A Phase 1b/2 Study of IPI-145 in Combination With Fludarabine, Cyclophosphamide, and Rituximab (iFCR) in Previously Untreated, Younger Patients With Chronic Lymphocytic Leukemia.
Phase: PHASE1
Conditions: Chronic Lymphocytic Leukemia
Sponsor: Dana-Farber Cancer Institute

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Protocol Version Date:  03.28.2017 
 
NCI Protocol #:  N/A 
 
Local Protocol #:14-193   
 
 
Title: A Phase I/II Study of IPI-145 in Combination with Fludarabine, Cyclophosphamide, and 
Rituximab (iFCR) in Previously Untreated, Younger Patients with Chronic Lymphocytic 
Leukemia 
 
Principal Investigator: Matthew S. Davids, MD 
 
Coordinating Center:  Dana-Farber Cancer Institute 
 
Statistician: Haesook Kim, PhD 
 
Study Coordinator: N/A 
 
Responsible Research Nurse:  N/A 
 
Responsible Data Manager: N/A 
 
Agent(s):   
IPI-145 – Verastem, Needham, MA 
Fludarabine (commercial) 
Cyclophosphamide (commercial) 
Rituximab (commercial) 
 
 

 
 
 
 
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SYNOPSIS 
Study Title:  A Phase I/II Study of IPI-145 in Combination with Fludarabine, 
Cyclophosphamide, and Rituximab (iFCR) in Previously Untreated, Younger Patients with 
Chronic Lymphocytic Leukemia 
Study Overview:  An open-label, phase I/II study of IPI-145 in combination with fludarabine, 
cyclophosphamide, rituximab (iFCR) will be performed.  The phase I part is a standard 3+3 
design with three dose levels. Patients will start on day -7 with one week of IPI-145 
monotherapy, which will allow time for mobilization of CLL cells from lymph nodes and 
marrow and will also allow for collection of patient samples for correlative studies.  FCR will 
subsequently be introduced on day 1, and administered at standard dosing for 6 cycles, with dose 
reductions permitted.  Patients achieving either a PR or CR will be allowed to continue on IPI-
145 maintenance for up to 2 years after completing chemotherapy.  Conversion to MRD 
negativity and 2 year progression-free survival will be assessed for these patients.   
 
Primary Objectives 
• To assess the safety of IPI-145 in combination with FCR in previously untreated younger 
patients with CLL  
• To determine the rate of minimal residual disease negative complete response (MRD 
negative CR) in the bone marrow at 2 months post last cycle of FCR 
 
Secondary Objectives 
• To determine clinical response, including overall response rate, complete and partial 
response rates, progression-free survival, overall  survival, and duration of remission as 
determined by 2008 IW-CLL criteria 
• To assess rate of minimal residual disease (MRD) in the peripheral blood 
• To determine rates of treatment-related adverse effects 
• To determine the association of established CLL prognostic factors (e.g. FISH 
cytogenetics, IGHV status, ZAP70 status) with clinical response 
 
Exploratory Objectives: 
• To assess for an association of novel prognostic factors such as BH3 profiling with 
clinical response  
• To assess the change in pharmacodynamic markers such as p-AKT, p-ERK, and Ki-67 
• To evaluate genomic analyses for association of response with mutation status of SF3B1, 
TP53, NOTCH1, MYD88 and the BCR/NFKB pathway  
Schedule of Administration 
IPI-145 will be administered orally daily or twice daily during each 28-day cycle.  FCR will be 
given at standard dosing, with dose reductions permitted as per usual standards of care.  Patients 
will be evaluated for DLTs throughout the course of the study.  At the conclusion of 6 cycles of 
iFCR therapy, patients with a partial or complete response will be able to continue on to a 
maintenance phase of IPI-145 monotherapy for up to 2 years in the absence of progressive 
disease. 

 
 
 
 
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Dose Escalation  
Three doses of IPI-145 will be considered to determine MTD of IPI-145 in combination 
of FCR: 15 mg QD (dose level -1), 25 mg QD (dose level 1, starting dose), 25 mg bid 
(dose level 2). Dose limiting toxicities (DLTs) and the observation period are defined 
below and in section 5.3.  
A cohort of 3 patients will enter at a dose level, starting dose level 1. If no DLT is seen 
in the first 3 patients, then a dose escalation will take place. If 2 or more of the first 3 
patients experience DLT at dose level 1 or 2, then the next cohort of 3 patients will be 
treated at the next lower dose level, unless 6 patients have already been treated at that 
dose level. If 2 or more of the first 3 patients experience DLT at dose level -1, then the 
study will be terminated early. If 1 of the 3 patients at a dose level experiences a DLT, 
then 3 additional patients will be treated at that dose level. If there is no DLT in the 3 
additional patients then dose escalation will take place. If this is dose level 2 or -1, then 
this dose level will be the MTD. If 1 or more of the 3 additional patients experience(s) 
DLT then the MTD is considered to have been exceeded, and 3 more patients will be 
treated at the next lower dose, unless 6 patients have already been treated at that dose 
level. If this is does level -1, then the study will be terminated early. A minimum of six 
patients must be entered at the MTD, and fewer than 2 patients in 6 should experience 
DLT. If 0 in 6 patients experience DLT at dose level 2, this dose level will be the RP2D 
(recommended Phase II dose). 
Definition of Dose-Limiting Toxicity (DLT) 
Dose-limiting toxicities (DLTs) occurring during the first cycle of treatment will be used in 
determining the recommended phase II dose (R2PD).  DLTs that occur at any time on treatment 
will be evaluated with regard to the stopping rules as detailed in the protocol. 
A DLT will be defined as: 
 
• Any Grade 3 or greater hematologic toxicity with exceptions for Grade 3 or Grade 4 
neutropenia or thrombocytopenia that persists for ≤ 10 days off treatment. 
• ny Grade 3 or greater non-hematologic toxicity with the following exceptions: 
o Grade 3 or greater nausea/vomiting/diarrhea despite optimal supportive care that 
persists for 7 days or less 
o Grade 3 infusion reactions 
o Grade 3 asymptomatic laboratory abnormalities that improve to grade 2 or less within 
3 days 
• Inability to receive day 1 therapy of Cycle 2 even after a three week treatment delay due to 
continued drug related toxicity from the prior cycle. 
• All toxicities will be considered relevant to determining DLT and to reporting unless the 
event can clearly be determined to be unrelated to the study drug(s). 
• Any Grade 4 or greater elevation in ALT/AST. 
The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) 
Version 4.0 will be used to grade toxicities during the trial unless otherwise specified. 

 
 
 
 
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Study Drug 
IPI-145 is administered orally as a capsule formulation. The IPI-145 drug product is supplied as 
5 mg and 25 mg formulated capsules. 
Inclusion Criteria 
• Must have a confirmed diagnosis of CLL and an indication for treatment as per IW-CLL 
2008 criteria 
• No prior therapy for CLL due to the patient’s meeting IW-CLL 2008 criteria for treatment 
• Age greater than or equal to 18 years and less than or equal to 65 
• Life expectancy of greater than 6 months 
• ECOG performance status <1 (see Appendix A) 
• Women of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and for the 
duration of study participation 
• Ability to understand and the willingness to sign a written informed consent document 
 
Exclusion Criteria 
• Patients receiving any other study agents 
• Patients with known CNS involvement 
• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations limiting compliance with study requirements 
• Pregnant women are excluded from this study because IPI-145 is an agent with the 
potential for teratogenic or abortifacient effects 
• Individuals with a history of a different malignancy are ineligible except for the following 
circumstances:  disease-free for at least 2 years and deemed by the Principal Investigator to 
be at low risk for recurrence of that malignancy. Individuals with the following cancers are 
eligible if diagnosed and treated with curative intent within the past 5 years: cervical cancer 
in situ, localized prostate cancer, and skin cancer including basal cell, squamous cell 
carcinoma, or melanoma in situ 
• HIV-positive individuals 
• Inadequate hepatic function defined by aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) >2.5 x upper limit of normal (ULN); direct bilirubin >1.5 x ULN 
unless due to hemolysis or Gilbert’s syndrome. 
• Inadequate renal function defined by serum creatinine >1.5 x ULN 
• Baseline QTcF >480 ms. NOTE: This criterion does not apply to patients with a left bundle 
branch block. 
• Concurrent treatment with any agent known to prolong the QTc interval (see Appendix E). 
• Patients with a history of active tuberculosis within the preceding two years 
• Patients who have had a venous thromboembolic event (e.g., PE or DVT) requiring 
anticoagulation and who meet any of the following criteria: 
• Have been on a stable dose of anticoagulation for <1 month 
• Have had a Grade 2, 3 or 4 hemorrhage in the last 30 days 

 
 
 
 
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• Are experiencing continued symptoms from their venous thromboembolic event (e.g. 
continued dyspnea or oxygen requirement) 
NOTE: Patients who have had a venous thromboembolic event but do not meet any of the 
above three criteria are eligible for participation. 
• Patients with a history of alcohol abuse, chronic hepatitis, or other chronic liver disease 
(other than direct CLL liver involvement). 
• NOTE: Chronic hepatitis includes active infection with hepatitis B or C. All patients will 
be tested for hepatitis C virus antibodies (HCV Ab) and hepatitis B surface antigen 
(HBsAg) at screening. Patients with a positive result for HBsAg or HCV Ab will be 
excluded from enrolling in this study. 
• Concurrent administration of medications or foods that are strong inhibitors or inducers of 
CYP3A (see Appendix C). 
• Presence of active infection within 72 hours of treatment. 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 
• Significant co-morbid condition or disease which in the judgment of the Principal 
Investigator would place the patient at undue risk or interfere with the study 
• Unable to receive prophylactic treatment for pneumocystis 
Statistical Methodology 
 
Phase I 
A standard 3 + 3 dose escalation design with 3 dose levels is used in the phase I portion for 
assessing safety and determining the recommended dose for the phase II portion of this study of 
IPI-145 in combination of FCR in previously untreated CLL patients.  IPI-145 will be the only 
escalating drug, with FCR given at standard dosing. 
 
