family members to measure mitochondrial priming, or how close a cell is to its apoptotic 
threshold.42 This tool is also extremely powerful in that it can identify which anti-apoptotic 
proteins (i.e., BCL-2, BCL-XL, MCL-1) the cell relies on for survival. To perform a BH3 
profile, individual BH3-only peptides are mixed with gently permeabilized living primary CLL 
cells, formalin-fixed, and then fluorescence activated cell sorting (FACS) is used to determine 
the amount of mitochondrial depolarization induced by each peptide as measured by cytochrome 
c release.
We have previously found that in a small, heterogeneously treated cohort of CLL 
patients, increased priming was associated with improved clinical response.32 We have also 
demonstrated that increased priming was associated with depth of clinical response in 
relapsed/refractory CLL patients on the M12-175 phase I study of venetoclax.43 Building on 
these initial studies, we will incorporate BH3 profiling into this trial to determine whether in vivo 
treatment with duvelisib enhances mitochondrial priming and or BCL-2 dependency and whether 
this correlates with response to combination therapy with venetoclax. We will also use BH3 
profiling to determine whether dependency of anti-apoptotic proteins other than BCL-2 (i.e., 
MCL-1 and BCL-XL) predicts resistance to therapy. In a similar fashion, we will utilize dynamic 
BH3 profiling to determine whether short incubations of CLL cells with duvelisib ex vivo, 
enhances mitochondrial priming or BCL-2 dependency, and if these results correlate with 
clinical response.44 
Cytometry by Time of Flight (CyTOF): 
Mass cytometry or cytometry by time-of-flight (CyTOF) is a technology for 
multiparameter single cell analysis that uses heavy metal ions as antibody labels, thus 
overcoming many of the limitations of fluorescence-based flow cytometry.45 Previous studies 
have demonstrated that treatment of CLL with PI3K inhibitors alters immune subsets, including 
the percentage of regulatory T-cells, which is associated with development of toxicity.46 As 
duvelisib is known to have effects on tumor-promoting effects of T-cell and myeloid cells in the 
microenvironment, we aim to characterize these changes and correlate our findings with both 
response to therapy (ORR) as well as toxicity. We will plan to use a panel of monoclonal 
antibodies targeting 35 markers, including 26 surface membrane and 9 intracellular markers. The 
Wilcoxon matched-pairs signed rank test will be used to compare percentages of T cell subsets 
obtained from CyTOF at various time points. 

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3. PARTICIPANT SELECTION
3.1
Eligibility Criteria 
Unless otherwise specified, laboratory tests required for eligibility must be completed within 28 
days prior to start of protocol therapy. Baseline tumor measurements by CT scan must be 
performed within approximately 4 weeks (28 days) of starting study treatment. Bone marrow 
biopsy within approximately 12 weeks (90 days) prior to study treatment will be acceptable if 
there has not been a significant change to the anti-cancer therapy given since the test was 
performed. 
Participants must meet the following criteria on screening examination to be eligible to 
participate in the study:
Inclusion:
3.1.1
Must have a confirmed diagnosis of chronic lymphocytic leukemia or small lymphocytic 
lymphoma per IW-CLL 200834 requiring therapy based on at least one of the following 
criteria as listed below: 
o
Evidence of progressive marrow failure as manifested by the development of, or 
worsening of, anemia (hemoglobin <11.0 g/L) and/or thrombocytopenia (platelets 
<100 x 109/L)
o
Massive (≥6 cm below the left costal margin), OR progressive, OR symptomatic 
splenomegaly
o
Massive nodes (at least 10 cm longest diameter), OR progressive, OR  
symptomatic lymphadenopathy
o
Progressive lymphocytosis with an increase of more than 50% over a 2-month 
period or LDT of <6 months. Lymphocyte doubling time may be obtained by 
linear regression extrapolation of absolute lymphocyte counts obtained at 
intervals of 2 weeks over an observation period of 2 to 3 months.
o
Autoimmune anemia and/or thrombocytopenia that is poorly responsive to 
corticosteroids or other standard therapy (also see Exclusion Criteria, Section 3.2)
o
Documented constitutional symptoms, defined as 1 or more of the following 
disease related symptoms or signs:
evidence of infection
night sweats for more than 1 month prior to screening without evidence of 
infection
OR

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Biopsy proven transformation to diffuse large B cell lymphoma (DLBCL), 
consistent with Richters Syndrome 
3.1.2
Disease that has progressed during or relapsed after at least one previous CLL/SLL 
therapy (CLL/SLL patients only)  
If Richters Syndrome, this criterion is not applicable
3.1.3
Age greater than or equal to 18 years 
3.1.4
ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)
3.1.5
Patients must meet the following hematologic criteria at screening, unless they have 
significant bone marrow involvement of CLL confirmed on biopsy:
o
Absolute neutrophil count ≥500 cells/mm3 (0.5 x 109/L).  Growth factor is 
allowed in order to achieve this
o
Platelet count ≥25,000 cells/mm3 (25 x 109/L) independent of transfusion within 7 
days of screening 
3.1.6
Adequate hepatic function defined as:
o
Serum aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 x 
local upper limit of normal (ULN), bilirubin ≤1.5 x local ULN (unless bilirubin 
rise is due to Gilberts syndrome or of non-hepatic origin 
3.1.7
Adequate renal function as defined as: 
o
Serum creatinine ≤1.5 times the local upper limit of normal or creatinine 
clearance ≥ 50 mL/min using a 24-hour urine collection 
3.1.8
Women of child-bearing potential and men must agree to use adequate contraception 
(hormonal, barrier method or abstinence) prior to study entry,for the duration of study 
participation, and for 3 months after the last dose of duvelisib. Male subjects must also 
refrain from donating sperm during their participation during the study and for 3 months 
after the last dose of duvelisib. Effective methods of contraception include:

True abstinence: When this is in line with the preferred and usual lifestyle of the subject.
o
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods), and withdrawal are not effective methods of contraception.

Sterilization
o
Female subject or female partner of male subject: When a woman of childbearing 
potential has had surgical bilateral oophorectomy (with or without hysterectomy) 
or tubal ligation at least 6 weeks prior to starting treatment. In case of 
oophorectomy alone, only when the reproductive status of the woman has been 

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confirmed by follow up hormone level assessment would they be eligible to begin 
treatment
o
Male subject or male partner of female subject: (with the appropriate post-
vasectomy documentation of the absence of sperm in the ejaculate).

Placement of an intrauterine device (IUD) or intrauterine system (IUS).

Hormonal methods of contraception associated with inhibition of ovulation: oral, 
implantable, injectable, intravaginal, or transdermal contraception
3.1.9
Negative serum human chorionic gonadotropin (hCG) pregnancy test within 7 days 
before first dose of study intervention if the subject is a woman of childbearing potential. 
3.1.10 Ability to understand and the willingness to sign a written informed consent document
3.2
Exclusion Criteria
3.2.1
Previous treatment with venetoclax or duvelisib (prior venetoclax allowed for RS patients 
and for CLL/SLL patients if they have been off venetoclax therapy for at least one year 
prior to enrollment)
3.2.2
Patients receiving cancer therapy (i.e., chemotherapy, radiation therapy, immunotherapy, 
biologic therapy, surgery within 2 weeks of Cycle 1/Day 1 with the following exceptions:
o
For patients on targeted therapies, a washout of least five half-lives is required
o
Patients who experience clinical deterioration may start therapy after a shorter 
washout period with prior approval by the PI
o
Corticosteroid therapy (prednisone or equivalent <20 mg daily) is allowed 
3.2.3
Confirmed central nervous system involvement 
3.2.4
Allogeneic hematologic stem cell transplant within 6 months of starting study treatment 
or active graft vs. host disease (GVHD) requiring treatment or prophylaxis
3.2.5
Administration of live or live attenuated vaccine within 6 weeks of initiation of therapy
3.2.6
 Unable to receive prophylactic treatment for pneumocystis, herpes simplex virus (HSV), 
or herpes zoster (VZV) at screening
3.2.7
Ongoing treatment with chronic immunosuppressants (e.g., cyclosporine)
3.2.8
Active malignancy other than CLL/SLL or RS requiring therapy with the exception of 
hormonal therapy, non-melanoma skin cancer or carcinoma in situ of the cervix, bladder 
cancer, or prostate cancer not requiring treatment. Subjects with previous malignancies 
are eligible if they have been disease-free for 2 years or more.

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3.2.9
Any active systemic infection requiring IV antibiotics or uncontrolled, active infections
3.2.10 Active Human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B 
virus (HBV) 

Subjects with a positive hepatitis B surface antigen [HBsAg] or hepatitis C antibody 
[HCV Ab] will be excluded

Subjects with a positive hepatitis B core antibody (HBcAb) must have negative 
hepatitis B virus (HBV) deoxyribonucleic acid (DNA) to be eligible, must receive 
prophylaxis with entecavir (or equivalent) concomitant with duvelisib treatment, and 
must be periodically monitored for HBV reactivation by institutional guidelines

Investigators who believe that a positive HBcAb is false due to passive immunization 
from previous immunoglobulin infusion therapy should consider the risk-benefit for 
the patient given the potential for reactivation
3.2.11 Major surgery within 4 weeks of first dose of study drug 
3.2.12 Currently active gastrointestinal disease, including colitis, inflammatory bowel disease 
and diarrhea requiring therapy 
3.2.13 Currently active, clinically significant cardiovascular disease, such as uncontrolled 
arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart 
Association Functional Classification; or a history of myocardial infarction, unstable 
angina,  acute coronary syndrome, stroke, or sustained ventricular arrhythmia within 6 
months of first dose of study drug
3.2.14 Any life-threatening illness, medical condition, or organ system dysfunction that, in the 
investigators opinion, could compromise the subjects safety or put the study outcomes 
at undue risk 
3.2.15 Use of Coumadin for anticoagulation (other anticoagulants permitted)
3.2.16 Lactating or pregnant 
3.2.17 Concurrent administration of medications or foods that are strong inhibitors or inducers 
of CYP3A (see Appendix D) . The concomitant use of drugs or foods that are strong or 
moderate inhibitors or inducers of CYP3A are not allowed beginning 1 week prior to the 
first dose of duvelisib.

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3.2.18 Patients with ongoing use of prophylactic antibiotics are eligible as long as there is no 
evidence of active infection and the antibiotic is not included on the list of prohibited 
medications
3.2.19 Unable to swallow capsules or malabsorption syndrome, disease significantly affecting 
gastrointestinal function, or resection of the stomach or small bowel, symptomatic 
inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction 
resulting in malabsorption or chronic diarrhea
3.2.20 History of chronic liver disease or veno-occlusive disease/sinusoidal obstruction 
syndrome  
3.2.21 History or concurrent condition of interstitial lung disease of any severity and/or 
            severely impaired lung function 
3.2.22 Active abuse of alcohol or illicit drug use
3.2.23 Known hypersensitivity to duvelisib and/or its excipients
3.2.24 History of tuberculosis treatment within the 2 years prior to initiation of therapy
3.3
Inclusion of Women and Minorities
Both men and women of all races and ethnic groups are eligible for this trial.

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4. REGISTRATION  PROCEDURES 
4.1
General Guidelines for DF/HCC Institutions
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of any protocol-specific therapy or 
intervention. Any participant not registered to the protocol before protocol-specific therapy or 
intervention begins will be considered ineligible and registration will be denied.
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist.
Following registration, participants may begin protocol-specific therapy and/or intervention. 
Issues that would cause treatment delays should be discussed with the Overall Principal 
Investigator (PI). If the subject does not receive protocol therapy following registration, the 
subject must be taken off-study in the CTMS (OnCore) with an appropriate date and reason 
entered.
4.2
Registration Process for DF/HCC Institutions
Applicable DF/HCC policy (REGIST-101) must be followed.  
4.3
General Guidelines for Other Investigative Sites
Eligible participants will be entered on study centrally at Dana-Farber Cancer Institute by the 
lead site project manager.  All sites should call the project manager to verify dose level and or 
slot availabilities.  
Following registration, participants should begin protocol therapy as soon as feasible. Issues that 
would cause treatment delays should be discussed with the Overall PI.  If the subject does not 
receive protocol therapy following registration, the subject must be taken off-study in the CTMS 
(OnCore) with an appropriate date and reason entered.
4.4
Registration Process for Other Investigative Sites
To register a participant, the following documents should be completed by the research nurse or 
data manager and faxed or e-mailed to the lead site project manager. 

Copy of relevant medical records that support the items on the eligibility checklist 
(with PMI redacted)

Participant consent form signed by both the consenting physician investigator, and the 
participant

HIPAA authorization form (if applicable)

Completed eligibility checklist

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The participating site will e-mail the lead site project manager to verify eligibility.  The project 
manager will follow DF/HCC policy (REGIST-101) and register the participant on the protocol.  
The lead site project manager will email the participant study number, and if applicable the dose 
treatment level, to the participating site.  The lead site may also contact the participating site and 
verbally confirm registration. 

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5. TREATMENT PLAN
Figure 2: Phase I dosing algorithm  
In the phase I portion of the study, patients will start with 25 mg BID of duvelisib for seven days. 
A traditional 3 + 3 design will be used to accrue patients to one of three dose levels of 
venetoclax, which will start on day 8 and will be given in combination with duvelisib. The 
starting dose level of venetoclax will be 100 mg daily (dose level +1) with escalation to 200 mg 
daily (dose level +2) and to 400 mg daily (dose level +3). De-escalation to 50 mg daily (dose 
level -1) will be performed if unexpected toxicity is observed. Patients will be admitted for initial 
dosing at the initial dose and at each dose escalation of venetoclax during the dose ramp-up for 
close monitoring for tumor lysis syndrome (TLS). 
At each dose level, patients be treated with 10 mg of venetoclax for one week, followed by a 
weekly dose ramp-up of venetoclax as per the label, with patients in the initial dosing cohort 

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stopping at a lower dose of venetoclax than the approved dose of 400 mg. Patients will continue 
combination therapy for a total of one year, followed by venetoclax monotherapy until the time 
of disease progression without clinical benefit, death, unacceptable toxicity, withdrawal of 
consent, or physician/patient discussion of discontinuation based on objective disease response.
Once the MTD of venetoclax in combination with duvelisib is determined, 3 additional patients 
will be accrued at that dose level who will start with venetoclax 20 mg and have a dose ramp up 
identical to the other patients in that cohort. Also, patients assigned to lower dose levels in the 
phase I portion of the trial will have the option to escalate their venetoclax dose to the MTD. 
Phase II: 
Figure 3: Phase II Dosing algorithm  
The phase II portion of the study will be designed in two stages. Patients will undergo a dose-
ramp up venetoclax as described in the phase I trial, with the exception that since there was no 
evidence of TLS in patients at 10 mg during phase I, participants in phase II will have the option 
of starting their dose ramp up at 20 mg of venetoclax for one week, followed by a weekly dose 
ramp-up to 400 mg daily. Patients who wish to start at 20 mg venetoclax will be required to do 
so inpatient for the first 2 dose ramp-ups (at 20 mg and 50 mg) and can then do the remaining 
ramp-ups (i.e. to 100, 200, and 400 mg) as an outpatient. 
Patients who are low- or medium risk for TLS and wish to be treated all in the outpatient setting 
will have to start at 10 mg and then the following week go up to 20 mg, and then complete the 
rest of the usual ramp-up to 50 mg, 100 mg, 200 mg, and 400 mg.
High risk patients will be hospitalized for the initial dose ramp-ups, but will have the option to 
start at 10 or 20 mg.  If they start at 10 mg then they will need to be hospitalized for the first 3 
dose ramp-ups (10 mg, 20 mg, and 50 mg), or for the first two dose ramp ups ( 20mg and 50mg) 
if they start at 20 mg.
Accelerated ramp up for RS patients:

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Given the potential for rapidly progressive RS, these RS patients will also have the option to 
undergo an accelerated venetoclax ramp-up in the inpatient setting modeled after another study 
of venetoclax plus chemotherapy that was recently reported (Davids et al., ICML, 2019).  In that 
study, venetoclax was safely ramped up in a daily fashion for 20 RS patients, who were 
monitored closely in the inpatient setting, with no evidence of tumor lysis syndrome.  The 
venetoclax is dosed at 20 mg for day 1, and if no TLS is observed on labs done 6-8 hours and 24 
hours later, then the dose is ramped up to 50 mg on day 2, 100 mg on day 3, 200 mg on day 4, 
and 400 mg on day 5 if the daily labs done 6-8 hours and 24 hours later continue to show no 
TLS.  If laboratory TLS does occur, the next days dose will be held until there is improvement 
in the TLS, at which point escalation to the next dose may occur 
Study visits will occur weekly through cycles 1-2, once per cycle during cycles 3-7, every two 
cycles from cycle 7-13, and every 3 cycles thereafter through cycle 60. After cycle 60, patients 
will return for study visits every six cycles until they are removed from treatment. Patients will 
be treated with duvelisib plus venetoclax for up to one year followed by venetoclax monotherapy 
until disease progression without clinical benefit, death, unacceptable toxicity, withdrawal of 
consent, physician/patient discussion of discontinuation based on objective disease response, or 
they elect to go on a new CLL or Richters directed therapy. 
CT of the neck, abdomen, pelvis and neck (CLL) or full body PET/CT (Richters) scans will be 
mandatory at C4D1, C7D1, C13D1, and then at the discretion of the treating investigator or 
approximately every six cycles thereafter.  Bone marrow biopsy will be mandatory at study entry 
and at the C7D1, C13D1, and C25D1 re-staging visits. Subsequent bone marrow biopsies will be 
performed as clinically indicated thereafter at the discretion of the treating investigator. 
Patients will be evaluated for MRD negativity in the peripheral blood approximately every three 
months and with each bone marrow biopsy (except the baseline biopsy).MRD testing will be 
performed by 4-color flow cytometry with a sensitivity of 10-4 and when possible also by 
ClonoSEQ (Adaptive), a next generation sequencing technology. 
If after at least one year of treatment, a patient achieves a complete remission (CR) or complete 
remission with incomplete count recovery (CRi) with MRD-negativity in the marrow, they will 
have the option to discontinue venetoclax. Patients with a PR with MRD-negativity will have the 
option of discontinuing venetoclax after 24 months of treatment. Those that come off treatment 
for this reason will be monitored for disease recurrence with peripheral blood MRD testing by 
flow cytometry approximately every 3 months. Patients who have detectable recurrence (at 
minimum, confirmed by two successive peripheral blood MRD positive assessments) in the 
peripheral blood will have the option to restart venetoclax. 
In the event that patients need to restart venetoclax due to disease recurrence, they will be re-
staged.  If they have MRD-detectable disease but no other evidence of clinical disease 
progression, venetoclax can be resumed at 400 mg daily in the outpatient setting with TLS 
monitoring 6-8 and 24 hours after the initial dose.  Patients with evidence of clinical disease 
progression on the re-staging evaluation will be treated with a venetoclax dose ramp up as per 
the label, starting with 20 mg daily and escalating to 400 mg daily. Prophylaxis against and 

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treatment of TLS will be performed as during initial therapy. Patients who do not achieve MRD 
negativity or have disease progression after reaching full dose venetoclax monotherapy have the 
option to add duvelisib at the highest dose they had previously tolerated and continue it until 
MRD negativity is achieved on two successive peripheral blood MRD assessments or 
indefinitely depending on tolerability. Patients who achieve maximal response and are allo 
transplant candidates can elect to go off study to move on to transplant. 
Participants who elect to come off therapy at the time of complete response must have received 
at least one year of treatment on study.  
Those that discontinue duvelisib during combination therapy may continue to receive venetoclax 
monotherapy. 
5.1
Treatment Regimen
5.1.1
Duvelisib: 
Duvelisib will be administered twice daily, with 28 consecutive days defined as a treatment cycle 
(up to 49 days for cycle 1), for up to a total of 12 cycles. Treatment will be administered on an 
outpatient basis with the exception of  doses given while inpatient for venetoclax ramp up/dose 
escalation.  Appropriate dose modifications are described in Section 6.  Reported adverse events 
and potential risks are described in Section 7.  No investigational or commercial agents or 
therapies other than those described below may be administered with the intent to treat the 
participant's malignancy.
5.1.2
Venetoclax: 
Venetoclax will be administered daily, with 28 consecutive days defined as a treatment cycle (up 
to 42 days for cycle 1) until the time of disease progression without clinical benefit, death, 
unacceptable toxicity, withdrawal of consent, or physician/patient discussion of discontinuation 
based on objective disease response, or they elect to go on a new CLL or Richters directed 
therapy. The first dose of venetoclax will be given on day 8 of cycle 1 at a starting dose of 10 
mg. All patients will be admitted for administration of the initial dose of venetoclax at each dose 
escalation. Patients will be started on allopurinol and IV hydration for TLS prophylaxis. TLS 
laboratories will be checked approximately 4, 8, 12, and 24 hours post venetoclax dose. Pre-dose 
laboratory values will be used as baseline to assess for potential electrolyte abnormalities 
following venetoclax. Patients can be discharged if no evidence of laboratory TLS 24 hours after 
dosing, according to the Cairo-Bishop criteria for TLS. If laboratory or clinical TLS is seen, as 
defined by Cairo-Bishop criteria, patients will be managed as per appendix C. Patients will be 
admitted weekly for each dose escalation (10 mg, 20 mg, 50 mg, 100 mg, 200 mg, 400 mg) for 
up to six weeks (42 days) depending on the target dose level. The same rules and TLS laboratory 
evaluations will be applied for each dose escalation, with the potential to escalate to 100 mg 
(dose level +1), 200 mg (dose level +2), and 400 mg (dose level +3). 