Phase II 
After RP2D is established in phase I, 20 additional patients will be enrolled in the phase II study 
and treated with IPI-145 at the RP2D + FCR so that a total of 26 patients will be treated at the 
RP2D.  The primary objective for the phase II portion of the study is to determine the rate of 
minimal residual disease negative complete response (MRD-negative CR) in the bone marrow at 
the re-staging evaluation 2 months after completing FCR chemotherapy.   
Study Design 
Phase I 
 
A standard 3+3 design with three doses of IPI-145.  
 
Phase II 
 
A single stage  study which consists of determining the MRD-negative CR rate in the bone 
marrow at 2 months post IPI-145 + FCR in previously untreated CLL patients.  An exact one 
sample binomial test is used to compute the sample size.  Twenty additional patients will be 
enrolled and analyzed in conjunction with the 6 patients from the phase I portion treated at the 

 
 
 
 
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MTD/RP2D for a total of 26 patients.  Twenty-six patients are needed in order to detect a 45% 
MRD-negative CR rate, assuming the MRD-negative CR rate for the null hypothesis is 20% 
(Boettcher et al., 2012) and 90% power and 6% one-sided type I error.  The null hypothesis will 
be rejected if 9 or more MRD-negative CRs are observed.  
 
Analysis of Secondary Endpoints 
 
Clinical response, including overall response rate, complete and partial response rates 
determined by IW-CLL criteria as well as rate of MRD negativity in the peripheral blood will be 
summarized as percentages and 90% CI will be calculated using exact binomial test.  The Kaplan 
Meier method will be used to summarize progression-free survival and overall survival 
descriptively.  Association of established CLL prognostic factors (e.g. FISH cytogenetics, IGHV 
status, ZAP70 status) and clinical response will be assessed using Fisher’s exact test for 
categorical variables and Wilcoxon’s rank sum test for continuous variables.  In addition, a 
correlation analysis between peripheral blood and bone marrow MRD negativity will be 
performed.  Toxicity will be reported descriptively. Association between clinical outcome and 
exploratory endpoints will be evaluated. Exploratory endpoints include BH3 profiling, change in 
pharmacodynamic markers such as p-AKT, p-ERK, and Ki-67, and genomic analysis with 
mutation status of SF3B1, TP53, NOTCH1, MYD88 and the BCR/NFKB pathway.   
 
Sample Size/Accrual Rate 
Planned Sample Size:  Minimum:  4,  Maximum:  32 
Estimated Monthly Accrual:  2-3 
Follow-up:  Patients completing 2 years of maintenance IPI-145 or those who do not go on to 
receive IPI-145 maintenance will be followed until initiation of new therapy, or death.  
 

iFCR in Previously Untreated, Younger Patients with CLL 
 
11.29.2015  
 
 
 
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SCHEMA 
 
Phase I 
 
If DLT in  
Then  
 
 
 
 
 
 
 
If DLT in Then 
 
0/3 
Escalate to the next dose  
-  
 
 
- 
level    
 
 
1/6 
Escalate to next dose level (or accrue 
20 additional if this is the MTD) 
1/3 
 
 
 
Add 3 
 
 
≥ 2/6  
 
 
De-escalate to previous dose level 
 
≥ 2/3  
 
 
MTD is the prior dose level 
 
 
 
 
 
 
 
 
 
 
 
 
Phase II 
 
Definitions 
    Treatment               Response        Treatment  
 Response 
 
 
 
CR - Complete Response 
 
             CR 
CR 
PR - Partial Response 
 
             PR                  3 Cycles iFCR 
  PR 
PD - Progressive Disease 
      3 Cycles iFCR          SD 
      
SD - Stable Disease 
  
FCR – Fludarabine, 
Cyclophosphamide, 
Rituximab 
                       P D           ( o f f s t ud y)  
   S D         ( o f f  s t ud y )  
   P D         
i – IPI-145 
 
 
  
 
Dose-Escalation Schedule 
1 cycle = 28 days (except cycle 1 [28 days plus 7 day lead in]) 
 
Dose Level 
Dose of IPI-145 
 
2 
25 mg BID 
Starting Dose → 
  1 
25 mg QD 
 
-1 
15 mg QD 
Up to 2 years 
IPI-145  
maintenance

iFCR in Previously Untreated, Younger Patients with CLL 
 
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TABLE OF CONTENTS 
 
1. 
OBJECTIVES .................................................................................................................................................... 1 
1.1 
Study Design ............................................................................................................................................................................ 1 
1.2 
Primary Objectives .................................................................................................................................................................. 1 
1.3 
Secondary Objectives .............................................................................................................................................................. 1 
1.4 
Exploratory Objectives ........................................................................................................................................................... 1 
2. 
BACKGROUND ................................................................................................................................................ 2 
2.1 
Study Disease ........................................................................................................................................................................... 2 
2.2 
Study Agents ............................................................................................................................................................................. 3 
2.3 
Rationale .................................................................................................................................................................................. 11 
2.4 
Correlative Studies Background .......................................................................................................................................... 12 
3. 
PARTICIPANT SELECTION ........................................................................................................................ 15 
3.1 
Inclusion Criteria  . ................................................................................................................................................................ 15 
3.2 
Exclusion Criteria ............................................................................................................................................................... 15 
3.3 
Inclusion of Women, Minorities and Other Underrepresented Populations ............................................................. 17 
4 
REGISTRATION PROCEDURES ................................................................................................................ 18 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions ....................................................................................... 18 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions .................................................................................. 18 
4.3 
General Guidelines for Other Participating Institutions ........................................................................................ 19 
4.4 
Registration Process for Other Participating Institutions ............................................................................................ 19 
5 
TREATMENT PLAN ...................................................................................................................................... 20 
5.1 
Pre-treatment Criteria ......................................................................................................................................................... 22 
5.2 
Agent Administration ......................................................................................................................................................... 22 
5.3 
Definition of Dose-Limiting Toxicity ................................................................................................................................ 24 
5.4 
General Concomitant Medication and Supportive Care Guidelines ...................................................................... 25 
5.5 
Duration of Therapy ........................................................................................................................................................... 28 
5.6 
Duration of Follow Up ....................................................................................................................................................... 28 
5.7 
Criteria for Removal from Study ..................................................................................................................................... 28 
6 
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS .................................... 29 
6.1 
Anticipated Toxicities ........................................................................................................................................................... 29 
6.2 
Dose Modifications/Delays................................................................................................................................................. 32 
6.3 
Stopping Rules ....................................................................................................................................................................... 34 
7 
DRUG FORMULATION AND ADMINISTRATION ................................................................................. 35 
7.1 
Fludarabine, Cyclophosphamide, Rituximab (FCR) ....................................................................................................... 35 

iFCR in Previously Untreated, Younger Patients with CLL 
 
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7.2 
IPI-145 .................................................................................................................................................................................... 38 
8 
CORRELATIVE/SPECIAL STUDIES .......................................................................................................... 41 
8.1 
Pharmacokinetic Studies ...................................................................................................................................................... 41 
8.2 
Pharmacodynamic Studies ................................................................................................................................................... 41 
9 
STUDY CALENDAR ...................................................................................................................................... 43 
9.1 
Pre-Treatment Evaluations .................................................................................................................................................. 43 
9.2 
Evaluations During Treatment .......................................................................................................................................... 44 
9.3 
Evaluations after Treatment ............................................................................................................................................... 44 
10 
MEASUREMENT OF EFFECT..................................................................................................................... 50 
10.1 
Definitions .............................................................................................................................................................................. 50 
10.2 
Methods for Evaluation of Measurable Disease .............................................................................................................. 50 
10.3 
Response Criteria ................................................................................................................................................................... 50 
10.4 
Response Review ................................................................................................................................................................... 53 
11 
ADVERSE EVENT REPORTING REQUIREMENTS ............................................................................... 53 
11.1 
Definitions .............................................................................................................................................................................. 53 
11.2 
Procedures for AE and SAE Recording and Reporting ................................................................................................. 54 
11.3 
Reporting Requirements....................................................................................................................................................... 55 
11.4 
Reporting to the Study Sponsor.......................................................................................................................................... 55 
11.5 
Reporting to Infinity ............................................................................................................................................................. 57 
11.6 
Reporting to the Institutional Review Board (IRB) ........................................................................................................ 57 
11.7 
Reporting to the Food and Drug Administration (FDA) .............................................................................................. 58 
11.8 
Reporting to the NIH Office of Biotechnology Activities (OBA) ............................................................................... 58 
11.9 
Reporting to the Institutional Biosafety Committee (IBC) ............................................................................................ 58 
11.10 
Reporting to Hospital Risk Management .......................................................................................................................... 58 
11.11 
Monitoring of Adverse Events and Period of Observation .......................................................................................... 58 
12 
DATA AND SAFETY MONITORING .......................................................................................................... 60 
12.1 
Data Reporting ....................................................................................................................................................................... 60 
12.2 
Safety Meetings ...................................................................................................................................................................... 60 
12.3 
Monitoring .............................................................................................................................................................................. 61 
13 
REGULATORY CONSIDERATIONS .......................................................................................................... 62 
13.1 
Protocol Review and Amendments.................................................................................................................................... 62 
13.2 
Informed Consent ................................................................................................................................................................. 62 
13.3 
Ethics and Good Clinical Practice (GCP) ......................................................................................................................... 62 
13.4 
Study Documentation ........................................................................................................................................................... 63 
13.5 
Records Retention ................................................................................................................................................................. 63 

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13.6 
Multi-center Guidelines ........................................................................................................................................................ 64 
13.7 
Cooperative Research and Development Agreement (CRADA)/Clinical Trials Agreement (CTA) ..................... 64 
14 
STATISTICAL CONSIDERATIONS ............................................................................................................ 65 
14.1 
Study Design/Endpoints ..................................................................................................................................................... 65 
14.2 
Toxicity Monitoring. ............................................................................................................................................................. 66 
14.3 
Sample Size/Accrual Rate .................................................................................................................................................... 67 
14.4 
Stratification Factors ............................................................................................................................................................. 67 
14.5 
Analysis of Secondary Endpoints ....................................................................................................................................... 67 
15 
PUBLICATION PLAN .................................................................................................................................... 68 
16 
REFERENCES ................................................................................................................................................. 68 
17 
APPENDICES .................................................................................................................................................. 71 

iFCR in Previously Untreated, Younger Patients with CLL 
 
 
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1. OBJECTIVES 
 
1.1 
Study Design 
An open-label, phase Ib/II study of IPI-145 in combination with fludarabine, cyclophosphamide, 
rituximab (iFCR) will be performed in previously untreated CLL patients age 65 or younger with 
good performance status.  The phase I part is a standard 3+3 design with three dose levels. 
Patients will start on day -7 with one week of IPI-145 monotherapy, which will allow time for 
mobilization of CLL cells from lymph nodes and marrow and will also allow for collection of 
patient samples for correlative studies.  FCR will subsequently be introduced on day 1, and 
administered at standard dosing for 6 cycles, with dose reductions permitted (see Section 6.2).  
Patients achieving either a PR or CR will be allowed to continue on IPI-145 maintenance for up 
to 2 years after completing chemotherapy.  Conversion to MRD negativity and 2 year 
progression-free survival will be assessed for these patients.   
 
1.2 
Primary Objectives 
 
• To assess the safety of IPI-145 in combination with FCR in previously untreated younger 
patients with CLL 
• To determine the rate of minimal residual disease negative complete response (MRD-
negative CR) in the bone marrow at 2 months post last cycle of FCR 
 
 
 
1.3 
Secondary Objectives 
 
• To determine clinical response, including overall response rate, complete and partial 
response rates, progression-free survival, event-free survival, and duration of remission 
as determined by 2008 IW-CLL criteria 
• To assess rate of minimal residual disease (MRD) in the peripheral blood 
• To determine rates of treatment-related adverse effects 
• To determine the association of established CLL prognostic factors (e.g. FISH 
cytogenetics, IGHV status, ZAP70 status) with clinical response 
 
 
1.4 
Exploratory Objectives 
 
• To evaluate the association of novel prognostic factors such as BH3 profiling and somatic 
mutations in SF3B1, NOTCH1, MYD88 and the BCR/NFKB with clinical response  
• To measure the change in pharmacodynamic markers such as p-AKT, p-ERK, and Ki-67 
during initial therapy 

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2. BACKGROUND 
 
2.1 
Study Disease 
 
Background 
Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western 
hemisphere, with about 16,000 new cases per year diagnosed in the U.S. alone.  Despite 
recent advances in treatment options, the disease remains incurable by conventional 
therapies.  This disease was initially treated with alkylating agents like chlorambucil, and 
increased complete remission rates and progression-free survival was later observed with the 
nucleoside analogue, fludarabine (Rai, et al., 2000).  Fludarabine-based combinations were 
then developed, demonstrating superior complete remission rates and progression-free survival 
with the addition of either cyclophosphamide and/or rituximab to fludarabine alone (O’Brien et 
al., 2001 and Byrd et al., 2005).  More recently, an overall survival benefit has been 
demonstrated for the inclusion of rituximab to fludarabine and cyclophosphamide (FCR) over 
fludarabine and cyclophosphamide alone (FC) in patients with previously untreated CLL 
(Hallek et al., 2010).  In that trial, FCR produced an OR rate of 90% with CR rate of 44% and 
a median PFS of nearly 5 years. 
 
Limitations of Current Therapy 
Because of these encouraging results, FCR has become the standard of care for previously 
untreated fit patients.  Despite the impressive overall response rates with FCR, only 20% 
of patients achieve minimal residual disease (MRD) negativity in the bone marrow at their 
final restaging (Boettcher et al., 2012), and it is unlikely that patients can achieve cure 
without first achieving MRD-negativity.   
Moreover, FCR has significant limitations.  For example, patients with high risk markers 
such as del(17p) have markedly inferior outcomes, with poor CR rate (5%) and 3-year 
progression-free (18%) and overall survival (38%).   Furthermore, patients in all risk 
groups receiving FCR inevitably relapse, with a median progression free survival (PFS) of 
about 4.5 years.  Younger patients with CLL typically exhaust conventional treatment 
options after a few years, and therefore improved treatment options for this patient 
population in particular are urgently needed. 
 
B Cell Receptor Pathway Inhibition 
Recently, it was recognized that the B cell receptor (BCR) pathway is a promising, novel 
target for the treatment of CLL.  Although not activated by somatic mutation, nonetheless 
the BCR pathway is constitutively active in CLL and further inducibly activated within 
microenvironmental niches.  Increasing evidence suggests that phosphatidylinositol 3-
kinase (PI3K) inhibitors can have a profound impact on modulating the CLL 
microenvironment.  For example, the delta-isoform specific PI3K inhibitor idelalisib 
(GS1101) was found in vitro to inhibit microenvironmental protection by releasing CLL 
cells from stroma, thereby leading to increased CLL cell susceptibility to cell death 
(Hoellenriegel et al, 2011).  These promising preclinical results of PI3K inhibition in CLL 
have translated into the clinic, where a phase I trial of idelalisib showed that 84% of CLL 

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3 
patients achieved a lymph node response (Furman et al., 2010).  Interestingly, the majority 
of patients had a greater than 50% increase in lymphocyte count from baseline, providing 
strong evidence of the ability of PI3K inhibition to cause decreased CLL cell adhesion 
from stroma in vivo, a phenomenon that has been named ‘lymphocyte redistribution’. 
 
Though promising, PI3K-δ specific inhibition has potential limitations.  For example, by 
targeting only the δ-isoform of PI3K, CLL cells could theoretically develop resistance 
through upregulation of other PI3K isoforms.  Furthermore, there is increasing interest in 
the protective role that the PI3K-γ isoform plays in T cells and other immune cells in the 
CLL microenvironment (Ciraolo, et al., 2011).  Therefore, exploring the use of a PI3K 
inhibitor with activity against both the δ and γ isoforms is appealing.   
 
IPI-145 
 
IPI-145 is a potent oral inhibitor of both PI3K-δ (Kd: 23 pM) and PI3K-γ (Kd: 243 pM).  
The drug has been well-tolerated in patients with relapsed or refractory CLL at doses up to 
75 mg bid, with the most common related AEs being respiratory and infectious events as 
well as cytopenias and ALT/AST elevations, neither of which were dose-related, and both 
of which were manageable by dose interruption or dose reduction.  As of 28 October 2013, 
47 subjects with relapsed/refractory CLL/SLL had available efficacy data (Flinn et al., 
2013).  Their median time on treatment was 5.5 months (range: 0.9 to 22.8 months).  
Subjects dosed at ≤25 mg BID (n=27) had been on study longer (median=7.6 months) 
compared to subjects dosed at 75 mg BID (n=20, median=3.6 months).  The investigator-
reported ORR [(CR + PR), as defined by the IWCLL/IWG] was 47% among the 47 
subjects with a response assessment, which included 1 CR, and 21 PR. 
 