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Phase II- 
Patients will undergo a dose-ramp up venetoclax as described in the phase I trial, with the 
exception that since there was no evidence of TLS in patients at 10 mg during phase I, 
participants in phase II will have the option of starting their dose ramp up at 20 mg of venetoclax 
for one week, followed by a weekly dose ramp-up to 400 mg daily. Patients who wish to start at 
20 mg venetoclax will be required to do so inpatient for the first 2 dose ramp-ups (at 20 mg and 
50 mg) and can then do the remaining ramp-ups (i.e. to 100, 200, and 400 mg) as an outpatient. 
Patients who are low- or medium risk for TLS and wish to be treated all in the outpatient setting 
will have to start at 10 mg and then the following week go up to 20 mg, and then complete the 
rest of the usual ramp-up to 50 mg, 100 mg, 200 mg, and 400 mg.
High risk patients will be hospitalized for the initial dose ramp-ups, but will have the option to 
start at 10 or 20 mg.  If they start at 10 mg then they will need to be hospitalized for the first 3 
dose ramp-ups (10 mg, 20 mg, and 50 mg), or for the first two dose ramp ups (20mg and 50mg) 
if they start at 20 mg.
Inpatient: 
When venetoclax dosing is performed as an inpatient, TLS labs must be performed STAT at least 
at the following time points: pre-dose (within 4 hours before venetoclax administration), and 
approximately 4, 8, 12, and 24 hours after the first dose of venetoclax and each subsequent dose 
escalation. Pre-dose laboratory values will be collected and used as baseline to assess potential 
electrolyte abnormalities occurring post venetoclax administration.
Outpatient: 
When venetoclax dosing is performed as an outpatient, TLS labs should be checked pre-
dose, approximately 6-8 hours after first dose and approximately 24 hours after treatment.
Accelerated ramp up for RS patients: Given the potential for rapidly progressive RS, these RS 
patients will also have the option to undergo an accelerated venetoclax ramp-up in the inpatient 
setting modeled after another study of venetoclax plus chemotherapy that was recently reported 
(Davids et al., ICML, 2019).  In that study, venetoclax was safely ramped up in a daily fashion 
for 20 RS patients, who were monitored closely in the inpatient setting, with no evidence of 
tumor lysis syndrome.  The venetoclax is dosed at 20 mg for day 1, and if no TLS is observed on 
labs done 6-8 hours and 24 hours later, then the dose is ramped up to 50 mg on day 2, 100 mg on 
day 3, 200 mg on day 4, and 400 mg on day 5 if the daily labs done 6-8 hours and 24 hours later 
continue to show no TLS.  If laboratory TLS does occur, the next days dose will be held until 
there is improvement in the TLS, at which point escalation to the next dose may occur 
 
Subjects should take venetoclax within approximately 30 minutes after the completion of 
breakfast or the subject's first meal of the day. Subjects may not consume: grapefruit or 
grapefruit products, Seville oranges (including marmalade containing Seville oranges) or 

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starfruit within the 3-day period prior to the first study drug administration and until the last day 
of treatment is completed due to possible CYP3A mediated metabolic interaction. 
The participant will maintain a medication diary of each dose of medication. The medication 
diary should be returned to clinic staff at the end of each cycle or visit period (every 2, 3 or 6 
cycles as outlined in the study calendar). If the patient has not taken their duvelisib dose within 4 
hours and venetoclax dose within 8 hours of the recommended time, they will be instructed to 
skip their dose.
Administration of venetoclax and duvelisib may be in any order. 
5.1.2.1
Phase I: 
Table 1: Dose Escalation Schedule of Duvelisib and Venetoclax 
Dose Escalation Schedule
Dose*
Dose Level
Duvelisib 
Venetoclax 
Level -1
25 mg BID
50 mg daily
Level +1(Starting Dose)
25 mg BID
100 mg daily
Level +2
25 mg BID
200 mg daily
Level +3
25 mg BID
400 mg daily
In the Phase I portion of the trial, we aim to determine the maximum tolerated dose (MTD) of 
venetoclax when given in combination with duvelisib. A standard 3+3 dose escalation design 
will be employed (Figure 4). Patients will be treated in cohorts of size three to six and the dosage 
will be escalated if the clinical toxicity is acceptable. 

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Figure 4: 3+3 dose escalation for the phase I trial: 
The MTD is defined as the highest dose studied for which the observed incidence of DLT is less 
than 33%. Frequencies of toxicities will be tabulated according to the NCI Common Toxicity.
Once the MTD of venetoclax in combination with duvelisib is determined, patients assigned to 
lower dose levels of venetoclax will have the option of escalating their venetoclax dose to the 
MTD. 
5.1.2.2
Phase II: 
Patients in the phase II portion of the trial will also begin duvelisib on day 1 and add venetoclax 
on day 8. Please refer to section 5.1.2 for full venetoclax dose ramp up instructions. Patients will 
continue combination therapy for up to 12 cycles followed by venetoclax monotherapy until 
unacceptable toxicity, patient withdrawal, disease progression without clinical benefit, physician 
decision, physician/patient discussion of treatment discontinuation based on objective disease 
response, or death.  Those patients who achieve CR/CRi with undetectable MRD in the bone 
marrow after 1 year of combination therapy have the option to discontinue study therapy and be 
monitored with the option to resume venetoclax monotherapy if at least 2 peripheral blood MRD 
tests come back as detectable.  If they do not achieve MRD negativity or have evidence of 
disease progression after reaching full dose venetoclax monotherapy, they have the option to add 
duvelisib at the highest dose they previously tolerated and continue it until MRD negativity is 
achieved on two successive peripheral blood MRD assessments or indefinitely depending on 
tolerability. 
Patients in the RS cohort will be treated similarly to those in the phase II CLL/SLL cohort with 
one week of duvelisib monotherapy prior to adding venetoclax.  RS patients will also start with 
20 mg of venetoclax with weekly ramp-up to 400 mg similar to the CLL/SLL cohort.  However, 
given the potential for rapidly progressive RS, these RS patients will also have the option to 
undergo an accelerated venetoclax ramp-up modeled after another study of venetoclax plus 
chemotherapy that was recently reported (Davids et al., ICML, 2019).  In that study, venetoclax 
was safely ramped up in a daily fashion for RS patients, who were monitored closely in the 

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inpatient setting.  The venetoclax is dosed at 20 mg for day 1, and if no TLS is observed on labs 
done 6-8 hours and 24 hours later, then the dose is ramped up to 50 mg on day 2, 100 mg on day 
3, 200 mg on day 4, and 400 mg on day 5 if the daily labs done 6-8 hours and 24 hours later 
continue to show no TLS.  If laboratory TLS does occur, the next days dose will be held until 
there is improvement in the TLS, at which point escalation to the next dose may occur.   If a 
treating investigator wishes to do this accelerated ramp-up, written approval must be obtained 
from the Overall PI (or delegate) prior to initiating venetoclax therapy.  
5.2
Pre-Treatment Criteria
5.2.1
Cycle 1, Day 1: 
Participants must meet all the inclusion criteria, have none of the exclusion criteria prior 
to treatment with the exception that patients laboratory evaluations on C1D1 do not need 
to meet eligibility criteria again provided that they did meet criteria at screening and any 
changes in the patient's condition or labs do not in the opinion of the investigator pose 
significant risk to the patient. Participants must be registered to the protocol prior to 
initiating therapy.  
5.2.2
Ramp-up cycles Day 1 of combination duvelisib and venetoclax therapy: 

ANC must be ≥ 500/mm3 (growth factor support allowed), unless they have 
significant bone marrow involvement of CLL confirmed on pretreatment biopsy

Platelet count must be ≥ 20K (transfusion support allowed), unless they have 
significant bone marrow involvement of CLL confirmed on pretreatment biopsy

Serum creatinine must be ≤1.5 times the upper limit of normal or creatinine clearance 
must be ≥ 50 mL/min using a 24-hour urine collection 

All non-hematologic toxicities must have resolved to ≤ Grade 2, or to the patients 
baseline condition

No evidence of active tumor lysis syndrome 
5.2.3
Combination cycles of duvelisib and venetoclax therapy and venetoclax monotherapy 
(maintenance) cycles 
The following treatment parameters must be met at visits when a new
cycle is being started:
 ANC must be ≥ 500/mm3, unless they have significant bone marrow involvement of 
CLL confirmed on pretreatment biopsy (growth factor support allowed)
 Platelet count must be ≥ 20K, unless they have significant bone marrow 
involvement of CLL confirmed on pretreatment biopsy (transfusion support allowed)

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 All non-hematologic toxicities must have resolved to ≤ Grade 2, or to
the patients baseline condition
5.3
 Definition of Dose-Limiting Toxicity (DLT) 
Dose-limiting toxicity (DLT) is based on the CTEP Active Version of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0. DLT refers to toxicities 
experienced at any time during the first cycle of study treatment, defined as the following:

Grade 4 neutropenia lasting more than 5 days 

Febrile neutropenia of any duration (ANC<1.0 x 109/L and fever 38.5F)

Grade ≥3 thrombocytopenia with clinically significant bleeding 

Grade 4 infection by NCI-CTCAE criteria

Any grade 3 or greater non-hematologic toxicity with the following exceptions:
o
Grade 3 or greater nausea/vomiting/diarrhea that persists for 7 days or less
o
Grade 3 asymptomatic laboratory abnormalities that improve to grade 2 or less 
within 3 days

Any grade  3 diarrhea or vomiting or diarrhea that requires tube feeding, total 
parenteral nutrition, or requires or prolongs hospitalization

Inability to receive Day 1 therapy of Cycle 2 after a delay in treatment of up to 21 
days due to continued drug related toxicity from the prior cycle

Severe cutaneous reaction (grade 3 or greater) 

Grade 4 elevation in ALT and/or AST or grade  3 elevation in ALT and/or AST 
occurring in the context of a Grade  2 elevation in bilirubin

Grade 5 treatment-related adverse events
All toxicities will be considered relevant to determining DLTs and to reporting unless the event
can clearly be determined to be unrelated to the study drug(s).  
The DLT observation period is considered the period from the first dose of combination therapy 
through the completion of cycle 1.  In the phase I study, if a patient comes off study due to a 
reason other than a DLT (e.g. disease progression) prior to the end of the DLT observation 
period, that patient can be replaced.

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Management and dose modifications associated with the above adverse events are outlined in 
Section 6.
5.3.1
Safety Rules and Data Safety and Monitoring Trigger for Enrollment Pause 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of medical oncologists, research 
nurses, pharmacists and biostatisticians with direct experience in cancer clinical research. 
Information that raises any questions about participant safety will be addressed with the Overall 
PI and study team. This information can also be found in Appendix E addressed in more detail.
The DSMC will review each protocol up to four times a year with the frequency determined by 
the outcome of previous reviews. Information to be provided to the committee may include: up-
to-date participant accrual; all grade 2 or higher unexpected adverse events that have been 
reported; summary of all deaths occurring within 30 days of intervention; any response 
information; audit results, and a summary provided by the study team. Other information (e.g. 
scans, laboratory values) will be provided upon request
5.4
General Concomitant Medication and Supportive Care Guidelines
Subjects should receive full supportive care, including transfusions of blood and blood products, 
antibiotics, hematopoietic growth factors, analgesics, and anti-emetics when appropriate. Local 
institutional standard of care may also be followed.
5.4.1
Tumor Lysis Syndrome (TLS) Prophylaxis:
Tumor lysis syndrome (TLS), characterized by hyperkalemia, hyperuricemia, and 
hyperphosphatemia resulting from the rapid release of potassium, uric acid, and phosphate, has 
been reported in patients receiving venetoclax, necessitating TLS prophylaxis. The risk of TLS is 
highest during initiation of venetoclax.

All patients should be started on an oral uric acid reducer (such as allopurinol 300 
mg/day) prior to initial study therapy administration (ideally at least 72 hours prior 
when possible) and continued until each subject has completed a week at their highest 
dose level of venetoclax, unless known allergy. 

Patients should remain well hydrated 
The following is recommended for prophylaxis in patients being admitted for TLS observation. 

Administration of an oral uric acid reducer (such as allopurinol 300 mg/day) prior to 
initial study therapy administration (ideally at least 72 hours prior when possible) and 
continued until each subject has completed a week at their highest dose level of 

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venetoclax. Patients with an allergy to allopurinol and thought to be at high risk for 
TLS, should receive a prophylactic dose of rasburicase prior to administration of 
venetoclax. 

IV hydration should be started the night before the first dose of 10 mg (during Phase 
II, before 10mg or 20mg as indicated), with a target of approximately 1.5  2 L/day, 
or as clinically appropriate, and continued for at least 24 hours after administration of 
venetoclax. 

Nephrology (or other acute dialysis service) consultation should be considered prior 
to dosing per institutional standards at the investigators' discretion to ensure 
emergency dialysis is available and the appropriate staff is aware and prepared to 
handle any necessary intervention for TLS.

Telemetry should also be considered.

Rasburicase (given at a flat dose of 6 mg IV x 1) must be administered per 
institutional guidelines for subjects with elevated uric acid level at baseline (> ULN) 
as prophylaxis prior to the initial dose of venetoclax. For subjects with a 
contraindication to rasburicase (i.e., glucose-6-phosphate dehydrogenase [G6PD] 
deficiency), the TLS risk mitigation plan must be reviewed with the Overall PI.

Chemistry laboratory tests must be performed STAT at least at the following time 
points: pre-dose (within 4 hours before venetoclax administration), and approximately 
4, 8, 12, and 24 hours after the first dose of venetoclax at 10 mg and each subsequent 
dose escalation. Pre-dose laboratory values will be collected and used as baseline to 
assess potential electrolyte abnormalities occurring post venetoclax administration.

If any laboratory changes in potassium, uric acid, phosphate, calcium, lactate 
dehydrogenase, or creatinine are observed within the first 24 hours after initiation of 
dosing, see Appendix C (Recommendations for Initial Management of Electrolyte 
Abnormalities and Prevention of Tumor Lysis Syndrome [TLS]) for additional 
laboratory assessments and management guidelines. 

Patients without evidence of TLS can be discharged 24 hours following venetoclax 
administration 
5.4.2
Treatment of TLS: 
All subjects meeting criteria of laboratory TLS or ≥ grade 1 TLS according to the Cairo-
Bishop Definition of Tumor Lysis Syndrome (see Appendix B) should receive vigorous 
intravenous hydration, aggressive electrolyte management, and should be considered for 
rasburicase therapy as needed to reduce hyperuricemia, until correction of electrolyte 
abnormalities. See Section 6, Dose Modification, for additional instructions.
5.4.3
Monitoring for skin reactions:  
Patients will be closely monitored for the development of a skin rash while being treated 
with duvelisib. Patients will also be informed to call their provider with any evidence of 
rash. 

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5.4.4
Prophylactic Antibiotics: 
Prophylaxis for Pneumocystis jiroveci pneumonia (PCP) with Bactrim or equivalent, and 
anti-herpetic viral prophylaxis with acyclovir or equivalent is mandated beginning with 
cycle one and continuing for the duration of the participants treatment on study.
5.4.5
CMV Monitoring: 
Based on data from the duvelisib phase I study in CLL, subjects taking duvelisib might 
be at an increased risk of cytomegalovirus (CMV) reactivation. Clinically significant 
CMV infection can generally be avoided by close monitoring and institution of anti-CMV 
therapy at time of positive viral load detection. Therefore, all subjects on study will have 
mandatory CMV viral measurement at study entry and monthly thereafter while on 
duvelisib therapy. Subjects whose CMV viral load becomes positive will be started on 
treatment dose valganciclovir and the CMV viral load will be checked weekly until it 
becomes undetectable. At that point, dosing of valganciclovir can be changed to the 
prophylactic dose for the remainder of the study. The subject should continue to undergo 
weekly CMV viral load surveillance for four consecutive negative tests and can then 
return to monthly testing thereafter. Alternative anti-herpetic viral prophylaxis should be 
stopped during valganciclovir dosing. Testing at outside laboratories will be allowed 
during months that the patient is not scheduled for clinic visits. 
5.4.6
Medications of Food that Inhibit or Induce CYP3A4/5: 
In vitro data also indicate that oxidative metabolism may play an important role in the 
elimination of duvelisib and venetoclax, with CYP3A4/5 identified as the primary 
enzymes for metabolism. As duvelisib and venetoclax are moderate inhibitors of 
CYP3A4/5, there is potential for drug-drug interactions and increased exposures.  
Preliminary data from a drug-drug interaction study with ketoconazole (a potent 
CYP3A4/5 inhibitor) indicate exposure to duvelisib increased approximately 4- fold in 
the presence of ketoconazole. For this reason, the concomitant use of drugs or foods that 
are strong or moderate inhibitors or inducers of CYP3A are not allowed for 7 days prior 
to the first dose of duvelisib. Additionally, the use of these drugs and foods are not 
allowed during study treatment. Appendix D provides a list of medications known to be 
strong or moderate inhibitors or inducers of CYP3A. Please note that Appendix D is not a 
comprehensive list of all medications which may modulate CYP3A4/5 activity. The 
Principal Investigator should be contacted with any questions regarding concomitant use 
of medications that are thought to modulate CYP3A activity. The concomitant use of 
weak inhibitors may be allowed in selected circumstances after consultation with the 
Principal Investigator.
5.5
Criteria for Taking a Participant Off Protocol Therapy

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Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue 
until one of the following criteria applies:  

Disease progression without clinical benefit

Intercurrent illness that prevents further administration of treatment

Unacceptable adverse event(s)

Physician discretion

After at least one year of treatment, if a patient achieves a complete remission (CR) or 
complete remission with incomplete count recovery (CRi) with MRD-negativity in 
the bone marrow, they will have the option to discontinue therapy and transition to 
active disease monitoring with the option to restart venetoclax if they experience 
disease recurrence as evidenced by at least two instances of MRD-detectability or 
clinical disease progression. If patients do not achieve MRD negativity or have 
evidence of disease progression after reaching full dose venetoclax monotherapy, 
they have the option to add duvelisib at the highest dose they previously tolerated and 
continue it until MRD negativity is achieved on two successive peripheral blood 
MRD assessments or indefinitely depending on tolerability

If after 24 months of treatment (Cycle 25 restage) a patient achieves a PR with MRD 
negativity in the bone marrow, they will have the option to discontinue therapy and 
transition to active disease monitoring with the option to restart venetoclax if they 
experience disease recurrence as evidenced by at least two instances of MRD-
detectability or clinical disease progression in the opinion of the investigator. If 
patients do not achieve MRD negativity or have evidence of disease progression after 
reaching full dose venetoclax monotherapy, they have the option to add duvelisib at 
the highest dose they previously tolerated and continue it until MRD negativity is 
achieved on two successive peripheral blood MRD assessments or indefinitely 
depending on tolerability

Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements

Participant decides to withdraw from the protocol therapy

General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator
Participants will be removed from the protocol therapy (treatment) when any of these criteria 
apply.  The reason for removal from protocol therapy, and the date the participant was removed, 

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must be documented in the case report form (CRF). Alternative care options will be discussed 
with the participant.
When a participant is removed from protocol therapy, they will remain on study in active follow 
up for up to one year or until withdrawal of consent, initiation of other CLL or Richters directed 
therapy, or death. They will then be followed for survival indefinitely.
When a participant is  off of the study completely (no longer in follow up or being followed for 
survival), the relevant Off-Treatment/Off-Study information will be relayed to the lead site study 
team, and updated in OnCore.
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI, Dr. Matthew Davids at 617-632-3352, pager 57215.
5.6
Duration of Follow Up and Active Disease Monitoring
Disease Monitoring: 
Participants who elect to discontinue treatment after having achieved MRD negative CR or CRi 
(or MRD- PR after C25) will be followed every 3 months (+/- 14 days) for active disease 
monitoring. Subjects are allowed to alternate visits with a local team so that they only need to be 
seen at the trial site every 6 months. They will be monitored until they resume treatment with 
venetoclax  (if they show signs of progression by MRD positivity or clinical manifestations) or 
are removed from active disease monitoring for other reasons such as withdrawal of consent, 
removal from monitoring by treating investigator, lost to follow up, elect to go on to other 
CLL/RS directed therapy, or death.  
Assessments for Active Disease Monitoring:

History and physical

CBC differential and platelet count

Serum Chemistry Panel including magnesium, uric acid, phosphorus and LDH

CT or PET CT scan and response assessment as clinically indicated
o
De-identified scans must continue to be sent to the lead site to be centrally read 
for response 

Bone marrow biopsy and aspirate as clinically indicated and MRD sent for analysis

MRD assessment in the peripheral blood every 3 months, or at minimum every 6 months
Follow Up:
Those who are removed from treatment for reasons other than MRD negativity will be followed 
every 3 months for up to one year (+/- 14 days). During active follow up (not those who are in 
active disease monitoring) participants will be offered the opportunity to have follow up visits at 
their treating institution every 6 months (versus every 3) to minimize travel burden if they 
choose, so long as they are being clinically followed by a hematologist/oncology team locally 
every other visit, and relevant clinical information is being conveyed to the lead site for follow 
up data entry purposes.

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Assessments for those who discontinue treatment for reasons other than MRD negative 
CR/Cri or PR after C25 :

History and physical

CBC differential and platelet count

Serum Chemistry Panel including magnesium, uric acid, phosphorus and LDH

CT or PET CT scan and response assessment as clinically indicated

Bone marrow biopsy and aspirate as clinically indicated 
After the active disease monitoring and follow up periods are complete, survival follow up data 
will be collected indefinitely unless one of the following occurs:

Death

Lost to survival follow up

Withdrawal of consent 
Survival status may be collected by phone, email, or other traditional data collection methods 
indefinitely. 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF).
5.7
 Resuming Treatment after Discontinuation 
If a patient elects to discontinue therapy and is currently in active follow up, and the participant 
exhibits MRD positivity at least two times in the peripheral blood or exhibits clinical disease 
progression in the opinion of the investigator, the participant may resume venetoclax 
monotherapy. 
If patients do not achieve MRD negativity or has evidence of disease progression after reaching 
full dose venetoclax monotherapy, they have the option to add duvelisib at the highest dose they 
previously tolerated and continue it until MRD negativity is achieved on two successive 
peripheral blood MRD assessments or indefinitely depending on tolerability.
A re-staging bone marrow evaluation (aspirate, core, FISH, cytogenetics, flow/MRD, pathology) 
and CT scan (or PET/CT if RS) is required prior to re-initiation of venetoclax.  If there is no 
clinical evidence of disease and only MRD detectable disease, venetoclax can be resumed at 400 
mg in the outpatient setting with TLS lab monitoring 6-8 hours and 24 hours after the initial 
dose.  If there is clinical evidence of disease, ramp up per package insert of venetoclax to the 
dose the participant received during their last cycle on treatment is required. The participant will 
have the opportunity to increase their dose of venetoclax to the MTD if tolerated after discussion 
with the treating investigator. Study visit frequency will coincide with where the participant left 
off while they were on treatment.  For example, if discontinuation occurred at the end of Cycle 

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37, the participant would resume a q3 month assessment schedule after the appropriate ramp up 
cycle
5.8
Criteria for Taking a Participant Off Study (No longer being followed for Survival).
Participants will be removed from study when any of the following criteria apply:

Lost to follow-up

Withdrawal of consent for data submission

Death

The study will no longer be collecting this data, and is considered complete
Participants may be followed for survival after completing the follow up portion of the study by 
phone, email, or other traditional data collection methods indefinitely. 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF).
For Decentralized Subject Registrations, the research team updates the relevant Off 
Treatment/Off Study information in OnCore. 

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6. DOSING DELAYS/DOSE MODIFICATIONS
Dose delays and modifications will be made as indicated in the following table(s). The 
descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0 will be utilized for dose delays and dose modifications. A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP website
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
6.1
Duvelisib: 
Participants will be monitored continuously for toxicity while on study therapy. Non-
hematologic toxicity will be assessed using the NCI-CTCAE Version 5.0. Hematologic toxicity 
will be assessed by 2008 IW-CLL criteria (see Appendix H) for both CLL and RS patients.47 
If a patient has an adverse event of particular severity (see Table 3) at least possibly related to 
duvelisib, then dose modifications can be made according to Table 2. There should be no 
attempt to make up for doses omitted due to toxicity.
Table 2: Dose levels of duvelisib 
Dose Level
Duvelisib Dose
-2
25 mg every other day
-1
25 mg daily
+1
25 mg BID
All duvelisib dose reductions should be discussed with the principal investigator. Duvelisib 
dosing may be withheld up to 28 days for toxicity.
 If dosing is withheld for >28 days for toxicities that are related to duvelisib this will result in 
discontinuation of duvelisib treatment on the study. In these cases, patients can continue on 
venetoclax monotherapy. 
In cases where duvelisib has been held >28 days, duvelisib may be resumed after discussion with 
the overall PI in cases where toxicity is thought to be due to a cause other than duvelisib. Any 
participant who requires > 2 dose reductions for the same toxicity will be discontinued from 
active treatment on the study. 
Patients who have a dose reduction due to toxicity may be eligible for a dose increase back to the
dose level prior to the reduction (i.e., the starting dose or dose of previous reduction if patient 
was dose reduced more than one level) if the following criteria are met:
1. Patient has tolerated the lower treatment dose for 2 or more treatment cycles
2. Patient has recovered to baseline levels from the toxicity which caused the dose 
reduction
3. Toxicity was not drug-induced colitis or pneumonitis

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Table 3: Recommended Management/Next Dose for Duvelisib 
Event
Recommended Management/Next Dose for Duvelisib
≤ Grade 1 
Hematologic or Non-
Hematologic 
Continue current dose 
Grade 2 Hematologic 
or Non-Hematologic  
Continue at current dose. If dose reduction considered, contact the 
principal investigator 
Grade 3 Hematologic 
or Non-Hematologic  
(non-DLT) 
Continue at current dose. If dose reduction considered, contact the 
principal investigator
Grade 3 Hematologic 
(DLT)
First occurrence: Withhold and provide growth factor or transfusion 
support if indicated until return to grade 2 or baseline level; re-initiate 
therapy at current dose if duration ≤ 10 days. If duration >10 days, re-
initiate therapy at one dose level lower.
Second occurrence: Withhold and provide growth factor or transfusion 
support if indicated until return to grade 2 or baseline level; re-initiate 
therapy at one dose level lower.
Third occurrence: Discontinue patient from study drug
Grade 3 Non-
hematologic (DLT)
First occurrence: Withhold until return to grade 1 or baseline level; re-
initiate therapy at 25 mg daily.
 
Second occurrence:
Withhold until return to grade 1 or baseline level; re-initiate therapy at 
25 mg every other day.
Third occurrence: 
Discontinue patient from study drug
Exceptions: 
Patients with pneumonitis and skin reactions will discontinue active 
treatment on protocol 
Grade 4 Non-
hematologic (DLT) 
other than 
asymptomatic lab 
abnormalities
Discontinue patient from the study
Grade 4 Hematologic 
(DLT or non-DLT)
First occurrence: Withhold and provide growth factor or transfusion 
support if indicated until return to grade 2 or baseline level; re-initiate 
therapy at current dose if duration ≤ 10 days. If duration >10 days, re-
initiate therapy at one dose level lower.

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Event
Recommended Management/Next Dose for Duvelisib
Second occurrence: Withhold and provide growth factor or transfusion 
support if indicated until return to grade 2 or baseline level; re-initiate 
therapy at one dose level lower.
Third occurrence: Discontinue patient from study drug
6.1.1
Management Guidelines for Hepatotoxicity:
For Grade 2 ALT/AST elevation (> 3 to 5 X ULN), maintain duvelisib dose and monitor at least 
weekly until return to < 3 X ULN. For Grade 3 ALT/AST elevation (> 5 to 20 X ULN), withhold 
duvelisib and monitor at least weekly until return to < 3 X ULN. Resume duvelisib at the same 
dose (first occurrence) or at a reduced dose for subsequent occurrences. For grade 4 ALT/AST 
elevation (> 20 X ULN), discontinue duvelisib.
6.1.2
Management Guidelines for Diarrhea and Colitis: 
Severe and/or serious diarrhea has been observed in subjects with hematologic malignancies 
receiving duvelisib. In some cases, diarrhea preceded a diagnosis of colitis. For patients 
presenting with mild or moderate diarrhea (Grade 1-2) (i.e., up to 6 stools per day over baseline) 
or asymptomatic (Grade 1) colitis, initiate supportive care with antidiarrheal agents, continue 
duvelisib at the current dose, and monitor the patient at least weekly until the event resolves. If 
the diarrhea is unresponsive to antidiarrheal therapy, withhold duvelisib and initiate supportive 
therapy with enteric acting steroids. Upon resolution of the diarrhea, consider restarting duvelisib 
at a reduced dose. For patients presenting with abdominal pain, stool with mucus or blood, 
change in bowel habits, peritoneal signs, or with severe diarrhea (Grade 3) (i.e., > 6 stools per 
day over baseline), withhold duvelisib and initiate supportive therapy with enteric acting steroids 
(e.g., budesonide) or systemic steroids. A diagnostic work-up to determine etiology, including 
colonoscopy when applicable, should be performed. Monitor at least weekly. Upon resolution of 
the diarrhea or colitis, restart duvelisib at a reduced dose. For recurrent Grade 3 diarrhea or 
recurrent colitis of any grade, discontinue duvelisib. Discontinue duvelisib for life-threatening 
diarrhea or colitis.
6.1.3
Skin Rash: 
For patients presenting with mild or moderate (Grade 1-2) cutaneous reactions, continue 
duvelisib at the current dose, initiate supportive care with emollients, antihistamines (for 
pruritus), or topical steroids, and monitor the patient closely. Withhold duvelisib for severe 
(Grade 3) cutaneous reaction until resolution. Initiate supportive care with steroids (topical or 
systemic) or antihistamines (for pruritus). Monitor at least weekly until resolved. Upon 
resolution of the event, restart duvelisib at a reduced dose. Discontinue duvelisib if severe 
cutaneous reaction does not improve, worsens, or recurs. For life-threatening cutaneous 

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reactions, discontinue duvelisb. In patients with SJS, TEN, or DRESS of any grade, discontinue 
duvelisib.
6.1.4
Treatment Related Lymphocytosis: 
Similar to other agents targeting B-cell receptor signaling, transient lymphocytosis is a 
pharmacodynamic effect of duvelisib, in which inhibition of PI3K-mediated cellular homing and 
adhesion results in a mobilization of tumor cells to the peripheral blood. Upon initiation of
duvelisib monotherapy, a rapid, but transient increase in lymphocyte count (i.e., ≥50%
increase from baseline and above absolute count 5000/μL), often associated with reduction of
lymphadenopathy, has been observed in the majority of patients with relapsed/refractory
CLL/SLL. This observed transient lymphocytosis is usually not associated
with an adverse event and should not be considered an adverse event or progressive disease in 
the absence of other clinical findings. Lymphocytosis occurs typically during the first few weeks 
of duvelisib monotherapy and resolves within a median of 6 months. 
6.2
Venetoclax: 
The cohort doses for venetoclax in the phase I trial after intra-patient dose ramp-up are 100 mg 
QD (dose level +1), 200 mg (dose level +2) and 400 mg (dose level +3). If known venetoclax 
toxicities such as TLS, diarrhea, or neutropenia are observed, dose reductions can occur by 50% 
at a time to as low as 50 mg (dose level -1). 
In the phase II trial, patients will ramp up to the MTD of venetoclax determined in the phase I 
trial. If known venetoclax toxicities such as TLS, diarrhea, or neutropenia are observed, dose 
reductions can occur by 50% at a time to as low as 50 mg. 
Venetoclax dosing may be withheld for up to 28 days for toxicity. Doses withheld for >28 days 
will result in discontinuation from venetoclax treatment on the study. In these cases, patients can 
continue with duvelisib monotherapy for up to 12 total cycles.
 In cases where venetoclax has been held >28 days, venetoclax may be resumed after discussion 
with the overall PI in cases where toxicity is thought to be due to a cause other than venetoclax. 
Any patient who requires > 3 dose reductions for the same toxicity will be discontinued from 
active treatment on the study.
Table 4: Dose Levels of Venetoclax for the Phase I Trial
Dose Level
Venetoclax Dose
-1
50 mg daily
+1
100 mg daily 
+2
200 mg daily
+3
400 mg daily

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6.2.1
Tumor Lysis Syndrome: 
If any significant laboratory changes consistent with TLS are observed within the first 24 hours 
after initiation of dosing, see Appendix C (Recommendations for Initial Management of 
Electrolyte Abnormalities and Prevention of Tumor Lysis Syndrome [TLS]), for additional 
laboratory assessments and management guidelines.
6.2.2
Management of Other Toxicities: 
If a patient has an adverse event assessed as at least possibly related to venetoclax, then dose 
modifications can be made according to the recommendations in the tables below.
The following tables provide recommended guidelines for venetoclax dose reduction based on 
specific toxicities. Management not consistent with these guidelines should be discussed with the 
PI. 
Table 5.  Recommended Management of Non-hematologic toxicities for Venetoclax
Event
Recommended Management/Next Dose for Venetoclax 
≤ Grade 1
Continue current dose 
Grade 2
Hold until grade   1. Resume at same dose level 
Grade 3 
Hold until grade   1 or baseline. Resume at one dose level lower if 
indicated 
Grade 4 (other than 
asymptomatic lab 
abnormalities)
Discontinue active treatment on protocol
Table 6: Recommended Management of Diarrhea for Venetoclax 
Event 
Recommended Management
Diarrhea 
Loperamide: 
Dosage schedule: 4 mg at first onset, followed by 2 mg with each 
loose motion until diarrhea-free for 12 hours (maximum dosage: 16 
mg/24 hours)
Adjunct anti-diarrheal therapy is permitted and should be recorded 
when used.
Table 7: Recommended Management of Thrombocytopenia for Venetoclax 
Event 
Recommended Management/Next Dose for Venetoclax
Thrombocytopenia
Grade 1, 2 or 3
No change in dose 
Grade 4
Hold until  Grade 3. 
First occurrence: Resume venetoclax at the same dose. 

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Second occurrence: If occurs within 28 days, the venetoclax dose 
should be reduced by 50%.  
Third occurrence: If occurs within 28 days, the venetoclax dose 
should be reduced by 50%.
Fourth occurrence: Discontinue patient from study drug
Table 8: Recommended Management of Neutropenia for Venetoclax 
Event 
Recommended Management/Next Dose for Venetoclax
Neutropenia 
Grade 1 or 2
No change in dose 
Grade 3
Hold until  Grade 2. If previously growth factor responsive 
administer growth factor and resume dosing as long as growth factor 
is administered. If not previously growth factor responsive, resume at 
one dose level lower, if indicated. 
Grade 4
Hold until  Grade 2. If previously growth factor responsive 
administer growth factor and resume dosing at current dose once  
Grade 3. If not previously growth factor responsive, resume at one 
dose level lower, if indicated.
At any time during the study, if the subject presents with febrile neutropenia, venetoclax 
dosing should be interrupted until resolution of the fever or infection. At the first 
occurrence, venetoclax may be re-initiated at the same dose. At a second or later 
occurrence, consideration should be given to venetoclax dose reduction. 
Growth factor support with filgrastim or pegfilgrastim may be utilized as necessary 
throughout the study and does not require holding venetoclax. 

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7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
The following list of reported and/or potential adverse events (AEs) and the characteristics of an 
observed AE will determine whether the event requires expedited reporting in addition to routine 
reporting.
7.1
Definitions: 
 
7.1.1
Adverse Event: 
An AE is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of an investigational medicinal product (IMP) or other protocol 
imposed intervention, regardless of attribution.
These include the following: 

AEs not previously observed in the patient that emerge during the protocol-specified 
AE reporting period, including signs or symptoms associated with venetoclax that 
were not present prior to the AE reporting period

Complications that occur as a result of protocol-mandated interventions (e.g., 
invasive procedures such as cardiac catheterizations)

If applicable, AEs that occur prior to assignment of study treatment associated with 
medication washout, no treatment run-in, or other protocol-mandated intervention

Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during 
the protocol-specified AE reporting period.
7.1.2
Adverse Event Characteristics

CTCAE term (AE description) and grade: The descriptions and grading scale found in 
the revised NCI Common Terminology Criteria for Adverse Events CTCAE) version 
5.0 will be utilized for AE reporting. All appropriate treatment areas should have 
access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.

For expedited reporting purposes only:
o
AEs for the agent(s) that are listed above should be reported only if the adverse 
event varies in nature, intensity or frequency from the expected toxicity 
information which is provided.
o
Other AEs for the protocol that do not require expedited reporting are outlined in 
the next section (Expedited Adverse Event Reporting) under the subheading of 
Protocol-Specific Expedited Adverse Event Reporting Exclusions.

Attribution of the AE:
o
Definite  The AE is clearly related to the study treatment.

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o
Probable  The AE is likely related to the study treatment.
o
Possible  The AE may be related to the study treatment.
o
Unlikely  The AE is doubtfully related to the study treatment.
o
Unrelated  The AE is clearly NOT related to the study treatment.
7.2
Serious Adverse Event: 
An AE should be classified as a serious adverse event (SAE) if the following criteria are 
met:

Results in death (i.e., the AE actually causes or leads to death)

Is life-threatening (i.e., the AE, in the view of the investigator, places the patient at 
immediate risk of death. It does not include an AE that, had it occurred in a more 
severe form, might have caused death.)

Requires or prolongs inpatient hospitalization

Results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the patients ability to conduct normal life functions)

Results in a congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to duvelisib plus venetoclax 

Important medical events that may not result in death, are not immediately life-
threatening, or do not require hospitalization may be considered SAEs when, based 
on appropriate medical judgment, they may jeopardize the subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.

Overdose of either drug involved in the clinical trial
7.3
Adverse Event List for Venetoclax:   
In the phase I trial of venetoclax for patients with relapsed/refractory CLL, the most 
common AEs with were grade 1 and 2 and included diarrhea (52%), upper respiratory tract 
infection (48%), nausea (47%), fatigue (40%), and cough (30%). Neutropenia was the most 
common grade 3 or 4 AE, occurring in 41% of patients. Serious adverse events included febrile 
neutropenia (6%), pneumonia (4%), upper respiratory tract infection (3%) and immune 
thrombocytopenia (3%). Dose limiting toxicities were rare and included TLS, muscle spasms, 
neutropenia, thrombocytopenia and vomiting.16,48 
7.3.1
Common AEs Associated with Venetoclax
7.3.1.1
Tumor Lysis Syndrome (TLS)
TLS, including fatal events and renal failure requiring dialysis, has occurred in previously treated 
CLL patients with high tumor burden when treated with venetoclax. Venetoclax can cause rapid 
reduction in tumor and thus poses a risk for TLS in the initial ramp-up phase. Changes in blood 

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chemistries consistent with TLS that require prompt management can occur as early as 6 to 8 
hours following the first dose of venetoclax and at each dose increase. The risk of TLS is a 
continuum based on multiple factors, including tumor burden and comorbidities. Reduced renal 
function further increases the risk. Patients should be assessed for risk and should receive 
appropriate prophylaxis for TLS, including hydration and anti-hyperuricemics. Blood 
chemistries must be monitored closely and abnormalities must be managed promptly. Dosing can 
be interrupted if needed and more intensive measures (intravenous hydration, frequent 
monitoring, hospitalization) can be employed as overall risk increases. Concomitant use of 
venetoclax with strong or moderate CYP3A inhibitors and P-gp inhibitors increases venetoclax 
exposure and may increase the risk of TLS.
7.3.1.2
Neutropenia
Neutropenia is an important identified risk for venetoclax, specifically in CLL. Clinical data 
from oncology studies suggest that neutropenia was observed among subjects who received 
venetoclax as a single agent or in combination with other therapeutic agents, with slightly higher 
frequency observed in some combination studies. Serious adverse events of neutropenia or 
neutropenia events that lead to discontinuations are few across the entire venetoclax oncology 
program. Neutropenia management guidelines are provided in the protocol. Granulocyte colony 
stimulating factors can be used concomitantly with venetoclax for supportive measures.
7.3.1.3
Infections
Infections have been reported in the oncology clinical studies; however, these events are 
confounded by the underlying disease, comorbidities, and other immunosuppressive medications. 
To date, no clear relationship has been noted between serious infectious events and neutropenia. 
The types of infectious events observed generally have been consistent with those anticipated in 
the elderly population of heavily pretreated subjects with hematologic malignancies and are 
similar across all indications. Infections are closely monitored in the venetoclax program across 
all indications. In the oncology studies, recommendations are included in the protocol regarding 
the need for anti-infective prophylaxis per standard of care (e.g., National Comprehensive 
Cancer Network guidelines [NCCN] for oncology subjects). In CLL patients, serious infections 
are potential risks. Upper respiratory tract infections are very common while pneumonia and 
urinary tract infections are commonly reported. Additional guidance for the investigator 
regarding venetoclax use: 
On the basis of nonclinical data and previous experience with BCL-2 inhibitors, as well 
as the available preliminary data in the venetoclax clinical oncology program, the following
guidance is provided for the investigator.
7.3.1.4
Contraindications
Concomitant use of venetoclax with strong CYP3A inhibitors at initiation and during the
dose-titration phase is contraindicated (Appendix D).

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7.3.1.5
Reproductive System Effects
Based on nonclinical studies, there is a potential for decreased spermatogenesis.
Non-reversible depletion of testicular germ cells has been observed in dogs at all doses
tested after 4 weeks of dosing. In the oncology studies, male subjects should be instructed to 
consider sperm banking before treatment with venetoclax if they are considering preservation of 
fertility.
7.3.1.6
Treatment-Emergent Malignancies (Second Primary Malignancies)
Events of second primary malignancies have been reported across the oncology program.
No pattern has been observed. 
7.3.1.7
Food Effect
Administration with a low-fat meal increased venetoclax exposure by approximately
3.4-fold and administration with a high-fat meal increased venetoclax exposure by 5.1- to
5.3-fold compared to fasting conditions. Venetoclax should be administered with a meal.
7.3.2
Special Patient Populations
7.3.2.1
Pregnancy
Although no potential risks have been identified in nonclinical studies, the effect of BCL-2 
inhibition on pregnancy has not been fully characterized. Venetoclax resulted in increased post 
implantation loss and decreased fetal body weights were observed in the mouse embryofetal 
development study at the highest dosage administered. Venetoclax was not teratogenic, and there 
were no other effects on development or fertility. Two pregnancies have been reported in the 
program, including 1 pregnancy of a partner. Venetoclax should not be administered to pregnant 
women. Female subjects enrolled in clinical studies with single agent venetoclax must be 
surgically sterile, postmenopausal (for at least 1 year), or have negative results for a pregnancy 
test. Female subjects enrolled in clinical studies with venetoclax must agree to use contraception 
from initial study drug administration until 30 days after the last dose of study drug. Venetoclax 
must be discontinued if a female subject becomes pregnant. Male subjects enrolled in clinical 
studies with single agent venetoclax must agree to use contraception from initial study drug 
administration until 30 days after the last dose of study drug. For clinical studies with venetoclax 
in combination with other agents, use of contraception may be longer.
7.3.2.2
Nursing Mothers
It is not known whether venetoclax is excreted in human milk. Hence, until further data
become available, venetoclax should not be administered to nursing mothers.
7.3.2.3
Children
Safety and effectiveness in pediatric patients under 18 years of age have not been
established; therefore, venetoclax should not be administered to this patient population.