2.2 
Study Agents 
 
2.2.1 Fludarabine, Cyclophosphamide, Rituximab (FCR) 
Fludarabine is an FDA-approved intravenous chemotherapy agent that forms the backbone of 
the FCR regimen.  Its mechanism of action is as a purine analogue, and it is 
dephosphorylated in plasma to its active metabolite, which is primarily excreted in the urine.  
Its safety profile is well-characterized and available on the package label.  Fludarabine will 
be dosed as per the standard of care dosing in the FCR regimen (Hallek et al., 2010). 
 
Cyclophosphamide is an FDA approved intravenous chemotherapy agent that when 
combined with fludarabine was found to have significantly higher efficacy than fludarabine 
alone (O’Brien et al., 2001).  Its mechanism of action is mainly as an alkylating agent, and it 
is hepatically metabolized to active metabolites that are primarily excreted renally.  Its safety 
profile is well-characterized and available on the package label.  Cyclophosphamide will be 
dosed as per the standard of care dosing in the FCR regimen. 
Rituximab is an FDA-approved chimeric anti-CD20 monoclonal antibody originally developed 
and approved for the treatment of low-grade non-Hodgkin’s lymphomas, in which it has high 
response rates as a single agent in the upfront and relapsed settings. Initial experience with 
single-agent rituximab at the standard approved dose of 375 mg/m2 weekly for 4 weeks in 

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4 
relapsed CLL was disappointing, with reported response rates between 7 and 35%; however, 
improved results in CLL have been seen with dose-intensification in both the relapsed setting 
and in upfront therapy, and in combination either with fludarabine, or fludarabine and 
cyclophosphamide (Hainsworth et al, 2003, Byrd et al., 2005, Hallek et al., 2010).  Rituximab 
is cleared by the reticuloendothelial system.  Its safety profile is well-characterized and 
available on the package label.  Rituximab will be dosed as per the standard of care dosing in 
the FCR regimen. 
2.2.2 IPI-145 
 
INTRODUCTION  
 
IPI-145 is a potent phosphoinositide-3-kinase (PI3K)-δ,γ inhibitor being developed by Infinity 
Pharmaceuticals, Inc. (Infinity) based in Cambridge, MA.  The PI3K-δ and PI3K-γ isoforms are 
necessary for adaptive and innate immunity, and are important mediators in inflammatory disorders 
and hematologic malignancies. Therefore, IPI-145 is being developed as an orally administered 
potential therapeutic in hematologic malignancy and inflammatory disease indications.  
 
BACKGROUND  
 
Functions of PI3K-δ and PI3K-γ  
There are four mammalian isoforms of class 1 PI3Ks: PI3K-α, β, δ (class 1a PI3Ks) and PI3K-γ (a 
class 1b PI3K) (reviewed in Davids et al., 2013). These PI3Ks catalyze the production of 
phosphatidylinositol (3,4,5)-trisphosphate (PIP3), leading to activation of the downstream effector 
pathways important for cellular survival, differentiation, and function.  PI3K-δ and P13K-γ are 
preferentially expressed in leukocytes, and are important in leukocyte function.  
 
PI3K-δ is activated by cellular receptors (e.g., receptor tyrosine kinases) through interaction with the 
SH2 domains of the PI3K regulatory subunit (p85), or through direct interaction with RAS.  
PI3K-γ is associated with G-protein coupled receptors (GPCRs), is responsible for the very rapid 
induction of PIP3 in response to GPCRs, and can be also activated by RAS downstream of other 
receptors. PIP3 produced by PI3K activates effector pathways downstream through interaction with 
pleckstrin homology (PH) domain containing enzymes (e.g., PDK-1 and AKT [PKB]).   It is clear 
that both PI3K-δ and PI3K-γ isoforms are also important for chemotaxis and cell migration. 
 
PI3K in Immune Cells 
 
PI3K-δ is important in B-cell function including development, activation, chemotaxis, migration, and 
homing to lymphoid tissue, and inhibitors of PI3K-δ block these functions.  In T-cells, PI3K-γ has 
demonstrated a role in receptor and cytokine signaling. PI3K-γ is important for T-cell function 
including proliferation, activation, and differentiation (Subramaniam et al., 2012).  PI3K-δ along 
with PI3K-γ, are important in the response to immune complexes and FCγRII signaling in 
neutrophils, including migration, and the neutrophil respiratory burst.  PI3K-γ is also critical for 
the migration and function of neutrophils, suggesting a role in tumor immunity and cancer 
progression (Randis et al., 2008). As such, PI3K-δ and PI3K-γ are important mediators of cancer 
pathogenesis. 
 
Non-Clinical Summary of IPI-145  

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Pharmacology of IPI-145  
In vitro enzymatic assays indicate that IPI-145 is a potent PI3K-δ,γ inhibitor and inhibits 
proliferation of stimulated human B and T lymphocytes in cell-based assays. Cellular analysis 
demonstrates IPI-145 inhibits the phosphorylation of downstream markers of PI3K activation, such 
as AKT and ribosomal S6, in a concentration-dependent manner. 
Summary of Absorption, Distribution, Metabolism, and Excretion (ADME) of IPI-145  
The single-dose pharmacokinetics of IPI-145 following oral (PO) and intravenous (IV) 
administration have been characterized in mouse, rats, dogs and monkeys.  
In general, the ADME studies demonstrated that IPI-145 was rapidly and extensively absorbed 
across the nonclinical species with bioavailability values ranging from 40 to 97%, with the 
exception of the mouse where the bioavailability was lower (7%). The half-life of IPI-145 was 5 
hours in monkeys, and less than or equal to 2 hours in the other nonclinical species. IPI-145 is a P-
gp substrate with the potential to inhibit the active transport of other P-gp substrates. Plasma 
protein binding of IPI-145 was high in human and across several nonclinical species, with the free 
fraction being concentration- and species-dependent. The oxidative metabolism of IPI-145 was 
primarily through CYP3A4 with potential minor involvement by CYP1A2, CYP2C8, and 
CYP2B6. In vitro, IPI-145 is an inhibitor of CYP3A4 and CYP2C8, and a weak inducer of 
CYP2B6 at high concentrations only.  
Summary of IPI-145 Toxicology  
IPI-145 has been assessed in a series of nonclinical studies which included safety pharmacology, 
genetic toxicology, and general toxicology studies with durations of treatment ranging from single-
dose administration in monkeys to 4 weeks of repeat-dose administration in rats and monkeys. The 
nonclinical safety assessment program was designed to support oral administration in healthy 
subjects as well as oncology patients.  The rat and monkey were selected for nonclinical safety 
assessment based on achievable exposure levels following oral administration, and the similarity of 
the in vitro metabolic profiles when compared to the human in vitro metabolic profile. 
Additionally, the monkey was chosen because of the similarity of its immune system to that of 
humans.  
IPI-145 treatment-related findings fell into two general types. The first type consisted of on-target 
effects of IPI-145, including depletion of lympho-hematopoietic cells in lymphoid and 
hematopoietic tissues. The second type consisted of inflammatory, degenerative and regenerative 
changes in various tissues. In monkeys, these changes were due to opportunistic infections 
(primarily viral, but also protozoal, fungal, and bacterial). It is likely that these findings were due to 
immune suppression as a secondary response to the first type of effects.  
The no observed adverse effect level (NOAEL) in rats was the low-dose of 5 mg/kg/day in the 
Good Laboratory Practice (GLP) 4-week repeat-dose toxicity study based on adverse changes in 
the lymphoid and hematopoietic systems, adrenal, gastrointestinal (GI) tract, testis, and uterine 
observed at ≥ 50 mg/kg/day. At the NOAEL, non-adverse, an on-target effect of increase in the 
cellularity of white pulp periarteriolar sheath accompanied by decrease in marginal zone cellularity 

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was observed in the spleen. The severely toxic dose to 10% of animals (STD10) in rats was the 
mid-dose of 50 mg/kg/day in the GLP 4-week repeat-dose toxicity study based on mortality at 350 
mg/kg/day.  
In cynomolgus monkeys, once daily oral administration of IPI-145 for 28 days elicited dose-
dependent, on-target immunosuppressive effects, characterized by lymphoid depletion and bone 
marrow changes. In monkeys, the highest non-severely toxic dose (HNSTD) was 5 mg/kg/day in 
the GLP 4-week study based on adverse clinical signs and/or moribundity observed at ≥ 30 
mg/kg/day.  
Clinical Studies in Humans 
Study IPI-145-01 (Phase 1, first-in-human study) 
 
Study IPI-145-01 was a randomized, double-blind, placebo-controlled, Phase 1 study in healthy 
adult subjects designed to evaluate the safety, tolerability, PK and pharmacodynamics of single 
and multiple ascending doses of IPI-145 and to assess the effect of food and ketoconazole on the 
PK of IPI-145. One-hundred and six (106) subjects were enrolled. In this setting IPI-145 was 
well tolerated at the doses evaluated. There were no deaths and no serious adverse events 
(SAEs).   
 
Pharmacokinetic assessments demonstrated that IPI-145 is rapidly absorbed following single and 
multiple oral dose administration, with the maximum plasma concentration observed typically 
1 hour after dosing.  Across the dose ranges evaluated, IPI-145 exposure increased 
proportionally to dose.  The mean elimination half-life ranged from 6.5 to 11.7 hours after repeat 
dosing and did not depend on the dose level administered.  IPI-145 accumulation was less than 
2-fold following 14 days of Q12 h oral administration.   
 