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7.3.2.4
Geriatric Patients
Venetoclax has been administered to elderly subjects (> 65 years) across the oncology program. 
The available data do not demonstrate any additional safety concerns when administrating 
venetoclax in the elderly population.
7.3.3
Concomitant Use with Other Medications and Overdose
Venetoclax should not be used with strong CYP3A inhibitors (e.g., ketoconazole, ritonavir, 
clarithromycin, itraconazole, voriconazole) at initiation and during ramp-up phase. Venetoclax 
dose should be reduced by at least 50% in the presence of moderate CYP3A4 inhibitors if 
concomitant use of venetoclax with moderate CYP3A inhibitors (e.g., erythromycin, 
ciprofloxacin, diltiazem, fluconazole, verapamil) cannot be avoided. These patients also require 
close monitoring for venetoclax toxicities.  Strong CYP3A inducers (i.e.., carbamazepine, 
phenytoin, rifampin, St. John's wort), or moderate CYP3A inducers (i.e., bosentan, efavirenz, 
etavirine) should be avoided. 
Venetoclax should be administered using caution with weak inhibitors or inducers of
CYP3A, substrates or inhibitors of P-gp, BCRP, or OATP1B1/B3. If venetoclax is
co-administered with warfarin, the international normalized ratio (INR) should be
monitored closely. A list of common medications that should either not be used or should
be used with caution with venetoclax can be found in Appendix D.
Live-virus vaccines should not be given within 28 days prior to the initiation of study
treatment, at any time during study treatment, or in the 30 days following the last dose of
study treatment.
7.3.3.1
Overdose
Dosing with venetoclax may vary with indication, with the maximum evaluated dose for
venetoclax being 1200 mg. Please refer to the protocol for the maximum dose that may
be allowed. In the event of an adverse event of overdose, appropriate supportive treatment should 
be initiated according to the subject's clinical signs and symptoms. A detailed discussion of 
venetoclax toxicology, metabolism, pharmacology and safety can be found in the Investigators 
Brochure.
7.4
Adverse Event List for Duvelisib: 
In the phase I trial of duvelisib for the treatment of relapsed/refractory (R/R) CLL/SLL, all 55 
subjects experienced a treatment emergent adverse event (TEAE). The most frequently occurring 
TEAEs in R/R CLL/SLL subjects were: diarrhea (47.3%); fatigue (38.2%); neutropenia and 
cough (each 36.4%); anemia and pyrexia (each 32.7%); upper respiratory tract infection (29.1%); 
AST increased (27.3%); pneumonia, ALT increased, nausea, decreased appetite, neutrophil 
count decreased, and arthralgia (each 25.5%); and dyspnea (23.6%).
Treatment-emergent serious adverse events (TESAEs) occurred in 36 (65.5%) R/R CLL/SLL 
subjects. TESAEs occurring in 2 or more subjects with R/R CLL/SLL were: pneumonia and 
febrile neutropenia (each 16.4%); disease progression and pneumonitis (each 7.3%); fatigue, 

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colitis, and diarrhea (each 5.5%); and pyrexia, constipation, stomatitis, pneumonia pseudomonas 
aeruginosa, sepsis, and hypercalcemia (each 3.6%).
As of 19 July 2017, 98 patients with CLL/SLL have enrolled in the IPI-145-12 study, an open-
label phase 3 extension study for subjects who experienced disease progression in the phase 3 
trial comparing duvelisib to ofatumumab. Of these, 89 subjects have received duvelisib 25 mg 
BID. For the subjects who have received duvelisib, the median exposure is 31.0 weeks (range 2.0 
to 126.7 weeks).
Of 85 of 89 (95.5%) subjects who received duvelisib had a treatment emergent adverse event 
(TEAE); of these,70 subjects (78.7%) experienced a TEAE assessed as related to duvelisib.  
TEAEs that occurred in ≥10% subjects included diarrhea (38.2%); neutropenia (24.7%); pyrexia 
(22.5%); rash (21.3%); colitis, vomiting, asthenia, pneumonia, and cough (each 11.2%); and 
nausea and decreased appetite (each 10.1%). TEAEs assessed as related to duvelisib that 
occurred in ≥ 10% subjects included diarrhea (32.6%), neutropenia (16.9%), and rash (14.6%).
Seventy-two subjects (80.9%) experienced at least 1 TEAE Grade 3 or higher, of which 
30 (46.2%) were assessed as related to duvelisib. Grade 3 or higher TEAE that occurred in ≥5% 
of subjects were neutropenia (22.5%), diarrhea (16.9%), pneumonia, (10.1%), colitis (9.0%), 
lipase increased (6.7%), and thrombocytopenia (5.0%). The only grade 3 or higher TEAEs 
assessed as related to duvelisib that occurred in ≥5% of subjects were diarrhea (15.7%), 
neutropenia (13.5%), colitis (9.0%), and lipase increased (6.7%).
7.4.1
Additional guidance for the investigator regarding duvelisib use: 
7.4.1.1
Reproductive effects: 
Based on embryo-fetal toxicity observed in preliminary studies in rats and rabbits, duvelisib may 
have effects on the embryo or fetus when administered to pregnant women. There are no 
available human data informing the drug-associated risk. In a preliminary rat developmental 
toxicity study, a decrease in fetal body weight in the absence of maternal toxicity was observed 
at a free exposure 43-fold greater than the free exposure at the intended commercial dose of 25 
mg BID. Higher exposures in rats and rabbits resulted in embryotoxicity (early resorption) in the 
presence of maternal toxicity. Duvelisib was not teratogenic and did not cause adverse 
developmental effects in pivotal studies at free exposures in the rabbit and rat that were 30- to 
40-fold greater than the free exposure at the intended commercial dose. Please refer to individual 
protocols for specific instructions regarding eligibility and additional contraindications, 
contraception, and pregnancy reporting. Testicular degeneration/atrophy was present in male rats 
in the 28-day and 13-week studies, with evidence of reversibility (13-week study). Sexual 
immaturity of animals in the monkey studies precluded the interpretation of any potential 
toxicological effects in the testes. There are no clinical data assessing the effect of duvelisib on 
spermatogenesis. Based on the effects observed in rats, duvelisib may impair fertility in men. 
The exposure margin identified between the intended commercial dose of 25 mg BID and the 
plasma exposure at which this finding was considered adverse (50 mg/kg/day, 28-day study) was 

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21-fold when duvelisib protein binding differences between human and rat are taken into 
account.
7.4.1.2
Effect of food: 
In 2 studies in healthy subjects (the first study using the clinical trial formulation and the second 
using the market-image formulation), concomitant administration of a high fat meal resulted in a 
minimal change in the bioavailability of duvelisib. On average, Cmax decreased by 10% in the 
first study and 37% in the second; median tmax was slightly delayed from 1 hour (fasted) to 
3 hours (fed) in the first study and 4 hours (fed) in the second. However, overall exposure, as 
assessed by AUC(0-last) and AUC(0-inf), increased by 8%-9% in the first study and decreased 
2%-6% in the second study. These data indicate that duvelisib may be administered without 
regard to meals. Please refer to individual study protocols for specific instructions related to 
fasting or fed status in relation to collection of PK or other clinical samples.
7.4.1.3
Concomitant use with other agents:  
CYP3A4 has been identified as the primary contributor to the metabolism of duvelisib. In Study 
IPI-145-01, exposure to duvelisib increased approximately 4-fold in the presence of the strong 
CYP3A inhibitor ketoconazole, and decreased approximately 80% in the presence of rifampin, a 
CYP3A inducer. For these reasons, the concomitant use of drugs or foods that are strong 
inhibitors or inducers of CYP3A is not allowed during treatment with duvelisib. 
In vitro studies in human liver microsomes demonstrated that duvelisib and its primary 
metabolite IPI-656 are reversible inhibitors of CYP3A4 and CYP2C8 and mechanism-based 
inhibitors of CYP3A4. 
Coadministration of duvelisib (25 mg BID for 5 days) with MDZ (a sensitive CYP3A substrate) 
resulted in an approximate 4-fold increase in MDZ systemic exposure (AUC) compared to 
administration of MDZ alone. Systemic exposure to other medications that are substrates for 
CYP3A4 may be increased in subjects receiving duvelisib. Caution should be used if duvelisib is 
administered concomitantly with drugs that are substrates for CYP3A, particularly those with a 
narrow therapeutic range. Drugs that are substrates for CYP3A should be used only if medically 
necessary and therapeutic alternatives are not available.
Based on plasma concentrations following administration of 25 mg BID, duvelisib is not 
expected to increase the exposure of medications metabolized via CYP2C8; however, a clinical 
study with a CYP2C8 substrate has not been conducted. Medications that are metabolized via 
CYP2C8 may be used as medically indicated but with caution. 
7.5
Expedited Adverse Event Reporting 
7.5.1
Investigators must report to the Overall PI any serious adverse event (SAE) that occurs 
after signing the consent form,  during treatment, or within 30 days of the last dose of 
treatment on the local institutional SAE form. 

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If the participant goes on to another SLL/CLL or RS directed therapy before the 30-day 
period, the reporting period ends when they begin new treatment. 
7.5.2
DF/HCC Expedited Reporting Guidelines
Investigative sites within DF/HCC will report SAEs directly to the DFCI Office for 
Human Research Studies (OHRS) per the DFCI IRB reporting policy. 
External (Non-DF/HCC) sites will send their report to the lead site project manager and 
Overall PI for review and submission to the appropriate entities according to DFCI IRB 
policies and procedures in reporting adverse events.
The following adverse events must be reported to the DFCI IRB according to the expedited 
reporting guidelines:

CTCAE Grade 2 and Grade 3 Events  that are Unexpected and there is a Reasonable 
Possibility that the Adverse Event is related to the study Intervention.

CTCAE Grade 4 Events  Report all events that are Unexpected. Events that are 
Expected and listed within the protocol and/or current consent form do not need to be 
reported to the DFCI IRB. 
o
Please note, an event that presents at a higher severity than what is currently listed 
within the protocol and/or current consent as expected would be considered 
unexpected and reportable. 

ALL CTCAE Grade 5 Events.
When assessing expectedness, investigators should consult the investigators brochure, 
package insert, and the most current version of the informed consent form. 
7.5.3
 External Site Adverse Event Reporting Guidelines 
In addition to following the SAE reporting requirements for DFCI and Secura Bio, other 
participating investigative sites will report SAEs to their respective IRB per the local 
IRBs policies and procedures. 

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For Multi-Center Trials where a DF/HCC investigator is serving as the Sponsor, each  
participating institution must abide by the reporting requirements set by the DF/HCC. 
Criteria for reporting to DFCI listed in section 7.5.3. The lead site will report external site 
SAEs to the DFCI IRB on the external sites behalf after review and approval by the 
overall PI. 
This applies to any medical event equivalent to an unexpected grade 2 or 3 with a 
possible, probable or definite attribution, unexpected 4 toxicities and grade 5 (death) 
regardless of study phase or attribution. 
7.6
Reporting to the Food and Drug Administration (FDA)
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDAs criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA.
7.7
Routine Adverse Event Reporting
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions.
7.8 Expedited Reporting to Hospital Risk Management
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy. 
8. PHARMACEUTICAL INFORMATION
8.1
Duvelisib
8.1.1
Description
Duvelisib is a potent oral inhibitor of the delta- and gamma-isoforms of PI3K. Duvelisib 
is rapidly absorbed following oral administration, with maximal concentrations occurring 
approximately 0.5 to 2 hours after dosing. Exposure (AUC) increased proportionally with 
doses through 75 mg PO BID. The half-life was 7 hours, regardless of dose. The mean 
pre-dose steady state plasma concentration following 25 mg BID was 425 ng/mL, 
indicating suppression of PI3K-delta (IC90=361 ng/mL) and PI3K-gamma (IC50=429 
ng/mL) throughout the dosing interval. Pharmacodynamic studies confirmed rapid, 
profound and sustained inhibition of AKT phosphorylation by duvelisib in CLL cells, as 
well as decreased levels of chemokines such as CCL3 and CCL4, which are important for 

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lymphocyte trafficking. The MTD of duvelisib as monotherapy for CLL has been 
determined to be 75 mg BID, but the recommended phase 2 dose is 25 mg bid, which was 
chosen as the optimal balance of safety and efficacy.
8.1.2
Form:
Duvelisib is supplied as 25 mg (size 2 white hard) gelatin capsules for oral delivery. 
Patients in this study will receive 25 mg BID as initial dosing. 
8.1.3
Storage and Stability
Duvelisib must be stored at room temperature (15 to 30°C) and protected from light.
If a temperature excursion is experienced at any investigational site/institution beyond the 
stated storage parameters, the site must report the excursion and associated details to the 
lead site project manager as soon as the excursion is identified.
8.1.4
Compatibility
NA 
8.1.5
Handling
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of the chemotherapeutic agent in a self-contained and protective environment. 
Caution is required when handling duvelisib. Pharmacists should follow standard 
procedure for the handling of investigational drugs, including avoidance of eye or skin 
contact with the drug product. If there is exposure to the drug product, provide treatment 
as necessary for physical exposure (skin washing) or inhalation (move to fresh air) and 
seek medical advice as necessary.
When duvelisib capsules are distributed for self-administration, they should only be 
handled by the study subject. After handling capsules, the subject should wash their 
hands thoroughly. If someone who is not enrolled in a clinical trial involving duvelisib 
swallows a capsule or inhales drug powder from a broken capsule of duvelisib, they 
should contact the relevant Principal Investigator to determine whether safety monitoring 
is necessary. Capsules should always be stored in the container provided to the study 
subject.
8.1.6
Availability
Duvelisib is an investigational agent and will be supplied by Secura Bio, Inc. 

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8.1.7
Preparation
Duvelisib will be supplied to the clinical trial site as open-label medication. Capsules are 
packaged in thermoform blister cards with peel and push child-resistant lidding. The label 
attached to each blister card will include, at a minimum, a statement limiting its use for 
investigational study only.
8.1.8
Administration
Duvelisib is administered orally as a capsule formulation as a fixed dose in mg and 
should be administered using the minimal number of capsules necessary.
8.1.9
Ordering
The DF/HCC pharmacy will order duvelisib from an investigational stock directly from 
Secura Bio, Inc. who will be providing the study drug.
External (Non-DF/HCC) investigative sites will be provided with a study specific drug 
order form by the lead site project manager once all necessary documents are collected, 
and the site is otherwise approved to enroll participants on the study.
The drug will be provided at no cost to the participant. 
If necessary, the drug may be shipped to the participants home from the investigative 
site pharmacy without specific approval from the overall PI. The shipment must be sent 
via traceable carrier, and confirmation of receipt must be filed in the participants study 
file
8.1.10 Accountability
The investigator, or a responsible party designated by the investigator, will maintain a
careful record of the inventory and disposition of duvelisib using a drug accountability 
form that is compliant with local and federal guidelines. 
Additionally, a designated study team member will complete drug 
accountability/reconciliation based on the participant actual drug return versus the 
anticipated drug return and document the findings according to local and federal 
regulations and guidance. 
8.1.11 Destruction and Return
After full drug accountability and reconciliation, all unused duvelisib will be destroyed 
according to local site procedures and policies. Destruction will be documented in the 
Drug Accountability Record Form. If any study drug is lost or damaged, the disposition 

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of the study drug should be documented. Patients should be instructed to bring all unused 
duvelisib to each study visit. The study site should count all capsules that the patient 
returns, and should take account for missed doses, doses reduced due to missing or lost 
capsules, etc., before dispensing new study drug to the patient. Any patient who does not 
take the prescribed dose should be requested to return the remaining drug to the clinical 
trial site for accountability.
8.2
Venetoclax

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8.2.1
Description: 
Venetoclax (ABT-199/GDC-0199) is a novel, orally bioavailable, small-molecule BCL-2 
family inhibitor in the biarylacylsulfonamide chemical class. Venetoclax binds with high 
affinity (Ki < 0.010 nM) to antiapoptotic protein BCL-2 and with lower affinity to other 
antiapoptotic Bcl-2 family proteins, like BCL-XL and BCL-w (> 4,800-fold and > 
24,500-fold lower affinity than to Bcl-2, respectively).
In vitro studies have shown that venetoclax was metabolized primarily by CYP3A4/5. 
Interaction of venetoclax with co-administered CYP3A inhibitors or inducers may cause 
an increase or decrease in the exposure of venetoclax. In vivo, venetoclax was also 
demonstrated to be metabolized by CYP3A4/5. Venetoclax is also substrate for P-
glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters. Renal 
contribution to the elimination of venetoclax is negligible, with < 0.1% of the dose being 
recovered in urine. Based on in vitro results, venetoclax was a P-gp, BCRP, and 
OATP1B1 inhibitor. It was not a potent in vitro inhibitor of CYP3A4, CYP1A2, 
CYP2B6, or CYP2D6 (IC50 > 30 μM); and it did not induce CYP3A4 or CYP1A2 at 
concentrations up to 10 μM. Venetoclax is also not predicted to cause inhibition of 
CYP2C19, CYP2C8, CYP2C9, and UGT1A1 at clinically relevant concentrations. It is 
not an inhibitor of UGT1A4, UGT1A6, UGT1A9 and UGT2B7. Following co-
administration of a single dose of venetoclax with warfarin, R- and S-warfarin Cmax and 
AUC∞ increased by approximately 18% to 28%. Relatively low variability was observed 
in warfarin PK.
The venetoclax formulation currently used in clinical studies is a tablet formulation with 
strengths of 10, 50, and 100 mg. The tablet formulation was orally administered after a 
low-fat meal. Food increased the bioavailability of venetoclax by 3- to 4-fold. 
Preliminary pharmacokinetic results indicated that the absorption of venetoclax after the 
oral dosing was relatively slow. Venetoclax plasma concentrations peaked at 
approximately 5 to 8 hours after dosing. Mean harmonic terminal phase half-life from 17 
to 41 hours and the mean oral clearance was approximately 13 L/hr after a single dose. 
Preliminary data did not suggest apparent pharmacokinetics differences among subjects 
with CLL/SLL, NHL, Multiple Myeloma (MM), Acute Myeloid Leukemia (AML), or 
SLE. The combined data from subjects with CLL/SLL and NHL suggested that 
venetoclax exposure was approximately dose proportional across the 150 to 800 mg dose 
levels at steady state. Additional information about venetoclax is available in the package 
insert.
8.2.2
Form: 
Venetoclax tablets are film coated and are available in strengths of 10 mg, 50 mg, or 100 
mg. Venetoclax will be packaged in high density polyethylene (HDPE) plastic bottles. 
Each bottle will be labeled per local regulatory requirements. Labels must remain affixed 
to the bottle.

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8.2.3
Storage and Compatibility: 
Venetoclax must be stored at 15° to 25°C (59° to 77°F) per package insert
Compatibility:  
N/A
8.2.4
Handling:  
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of the agent in a self-contained and protective environment.
8.2.5
Availability:
Patients are required to have access to a commercial supply of venetoclax. 
8.2.6
Preparation 
N/A
8.2.7
Administration: 
Oral. Patients should take venetoclax tablets with a meal and water at approximately
the same time each day, preferably about 30 minutes after breakfast. Venetoclax tablets 
should be swallowed whole and not chewed, crushed, or broken prior to swallowing.
8.2.8
Ordering
Supplies of venetoclax will be procured through the participants insurance via 
commercial supply through an appropriate specialty pharmacy.
8.2.9
Accountability:   
Venetoclax is commercially sourced therefore, no drug accountability records are 
required. 
8.2.10 Destruction and Return: 
Destruction of used and unused study drug may be performed as per institutional policy.

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9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES
While the goal of the correlative studies is to provide supportive data for the clinical study, there 
may be circumstances when a decision is made to stop a collection, not perform, or discontinue 
an analysis due to either practical reasons (e.g., inadequate sample number, issues related to the 
quality of the sample or issues related to the assay that preclude analysis, impossibility to 
perform correlative analyses, etc). Therefore, depending on the results obtained during the study, 
sample collection/analysis may be omitted at the discretion of the PI.
Samples collected on this study may be used for future research studies, including genetic 
research. Samples may also become part of a biobank, a biorepository that accepts, processes, 
stores and distributes biospecimens and associated data for use in research and clinical care. 
9.1
BH3 Profiling: 
BH3 profiling is a functional assay that detects the proximity of cells to the threshold of 
apoptosis (i.e. priming) through interrogation of BCL-2 family members. To perform a BH3 
profile, we add individual peptides, which bind to the BH3-only region of anti-apoptotic 
proteins, to gently permeabilized malignant cells. We then use Fluorescence-activated cell 
sorting (FACS) to measure the amount of mitochondrial depolarization induced by each peptide, 
as measured by cytochrome c release. Previous trials at our institution have suggested that this 
technique may be useful as an effective predictor of response in CLL.43
We hypothesize that patients whose cells undergo significant depolarization to the BIM BH3
peptide (primed) will have superior clinical response to duvelisib plus venetoclax as compared to 
patients whose cells undergo minimal BIM BH3 depolarization (unprimed). These assessments 
will be made on circulating CLL cells from the peripheral blood drawn from patients at baseline 
and after three and six months of combination therapy.
If we have bone marrow aspirates available, we will also perform BH3 profiling to see
whether the level of priming in CLL cells from these tissues is a better predictor of response
than peripheral blood CLL cells.
After 1 week of duvelisib monotherapy on cycle 1 day 8 (prior to receiving venetoclax), we
will obtain another peripheral blood sample. We will compare the BH3 profile of this
steady-state sample to a baseline sample, which will allow us to assess the short term
change in apoptotic priming induced by in vivo duvelisib as a single agent. 
Lastly, peripheral blood will be collected from subjects at the time of disease progression, and 
the BH3 profile of these samples will be compared to subjects baseline.  By measuring the 
cytochrome c loss in response to other BH3 peptides, such as BAD, MS-1 and HRK, it will be 
possible to determine whether dependencies on anti-apoptotic proteins other than BCL-2 predicts 

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68
resistance to therapy. We can also determine whether BCL-2 dependency predicts response to 
therapy or risk of tumor lysis syndrome. 
We will simultaneously perform dynamic BH3 profiling, in which CLL cells will be treated with 
duvelisib ex-vivo, prior to traditional BH3 profiling. This will also allow us to see the change in 
mitochondrial priming as well as changes in anti-apoptotic dependencies following treatment 
with duvelisib. 
All peripheral blood samples will promptly be delivered to the laboratory of Dr. Jennifer Brown, 
where they will undergo Ficoll purification and then be viably frozen in FBS with 10% DMSO. 
The viably-frozen samples will be batched and later transported to the laboratory of Dr. Matthew 
Davids, where the BH3 profiling assays will be performed.
CLL Center, J. Brown lab  
Dana Farber Cancer Institute 
1 Jimmy Fund Way  SM 648
Boston, 02115
M. Davids Lab
Dana Farber Cancer Institute 
440 Brookline Ave
Mayer-540
Boston, 02215
9.2
Cytometry by Time of Flight (CyTOF): 
We will obtain samples prior to therapy, after one week of duvelisib monotherapy (cycle 1, day 
8) and after three and six months of combination therapy. We will plan to use a panel of 
monoclonal antibodies targeting 35 markers, including 26 surface membrane and 9 intracellular 
markers. The Wilcoxon matched-pairs signed rank test will be used to compare percentages of T-
cell subsets, NK cells, and monocytes obtained from CyTOF at various time points. As duvelisib 
is known alter the tumor-promoting effects of T-cell and myeloid cells in the microenvironment, 
we aim to characterize these changes and correlate our findings with both response to therapy 
(ORR), complete response (CR) rate as well as toxicity. In particular we will assess how changes 
in the ratio of regulatory to conventional T cells correlates with immune-mediated toxicities, as 
has been observed with other PI3K inhibitors.46 
9.3
Minimal Residual Disease (MRD): 
All participants will be assessed for minimal residual disease (MRD) on both blood and bone 
marrow throughout the course of the study. Such patients who have fewer than 0.01% (10-4) CLL 
cell percentage of leukocytes in the bone marrow, as assessed by four-color flow cytometry will 
be considered to be MRD negative.  