Data from the drug-drug interaction (DDI) portion indicated that concomitant administration of 
200 mg ketoconazole every 12 hours (Q12 hr) increased exposure to IPI-145.  On average, Cmax, 
AUC0-last and AUC0-inf increased by approximately 66%, 285% and 295%, respectively, in the 
presence of ketoconazole compared to IPI-145 administered alone.   
Study IPI-145-02 (Phase 1, Hematologic Malignancies)  
 
Study IPI-145-02 is a Phase 1, open-label, dose-escalation study of IPI-145 administered orally 
twice daily during each 28-day cycles at doses ranging from 8 mg BID to 100 mg BID in adult 
subjects with advanced hematologic malignancies. The dose-escalation phase of the trial is 
complete and the expansion phase is ongoing.  As of 28 October 2013, a total of 193 subjects, 
including 67 patients diagnosed with CLL/SLL (15 patients were treatment naïve and 52 patients 
were relapsed/refractory), have been dosed in the study. The maximum tolerated dose (MTD) 
was determined to be 75 mg BID based upon two dose limiting toxicities (DLTs) experienced by 
two subjects receiving 100 mg BID (Grade 3 rash and Grade 3 alanine aminotransferase 
[ALT]/aspartate aminotransferase [AST] elevations). 
 

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Clinical Safety 
 
As of 28 October 2013, 193 patients have received at least one dose of IPI-145 at doses ranging 
from 8 mg BID to 100 mg BID.  Overall, 61 patients have received the proposed dose of 25 mg 
BID in 28-day cycles. Of the 52 relapsed/refractory CLL/SLL patients enrolled, 25 patients have 
received a dose of 25 mg BID of IPI-145.  
 
The clinical safety data as of 28 October 2013 collected for patients on 25 mg BID in the overall 
population (n=61) and in the relapsed/refractory CLL/SLL population (n=25 patients who 
received 25 mg BID), suggest this dose is well tolerated with a safety profile similar to what 
might be expected in patients with advanced hematologic malignancies.   
 
Frequently occurring (≥ 20% patients) adverse events observed in relapsed/refractory CLL/SLL 
patients receiving 25 mg BID included neutropenia (40%), diarrhea (32%), rash (combined 
terms) (32%), fatigue (28%), anemia (24%), ALT or AST increased (24%), cough (24%), 
pyrexia (24%), hyperglycemia (20%), nausea (20%) and sinus congestion (20%).  Serious 
adverse events occurring in more than 1 relapsed/refractory CLL/SLL patient at 25 mg BID 
included febrile neutropenia (3 [12%]), disease progression (2 [8%]), and stomatitis (2 [8%]).  
Other notable serious events were infections, including upper respiratory infections and 
pneumonias.   
 
These events are not unexpected based on the patient population and the mechanism of action of 
IPI-145.  Infection prophylaxis and dose modifications included in this protocol are intended to 
reduce the risk of the frequently occurring events.   
 
Clinical Efficacy 
 
As of 28 October 2013, 47 subjects with relapsed/refractory CLL/SLL had available efficacy 
data.  Their median time on treatment was 5.5 months (range: 0.9 to 22.8 months).  Subjects 
dosed at ≤25 mg BID (n=27) had been on study longer (median=7.6 months) compared to 
subjects dosed at 75 mg BID (n=20, median=3.6 months). 
 
The investigator-reported ORR [(CR + PR), as defined by the IWCLL/IWG] was 47% among 
the 47 subjects with a response assessment, which included 1 CR, and 21 PR.  Table 1 below 
shows the response rate by IWCLL/IWG in CLL/SLL subjects. 

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administration of 25 mg BID, mean Cmax and AUC0-12 values are 1460 ng/mL and 8129 
ng*h/mL, respectively.  IPI-145 elimination half-life (t1/2) does not appear to vary with dose and 
the mean t1/2 was 4.5 hours following 25 mg BID administration. 
RATIONALE FOR IPI-145 AS A POTENTIAL THERAPY FOR PATIENTS WITH CLL 
In CLL, activation of the B cell receptor (BCR) pathway leads to upregulation of PI3K-δ, 
suggesting that PI3K-δ inhibition could have therapeutic benefit in these cancers.  We previously 
showed that primary CLL cells are inhibited from undergoing apoptosis through BCR stimulation 
by stromal cells or anti-IgM stimulation.  The PI3K-δ isoform specific inhibitor idelalisib (also 
known as CAL-101 or GS-1101) was able to de-adhere CLL cells from stroma and increase their 
susceptibility to apoptosis induced by other agents (Davids et al., 2012).   
Idelalisib has demonstrated promising clinical activity in patients with hematologic malignancies. 
In heavily pre-treated patients with refractory CLL and bulky lymphadenopathy, single agent 
idelalisib was highly active and clinically efficacious, providing a durable clinical benefit (Brown 
et al., 2014). Moreover, inhibition of PI3K-δ not only affected cancer cells directly, but it also 
affected the ability of the cancer cells to interact with their microenvironment.  In refractory or 
relapsed CLL patients, idelalisib has been combined with bendamustine and rituximab, and this 
combination of PI3K inhibitor and chemotherapy was well-tolerated with robust clinical activity 
(Barrientos et al., 2013). 
IPI-145 is a potent PI3K-δ inhibitor and would be expected to have at least comparable activity in 
CLL in combination with chemotherapy.  In addition, the ability of IPI-145 to inhibit the gamma 
isoform of PI3K suggests that the drug may be even more potent than delta-specific inhibitors. 
DETERMINATION OF IPI-145 STARTING DOSE AND REGIMEN  
 
Dose levels of IPI-145 ranging from 8 mg BID to 100 mg BID were evaluated in 
Study IPI-145-02, a Phase 1, open-label, dose-escalation study in subjects with advanced 
hematologic malignancies where IPI-145 was administered orally twice daily (BID) continuously 
in 28-day cycles as a single agent. The dose-escalation phase of Study IPI-145-02 is complete 
and the maximum tolerated dose was determined to be 75 mg BID.  Enrollment is complete and 
a total of 193 subjects have been dosed in the study as of 28 October 2013.   
Based on the available data, the following findings were considered in determining the dose and 
schedule for this study: 
• 
Of the 27 relapsed/refractory CLL/SLL patients with evaluable efficacy data who 
received ≤ 25 mg BID of IPI-145, the best response to date shows 1 patient achieved a 
CR and 12 patients have achieved a PR based on IWCLL 2008 response criteria;  
• 
The median time to response (n=12) was rapid (1.9 months) with a PR observed in 6 
patients after 2 cycles, in 4 patients after 4 cycles, and in 2 patients after 6 cycles of IPI-
145 treatment; 
• 
85% (11/13) of the relapsed/refractory CLL/SLL patients with evaluable efficacy data 
who received ≤ 25 mg BID of IPI-145 with stable disease have demonstrated a nodal 
response, defined as >50% reduction in adenopathy based on CT scans.  Eight of 11 
patients experienced a nodal response after 2 cycles of IPI-145 treatment; and  

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patients will have persistent disease and will inevitably progress.  For younger patients with a 
long life expectancy, achieving only a few years of remission is inadequate. 
The high level of activity of single-agent IPI-145, its mechanism of action (which is distinct from 
cytotoxic therapy), and its ability to mobilize CLL cells from protective niches all suggest that 
combining it with the most effective standard therapy, FCR, might potentially lead to cure.  
Since younger patients typically tolerate combination chemotherapy well and desire to maximize 
long-term remission, they may benefit from an intensive therapeutic approach designed to 
optimize curative potential, similar to the treatment paradigm used for curable aggressive 
lymphomas like diffuse large B cell lymphoma. 
Unlike older patients who may benefit from a non-chemotherapy approach, for younger patients, 
it may be appropriate to accept some toxicity with IPI-145 + FCR (iFCR) with the goal of 
achieving a more durable response, potentially even a cure.  The side effect profiles of IPI-145 
and FCR are generally non-overlapping, but given that this combination has not previously been 
explored, the current study includes an initial phase I 3+3 dose escalation cohort starting at 25 
mg QD of IPI-145, which is below the single agent MTD of 25 mg bid being used in 
monotherapy studies.  This phase Ib/II study of iFCR will evaluate the safety and efficacy of this 
combination in the upfront treatment of younger patients with CLL, with the primary objective 
of improving the rate of MRD-negative CR in the bone marrow in this patient population.   
The primary objective of our study is to improve the rate of MRD-negative CR in the bone 
marrow in this patient population.  From a theoretical perspective, achieving and sustaining 
MRD negative CR is the first step toward possible cure.  In practice, many studies have 
established that achievement of MRD negativity correlate with longer progression-free survival 
to a variety of different regimens.  For example, in the phase 3 CLL8 FCR study, patients who 
achieved MRD-negativity after 3 cycles of therapy had a similar PFS as patients who achieved 
MRD-negativity after the full 6 cycles, suggesting that achieving MRD-negativity is the key to 
having a durable response (Boettcher et al., 2012).  We will be measuring MRD-negativity by 
four-color flow cytometry with a detection level of 10-4, which has been validated as highly 
accurate in comparison to PCR-based assays (Rawstron et al., 2013).  By utilizing MRD-
negativity as our primary endpoint, we will be able to obtain a rapid assessment of efficacy 
without having to wait several years for PFS and OS data to mature.  This will allow us to 
efficiently determine whether the iFCR regimen is worthy of exploration in a larger, randomized 
clinical trial to more definitively assess its efficacy. 
Preliminary Results from Phase I 
As of April 7, 2015, 12 subjects had been enrolled in the phase I portion of this trial.  In the 
initial dosing cohort 1 (IPI-145 25 mg daily, 3 subjects), one subject experienced a DLT (febrile 
neutropenia), and therefore 3 additional subjects were accrued in cohort 1.  None of the 
additional 3 subjects experienced a DLT, and therefore a dosing cohort 2 was opened (IPI-145 25 
mg bid, 3 subjects).  None of these three subjects experienced a DLT, and therefore 3 additional 
subjects were accrued in cohort 2 at 25 mg bid of IPI-145.  None of these three additional 
subjects experienced a DLT.  Since 0/6 subjects at 25 mg bid of IPI-145 in cohort 2 experienced 
a DLT, this dose was chosen as the recommended phase 2 dose, and will be the dose utilized in 
the phase II portion of this study. 
 

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2.4 
Correlative Studies Background 
 
BH3 Profiling 
This study will incorporate a laboratory technique known as BH3 profiling, which is a functional 
assay we previously developed that detects the proximity of malignant cells to the threshold of 
apoptosis (what we call ‘priming’) through physiologic interrogation of BCL-2 family members.  
To perform a BH3 profile, we add individual BH3-only peptides to gently permeabilized primary 
CLL cells and use FACS to determine the amount of mitochondrial depolarization induced by 
each peptide, as measured by cytochrome c release.  
 
We previously showed using primary CLL samples co-cultured with stroma in vitro that PI3K-
delta inhibition can release CLL cells from stroma, and thereby increase priming for apoptosis 
(Davids et al., 2012).  We also found that in a small, heterogeneously treated cohort of CLL 
patients, increased priming was associated with improved clinical response.  Building on these 
initial studies, we will incorporate BH3 profiling into the iFCR clinical trial to determine 
whether priming predicts degree of clinical response in this larger, homogeneously treated 
patient population. 
 
We hypothesize that patients whose cells undergo significant depolarization to BIM BH3 peptide 
(highly primed) will have superior clinical response to iFCR 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 correlated 
with our primary endpoint of MRD-negative CR rate in the bone marrow.  If we have positive 
bone marrow aspirates available, we will also perform BH3 profiling to see whether the level of 
priming in CLL cells from the marrow is a better predictor of response than the level of priming 
in peripheral blood CLL cells. 
 
After 1 week of IPI-145 monotherapy, we will obtain a steady-state blood sample.  We will 
compare the BH3 profile of this sample to a baseline sample, which will allow us to assess in 
vivo the short term change in apoptotic priming induced by IPI-145 as a single agent.  BH3 
profiling also has the ability to determine the relative dependence of CLL cells on anti-apoptotic 
proteins such as BCL-2, BCL-XL, and MCL-1.  To determine whether anti-apoptotic 
dependence affects response, we will look to see whether patients who do not achieve an MRD-
negative CR have a different pattern in their upfront BH3 profiles from those who do achieve 
MRD-negative CR.  Finally, we will obtain peripheral blood and bone marrow samples from 
patients at the time of disease progression and look to see whether, compared to the baseline 
samples, apoptotic priming is decreased and/or the pattern of anti-apoptotic protein dependence 
has changed. 
 
Genomic Markers 
We will perform whole exome sequencing on CLL cells and normal tissue from patients at 
baseline to evaluate for somatic mutations that may confer drug sensitivity and resistance.  Our 
group and others have recently identified recurrent somatic mutations in the CLL genome which 
appear to associate with prognosis; these include NOTCH1, MYD88 and SF3B1 (Wang et al, 
2011).  At present, whether other recurrent mutations associate with prognosis is less clear, 
although our group also recently reported a shorter time to first therapy in patients carrying 

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mutations in NFKB pathway genes (Improgo et al, 2012), which could interact with sensitivity to 
IPI-145 depending on where in the pathway the mutations occur.  Our group has also recently 
found that the presence of subclonal driver mutations was associated in a retrospective analysis 
with time to next treatment (Landau et al, 2013).  In this trial, we will assess all of these recently 
described mutations as potential predictors of response and progression-free survival.  We may 
also bank samples at time of relapse for repeat analysis by whole exome sequencing to assess for 
the acquisition of resistance mutations. 
 
We will also evaluate established CLL prognostic markers such as cytogenetics by FISH, TP53 
mutation, IGHV status, and ZAP-70 status, and will determine whether these factors are 
associated with response to iFCR. 
 
Pharmacodynamic Markers 
Pharmacodynamic markers will be assessed to determine how effectively IPI-145 is hitting its 
proposed target in vivo in these previously untreated CLL patients.  Using pretreatment and week 
1 patient samples, we will use phosphoflow cytometry to determine the levels of phospho-AKT 
and phospho-ERK compared to total AKT and ERK, respectively.  These analyses may be 
confirmed in a subset of patients by Western Blot.  In addition, recent work has suggested that 
reduction in the cell proliferation marker Ki-67 in peripheral blood CLL cells occurs rapidly in 
patients treated with BCR pathway antagonists, and we may assess this also by phosphoflow 
cytometry. 
 

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3. PARTICIPANT SELECTION 
 
3.1 
Inclusion Criteria 
 
Unless otherwise specified, laboratory tests required for eligibility must be completed 
within 2 weeks prior to study entry. Baseline tumor measurements by CT scan (neck, 
chest, abdomen/pelvis), as well as bone marrow biopsy must be performed within 8 
weeks of starting study treatment. Outside scans that are used for eligibility will need to 
be reviewed by the study team prior to registration. 
 
Participants must meet the following criteria on screening examination to be eligible to 
participate in the study: 
3.1.1 Must have a confirmed diagnosis of CLL and an indication for treatment as per IW-
CLL 2008 criteria 
3.1.2 No prior therapy for CLL due to the patient’s meeting IW-CLL 2008 criteria for 
treatment 
3.1.3 Age greater than or equal to 18 years and less than or equal to 65.  Because CLL is 
extremely rare in persons <18 years of age, children are excluded from this study.  
Because iFCR is an aggressive therapy that is likely to be poorly tolerated in 
elderly subjects, persons > 65 years of age are excluded 
3.1.4 ECOG performance status <1 (see Appendix A) 
3.1.5 The effects of IPI-145 on the developing human fetus are unknown. For this reason 
and because similar agents are known to be teratogenic, women of child-bearing 
potential and men must agree to use adequate contraception (hormonal or barrier 
method of birth control; abstinence) prior to study entry and for the duration of 
study participation. Should a woman become pregnant or suspect she is pregnant 
while participating in this study, she should inform her treating physician 
immediately 
3.1.6 Ability to understand and the willingness to sign a written informed consent 
document 
 
3.2 Exclusion Criteria 
Participants who exhibit any of the following conditions at screening will not be eligible for 
admission into the study: 
 
3.2.1 May not be receiving any other study agents 
3.2.2 Patients with known CNS involvement are excluded from this clinical trial 
because of their poor prognosis and because they often develop progressive 
neurologic dysfunction that would confound the evaluation of neurologic and 
other adverse events 
3.2.3 Uncontrolled intercurrent illness including, but not limited to ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, 