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9.3.1
Adaptive Sequencing Studies
Depending on sample and funding availability, additional testing may also be performed at 
Adaptive Biotechnologies in Seattle, WA for MRD testing by their NGS platform known as 
ClonoSEQ. Peripheral blood and/or bone marrow samples will be collected, processed and stored 
at Dana-Farber Cancer Institute for possible future analysis at Adaptive. Using Adaptive s 
ClonoSEQ platform, rearranged immunoreceptor loci from genomic DNA will be extracted, 
amplified, and sequenced using V and J segment primers for each immunoreceptor gene.  
Tumor-specific clonotypes will be identified for each patient based on their high prevalence in 
peripheral blood or bone marrow.  Sequences will be analyzed using standardized algorithms for 
clonotype determination.  Adaptive MRD levels will be quantified using spiked-in reference 
sequences.
Adaptive Biotechnologies
151 Eastlake Ave E, Ste 200
Seattle, WA 098102
9.3.2
Mayo Clinic Minimal Residual Disease/ Flow Cytometry
Bone marrow and blood samples will be collected for minimal residual disease analysis by Mayo 
Clinic Genetics by flow cytometry as part of standard of care required disease monitoring per the 
study calendar in section 10, and also in Table 9. 
These samples will be shipped  priority overnight to:  
Mayo Medical Laboratories 
3050 Superior Drive NW
       Rochester, MN 55901
For Customer Service regarding lab results, or changes in an order, please call Mayo Clinic lab 
services at: 855-516-8404
Investigative sites both local and external must create an account for their institution with Mayo 
Clinics if they do not already have an existing account. 
Tests can be ordered online via the MayoAccess Portal at https://mmlaccess.com/  or via the Mayo 
Clinic Laboratories Hematopathology Test Request form must accompany the sample shipment. 
Results will be faxed to the number provided by the team in the portal, or on the order form.  
Source
Collection Container
 Catalog ID
Shipment Conditions*
Blood
1 x 6 ml Lavender Tube
CLLMV
Ambient

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Bone Marrow Aspirate
1 x 6 ml Lavender Tube
CLLMV
Ambient
* Sent same day, first overnight
9.4
Exome sequencing of tumor cells
Whole-exome capture libraries will be constructed from 100ng of tumor and normal DNA 
followed by shearing, end repair, phosphorylation and ligation to barcoded sequencing adapters. 
The DNA will be size-selected to exonic hybrid capture using SureSelect v2 Exome bait (Agilent, 
CA). Samples will be multiplexed and sequenced on Illumina HiSeq flowcells with the goal of an 
average depth of coverage of 100x. The resulting data will be analyzed with the current Illumina 
pipeline, which generates data files (BAM files). The details of the current analysis pipeline are 
published elsewhere. Briefly, somatic single nucleotide variants are determined using the MuTect 
algorithm.  Indels and translocations are determined by the algorithms IndelLocator and dRanger, 
respectively. The MutSig algorithm identifies genes in which the observed mutations are 
inconsistent with what would be expected at random. To accurately assess the significance of 
mutations, MutSig takes into account several covariates, which influence the background mutation 
model. These include the expression level of genes (for which published gene expression data of 
MM samples can be used), and other gene characteristics observed empirically to co-vary with 
mutation rate: local relative replication time, and open vs. closed chromatin status. Focal as well 
as arm-level copy number variations will be determined based on whole exome sequencing and 
subsequent application of the GISTIC algorithm.
The DNA library will be prepared at the Brown Lab, and then sequencing will be done at the 
following external lab:
Broad Institute Genomics Services
320 Charles Street
Cambridge, MA 02141
Sequencing data will then be provided back to Brown and Davids Lab in the form of BAM file. 
The samples that are sent for analysis are exhausted during the process, and thus not able to be 
returned. 
9.4.1
RNA sequencing of tumor cells 
For RNA Sequencing, poly-A selection and cDNA synthesis will be performed, followed by 
library preparation, sequencing (76bp or 101bp paired reads), and sample identification with 
quality control. We will perform library construction using a non-strand specific Illumina TruSeq 
Protocol and sequence coverage to 100M total reads. Analysis will be performed as described in 
the preliminary data and in previous studies.
The RNA library will be prepared at the Brown Lab, and then sequencing will be done at the 
following external lab:

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71
 Broad Institute Genomics Services
320 Charles Street
Cambridge, MA 02141
Sequencing data will then be provided back to Brown and Davids lab in the form of BAM file. 
The samples that are sent for analysis are exhausted during the process, and thus not able to be 
returned
9.5
Pharmacokinetic (PK) Testing (Phase I) :
 
In the phase I study, PK testing for duvelisib will be performed at baseline, 0.5, 1, 2, 4, 6, 8, 10, , 
and 24 hours following the initial dose of duvelisib on Day 1. PK testing will be performed at 
baseline, 0.5, 1, 2, 4, 6, 8, 10, and 24 hours following the initial venetoclax dosing on Day 8 to 
analyze both duvelisib and venetoclax PK. The 10-hour post dose PK is strongly encouraged, but 
optional. PK analysis for both drugs will be performed at pre-dose, 1 and 4 hours in subsequent 
weeks to assess steady-state levels prior to cycle 2 at each venetoclax dose escalation. 
Cycle 1 Day 1
(duvelisib)
Cycle 1 Day 8
(duvelisib + venetoclax)
Cycle 1 
On days of venetoclax dose 
escalation
Pre-dose (-2 hrs)
X
X
X
0.5h post dose
(± 5 mins)
X
X
1h post dose  
(± 5 mins)
X
X
X
2h post dose
(± 5 mins)
X
X
4h post dose 
(± 15 mins)
X
X
X
6h post dose
(± 15 mins)
X
X
8h post dose
(± 15 mins)
X
X
10h post dose
(± 15 mins) 
(optional)
X
X
24h post dose 
(± 15 mins)
X
X

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Blood will be collected in vacutainers (4.0 ml BD Vacutainer® K2 EDTA Purple Top) at above 
mentioned time points and centrifuged (within 30 minutes) at a standard speed and time in a 
refrigerated centrifuge to process the plasma. The processed plasma will be divided and 
transferred into two cryotubes (primary and secondary; 2X1.8 mL white cryotubes) using 
transfer pipette. The cryotubes will be stored at -80C freezer until shipment to bioanalytical 
laboratory. 
Duvelisib and Venetoclax PK analyses will be performed at: 
inVentiv Health
2500 Einstein Street,
Quebec, Quebec, G1P 0A2
CANADA
9.6
Jennifer Brown Lab Sample Collection and Shipping Instructions 
9.6.1
DF/HCC Local Samples:  DFCI patient samples will be hand-delivered to the Brown 
lab. Other DF/HCC sites may send samples via preferred courier service, or hand 
delivery to the lab. 
9.6.2
External Investigative Site Sample Preparation and Shipment:
Once fresh samples (blood and bone marrow aspirate) are collected, the vacutainers will be 
refrigerated and stored per instructions below. There is no required processing for any of the 
samples by the participating site prior to shipment.
1. Package tubes at room temperature and wrap in a liberal amount of paper towel around 
the tubes to ensure adequate insulation of the specimen(s) and absorption in the event of a 
breakage. 
2. Place wrapped specimen in a biohazard labeled Ziploc bag or sealable bag with a fridge 
pack and securely close. 
3. Wrap bubble wrap around the bag and place in a cardboard box. If space remains in the 
box, stuff with extra paper towel to reduce shifting of samples.
4.  Complete the shipping requisition form using the address listed below. Prepare the 
package for shipping, applying packing tape as needed. 
5. Ship the package using FedEx or UPS next day or overnight delivery the same day the 
sample was collected. 
6. Only ship Monday-Thursday and avoid shipping before a holiday as the lab does not 
receive packages on Saturday or on holidays. 
7. With each shipment, please include the following:
a.  An inventory sheet including a complete list of samples shipped (patient number, 
timepoint, study #) must accompany each shipment. Please sign and date the form 
and retain a copy for site record maintenance. A sample requisition form will be 
provided by the lead site for use in sample shipment inventory.

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73
b.  An electronic copy (Word or pdf) of the sample requisition must also be sent via 
email and include the tracking number of the package. The listing must also 
include a contact name, address and phone number of the person who is 
responsible for the shipment.
8. Please email the Lead Site Research Project Manager to notify of an incoming shipment 
at least 48 hours prior to a shipment
9. Samples may be shipped via overnight air to:
      Stacey Fernandes, Principal Research Technician 
CLL Center, J. Brown lab  
Dana Farber Cancer Institute 
      1 Jimmy Fund Way, SM 648                                     
      Boston, MA 02115, U.S.A. 
      617-632-5828 (phone)
Please retain a copy of both the Fed-Ex or UPS tracking number, and of the completed 
requisition form for each sample sent.

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10. STUDY CALENDAR
Baseline evaluations are to be conducted within 4 weeks (28 days) prior to patient registration 
with the exception of the required bone marrow biopsy, which can be done within 12 weeks (90 
days) prior to registration if no significant intervening treatment has occurred since the biopsy. 
Treatment should begin as soon as possible after registration. In the event that the participants 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next cycle of therapy.
Assessments and correlative lab draws must be performed prior to administration of any study 
agent. Study assessments and agents should be administered within +/- 3 days of the protocol-
specified date during the dose ramp up period, +/- 7 days during the rest of the combination 
portion, and +/- 14 days after the completion of the combination portion (Cycle 12), unless 
otherwise noted. 
For venetoclax ramp-up instructions, please refer to section 5.1.2. 
If after at least one year of treatment, a patient achieves a complete remission (CR) or complete 
remission with incomplete count recovery (CRi) with MRD-negativity in the peripheral blood 
and bone marrow, they will have the option to discontinue venetoclax in favor of active disease 
monitoring in follow up. If after at least two years of treatment (Cycle 25 restage), a participant 
achieves a partial remission (PR) with MRD-negativity in the bone marrow, they will have the 
option to discontinue venetoclax in favor of active disease monitoring.
In the event that the participants who have discontinued treatment in favor of disease monitoring  
have recurrent disease as defined by MRD testing (>10-4) in at least two MRD assessments they 
can restart venetoclax. Patients will be treated with a dose ramp up as per the label, starting with 
20 mg daily and escalating to 400 mg daily. Prophylaxis against and treatment of TLS will be 
performed as during initiation of venetoclax therapy. If patients do not achieve MRD negativity 
after reaching full dose venetoclax monotherapy, they have the option to add duvelisib at the 
highest dose they previously tolerated and continue it until MRD negativity is achieved on two 
successive peripheral blood MRD assessments or indefinitely depending on tolerability.

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Table 9: Study Calendar: 
Cycle = 28 days
(except for cycle 1 which 
will vary in length)
Screeni
ng**
Cycle 1 
 (+-3 Days)
Cycle 2 
(+-7 Days)
Cycles
3-6
(+-7 Days)
Cycles 7+ 
( 2 cycles +/- 
7d until C13, 
then q3 cycles 
+/-14d 
through cycle 
60, then q6 
months +/- 14 
days 
End of 
Treatment12 
Active 
Follow Up 
(q3 months 
+/- 14 days ) 
and Disease 
Monitoring 
14,16
Survival 
Status  
Procedure / Days
-28-0
Day 11
Day 2
Day 82
Day 153
Day 22
Day 29 
Day 36
Day 43
Day 1
Day 8
Day 15
Day 22
Day 1
Day 1
Informed consent 
X
Duvelisib 
X
X 
X
X
X
X
X
X
X
X
X (through 
cycle 12)
Venetoclax 
X
X
X
X
X
X
X
X
X
Survival Status 
X
PK assessments (phase I 
study only)
X
X
X
X
X
History and Physical 
Exam + Vital signs17
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum pregnancy test
 Х*
Physical Exam Lymph 
node measurements 
X17
X17
Quality of life survey 
(appendix F)
X
X
Concurrent Medications
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis 
X
BM aspirate/biopsy5,6  
Х4
X
X
    X
X
SPEP + 
Immunoglobulins7 
X
X
X

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Cycle = 28 days
(except for cycle 1 which 
will vary in length)
Screeni
ng**
Cycle 1 
 (+-3 Days)
Cycle 2 
(+-7 Days)
Cycles
3-6
(+-7 Days)
Cycles 7+ 
( 2 cycles +/- 
7d until C13, 
then q3 cycles 
+/-14d 
through cycle 
60, then q6 
months +/- 14 
days 
End of 
Treatment12 
Active 
Follow Up 
(q3 months 
+/- 14 days ) 
and Disease 
Monitoring 
14,16
Survival 
Status  
Procedure / Days
-28-0
Day 11
Day 2
Day 82
Day 153
Day 22
Day 29 
Day 36
Day 43
Day 1
Day 8
Day 15
Day 22
Day 1
Day 1
ECOG performance 
status
Х
X
X
X
X
X
EKG
Х18
Serology: SARS 
CoV2-,HIV, HCV, 
HBV20
Х
CT or PET/CT scan and 
Response Assessment8,9 
X
X
X
X
X
Hematology (CBC with 
differential and platelets) 
X
X
Х
X
Х
X
X
X
X
X
X
X
X
Serum Chemistry (CMP, 
magnesium, uric acid, 
phosphate, LDH, amylase 
and lipase)15
X
X
Х
X
Х
X
X
X
X
X
X
X
X
CMV viral load11
X
X
X
X
PT/PTT/INR
X
FISH, TP53, NOTCH1, 
SF3B1, and IGHV 
testing10 
X
Correlative studies**
X13
X13
X
X
X
X
X
X
Adverse Event 
Evaluation 
X
X
X
X
X
X
X
X
X
X
X
X
MRD assessment14 
X
X
X
X
1 During cycle 1, patients will start with duvelisib alone on days 1-7. Dose ramp up of venetoclax will begin on C1D8. Please refer to section 5.1.2 for admission requirement, TLS monitoring, 
and inpatient versus outpatient dosing of venetoclax and ramp up instructions.

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2 C1D8 patients will initiate venetoclax ramp up and continue duvelisib 
3 Please refer to section 5 for venetoclax ramp-up dosing per arm.
4 Unilateral bone marrow aspirate and/or biopsy required within 12 weeks (90 days) prior to C1D1.
5 Bone marrow biopsy and aspirate will be mandatory at study entry and at C7D1 (+-7 days), C13D1 (+-7 days), and C25D1 (+-14 days). Bone marrow biopsies will be at the discretion 
of the treating investigator thereafter. MRD will be tested in the bone marrow each time a standard of care or clinically indicated biopsy is performed both during venetoclax maintenance 
and during active follow up through the Mayo Clinic Lab. Please refer to Section 9 and Table 10 for additional details on schedule and ordering instructions. 
6 Marrow sample requested for correlative studies if bone marrow is done as standard of care, or part of protocol schedule. 
7 SPEP required at baseline and then at Cycles 3, 6, 9, 13 and every 3 cycles thereafter only if M protein detected at baseline; If no M protein detected at baseline, IgG, IgA, IgM to be 
checked Cycles 3, 6, 9, 13 and  every 3 cycles thereafter (B2M only at baseline, C6 and C13).
8 C4D1, C7D1, and C13D1 (+/- 7 days for each). De-identified scans (Initials, assigned patient number, study number, date of scan, and timepoint must be included) will be sent to the 
DFCI/Lead site project manager to then send for analysis by the Tumor Imaging Metrics Core- Scans may also be uploaded to the TIMC portal by local radiology
9 After Cycle 13, CT (Chest, Neck, Abdomen and Pelvis) or PET/CT (Richters Patients) scans may occur just prior to every 6 cycles (+/- 14 days), or per investigator discretion. De-
identified scans (Initials, assigned patient number, study number, date of scan, and timepoint must be included) will be sent to the DFCI/Lead site project manager to then send for analysis 
by the Tumor Imaging Metrics Core- Scans may also be uploaded to the TIMC portal by local radiology- For instructions on sending scans to Dana-Farber for central review, please refer 
to section 11.1.3
10 FISH for both CLL/SLL are to be done locally- IGHV, TP53 testing can be performed locally or externally via Mayo Clinic Laboratories; If ordering through Mayo Clinic Laboratories, 
please refer to section 9 and table 10.  SF3B1 and NOTCH1 to be ordered for DFCI patients only.
11 CMV viral load testing should be performed at the time of screening and monthly thereafter in patients while on duvelisib. Local testing is permitted.
12 End of treatment visit should  occur at the next study visit following a completed cycle after study drug was administered and include adverse event monitoring for 30 days following drug 
discontinuation (visit window +/-14 days). End of treatment due to MRD-CR or MRD- PR does not require labs or exam to be repeated after the C13 or C25  restaging unless clinically 
indicated. 
13 Baseline correlative studies may be obtained either at the screening visit or prior to study drug administration on C1D1.
* Within 3 days of  Cycle 1 Day 1
** Please see section 5.2 for requirements for treatment and Table 10 for full correlative and send out sample collection schedule
14 MRD will be evaluated in the bone marrow prior to cycle 7, 13, and 25 (+/-7 days) and any time a clinically indicated bone marrow procedure is done thereafter- MRD assessments will 
also be performed in the peripheral blood prior to cycle 4, 7, 11, 13, 16, 19, 22, 25 and every three cycles up to Cycle 60, then every 6 cycles thereafter- MRD of the blood will be assessed 
every 3 months or every 6 months at minimum during follow up/active disease monitoring. Please refer to section 9 and Table 10 for directions on ordering, collection, and shipping of 
samples to Mayo Clinic Laboratories 
15 Amylase and lipase required only while on duvelisib 
16 Please refer to section 5.6 for more specific follow up and active disease monitoring requirements 
 17 Includes history and physical exam (with standard review of systems) in addition to blood pressure, pulse rate, and temperature- On Cycle 1 Day 1 and Cycle 1 Day 8, the physical exam 
will also include measurement and assessments of palpable lymph nodes 
18 Local EKG machine; single test
19 Participants will be followed for survival status indefinitely after active follow up unless they have withdrawn consent, died, or are lost to follow up
20   SARS- COV2, Hepatitis B ,C, and HIV serologies: HBV surface antigen, HBV surface antibody, HBV core antibody: if HBV core antibody is positive, must have a negative HBV viral 
load to enroll. HCV antibody: if positive, must have negative HCV viral load to enroll. HIV 1/2 antibody: must have negative result to enroll. SARS-COV2 must have negative PCR to enroll.

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Table 10:  Correlative and Required Send out Sample Schedule: 
Sample Time 
Point
Container 2
Sample 
Type
Shipping 
Method1,8
Recipient3,6
6x6mL Green
1x6ml Red
Peripheral 
Blood
Hand-delivered or 
Fridge pack 
overnight 
shipping
Brown Lab
1x6ml Green
Bone 
Marrow 
Aspirate
Hand-delivered or 
Fridge pack 
overnight 
shipping
Brown Lab
MUTATIONS
Peripheral 
Blood
Ambient
Mayo Clinic  or 
Local Assay
Baseline or 
C1D1 Predose
1x Oragene Kit
Saliva2
Ambient 
Brown Lab
C1D8 Predose
6x6mL Green
1x6ml Red
Peripheral 
Blood
Hand-delivered or 
Fridge pack 
overnight 
shipping
Brown Lab
C2D1
6x6mL Green
1x6ml Red
Peripheral 
Blood
Hand-delivered or 
Fridge pack 
overnight 
shipping
Brown Lab
1x6ml Lavender
Peripheral 
Blood
Ambient
Mayo Clinic
MRD
C4D1
6x6mL Green
1x6ml Red
Peripheral 
Blood
Hand-delivered or 
Fridge pack 
overnight 
shipping
Brown Lab
6x6mL Green
1x6ml Red
Peripheral 
Blood
1x6ml Green
Bone 
marrow 
Aspirate
Hand-delivered or 
Fridge pack 
overnight 
shipping
Brown Lab
1x6ml Lavender
Bone 
marrow 
Aspirate
Ambient 
Mayo Clinic 
MRD
C7D1, C13D1, 
C25D1
1x6ml Lavender
Peripheral 
Blood
Ambient
Mayo Clinic
MRD

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C11D1
1x6ml Lavender
Peripheral 
Blood
Ambient
Mayo Clinic
MRD
C16D1
1x6ml Lavender
Peripheral 
Blood
Ambient
Mayo Clinic
MRD
C19D1
6x6mL Green
1x6ml Red
Peripheral 
Blood
Hand-delivered or 
Fridge pack 
overnight 
shipping
Brown Lab
1x6ml Green
Bone 
marrow 
Aspirate
Hand-delivered or 
Fridge pack 
overnight 
shipping
Brown Lab
Clinically 
Indicated5
1x6mL Lavender
Bone 
Marrow 
Aspirate
Ambient
Mayo Clinic
MRD
6x 6mL Green
1x6ml Red
Peripheral 
Blood
Hand-delivered or 
Fridge pack 
overnight 
shipping
Brown Lab
1x6ml Green4
Bone 
Marrow 
Aspirate
Hand-delivered or 
Fridge pack 
overnight 
shipping
Brown Lab
1x6mL Lavender5
Bone 
Marrow 
Aspirate
Ambient
Mayo Clinic
MRD
Confirmation of 
Complete 
Response
1x6ml Lavender
Peripheral 
Blood
Ambient
Mayo Clinic
MRD
6x6mL Green
1x6ml Red
Peripheral 
Blood
Hand-delivered or 
Fridge pack 
overnight 
shipping
Brown Lab
1x6ml Green
Bone 
Marrow 
Aspirate
Hand-delivered or 
Fridge pack 
overnight 
shipping
Brown Lab
End of 
Treatment or
Suspected 
Progression  
OR
Prior to 
Resuming 
Venetoclax after 
Discontinuation
1x6mL Lavender
Bone 
Marrow 
Aspirate
Hand-delivered or 
Fridge pack 
overnight 
shipping
Mayo Clinic
MRD

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Every 3 Cycles 
from C25D1 
through C606
  