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cardiac arrhythmia, or psychiatric illness/social situations that would limit 
compliance with study requirements 
3.2.4 Pregnant women are excluded from this study because IPI-145 has the potential 
for teratogenic or abortifacient effects. Because there is an unknown but 
potential risk of adverse events in nursing infants secondary to treatment of the 
mother with IPI-145, breastfeeding should be discontinued if the mother is 
treated with IPI-145. These potential risks may also apply to other agents used 
in this study 
3.2.5 Individuals with a history of a different malignancy are ineligible except for the 
following circumstances. Individuals with a history of other malignancies are 
eligible if they have been disease-free for at least 5 years and are deemed by the 
investigator to be at low risk for recurrence of that malignancy. Individuals with 
the following cancers are eligible if diagnosed and treated with curative intent 
within the past 5 years: cervical cancer in situ, localized prostate cancer, and 
basal cell or squamous cell carcinoma of the skin 
3.2.6 HIV-positive individuals on combination antiretroviral therapy are ineligible 
because of the potential for pharmacokinetic interactions with IPI-145. In 
addition, these individuals are at increased risk of lethal infections when treated 
with marrow-suppressive therapy 
3.2.7 Inadequate hepatic function defined by aspartate aminotransferase (AST) and/or 
alanine aminotransferase (ALT) >2.5 x upper limit of normal (ULN); direct 
bilirubin >1.5 x ULN unless due to hemolysis or Gilbert’s syndrome 
3.2.8 Inadequate renal function defined by serum creatinine >1.5 x ULN. 
3.2.9 Baseline QTcF >480 ms. NOTE: This criterion does not apply to patients with a 
left bundle branch block 
3.2.10 Concurrent treatment with any agent known to prolong the QTc interval (see 
Appendix E) 
3.2.11 Patients with a history of active tuberculosis within the preceding two years. 
3.2.12 Patients who have had a venous thromboembolic event (e.g., pulmonary 
embolism or deep vein thrombosis) requiring anticoagulation and who meet any 
of the following criteria: 
• Have been on a stable dose of anticoagulation for <1 month 
• Have had a Grade 2, 3 or 4 hemorrhage in the last 30 days 
• Are experiencing continued symptoms from their venous thromboembolic event 
(e.g. continued dyspnea or oxygen requirement) 
NOTE: Patients who have had a venous thromboembolic event but do not meet 
any of the above three criteria are eligible for participation 
3.2.13 Patients with a history of alcohol abuse, chronic hepatitis, or other chronic liver 
disease (other than direct CLL liver involvement) 
NOTE: Chronic hepatitis includes active infection with hepatitis B or C. All 
patients will be tested for hepatitis C virus antibodies (HCV Ab) and hepatitis B 
surface antigen (HBsAg) at screening. Patients with a positive result for HBsAg 
or HCV Ab will be excluded from enrolling in this study 
3.2.14 Foods or medications that are strong or moderate inhibitors or inducers of 
CYP3A (see Appendix C) taken within 1 week prior to study treatment and 
for the duration of the study 

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3.2.15 Presence of active infection within 72 hours of treatment. 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 
3.2.16 Significant co-morbid condition or disease which in the judgment of the 
Investigator would place the patient at undue risk or interfere with the study. 
Examples include, but are not limited to cirrhotic liver disease, sepsis, or recent 
significant traumatic injury. 
3.2.17  Unable to receive prophylactic treatment for pneumocystis 
3.3 Inclusion of Women, Minorities and Other Underrepresented Populations 
 
Inclusion of women, minorities and other underrepresented populations is encouraged. 

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4 REGISTRATION PROCEDURES 
   
4.1 General Guidelines for DF/HCC and DF/PCC Institutions 
 
Institutions will register eligible participants with the DF/HCC Quality Assurance 
Office for Clinical Trials (QACT) central registration system. Registration must 
occur prior to the initiation of therapy. Any participant not registered to the protocol 
before treatment begins will be considered ineligible and registration will be denied.  
 
A member of the study team will confirm eligibility criteria and complete the 
protocol-specific eligibility checklist. 
  
Following registration, participants may begin protocol treatment. Issues that 
would cause treatment delays should be discussed with the Principal Investigator. If 
a participant does not receive protocol therapy following registration, the participant’s 
protocol status must be changed. Notify the QACT Registrar of participant status 
changes as soon as possible. 
 
4.2 Registration Process for DF/HCC and DF/PCC Institutions 
 
The QACT registration staff is accessible on Monday through Friday, from 8:00 AM to 
5:00 PM Eastern Standard Time. In emergency situations when a participant must begin 
treatment during off-hours or holidays, call the QACT registration line at 617-632-3761 
and follow the instructions for registering participants after hours. 
   
The registration procedures are as follows: 
 
1. 
Obtain written informed consent from the participant prior to the performance 
of any study related procedures or assessments. 
 
2. 
Complete the protocol-specific eligibility checklist using the eligibility 
assessment documented in the participant’s medical/research record. To be 
eligible for registration to the study, the participant must meet each 
inclusion and exclusion criteria listed on the eligibility checklist. 
  
Reminder: Confirm eligibility for ancillary studies at the same time as 
eligibility for the treatment study. Registration to both treatment and ancillary 
studies will not be completed if eligibility requirements are not met for all 
studies. 
  
3. 
Fax the eligibility checklist(s) and all pages of the consent form(s) to the 
QACT at 617-632-2295. 
  
 
  

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4. 
The QACT Registrar will (a) validate eligibility, and (b) register the 
participant on the study 
  
5. 
The QACT Registrar will send an email confirmation of the registration 
and/or randomization to the person initiating the registration immediately 
following the registration and/or randomization. 
  
4.3 General Guidelines for Other Participating Institutions 
 
Eligible participants will be entered on study centrally at DFCI by the Study 
Coordinator. All sites should call the DFCI Study Coordinator to verify treatment 
availability. 
 
Following registration, participants should begin protocol treatment within 96 
hours or as soon as possible. Issues that would cause treatment delays should be 
discussed with the Principal Investigator. If a participant does not receive protocol 
therapy following registration, the participant’s protocol status must be changed. The 
Study Coordinator should be notified of participant status changes as soon as possible. 
 
Except in very unusual circumstances, each participating institution will order the study 
agent(s) directly from the supplier. A participating site may order the agent(s) only 
after the initial IRB approval for the site has been forwarded by the Coordinating 
Center to the supplier. 
 
4.4 Registration Process for Other Participating Institutions 
 
To register a participant, the following documents should be completed by the research 
nurse or data manager and faxed or emailed to the DFCI Study Coordinator (contact 
information on study contact list): 
• 
Signed study consent form 
• 
HIPAA authorization form 
• 
Eligibility Checklist 
 
The research nurse or data manager at the participating site will then call  or email 
the DFCI Study Coordinator (contact information on study contact list) to verify 
eligibility. To complete the registration process, the Coordinator will: 
• Register the participant on the study with QACT 
• Fax or e-mail the participant study number, and if applicable the dose 
treatment level, to the participating site 
• Call the research nurse or data manager at the participating site and 
verbally confirm registration 
Note: Registration and randomization with the QACT can only be conducted during 
the business hours of 8am – 5pm EST Monday through Friday. Same day treatment 
registrations will only be accepted with prior notice and discussion with the DF/HCC 
Lead Institution. 
 
 

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5 TREATMENT PLAN  
 
Treatment will be administered on an outpatient basis. Expected toxicities and potential risks as 
well as dose modifications for fludarabine, cyclophosphamide, rituximab, and IPI-145 are 
described in Section 6 (Expected Toxicities and Dosing Delays/Dose Modification). No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the participant’s malignancy. 
 
Overview of Treatment Plan 
In the phase Ib portion of the study, a standard 3 + 3 dose escalation will be performed, with IPI-
145 starting at a dose of 25 mg QD.  Patients will start with one week of IPI-145 monotherapy on 
cycle 1, day -7, and FCR will subsequently be introduced one week later on cycle 1, day 1, and 
administered at standard dosing for 6 cycles.  Depending on the number of DLTs observed, 
escalation to IPI-145 25 mg bid or de-escalation to IPI-145 15 mg QD will be allowed.  Once a 
recommended phase II dose (RP2D) is identified, the phase II expansion portion of the study will 
open using the RP2D plus FCR.  At the conclusion of the portion of the study that includes FCR, 
responders will be allowed to continue on IPI-145 maintenance until time of progression for up 
to 2 years after completing FCR. If patients have discontinued IPI-145 but have continued to 
receive FCR on treatment, they may proceed to active follow-up for a period up to 2 years after 
completing FCR.    
 
Table 2.  Overview of Study Agents 
 
iFCR 
Agent 
Dose 
Route 
Schedule 
Cycle Length 
IPI-145 
5 or 25 mg 
capsule 
PO at same time(s) 
each day 
QD or BID starting d-7, 
then continuous for 6 
cycles and up to 2 yrs. 
maintenance 
C1:  
 28 days  plus 
7 day lead in 
time(5 weeks) 
 
C2-6:  
28 days 
(4 weeks) 
Fludarabine* 
25  mg/m2 
IV over approximately 
30 to 60 min., given 
before rituximab 
unless clinically 
contraindicated 
Days 1-3, week 1 
Cyclophosphamide* 
250 mg/m2 
IV over approximately 
30 to 60 min., given 
before rituximab 
unless clinically 
contraindicated 
Days 1-3, week 1 
Rituximab 
C1: 375 mg/m2 
C2-6: 500 
mg/m2 
IV over protocol-
mandated duration, 
given after FC unless 
clinically 
contraindicated 
Day 1**, week 1 
 
* Fludarabine and cyclophosphamide may be dose-reduced beginning with cycle 1 as per 
standard of care at the discretion of the investigator, if approved by the PI.  Standard dose 

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reductions for fludarabine include reducing to 20 mg/m2 or 15 mg/m2 and for cyclophosphamide 
to 200 mg/m2 or 150 mg/m2. 
**In cycle 1, rituximab dose may be split between day 1 (50 mg/m2) and days 2 or 3 (325 
mg/m2) at the discretion of the treating investigator, as specified in the protocol. 