1x6ml Lavender
Peripheral 
Blood
Ambient
Mayo Clinic
MRD
Every 6 Cycles 
from Cycle 25 
onward7 
6x6mL Green
1x6ml Red
Peripheral 
Blood
Hand-delivered or 
Fridge pack 
overnight 
shipping
Brown Lab
Active Disease 
Monitoring 
Every 3 months 
1x6ml Lavender6
Peripheral 
Blood
Ambient
Mayo Clinic
MRD
1Local samples from DFCI, MGH, or BIDMC will be refrigerated and hand-delivered as soon as possible same day 
to Dr. Jennifer Browns lab- For external investigative sites, shipping instructions are in section 9. Samples are to be 
shipped to the Brown lab by overnight, trackable shipping on fridge packs
2Green=Sodium Heparin Tube; Red= No additive; Purple = K2EDTA; Oragene saliva collection kit provided by 
lead site and can be collected at any time before or during the trial
3 Requisition form for Mayo Labs and for Jennifer Brown lab provided by the lead site project manager
4 Only required in patients who had a positive marrow at baseline   
5 After C25 (both patients on treatment or in active follow up) bone marrow aspirate samples will be collected each 
time a bone marrow biopsy is done as part of routine standard of care or the investigators discretion 
6  MRD testing of the peripheral blood will be sent to Mayo Clinic Laboratory just prior to cycles 4, 7, 11, 13, 16, 19, 
22, 25 and every three cycles until cycle 60, then at minimum q6 cycles thereafter  During active follow up, MRD 
of the blood should be tested q3 months or at minimum, q6 months for up to one year.
7 Correlative samples requested for all patients who remain on study past cycle 25, i.e.  30, 36, 42, 48, 54, and 60 to 
be sent to Brown Lab at DFCI.
8 Both blood and aspirate MRD samples are to be sent ambient, priority overnight to Mayo Clinic Laboratories at the 
address listed in section 9.3.2
9  Please refer to section 5.6 for full details on active disease monitoring and follow up

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11. MEASUREMENT OF EFFECT
11.1
Definitions: 
Evaluable for toxicity: All participants who receive at least one dose of study treatment
will be evaluable for toxicity from the time of their first treatment. 
Evaluable for DLT: All participants who complete the first cycle of combination therapy 
will be evaluable for DLT from the time of their first treatment.  Any patient who 
experiences a DLT after receiving at least one dose of combination study treatment will 
also be considered evaluable for DLT.  In the phase I portion of the study, if a patient 
comes off study due to a reason other than a DLT (e.g. disease progression) prior to the 
end of the DLT observation period, that patient can be replaced.
Evaluable for objective response: Only those participants who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for response. These participants will have their 
response classified according to the definitions stated below. (Note: Participants who 
exhibit objective disease progression or die prior to the end of cycle 1 will also be 
considered evaluable.)
11.2
Methods for Evaluation of Measurable Disease: 
 
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment.
The same method of assessment and the same technique should be used to characterize
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination when both methods have 
been used to assess the anti-tumor effect of a treatment.
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, 
is recommended.
Conventional CT: These techniques should be performed with cuts of 10 mm or less in 
slice thickness contiguously. Spiral CT should be performed using a 5 mm contiguous 
reconstruction algorithm. Although CT scan is the preferred imaging modality for this 
study, MRI or PET/CT will also be considered acceptable. Images of the Chest, Neck, 
Abdomen and Pelvis are required at each timepoint listed in the study calendar. 
PET/CT:  For patients with Richters Syndrome, PET/CT evaluation is preferred over 
contrast CT, though the latter can be used if necessary.

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11.3
Response Criteria 
Response and progression will be evaluated in this study using the 2008 IW-CLL criteria 
for CLL (Hallek et al., 2008) or for RS by Lugano criteria (Cheson et al., 2014).
If a bone marrow biopsy was done to confirm a response, sites may use the blood MRD 
results within 2 months of the biopsy to confirm that MRD status.  
     
11.3.1 2008 IW-CLL Criteria ( CLL/SLL patients only)
11.3.1.1
Complete Remission (CR):   

Evaluation of Non-Target Lesions CR requires all of the following criteria: 
Peripheral blood lymphocytes (evaluated by blood and differential count) 
below 4 x109/L (4,000/μL). The presence of minimal residual disease (MRD) 
after therapy should be assessed. The sensitivity of the method used to 
evaluate for MRD should be reported.

Absence of significant lymphadenopathy (eg, lymph nodes >1.5 cm in 
diameter) by physical examination. A CT scan of the abdomen, pelvis, and 
thorax is desirable if previously abnormal. Lymph nodes should not be larger 
than 1.5 cm in diameter.

No hepatomegaly or splenomegaly by physical examination. A CT scan of the 
abdomen should be performed at response assessment if found to be abnormal 
before therapy or if physical examination is inconclusive at the time of 
evaluation.

Absence of constitutional symptoms.

Blood counts above the following values: Neutrophils more than 1.5 x 109/L 
(1,500/μL) without need for exogenous growth factors, Platelets more than 
100 x 109/L (100,000/μL) without need for exogenous growth factors, 
Hemoglobin more than 110 g/L (11.0 g/dL) without red blood cell transfusion 
or need for exogenous erythropoietin.

Bone marrow sample must be at least normocellular for age, with less than 
30% of nucleated cells being lymphocytes. Lymphoid nodules should be 
absent.
11.3.1.2
Complete Response with incomplete marrow recovery (CRi):

Complete response as defined above, but without normal blood counts. 
11.3.1.3
Minimal Residual Disease: 

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
Patients with CR or CRi or patients with PR with resolution of lymphocytosis 
will be assessed for minimal residual disease (MRD) at every three months. 
Such patients who have fewer than 0.01% (10-4) CLL cell percentage of 
leukocytes in the bone marrow, as assessed by four-color flow cytometry, will 
be considered to be MRD negative.
11.3.1.4
Partial Response (PR): 

A decrease in the number of blood lymphocytes by 50% or more from the 
value before therapy.

Reduction in lymphadenopathy as defined by the following:
o
A decrease in lymph node size by 50% or more either in the sum 
products of up to 6 lymph nodes, or in the largest diameter of the 
enlarged lymph node(s) detected prior to therapy.
o
No increase in any lymph node, and no new enlarged lymph node. In 
small lymph nodes (< 2 cm), an increase of less than 25% is not 
considered to be significant.

A reduction in the noted pretreatment enlargement of the spleen or liver by 
50% or more

The blood count should show one of the following results: Neutrophils more 
than 1.5 x 109/L (1,500/μL) without need for exogenous growth factors, 
Platelet counts greater than 100 x 109/L (100,000/μL) or 50% improvement 
over baseline without need for exogenous growth factors, Hemoglobin greater 
than 110 g/L (11.0 g/dL) or 50% improvement over baseline without requiring 
red blood cell transfusions or exogenous erythropoietin.
11.3.1.5
Nodular Partial Response (nPR): 

All criteria for CR are met, but lymphoid nodules can be found in the bone 
marrow biopsy. Note, if flow cytometry and immunohistochemistry are negative 
for a clonal B-cell population then these patients can be considered as CR or CRi.
11.3.1.6
Partial Response with Lymphocytosis (PR-L): 

Evidence of a radiographic PR but persistent lymphocytosis with >5,000 B-
lymphocytes per μL where the absolute lymphocyte count has not decreased by 
50% or more compared to baseline are considered to have a PR with 
lymphocytosis.
11.3.1.7
Progressive Disease: 

Progressive disease during or after therapy is characterized by at least one of the 
following:
o
Lymphadenopathy: Progression of lymphadenopathy is often discovered 
by physical examination and should be recorded. For CT scans used to 

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confirm progression or relapse of lymphadenopathy, progression is 
defined as:

An increase by 50% or more in greatest determined diameter of 
any previous site.

An increase in the previously noted enlargement of the liver or 
spleen by 50% or more or the de novo appearance of hepatomegaly 
or splenomegaly.
o
An increase in the number of blood lymphocytes by 50% or more with at 
least 5,000 B lymphocytes per microliter (Note: because of the well-
described lymphocyte redistribution phenomenon, any increase in 
lymphocyte count during duvelisib monotherapy or any increase during 
combination therapy in the setting of improvement of lymph nodes or 
cytopenias will not be considered disease progression)
o
Transformation to a more aggressive histology (i.e., Richter syndrome). 
This diagnosis must be established by lymph node biopsy.
o
Occurrence of cytopenias (neutropenia, anemia, or thrombocytopenia) due to 
CLL.

During therapy, cytopenias cannot be used to define disease 
progression.

After therapy, the progression of any cytopenia (unrelated to 
autoimmune cytopenia), as documented by a decrease of Hb levels 
by more than 20 g/L (2 g/dL) or to less than 100 g/L (10 g/dL), or 
by a decrease of platelet counts by more than 50% or to less than 
100 x 109/L (100,000/μL), which occurs at least 3 months after 
treatment, defines disease progression, if marrow biopsy 
demonstrates an infiltrate of clonal CLL cells.
11.3.1.8
Stable Disease: Patients who have not achieved a CR or a PR, and who have not 
exhibited progressive disease, will be considered to have stable disease.
11.3.1.9
Treatment Failure: Responses that should be considered clinically beneficial 
include CR and PR; all others (eg, stable disease, nonresponse, progressive disease, or 
death from any cause) should be rated as a treatment failure.
11.3.1.10 Relapse: Relapse is defined as a patient who has previously achieved the above 
criteria of a CR or PR, but after a period of 6 or more months, demonstrates evidence 
of disease progression.
11.3.1.11 Refractory Disease: Refractory disease is defined as treatment failure or disease 
progression within 6 months to the last anti-leukemic therapy.
11.3.2 2014 Lugano Criteria (Richters Patients Only):

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Response 
and Site
PET-CTBased Response
CT-Based Response
Complete
Complete metabolic response
Complete radiologic response (all of 
the following)
Score 1, 2, or 3* with or without a residual 
mass on 5PS
Target nodes/nodal masses must 
regress to ≤ 1.5 cm in LDi
Lymph nodes and 
extralymphatic 
sites
It is recognized that in Waldeyer's ring or 
extranodal sites with high physiologic uptake 
or with activation within spleen or marrow (eg, 
with chemotherapy or myeloid colony-
stimulating factors), uptake may be greater 
than normal mediastinum and/or liver. In this 
circumstance, complete metabolic response 
may be inferred if uptake at sites of initial 
involvement is no greater than surrounding 
normal tissue even if the tissue has high 
physiologic uptake
No extralymphatic sites of disease
Nonmeasured 
lesion
Not applicable
Absent
Organ 
enlargement
Not applicable
Regress to normal
New lesions
None
None
Bone marrow
No evidence of FDG-avid disease in marrow
Normal by morphology; if 
indeterminate, IHC negative
Partial
Partial metabolic response
Partial remission (all of the 
following)
Lymph nodes and 
extra-lymphatic 
sites
Score 4 or 5 with reduced uptake compared 
with baseline and residual mass(es) of any size
≥ 50% decrease in SPD of up to 6 
target measurable nodes and 
extranodal sites
At interim, these findings suggest responding 
disease
When a lesion is too small to 
measure on CT, assign 5 mm × 5 
mm as the default value
At end of treatment, these findings indicate 
residual disease
When no longer visible, 0 × 0 mm
For a node > 5 mm × 5 mm, but 
smaller than normal, use actual 
measurement for calculation
Nonmeasured 
lesions
Not applicable
Absent/normal, regressed, but no 
increase
Organ 
enlargement
Not applicable
Spleen must have regressed by > 
50% in length beyond normal
New lesions
None
None

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Response 
and Site
PET-CTBased Response
CT-Based Response
Bone marrow
Residual uptake higher than uptake in normal 
marrow but reduced compared with baseline 
(diffuse uptake compatible with reactive 
changes from chemotherapy allowed). If there 
are persistent focal changes in the marrow in 
the context of a nodal response, consideration 
should be given to further evaluation with MRI 
or biopsy or an interval scan
Not applicable
No response or 
stable disease
No metabolic response
Stable disease
Target 
nodes/nodal 
masses, 
extranodal 
lesions
Score 4 or 5 with no significant change in 
FDG uptake from baseline at interim or end of 
treatment
< 50% decrease from baseline in 
SPD of up to 6 dominant, 
measurable nodes and extranodal 
sites; no criteria for progressive 
disease are met
Nonmeasured 
lesions
Not applicable
No increase consistent with 
progression
Organ 
enlargement
Not applicable
No increase consistent with 
progression
New lesions
None
None
Bone marrow
No change from baseline
Not applicable
Progressive 
disease
Progressive metabolic disease
Progressive disease requires at least 
1 of the following
Individual target 
nodes/nodal 
masses
Score 4 or 5 with an increase in intensity of 
uptake from baseline and/or
PPD progression:
Extranodal 
lesions
New FDG-avid foci consistent with lymphoma 
at interim or end-of-treatment assessment
An individual node/lesion must be 
abnormal with:
LDi > 1.5 cm and
Increase by ≥ 50% from PPD nadir 
and
An increase in LDi or SDi from 
nadir
0.5 cm for lesions ≤ 2 cm
1.0 cm for lesions > 2 cm
In the setting of splenomegaly, the 
splenic length must increase by > 
50% of the extent of its prior 
increase beyond baseline (eg, a 15-
cm spleen must increase to > 16 
cm). If no prior splenomegaly, must 
increase by at least 2 cm from 

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Response 
and Site
PET-CTBased Response
CT-Based Response
baseline
New or recurrent splenomegaly
Nonmeasured 
lesions
None
New or clear progression of 
preexisting nonmeasured lesions
New lesions
New FDG-avid foci consistent with lymphoma 
rather than another etiology (eg, infection, 
inflammation). If uncertain regarding etiology 
of new lesions, biopsy or interval scan may be 
considered
Regrowth of previously resolved 
lesions
A new node > 1.5 cm in any axis
A new extranodal site > 1.0 cm in 
any axis; if < 1.0 cm in any axis, its 
presence must be unequivocal and 
must be attributable to lymphoma
Assessable disease of any size 
unequivocally attributable to 
lymphoma
Bone marrow
New or recurrent FDG-avid foci
New or recurrent involvement

Abbreviations: 5PS, 5-point scale; CT, computed tomography; FDG, fluorodeoxyglucose; IHC, 
immunohistochemistry; LDi, longest transverse diameter of a lesion; MRI, magnetic resonance 
imaging; PET, positron emission tomography; PPD, cross product of the LDi and perpendicular 
diameter; SDi, shortest axis perpendicular to the LDi; SPD, sum of the product of the perpendicular 
diameters for multiple lesions.

↵* A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at 
the time of an interim scan. However, in trials involving PET where de-escalation is investigated, it 
may be preferable to consider a score of 3 as inadequate response (to avoid undertreatment). Measured 
dominant lesions: Up to six of the largest dominant nodes, nodal masses, and extranodal lesions 
selected to be clearly measurable in two diameters. Nodes should preferably be from disparate regions 
of the body and should include, where applicable, mediastinal and retroperitoneal areas. Non-nodal 
lesions include those in solid organs (eg, liver, spleen, kidneys, lungs), GI involvement, cutaneous 
lesions, or those noted on palpation. Nonmeasured lesions: Any disease not selected as measured, 
dominant disease and truly assessable disease should be considered not measured. These sites include 
any nodes, nodal masses, and extranodal sites not selected as dominant or measurable or that do not 
meet the requirements for measurability but are still considered abnormal, as well as truly assessable 
disease, which is any site of suspected disease that would be difficult to follow quantitatively with 
measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal 
masses, and other lesions that cannot be confirmed and followed by imaging. In Waldeyer's ring or in 
extranodal sites (eg, GI tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum 
with complete metabolic response, but should be no higher than surrounding normal physiologic 
uptake (eg, with marrow activation as a result of chemotherapy or myeloid growth factors).

↵ PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but 
≤ liver; 4, uptake moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new 
areas of uptake unlikely to be related to lymphoma.

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11.3.3 Progression free Survival 
Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from 
registration to the earlier of progression or death due to any cause. Participants alive 
without disease progression are censored at date of last disease evaluation.
Overall Survival: Overall Survival (OS) is defined as the time registration to death due to 
any cause, or censored at date last known alive.
11.3.4 Central Radiology Interpretation 
All scans will be reviewed centrally by the Tumor Imaging Metrics Core (TIMC) either by 
submission through their secure portal, or by mailing de-identified (only including subject 
number, trial number, date of scan, timepoint, and site contact information).
Radiographic responses will then be communicated to the investigative sites for entry in to the 
EDC. 
Scans will be uploaded to the secure file transfer portal at: 
https://transfer.partners.org/courier/web/1000@/wmLogin.html 
External Site Access: 
External collaborators must be invited to use the system. Please email the study lead if a new 
staff member needs access to this portal.
1. If you used the old system, type in your email address, click Next, then select the "forgot 
password" link to reset your password
2. If you're new, please ask your MGB collaborator to send you an email 
from https://transferkw.partners.org
3. Email Tumor Imaging Metrics Core help desk (tumormetrics@partners.org) and provide 
two email addresses for account registration (a primary and a backup)
4. TIMC will send an invite via the Partners Healthcare Secure File Sharing service
5. Click the link in the email to accept the invitation and register your account
a.
Invitations will expire after 7 days
b. Check Spam and Junk email folders for invite if not received in Inbox 
6. Create a password
7. Click Register
Send Files
1. Create a desktop folder 
2. Copy DICOM data from CD into the desktop folder

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a.
Remove any image viewers as this will interfere with data upload to the local 
analysis software
3. Right click folder > Send To > Compressed (zipped) folder
1. Log in to the system: https://transferkw.partners.org
4. Select Send File tab
5. Enter tumormetrics@partners.org into the To field
6. Enter a subject into the Subject field
7. Select Choose File > browse the desktop for the zipped file 
8. Add patient initials, trial number, and any notes pertaining to the scan or assessment in 
the body of the email
a.
Do not include any protected health information (PHI) in the email subject line 
9. Select notification preferences from the Additional Options field (optional)
10. Click Mark as secure (fingerprint)
11. Click Send
12. Click OK after receiving confirmation that the files have been sent
13. Notify the lead site PM that a file has been uploaded, so that an order can be placed 
for   the scan to be read.  
12. DATA REPORTING / REGULATORY REQUIREMENTS
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements).
12.1
Data Reporting
12.1.1 Method
The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on 
the data for this study. 
12.1.2 Responsibility for Data Submission
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or 
data forms to the Office of Data Quality in accordance with DF/HCC SOPs. 
12.2
Data Safety Monitoring
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Overall PI and study 
team.

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The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring with 30 
days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths 
while being treated and during active follow-up; any response information; audit results, and a 
summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request. 
12.3
Multicenter Guidelines: 
This protocol will adhere to the policies and requirements of the DF/HCC Multi-Center Data and 
Safety Monitoring Plan.  The specific responsibilities of the Overall PI, Coordinating Center, and 
Participating Institutions and the procedures for auditing are presented in Appendix B.

The Overall PI/Coordinating Center is responsible for distributing all IND Action Letters 
or Safety Reports to all participating institutions for submission to their individual IRBs 
for action as required.

Mechanisms will be in place to ensure quality assurance, protocol compliance, and 
adverse event reporting at each site.

Except in very unusual circumstances, each participating institution will order the study 
agent(s) directly from supplier.  A participating site may order the agent(s) only after the 
initial IRB approval for the site has been forwarded to the Coordinating Center.
12.4
Collaborative Agreements Language: N/A

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13. STATISTICAL CONSIDERATIONS
13.1
Study Design/Endpoints
Phase I Study: Evaluation of Toxicity
Primary Endpoint: The primary endpoint in the phase I study is the dose limiting toxicity 
(DLT), and the maximum tolerated dose (MTD) as well as the recommended phase II dose for 
this combination regimen of duvelisib plus venetoclax.
A standard 3+3 dose escalation design will be employed with three dose levels of venetoclax. 
Patients will be treated in cohorts of size three to six and the dosage will be escalated if the 
clinical toxicity is acceptable. A dose-limiting toxicity (DLT) is defined as per section 5.3, and 
the DLT observation period is the first cycle of combination treatment.
The design is constructed to reduce the chance of escalating the dose when the probability of 
DLT is high, and increase the chance of escalating the dose when the probability of DLT is low. 
The maximum tolerated dose (MTD) is defined as the highest dose level where a DLT occurs 
within at most one out of six patients treated. The escalation scheme is as follows: 
(1) If none of the initial three patients in a cohort experiences a DLT, then a new cohort of three 
patients will be treated at the next higher dose level. 
(2) If one of the three patients in a cohort experiences a DLT, then up to three additional patients 
will be treated at the same dose. Escalation will continue if only one of the six patients 
experiences DLT. 
(3) If two or more patients in a cohort experience DLT, then the MTD will have been exceeded, 
and no further dose escalation will occur. The previous dose level will be considered the MTD. 
(4) If only three patients were treated at a dose level under consideration as the MTD, then up to 
three additional patients will be accrued. If no more than one of the six patients at that dose level 
experience a DLT, then that dose level will be confirmed as the MTD. If two or more patients in 
that cohort experience DLT, then the previous dose level will be studied in the same fashion. 
The MTD is defined as the highest dose studied for which the observed incidence of DLT is less 
than 33%. Frequencies of toxicities will be tabulated according to the NCI Common Toxicity 
Criteria. Patients will be continued to be followed for one year for evidence of late toxicity. 
Table 10: Below gives the probabilities of dose escalation based on true DLT risk in the 3+3 
design. 
True DLT rate: 
10%
20%
30%
40%
50%
60%
70%
80%
90%
Probability of 
0.91
0.71
0.49
0.31
0.17
0.08
0.03
0.01
0.001

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escalation
In the phase I study, if a patient comes off study due to a reason other than a DLT (e.g. disease 
progression) prior to the end of the DLT observation period, that patient can be replaced.
Phase II Study (CLL/SLL patients): 
Treatment Efficacy
The primary endpoint for the phase II study is the rate of complete response (CR) at 12 months 
according to 2008 IW-CLL criteria. The CR rate will be obtained for all patients at 12 months 
and will be reported as a percentage of total patients. 
Evaluation of Toxicity in Phase II
We will closely monitor treatment-related toxicity for all participants.  Participants in the phase 
II portion of the study who meet DLT criteria during the first cycle of combination treatment as 
specified in section 5.3 will be analyzed by the following method:
Sequential Pocock-type stopping boundaries will be used to monitor the unexpected toxicity rate 
(Ivanova et al., 2005).  Accrual will be halted and the Data Safety Monitoring Committee 
consulted if excessive numbers of unexpected toxicities are seen, that is, if the number of 
toxicities is equal to or exceeds bn out of n patients who received at least one dose of 
combination therapy (see table 11). For example, if 6 or more out of the first 20 patients (40%) 
experience unacceptable toxicities the study will be stopped; or if 8 or more out of the first 30 
patients (26%) experience unacceptable toxicities the study will be stopped. With these rules, 
the probability of early stopping the trial if the true rate of toxicity is 10% does not exceed 0.05, 
if the true toxicity rate is 30% the probability of early stopping is 0.865 (table 12).
Table 11: The trial will be stopped if the number of toxicities is equal to or exceeds bn out 
of n patients evaluable for toxicity. 
 

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Table 12: Probabilities of early stopping at different true but unobserved toxicity rates.
Toxicity 
Rate
0.10
0.20
0.30
0.40
0.50
0.60
Probability 
of early 
stopping
0.048
0.436
0.865
0.988
0.999
1.00
Phase II Study (Richters Syndrome Cohort):
In a previous study with a commonly used chemoimmunotherapy regimen for RS, dose-adjusted 
EPOCH-R, the CR rate was 20%.15  We base this as the null hypothesis. With the addition of 
Number of 
Patients, n
Boundary,
 bn
1
-
2
2
3
3
4
3
5
3
6
3
7
4
8
4
9
4
10
4
11
5
12
5
13
5
14
5
15
5
16
6
17
6
18
6
19
6
20
6
21
6
22
7
23
7
24
7
25
7
26
7
27
7
28
8
29
8
30
8
31
8
32
8
33
8
34
9
35
9

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venetoclax, we hypothesize that the CR rate will be 45% or higher. Twenty patients will be 
enrolled and if 7 or more patients achieve CR we will regard the treatment efficacious. 
Conversely, if 6 or fewer patients achieve CR, we will regard the treatment inefficacious. With 
this design, the probability of concluding the treatment efficacious is 0.87 if the true but 
unknown response rate is 45% and 0.09 if the true rate is 20%. This decision rule is calculated 
using the exact binomial method. Table 1 below shows the operating characteristics of this 
design. 
Table 1. Operating Characteristics
 
True but Unknown CR Rate
 
20%
25%
30%
35%
40%
45%
Prob(≥7 CR in 20)
0.09
0.21
0.39
0.58
0.75
0.87
13.2
Sample Size, Accrual Rate and Study Duration
We anticipate approximately 12 CLL/SLL patients will be enrolled in the phase I study, using 
the traditional 3+3 design as described above. 
For the phase II study, a Simon two-stage design will be employed whereby a 10% complete 
response (CR) rate is considered not promising, a 30% complete response rate is considered 
promising, and the probabilities of a type I error (falsely accepting a non-promising therapy) and 
type II error (falsely rejecting a promising therapy) are set at 0.10 and 0.10, respectively.23 In the 
first stage of this design, 12 CLL/SLL patients will be accrued. All patients will be followed for 
up to one year. If at least 2 patients achieve CR then an additional 23 CLL/SLL patients will be 
accrued to the second stage.  If 0 or 1 patients achieve CR the study will be terminated and 
declared negative. The probability of early stopping based on an optimal Simons two stage 
design is 65%. At the end of the trial, if 6 or more patients respond out of a total of 35 patients, 
then this combination will be considered worthy of further investigation.  This design yields at 
least a 0.90 probability of a positive result if the true response rate is at least 30% and yields a 
0.90 probability of a negative result if the true response rate is 10%. 
Of note, all patients in the phase I study will be evaluated for response and can be counted in 
efficacy evaluations in stage 1 of the phase II portion of the trial. An exploratory analysis will 
also be performed to estimate the rate of CR with confidence intervals in the 29 patients treated 
at the venetoclax MTD.
For the Richters Syndrome Cohort, we plan to accrue 20 additional patients.  Given the poor 
prognosis and lack of a standard of care for this population, we will not have an early stopping 
rule for this cohort based on efficacy or toxicity.
13.3
Analysis of Secondary Endpoints
Phase I Study: 

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Secondary endpoints in the phase I trial include PK assessments. Pharmacokinetic parameters 
including half-life, Cmax, AUC, volume of distribution, and clearance will be determined using 
non-compartmental methods. Standard descriptive statistics (mean, standard deviation, median, 
range) will be presented on all parameters. These analyses will be performed in all patients accrued 
to the phase I component of the trial.
Phase II Study: 
Secondary endpoints in the phase II trial include, response assessments including ORR, defined 
as partial response and complete response or complete response with incomplete count recovery 
according to the 2008 IW-CLL or Lugano 2014 criteria the duration of response (DOR) among 
patients who have achieved a PR or CR/CRi, defined as the time from first response to 
progression or last follow-up, progression free survival (PFS), defined as the time from treatment 
start to progression, death or last follow-up, whichever comes first, overall survival (OS), 
defined as time from treatment start to death or last follow-up, MRD negativity, determined by 
4-color flow cytometry with a sensitivity of 10-4 and a complete response in the bone marrow at 
6 and 12 months, and the association FISH abnormalities, TP53, NOTCH1, or SF3B1mutations, 
and IGHV mutational status with ORR and CR rate. 
ORR (defined as proportion of patients who achieve a complete and partial response) will be 
estimated along with a 95% confidence interval, and rate of best response and MRD will be 
calculated. For patients who respond to treatment (complete or partial response), duration of 
response will be calculated from the date of response to the date of progression of disease.  
Patients still responding at date of last follow-up will be censored. PFS will be calculated as the 
time from start of treatment to the date of progression, death or last follow-up. OS will be 
calculated as the time from the start of treatment to the date of death or last follow-up. OS, PFS 
and DOR will be calculated using Kaplan-Meier methodology. The rate of MRD negativity and 
pathologic CR/CRi will be estimated along with a 95% confidence interval. The association 
between baseline characteristics (such as FISH abnormalities, TP53, NOTCH1, or 
SF3B1mutations, and IGHV mutational status) and response will be assessed using Fishers exact 
test.
Exploratory endpoints: 
Associations between the change in mitochondrial priming at baseline as compared to at the time 
of duvelisib monotherapy and between baseline and combination therapy and ORR will be 
assessed using Wilcoxon rank test. Associations between change in the percentage of 
cytochrome c release in response to the Bad, HRK and MS-1 peptides and ORR will be assessed 
using the Wilcoxon rank test. We will determine whether the percentage of regulatory T-cells, 
NK cells or monocytes at the start of therapy, after one week of duvelisib monotherapy, and after 
three months of combination therapy correlates with ORR, CR rate or toxicity using the 
Wilcoxon rank test. 
The average change in lymph node diameter measured on day 1 and day 8 will be measured on 
physical exam and recorded in the medical record. 

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We will also measure the change in total score using the quality of life (QoL) questionnaire in 
appendix F. 
13.4
Reporting and Exclusions
Participants who never start combination therapy will be excluded from analysis in both the 
phase I and phase II study 
13.4.1 Evaluation of Toxicity
All participants who receive at least one dose of combination therapy (duvelisib and venetoclax) 
will be evaluable for toxicity from the time of their first treatment.
14. PUBLICATION PLAN
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study. 

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

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APPENDIX B: CAIRO BISHOP DEFINITIONS OF LABORATORY AND CLINICAL 
TUMOR LYSIS SYNDROME 

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APPENDIX C:  MANAGEMENT OF TUMOR LYSIS SYNDROME

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APPENDIX D: LIST OF EXCLUDED OR CAUTIONARY MEDICATIONS: 

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APPENDIX E: PATIENT WALLET CARD 
INFORMATION ON POSSIBLE DRUG INTERACTIONS 
You are enrolled on a clinical trial using the experimental agent 
__________________.  This clinical trial is sponsored by the NCI.  
__________________ interacts with drugs that are processed by your 
liver.  Because of this, it is very important to:
Tell your doctors if you stop taking regular medicine or if you start 
taking a new medicine.
Tell all of your prescribers (doctor, physicians assistant, nurse 
practitioner, and pharmacist) that you are taking part in a clinical 
trial.
Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement.
__________________ interacts with a specific liver enzyme called 
CYP______, and must be used very carefully with other medicines 
that interact with this enzyme. 
Before you start the study, your study doctor will work with your 
regular prescriber to switch any medicines that are considered 
strong inducers/inhibitors or substrates of CYP______.
Before prescribing new medicines, your regular prescribers should 
go to http://medicine.iupui.edu/clinpharm/ddis/table.aspx for a 
list of drugs to avoid, or contact your study doctor.  
Your study doctors name is _____________________________ 
and can be contacted at _________________________________. 

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APPENDIX F: DRUG DIARY
PATIENT INSTRUCTIONS: Take your medications exactly as prescribed by your doctor. See the next page 
for specific doses for each medication that you are taking. Both duvelisib and venetoclax should be kept in the 
provided bottles. You can take the medications in any order. Store drugs at room temperature.
Duvelisib:
 Unless otherwise instructed by our study physician, duvelisib should be taken by mouth twice per day, once in 
the morning and once in the evening. Duvelisib can be taken with or without food.
 Do not split or crush tablets or empty into any food or drink for oral ingestion. Tablets must be swallowed 
whole.
 If you vomit after taking duvelisib, do NOT take another dose. Please note any vomiting in the Comments 
section of the diary on the next page.
 Do not consume grapefruit, grapefruit juice or Seville oranges while taking duvelisib. Do not take fish oil or 
vitamin E supplements. Consult your doctor before making any changes to medications or supplements.
 If a dose is missed and it is less than 4 hours from usual time of dosing, then you may take that dose. 
Otherwise that dose should be skipped and NOT taken. You should resume regular dosing for the next planned 
dose. If you miss a dose record 0 for Number Taken on the next page.
 If you accidentally take an extra dose during a day, hold the next planned dose and resume normal dosing for 
the following dose.
 Please bring any unused duvelisib tablets, all empty duvelisib containers and diary to your next visit.
Venetoclax:
 Venetoclax should be taken by mouth once per day, preferably in the morning. Venetoclax should be taken 
with food, preferably within 30 minutes of a meal and with a full glass of water (approximately 8 oz). 
 Do not consume grapefruit, grapefruit juice or Seville oranges while taking venetoclax. Do not take fish oil or 
vitamin E supplements. Consult your doctor before making any changes to medications or supplements.
 If a dose is missed and it is less than 8 hours from the usual time of dosing, then you may take that dose. 
Otherwise that dose should be skipped and NOT taken. You should resume regular dosing the following day. If 
you miss a dose record 0 for Number Taken on the next page.
 If you vomit drug, please record this in diary as a missed dose and do not take another dose of drug that day.
FOR CLINIC USE ONLY
Give patient all 2 pages of Drug Diary stapled together.
Provide one diary per cycle (28 days).
 Complete patient identifiers and medical team contact
information on page 2.
 Complete correct dose levels for venetoclax on page 2.
 When patient returns pill bottles and diary perform a 
duvelisib and venetoclax pill count and record adherence 
information in the box to the right

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DFCI Trial 18-089 Duvelisib + Venetoclax for CLL or Richters Syndrome
SELF-ADMINISTERED DIARY
Participant Identifier: ____________  Cycle #: __________
Your MD:____________       Phone: ___________
Your RN:_____________      Phone: ___________
Duvelisib AM
Duvelisib PM
Venetoclax 
Comments
Date
Number
Taken
Time 
Taken
Number 
Taken
Time 
Taken
Number 
Taken
Time 
Taken
Example
9/12/17
1
8:00 
AM
1
8:00 
PM
1
8:00 
AM
With 
breakfast
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 11
Day12
Day 13
Day 14
Day 15
Day 16
Day 17
Day 18
Day 19
Day 20
Day 21
Day 22
Day 23
Day 24
Day 25
Day 26
Day 27
Day 28

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DFCI Trial 18-089 Duvelisib + Venetoclax for CLL or Richters Syndrome
SELF-ADMINISTERED DIARY  CYCLE 1 ONLY
Participant Identifier:____________  
Cycle #: ___1______
Your MD:_____________
Phone: ___________
Your RN: _____________
Phone: ____________
Duvelisib AM
Duvelisib PM
Venetoclax 
Comments
Date
Number
Taken
Time 
Taken
Number 
Taken
Time 
Taken
Number 
Taken
Time 
Taken
Example
9/12/17
1
8:00 
AM
1
8:00 
PM
1
8:00 
AM
With 
breakfast
Day 29
Day 30
Day 31
Day 32
Day 33
Day 34
Day 35
Day 36
Day 37
Day 38
Day 39
Day 40
Day 41
Day 42
Day 43
Day 44
Day 45
Day 46
Day 47
Day 48
Day 49

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APPENDIX G: QUALITY OF LIFE QUESTIONNAIRE 
Participant Identifier: __________________________
Visit:   C1D1____        
C1D8____
Please answer the following questions about your lymph nodes. If you answer Yes to any question, please 
circle the number on the scale that best describes the severity (1=none at all, 10=severe).
1. Do your lymph nodes cause pain? Y__ N__
0 (none)_1_2_3_4_5_6_7_8_9_10 (severe)
2. Do your lymph nodes cause you embarrassment? Y__ N__
0 (none)_1_2_3_4_5_6_7_8_9_10 (severe)
3. Do your lymph nodes affect how your clothes fit? Y__ N __
0 (none)_1_2_3_4_5_6_7_8_9_10 (severe)
4. Do your lymph nodes cause discomfort when you swallow? Y__ N__
0 (none)_1_2_3_4_5_6_7_8_9_10 (severe)
5. Do your lymph nodes cause you to feel full early when eating? Y__ N__
0 (none)_1_2_3_4_5_6_7_8_9_10 (severe)
6. Do your lymph nodes prevent you from doing activities that you normally enjoy? Y__ N__
0 (none)_1_2_3_4_5_6_7_8_9_10 (severe)
7. Do your lymph nodes affect your sleep? Y__ N__
0 (none)_1_2_3_4_5_6_7_8_9_10 (severe)
Signature: _________________________________
Date: _______________

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APPENDIX H: GRADING SCALE FOR HEMATOLOGIC TOXICITY IN CLL 
STUDIES
1. Hallek, M et. al. Guidelines for diagnosis and treatment, of chronic lymphocitic leukemia: a 
report from the international Workshop on Chronic Lymphocytic Leukemia updating the 
National Cancer Institute- Working Group 1006 guidelines. Blood, 2008 2008;111:5446-5456. 
DOI 10.1182/blood-2007-06-093906.

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APPENDIX I: DF/HCC MULTICENTER DATA SAFETY AND MONITORING PLAN
  
    DFCI IRB Protocol #:18-089
Dana-Farber/Harvard Cancer Center
Multi-Center Data and Safety Monitoring Plan

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TABLE OF CONTENTS
SCHEMA.........................................................................................................................................2
1.
OBJECTIVES....................................................................................................................15
1.1
Study Design..........................................................................................................15
1.2
Primary Objectives.................................................................................................15
1.3
Secondary Objectives.............................................................................................16
2.
BACKGROUND: ..............................................................................................................17
2.1
Chronic Lymphocytic Leukemia ...........................................................................17
2.2
Richters Syndrome ...............................................................................................17
2.3
Venetoclax .............................................................................................................18
2.4
Duvelisib................................................................................................................20
2.5
Rationale for Duvelisib and Venetoclax Combination Therapy............................21
2.6
Rationale for inclusion of Richters Syndrome patients........................................22
2.7
Correlative Studies Background ............................................................................23
3.
PARTICIPANT SELECTION...........................................................................................24
3.1
Eligibility Criteria..................................................................................................24
3.2
Exclusion Criteria ..................................................................................................26
3.3
Inclusion of Women and Minorities ......................................................................28
4.
REGISTRATION  PROCEDURES ..................................................................................29
4.1
General Guidelines for DF/HCC Institutions ........................................................29
4.2
Registration Process for DF/HCC Institutions.......................................................29
4.3
General Guidelines for Other Investigative Sites ..................................................29
4.4
Registration Process for Other Investigative Sites.................................................29
5.
TREATMENT PLAN........................................................................................................31
5.1
Treatment Regimen................................................................................................34
5.2
Pre-Treatment Criteria ...........................................................................................38
5.3
Definition of Dose-Limiting Toxicity (DLT) ........................................................39
5.4
General Concomitant Medication and Supportive Care Guidelines......................40
5.5
Criteria for Taking a Participant Off Protocol Therapy.........................................42
5.6
Duration of Follow Up and Active Disease Monitoring........................................44
5.7
Resuming Treatment after Discontinuation...........................................................45

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5.8
Criteria for Taking a Participant Off Study (No longer being followed for Survival).
46
6.
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................47
6.1
Duvelisib:...............................................................................................................47
6.2
Venetoclax: ............................................................................................................50
7.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................53
7.1
Definitions: ............................................................................................................53
7.2
Serious Adverse Event:..........................................................................................54
7.3
Adverse Event List for Venetoclax:.......................................................................54
7.4
Adverse Event List for Duvelisib: .........................................................................57
7.5
Expedited Adverse Event Reporting......................................................................59
7.6
Reporting to the Food and Drug Administration (FDA) .......................................61
7.7
Routine Adverse Event Reporting .........................................................................61
7.8 Expedited Reporting to Hospital Risk Management ...................................................61
8.
PHARMACEUTICAL INFORMATION..........................................................................61
8.1
Duvelisib................................................................................................................61
8.2
Venetoclax .............................................................................................................64
9.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................67
9.1
BH3 Profiling:........................................................................................................67
9.2
Cytometry by Time of Flight (CyTOF):................................................................68
9.3
Minimal Residual Disease (MRD): .......................................................................68
9.4
Exome sequencing of tumor cells..........................................................................70
9.5
Pharmacokinetic (PK) Testing (Phase I) : .............................................................71
9.6
Jennifer Brown Lab Sample Collection and Shipping Instructions.......................72
10.
STUDY CALENDAR .......................................................................................................74
11.
MEASUREMENT OF EFFECT .......................................................................................81
11.1
Definitions: ............................................................................................................81
11.2
Methods for Evaluation of Measurable Disease:...................................................81
11.3
Response Criteria...................................................................................................82
12.
DATA REPORTING / REGULATORY REQUIREMENTS...........................................89
12.1
Data Reporting.......................................................................................................89
12.2
Data Safety Monitoring..........................................................................................89
12.3
Multicenter Guidelines: .........................................................................................90
12.4
Collaborative Agreements Language: N/A............................................................90
13.
STATISTICAL CONSIDERATIONS...............................................................................91
13.1
Study Design/Endpoints ........................................................................................91
13.2
Sample Size, Accrual Rate and Study Duration ....................................................94
13.3
Analysis of Secondary Endpoints..........................................................................94

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13.4
Reporting and Exclusions ......................................................................................96
14.
PUBLICATION PLAN .....................................................................................................96
APPENDIX A: PERFORMANCE STATUS CRITERIA...........................................................101
APPENDIX B: CAIRO BISHOP DEFINITIONS OF LABORATORY AND CLINICAL TUMOR LYSIS 
SYNDROME...................................................................................................................102
APPENDIX C:  MANAGEMENT OF TUMOR LYSIS SYNDROME.....................................103
APPENDIX D: LIST OF EXCLUDED OR CAUTIONARY MEDICATIONS:.......................105
APPENDIX E: PATIENT WALLET CARD..............................................................................106
APPENDIX F: DRUG DIARY ...................................................................................................107
Appendix G: Quality of Life Questionnaire ................................................................................110
APPENDIX H: Grading scale for hematologic toxicity in CLL studies .....................................111
APPENDIX I: DF/HCC Multicenter Data Safety and Monitoring PLan....................................112
15.
INTRODUCTION ...........................................................................................................116
15.1
Purpose.................................................................................................................116
15.2
Multi-Center Data and Safety Monitoring Plan Definitions................................116
16.
GENERAL ROLES AND RESPONSIBILITIES ...........................................................117
16.1
DF/HCC Sponsor.................................................................................................117
16.2
Coordinating Center.............................................................................................118
16.3
Participating Institution........................................................................................119
17.
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS ...........................119
17.1
Protocol Distribution............................................................................................119
17.2
Protocol Revisions and Closures .........................................................................119
17.3
Informed Consent Requirements .........................................................................120
17.4
IRB Documentation .............................................................................................120
17.5
IRB Re-Approval.................................................................................................121
17.6
Participant Confidentiality and Authorization Statement....................................121
17.7
DF/HCC Multi-Center Protocol Registration Policy...........................................121
17.8
DF/HCC Protocol Case Number..........................................................................122
17.9
Safety Assessments and Toxicity Monitoring .....................................................123
17.10 Data Management................................................................................................124
18.
REQUISITIONING INVESTIGATIONAL DRUG........................................................125

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19.
MONITORING: QUALITY CONTROL........................................................................125
19.1
Ongoing Monitoring of Protocol Compliance.....................................................125
19.2
Monitoring Reports..............................................................................................126
19.3
Accrual Monitoring..............................................................................................126
20.
AUDITING: QUALITY ASSURANCE .........................................................................126
20.1
DF/HCC Internal Audits......................................................................................126
20.2
Audit Notifications...............................................................................................126
20.3
Audit Reports.......................................................................................................126
20.4
Participating Institution Performance ..................................................................127
15. INTRODUCTION
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan (DF/HCC DSMP) 
outlines the procedures for conducting a DF/HCC Multi-Center research protocol. The DF/HCC DSMP 
serves as a reference for any sites external to DF/HCC that are participating in a DF/HCC clinical trial. 
15.1
Purpose
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi-Center protocol 
will comply with Federal Regulations, Health Insurance Portability and Accountability Act (HIPAA) 
requirements and applicable DF/HCC Standard Operating Procedures.
 
15.2
Multi-Center Data and Safety Monitoring Plan Definitions
DF/HCC Multi-Center Protocol:  A research protocol in which one  or more outside institutions are 
collaborating with Dana-Farber/Harvard Cancer Center where  a DF/HCC investigator is the sponsor. 
DF/HCC includes Dana-Farber/Partners Cancer Care (DF/PCC) Network Clinical Trial Affiliates. 
Lead Institution:  One of the Dana-Farber/Harvard Cancer Center consortium members (Dana-Farber 
Cancer Institute (DFCI), Massachusetts General Hospital (MGH), Beth Israel Deaconess Medical Center 
(BIDMC), Boston Childrens Hospital (BCH), Brigham and Womens Hospital (BWH) responsible for the 
coordination, development, submission, and approval of a protocol as well as its subsequent amendments 
per the DFCI IRB and applicable regulatory guidelines (CTEP, Food and Drug Administration (FDA), 
Office of Biotechnology Activities (OBA) etc.).  The Lead Institution is typically the home of the DF/HCC 

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Sponsor. The Lead Institution also typically serves as the Coordinating Center for the DF/HCC Multi-
Center Protocol.  
DF/HCC Sponsor:  The person sponsoring the submitted Multi-Center protocol who takes responsibility 
for initiation, management and conduct of the protocol at all research locations. In applicable protocols, 
the DF/HCC Sponsor will serve as the single liaison with any regulatory agencies (i.e. FDA). The DF/HCC 
Sponsor has ultimate authority over the protocol and is responsible for the conduct of the study at DF/HCC 
and all Participating Institutions. In most cases the DF/HCC Sponsor is the same person as the DF/HCC 
Overall Principal Investigator; however, both roles can be filled by two different people. 
Participating Institution:  An institution that is outside the DF/HCC and DF/PCC consortium that is 
collaborating with DF/HCC on a protocol where the sponsor is a DF/HCC Investigator.  The Participating 
Institution acknowledges the DF/HCC Sponsor as having the ultimate authority and responsibility for the 
overall conduct of the study.   
Coordinating Center: The entity (i.e. Lead Institution, Medical Monitor, Contract Research Organization 
(CRO), etc) that provides administrative support to the DF/HCC Sponsor in order that he/she may fulfill 
the responsibilities outlined in the protocol document and DSMP, and as specified in applicable regulatory 
guidelines (i.e. CTEP Multi-Center Guidelines). In general, the Lead Institution is the Coordinating Center 
for the DF/HCC Multi-Center Protocol. 
DF/HCC Office of Data Quality (ODQ): A group within DF/HCC responsible ensuring high-quality 
standards are used for data collection and the ongoing management of clinical trials, auditing, and data and 
safety monitoring. ODQ also coordinates quality assurance efforts related to multi-center clinical research.
DF/HCC Research Informatics for Operations (RIO): A group within DF/HCC responsible for 
providing a comprehensive data management platform for managing clinical trial data.
16. GENERAL ROLES AND RESPONSIBILITIES
For DF/HCC Multi-Center Protocols, the DF/HCC Sponsor, the Coordinating Center, and the Participating 
Institutions are expected to adhere to the following general responsibilities: 
16.1
DF/HCC Sponsor
The DF/HCC Sponsor, Matthew Davids, MD will accept responsibility for all aspects of conducting a 
DF/HCC Multi-Center protocol which includes but is not limited to: 

Oversee the coordination, development, submission, and approval of the protocol as well as 
subsequent amendments. 

Ensure that the investigators, study team members, and Participating Institutions are qualified and 
appropriately resourced to conduct the protocol.  

Include the Multi-Center Data and Safety Monitoring Plan as an appendix to the protocol.

Ensure all Participating Institutions are using the correct version of the protocol.

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
Ensure that each participating investigator and study team member receives adequate protocol 
training (and/or a Site Initiation Visit prior to enrolling participants) and throughout trials conduct 
as needed.

Ensure the protocol will be provided to each participating site in a language understandable to all 
applicable site personnel when English is not the primary language. 

Monitor progress and overall conduct of the study at all Participating Institutions. 

Ensure all DFCI Institutional Review Board (IRB), DF/HCC and other applicable (i.e. FDA) 
reporting requirements are met. 

Review data and maintain timely submission of data for study analysis. 

Act as the single liaison with the FDA 

Ensure compliance with all requirements as set forth in the Code of Federal Regulations, applicable 
DF/HCC requirements, HIPAA requirements, and the approved protocol.

Commit to the provision that the protocol will not be rewritten or modified by anyone other than 
the DF/HCC Sponsor.

Identify and qualify Participating Institutions and obtain accrual commitments prior to extending 
the protocol to that site.

Monitor accrual and address Participating Institutions that are not meeting their accrual 
requirements. 
16.2
Coordinating Center 
The general responsibilities of the Coordinating Center may include but are not limited to:

Assist in protocol development. 

Maintain FDA correspondence, as applicable.

Review registration materials for eligibility and register participants from Participating 
Institutions in the DF/HCC clinical trial management system (CTMS).

Distribute protocol and informed consent document updates to Participating Institutions as needed.

Oversee the data collection process from Participating Institutions.

Maintain documentation of Serious Adverse Event (SAE) reports and deviations/violation 
submitted by Participating Institutions and provide to the DF/HCC Sponsor for timely review and 
submission to the DFCI IRB, as necessary. 

Distribute serious adverse events reported to the DF/HCC Sponsor that fall under the DFCI IRB 
Adverse Event Reporting pPolicy to all Participating Institutions.

Provide Participating Institutions with information regarding DF/HCC requirements that they will 
be expected to comply with.

Carry out plan to monitor Participating Institutions either by on-site or remote monitoring. 

Maintain Regulatory documents of all Participating Institutions which includes but is not limited 
to the following: local IRB approvals/notifications from all Participating Institutions, 
confirmation of Federalwide Assurances (FWAs) for all sites,  all SAE submissions, Screening 
Logs for all sites, IRB approved consents for all sites

Conduct regular communications with all Participating Institutions (conference calls, emails, etc) 
and maintain documentation all relevant communications.

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16.3
Participating Institution
Each Participating Institution is expected to comply with all applicable federal regulations and DF/HCC 
requirements, the protocol and HIPAA requirements. 
The general responsibilities for each Participating Institution may include but are not limited to:

Document the delegation of research specific activities to study personnel.

Commit to the accrual of participants to the protocol.

Submit protocol and/or amendments to their local IRB of record.

Maintain regulatory files as per sponsor requirements.

Provide the Coordinating Center with regulatory documents or source documents as requested.

Participate in protocol training prior to enrolling participants and throughout the trial as required 
(i.e. teleconferences).

Update Coordinating Center with research staff changes on a timely basis.

Register participants through the Coordinating Center prior to beginning research related activities. 

Submit Serious Adverse Event (SAE) reports to local IRB per institutional requirements and to the 
Coordinating Center, in accordance with DF/HCC requirements. 

Submit protocol deviations and violations to local IRB per institutional requirements and to the 
DF/HCC Sponsor in accordance with DF/HCC requirements.

Order, store and dispense investigational agents and/or other protocol mandated drugs per federal 
guidelines and protocol requirements.

Have office space, office equipment, and internet access that meet HIPAA standards.

Participate in any quality assurance activities and meet with monitors or auditors at the conclusion 
of a visit to review findings.

Promptly provide follow-up and/or corrective action plans for any monitoring queries or audit 
findings.
17. DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS
The following section will clarify DF/HCC Requirements and further detail the expectations for participating 
in a DF/HCC Multi-Center protocol. 
17.1
Protocol Distribution
The Coordinating Center will distribute the final DFCI IRB approved protocol and any subsequent 
amended protocols to all Participating Institutions.   
17.2
Protocol Revisions and Closures
The Participating Institutions will receive notification of protocol revisions and closures from the 
Coordinating Center.  It is the individual Participating Institutions responsibility to notify its IRB of these 
revisions.

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
Non life-threatening revisions: Participating Institutions will receive written notification of 
protocol revisions regarding non life-threatening events from the Coordinating Center. Non-life-
threatening protocol revisions must be IRB approved and implemented within 90 days from receipt 
of the notification. 

Revisions for life-threatening causes: Participating Institutions will receive immediate 
notification from the Coordinating Center concerning protocol revisions required to protect lives 
with follow-up by fax, mail, e-mail, etc.  Life-threatening protocol revisions will be implemented 
immediately followed by IRB request for approval.

Protocol closures and temporary holds: Participating Institutions will receive notification of 
protocol closures and temporary holds from the Coordinating Center. Closures and holds will be 
effective immediately.  In addition, the Coordinating Center, will update the Participating 
Institutions on an ongoing basis about protocol accrual data so that they will be aware of imminent 
protocol closures.
17.3
Informed Consent Requirements
The DF/HCC approved informed consent document will serve as a template for the informed consent for 
Participating Institutions. The Participating Institution consent form must follow the consent template as 
closely as possible and should adhere to specifications outlined in the DF/HCC Guidance Document on 
Model Consent Language for Investigator-Sponsored Multi-Center Trials.  This document will be provided 
separately to each Participating Institution upon request.
Participating Institutions are to send their version of the informed consent document and HIPAA 
authorization, if a separate document, to the Coordinating Center for review and approval prior to 
submission to their local IRB. The approved consent form must also be submitted to the Coordinating 
Center after approval by the local IRB for all consent versions.
The Principal Investigator (PI) at each Participating Institution will identify the physician members of the 
study team who will be obtaining consent and signing the consent form for therapeutic protocols. 
Participating institutions must follow the DF/HCC requirement that for all interventional drug, biologic, or 
device research, only attending physicians may obtain initial informed consent and any re-consent that 
requires a full revised consent form.  
17.4
IRB Documentation
The following must be on file with the Coordinating Center:

Initial approval letter of the Participating Institution's IRB. 

Copy of the Informed Consent Form(s) approved by the Participating Institutions IRB. 

Participating Institutions IRB approval for all amendments.

Annual approval letters by the Participating Institution's IRB.

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17.5
IRB Re-Approval
Verification of IRB re-approval from the Participating Institutions is required in order to continue research 
activities.  There is no grace period for continuing approvals.
The Coordinating Center will not register participants if a re-approval letter is not received from the 
Participating Institution on or before the anniversary of the previous approval date.  
17.6
Participant Confidentiality and Authorization Statement
In 1996, congress passed the first federal law covering the privacy of health information known as the 
Health Insurance Portability and Accountability Act (HIPPA). Any information, related to the physical or 
mental health of an individual is called Protected Health Information (PHI). HIPAA outlines how and under 
what circumstances PHI can be used or disclosed. 
In order for covered entities to use or disclose protected health information during the course of a study, 
the study participant must sign an authorization statement.  This authorization statement may or may not 
be separate from the informed consent document.  The Coordinating Center, with the approval from the 
DFCI IRB, will provide a consent template, with information regarding authorization for the disclosure of 
protected health information. 
The DF/HCC Sponsor will use all efforts to limit its use of protected health information in its trials. 
However, because of the nature of these trials, certain protected health information must be collected. 
DF/HCC has chosen to use authorizations, signed by the participant in the trial, rather than limited data 
sets with data use agreements.
17.6.1  DF/HCC Multi-Center Protocol Confidentiality
All documents, investigative reports, or information relating to the participant are strictly confidential. 
Whenever reasonably feasible, any participant specific reports (i.e. Pathology Reports, MRI Reports, 
Operative Reports, etc.) submitted to the Coordinating Center should be de-identified. It is recommended 
that the assigned protocol case number (as described below) be used for all participant specific documents. 
Participant initials may be included or retained for cross verification of identification. 
17.7
DF/HCC Multi-Center Protocol Registration Policy
17.7.1  Participant Registration and Randomization 
To register a participant, the following documents should be completed by the Participating Institution 
and faxed or e-mailed to the Coordinating Center lead project manager

Copy of required laboratory tests and documents that support all aspects of the eligibility checklist 

Signed informed consent document

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
HIPAA authorization form (if separate from the informed consent document)

Completed Eligibility Checklist 
The Coordinating Center will review the submitted documents in order to verify eligibility and consent. 
To complete the registration process, the Coordinating Center will:

Register the participant on the study with the DF/HCC Clinical Trial Management System (CTMS).

Upon receiving confirmation of registration, the Coordinating Center will inform the Participating 
Institution and provide the study specific participant case number, and, if applicable, assigned 
treatment and/or dose level. 
Treatment or other protocol-specific interventions may not begin without confirmation from 
the Coordinating Center that the participant has been registered. 
17.7.2  Initiation of Therapy
Participants must be registered with the DF/HCC CTMS before the initiation of treatment or other protocol-
specific interventions. Treatment and other protocol-specific interventions may not be initiated until the 
Participating Institution receives confirmation of the participants registration from the Coordinating 
Center. The DF/HCC Sponsor and DFCI IRB must be notified of any violations to this policy.
17.7.3  Eligibility Exceptions
No exceptions to the eligibility requirements for a protocol without DFCI IRB approval will be permitted. 
All Participating Institutions are required to fully comply with this requirement. The process for requesting 
an eligibility exception is defined below.
17.8
DF/HCC Protocol Case Number
At the time of registration, the following identifiers are required for all subjects: initials, date of birth, 
gender, race and ethnicity. Once eligibility has been established and the participant successfully registered, 
the participant is assigned a unique protocol case number.  Participating Institutions should submit all de-
identified subsequent communication and documents to the Coordinating Center, using this case number 
to identify the subject.  
17.8.1 Protocol Deviations, Exceptions and Violations
Federal Regulations require an IRB to review proposed changes in a research activity to ensure that 
researchers do not initiate changes in approved research without IRB review and approval, except when 
necessary to eliminate apparent immediate hazards to the participant. DF/HCC requires all departures 

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from the defined procedures set forth in the IRB approved protocol to be reported to the DF/HCC Sponsor, 
who in turn is responsible for reporting to the DFCI IRB.
For reporting purposes, DF/HCC uses the terms violation, deviation and exception to describe 
departures from a protocol. All Participating Institutions must adhere to these requirements for reporting 
to the DF/HCC Sponsor and will follow their institutional policy for reporting to their local IRB.
17.8.2  Definitions
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-approved protocol 
which is prospectively approved prior to its implementation.
Protocol Exception:  Any protocol deviation that relates to the eligibility criteria, e.g.
enrollment of a participant who does not meet all inclusion/exclusion criteria.
Protocol Violation: Any protocol departure that was not prospectively approved by the IRB prior to its 
initiation or implementation. 
17.8.3  Reporting Procedures
DF/HCC Sponsor: is responsible for ensuring that clear documentation is available in the medical record 
and/or regulatory documents to describe all protocol exceptions, deviations and violations. The DF/HCC 
Sponsor will also be responsible for ensuring that all protocol violations/deviations are promptly reported 
per DFCI IRB guidelines. 
Participating Institutions: Protocol deviations require prospective approval from the DFCI IRB. The 
Participating Institution must submit the deviation request to the Coordinating Center who will then submit 
the deviation request to the DFCI IRB. Upon DFCI IRB approval the deviation is submitted to the 
Participating Institution IRB, per institutional policy. A copy of the Participating Institutions IRB report 
and determination will be forwarded to the Coordinating Center within 10 business days after the original 
submission.  The deviation may not be implemented without all required approvals.
All protocol violations must be sent to the Coordinating Center in a timely manner. The Coordinating 
Center will provide training for the requirements for the reporting of violations. 
Coordinating Center:  Upon receipt of the violation/deviation report from the Participating Institution, the 
Coordinating Center will submit the report to the DF/HCC Sponsor for review. Subsequently, the 
Participating Institutions IRB violation/deviation report will be submitted to the DFCI IRB for review per 
DFCI IRB reporting guidelines. 
17.9
Safety Assessments and Toxicity Monitoring

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The study teams at all participating institutions are responsible for protecting the safety, rights and well-
being of study participants. Recording and reporting of adverse events that occur during the course of a 
study help ensure the continuing safety of study participants. 
All participants receiving investigational agents and/or other protocol mandated therapy will be evaluated 
for safety. The safety parameters include all laboratory tests and hematological abnormalities, physical 
examination findings, and spontaneous reports of adverse events reported by participants.  All toxicities 
encountered during the study will be evaluated according to the NCI criteria specified in the protocol. 
Life-threatening toxicities must be reported immediately to the DF/HCC Sponsor via the Coordinating 
Center. 
Additional safety assessments and toxicity monitoring will be outlined in the protocol.
17.9.1 Guidelines for Reporting Serious Adverse Events 
Guidelines for reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) are detailed in protocol 
section 7.
Participating Institutions must report the SAEs to the DF/HCC Sponsor/Coordinating Center following the 
DFCI IRB Adverse Event Reporting Policy of the IRB of record.
The Coordinating Center will maintain documentation of all Participating Institution Adverse Event reports 
and be responsible for communicating to all participating investigators, any observations reportable under 
the DFCI IRB Reporting Requirements.  Participating Institutions will review and submit to their IRB 
according to their institutional policies and procedures
17.9.2 Guidelines for Processing IND Safety Reports 
The DF/HCC Sponsor will review all IND Safety Reports and ensure that all IND Safety Reports are 
distributed to the Participating Institutions. Participating Institutions will review/submit to the IRB 
according to their institutional policies and procedures.
17.10 Data Management
DF/HCC RIO develops case report forms (CRF/eCRFs), for use with the protocol.  These forms are 
designed to collect data for each study. DF/HCC RIO provides a web based training for all eCRF users.
  
Data submissions are monitored for timeliness and completeness of submission. If study forms are received 
with missing or questionable data, the submitting institution will receive a written or electronic query from 
the DF/HCC Office of Data Quality, Coordinating Center, or designee. 

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Responses to all queries should be completed and submitted within 14 calendar days.  
Responses may be returned on the written query or on an amended paper case report form, or in the case 
of electronic queries, within the electronic data capture (eDC) system. In the case of a written query for 
data submitted on a paper case report form, the query must be attached to the specific data being re-
submitted in response.  
If study forms are not submitted on schedule, the Participating Institution will periodically receive a 
Missing Form Report from the Coordinating Center noting the missing forms. 
18. REQUISITIONING INVESTIGATIONAL DRUG
The ordering of investigational agent is specified in the protocol under investigational agent ordering.
19. MONITORING: QUALITY CONTROL
The quality control process for a clinical trial requires verification of protocol compliance and data 
accuracy. The Coordinating Center, with the aid of the DF/HCC Office of Data Quality, provides quality 
control oversight for the protocol.
19.1
Ongoing Monitoring of Protocol Compliance
The Participating Institutions may be required to submit participant source documents to the Coordinating 
Center for monitoring on a periodic basis. Participating Institution may also be subject to on-site monitoring 
conducted by the Coordinating Center. A study specific monitoring plan will be shared with your site 
during the site initiation visit. 
The Coordinating Center will implement ongoing monitoring activities to ensure that Participating 
Institutions are complying with regulatory and protocol requirements, data quality, and participant safety. 
Monitoring practices may include but are not limited to source data verification, and review and analysis 
of eligibility requirements, informed consent procedures, adverse events and all associated documentation, 
review of study drug administration/treatment, regulatory files, protocol departures reporting, pharmacy 
records, response assessments, and data management. 
Participating institutions will be required to participate in occasional (usually monthly) Coordinating 
Center initiated teleconferences. Minutes of these meetings should be kept and referenced when needed.  
At least one member of the study team should be able to join the teleconference each time one is held, and 
at minimum provide updates about the sites patients if they are unable to join. 
Participating Institutions will be required to forward de-identified copies of participants medical record 
and source documents to the Coordinating Center to aid in source data verification under special 
circumstances. 

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On-Site Monitoring will occur according to the study specific monitoring plan. Source documentation 
verification (SDV) will be conducted by having access to participants complete medical record and source 
documents. A letter outlining what will be reviewed will be sent prior to each visit. 
19.2
Monitoring Reports
The DF/HCC Sponsor will review all monitoring reports to ensure protocol compliance. The DF/HCC 
Sponsor may increase the monitoring activities at Participating Institutions that are unable to comply with 
the protocol, DF/HCC Sponsor requirements or federal and local regulations. 
19.3
Accrual Monitoring
Prior to extending a protocol to an external site, the DF/HCC Sponsor will establish accrual requirements 
for each participating institution. Accrual will be monitored for each participating institution by the 
DF/HCC Sponsor or designee. Sites that are not meeting their accrual expectations may be subject to 
termination.
The following minimum accrual requirements are recommended: 
1) Phase I: 2 per site/annually
2) Note: Diseases that are extremely rare may have accrual expectations of 0-1 accruals/year.
20. AUDITING: QUALITY ASSURANCE
Auditing is a method of Quality Assurance and involves the systematic and independent examination of all 
trial related activities and documents.  Audits determine if evaluated activities were appropriately 
conducted and whether data was generated, recorded and analyzed, and accurately reported per the 
protocol, applicable Policies, and the Code of Federal Regulations (CFR).
20.1
DF/HCC Internal Audits
 
All Participating Institutions are subject to audit by the DF/HCC Office of Data Quality (ODQ). Typically, 
approximately 3-4 participants would be audited at the site over a 2-day period. If violations which impact 
participant safety or the integrity of the study are found, more participant records may be audited. 
20.2
Audit Notifications
It is the Participating Institutions responsibility to notify the Coordinating Center of all external audits or 
inspections (e.g., FDA, EMA, NCI) that involve this protocol. All institutions will forward a copy of final 
audit and/or re-audit reports and corrective action plans (if applicable) to the Coordinating Center, within 
12 weeks after the audit date. 
20.3
Audit Reports 

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The DF/HCC Sponsor will review all final audit reports and corrective action plans, if applicable. The 
Coordinating Center, must forward any reports to the DF/HCC ODQ per DF/HCC policy for review by the 
DF/HCC Audit Committee. For unacceptable audits, the DF/HCC Audit Committee would forward the 
final audit report and corrective action plan to the DFCI IRB as applicable.
20.4
Participating Institution Performance
The DF/HCC Sponsor and the IRB of record are charged with considering the totality of an institutions 
performance in considering institutional participation in the protocol.
Participating Institutions that fail to meet the performance goals of accrual, submission of timely and accurate 
data, adherence to protocol requirements, and compliance with state and federal regulations, may be 
recommended for a six-month probation period. Such institutions must respond with a corrective action plan 
and must demonstrate during the probation period that deficiencies have been corrected, as evidenced by the 
improved performance measures. Participating Institutions that fail to demonstrate significant improvement will 
be considered by the DF/HCC Sponsor for revocation of participation. A DF/HCC Sponsor and/or the DFCI 
IRB may terminate a sites participation if it is determined that a site is not fulfilling its responsibilities as 
described above.