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Dose escalation will proceed according to the following scheme:  
 
 
If DLT in  
Then  
 
 
 
 
 
 
 
If DLT in Then 
 
0/3 
Escalate to the next dose  
-  
 
 
- 
level    
 
 
1/6 
Escalate to next dose level (or accrue 
20 additional if this is the MTD) 
1/3 
 
 
 
Add 3 
 
 
≥ 2/6  
 
 
De-escalate to previous dose level 
 
≥ 2/3  
 
 
MTD is the prior dose level 
 
Dose-Escalation Schedule 
1 cycle = 28 days (except cycle 1 [28 days plus 7 day lead in]) 
 
Dose Level 
Dose of IPI-145 
 
2 
25 mg BID 
Starting Dose → 
1 
25 mg QD 
 
-1 
15 mg QD 

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5.1 Pre-treatment Criteria 
   
5.1.1 Cycle 1, Day 1 
 
Participants must meet all of the inclusion criteria, have none of the exclusion criteria, and 
must be registered to the protocol prior to initiating therapy. 
5.1.2 Subsequent Cycles 
 
5.1.2.1 ANC must be ≥ 1000/mm3 
 
5.1.2.3 Platelet count must be ≥ 75K or ≥100% of baseline 
 
5.1.2.3 All non-hematologic toxicities except for alopecia must have resolved to ≤ Grade 2, 
or to the patient’s baseline condition 
 
5.2 Agent Administration  
 
In general, there is a +/- 4 day window for chemotherapy administration to allow for scheduling 
related issues. 
5.2.2  Fludarabine 
 
Fludarabine (commercial supply from various manufacturers) will be administered 
prior to rituximab unless clinically contraindicated.  Fludarabine and 
cyclophosphamide may be administered either with fludarabine followed by 
cyclophosphamide or with cyclophosphamide followed by fludarabine, at the discretion 
of the treatment team. Fludarabine will be dosed at 25 mg/m2 on days 1, 2, and 3 of 
each 28 day cycle. Fludarabine may be dose reduced beginning with cycle 1 as per 
standard of care at the discretion of the investigator, if approved by the PI. Standard 
dose reductions for fludarabine include reducing to 20 mg/m2 or 15 mg/m2.  It will be 
administered IV over approximately 30 to 60 minutes per institutional routine. No 
pre-hydration or post-hydration is mandated.  Anti-emetics will also be given per 
institutional routine.  If patients experience Grade 1-3 infusion reactions with 
fludarabine administration, measures to prevent severe infusion reactions, including 
antihistamines, antipyretics and corticosteroids should be considered. Patients with 
grade 4 infusion reactions will be discontinued from the chemotherapy portion of 
the study.  If they have completed at least 3 cycles of chemotherapy and have 
achieved a PR or better, they will be given the option of continuing on IPI-145 
maintenance for 2 years or coming off study. 
5.2.3  Cyclophosphamide 
 
Cyclophosphamide (commercial supply from various manufacturers) will be 
administered prior to rituximab unless clinically contraindicated.  Fludarabine and 

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cyclophosphamide may be administered either with fludarabine followed by 
cyclophosphamide or with cyclophosphamide followed by fludarabine, at the discretion 
of the treatment team.  Cyclophosphamide will be dosed at 250 mg/m2 on days 1, 2, 
and 3 of each 28 day cycle. Cyclophosphamide may be dose reduced beginning with 
cycle 1 as per standard of care at the discretion of the investigator, if approved by the 
PI.  Standard dose reductions for cyclophosphamide including reducing to 200 mg/m2 
or 150 mg/m2.It will be administered IV over approximately 30 to 60 minutes, per 
institutional routine.  Pre-hydration with D5 ½ NS @ 500 mL/hr x 0.5 liters is 
recommended.  Anti-emetics will also be given per institutional routine.  If patients 
experience Grade 1-3 infusion reactions with cyclophosphamide administration, 
measures to prevent severe infusion reactions, including antihistamines, antipyretics 
and corticosteroids should be considered. Patients with grade 4 infusion reactions 
will be discontinued.  If they have completed at least 3 cycles of chemotherapy and 
have achieved a PR or better, they will be given the option of continuing on IPI-145 
maintenance for 2 years or coming off study. 
5.2.4  Rituximab 
 
Rituximab will be administered after the chemotherapeutic agents unless clinically 
contraindicated. Rituximab from a commercial supply (Genentech, S. San 
Francisco, CA) will be administered IV at a dose of 375 mg/m2 on day 1 of cycle 1. 
Patients with ≥ 15,000 circulating malignant cells/ mm3 or at the discretion of the 
treating physician will receive only 50 mg/m2 on day 1 of cycle 1 to reduce the 
incidence of tumor lysis syndrome and infusion reactions, with the remaining 325 
mg/m2 given on days 2 or 3 of cycle 1. If the day 1 infusion cannot be completed 
within 1 day, the patient is allowed to receive the remainder of the infusion the 
following day on day 2. For patients receiving split dose rituximab with cycle 1, if 
the day 2 or 3 infusion cannot be completed within 1 day, the patient is allowed to 
receive the remainder of the infusion the following day. Unless allergic, all patients 
will receive allopurinol for tumor lysis syndrome prophylaxis with the first cycle. 
 
In cycles 2-6, rituximab will be escalated to 500 mg/m2 and will be administered on 
day 1 of each remaining cycle. If the day 1 infusion cannot be completed within 1 
day, the patient is allowed to receive the remainder of the infusion the following day 
on day 2. Actual body weight measured at each treatment day will be used for 
calculations of body surface area.  Patients with circulating disease ≥ 15,000 
circulating malignant cells/mm3 or bulky disease may continue to receive 
allopurinol for prophylaxis of tumor lysis syndrome during cycles 2-6, at the 
discretion of the investigator. 
 
Rituximab will be administered and hypersensitivity reactions will be treated per 
Dana-Farber Harvard Cancer Center institutional guidelines (please refer to section 
7.1.3 for administration guidelines). 
5.2.5  IPI-145 
 

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IPI-145 (Verastem, Needham, MA) will be administered orally once or twice per day in 
28 day cycles (except for cycle 1, which is 28 days plus 7 day lead in). IPI-145 is 
administered orally as a capsule formulation and will be supplied free of charge by 
Verastem. IPI-145 will be administered as a fixed dose in mg/day and should be 
administered using the minimal number of capsules necessary.  Starting on Cycle 1, 
Day -7, IPI-145 will be administered once a day or twice per day at the specified cohort 
dose.  Doses must be taken within ±3 hours of the scheduled dose.  
 
The date, time, and quantity of each capsule strength taken will be recorded in a drug 
self-administration diary.  Patients should record any deviation from taking the full 
daily dose (e.g., vomited doses, missed doses, doses reduced due to missing or lost 
capsules). An attempt should be made to enable each dose to be taken at approximately 
the same time(s) of day. Missed doses outside the windows defined above or vomited 
doses should not be taken or repeated.  At each visit, a sufficient number of doses will 
be dispensed so that the patient will have the required number of doses until the next 
visit, taking into account the window for the next visit.  
 
IPI-145 capsules should be swallowed whole with a glass of water (approximately 8 
ounces or 240 mL) at approximately the same time(s) each day. Patients must avoid 
grapefruit or grapefruit juice. There are no restrictions with regard to fasting or fed state 
at the time of IPI-145 dosing. 
5.3 Definition of Dose-Limiting Toxicity 
 
Dose-limiting toxicity (DLT) is based on the CTEP Active Version of the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.  
 
DLT refers to toxicities experienced at any time during the study treatment, defined 
as the following:  
 
• Any Grade 3 or greater hematologic toxicity with exceptions for Grade 3 or Grade 4 
neutropenia or thrombocytopenia that persists for ≤ 10 days off treatment. 
• ny Grade 3 or greater non-hematologic toxicity with the following exceptions: 
o Grade 3 or greater nausea/vomiting/diarrhea despite optimal supportive care that 
persists for 7 days or less 
o Grade 3 infusion reactions 
• Grade 3 asymptomatic laboratory abnormalities that improve to grade 2 or less within 3 days.  
Inability to receive day 1 therapy of Cycle 2 even after a three week treatment delay due to 
continued drug related toxicity from the prior cycle. 
• Any Grade 4 or greater elevation in ALT/AST. 
 
All toxicities will be considered relevant to determining DLT and to reporting unless the event 
can clearly be determined to be unrelated to the study drug(s). 
 
 
 

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Management and dose modifications associated with the above adverse events 
are outlined in Section 6 (Expected Toxicities and Dosing Delays/Dose 
Modifications).   
 
Dose escalation will proceed within each cohort according to the following 
scheme: 
 
Number of Subjects with DLT at a Given Dose Level Escalation Decision 
Rule:  If there are 0 in 3 or ≤1 in 6 DLT at a given dose level then 
escalation will occur.  If this is dose level 2 then this will be declared the 
RP2D 
 
5.4 General Concomitant Medication and Supportive Care Guidelines 
 
5.4.1  Supportive Care 
 
Subjects should receive full supportive care, including transfusions of blood 
and blood products, antibiotics, hematopoietic growth factors, analgesics, and 
antiemetics when appropriate.  
 
White cell growth factor support with Neulasta or Neupogen will be 
mandatory for all patients beginning with cycle 1.  Neulasta will be 
administered at 6 mg SC x 1 on day 4 (or day 5 if necessary for scheduling 
reasons) of each cycle. Alternatively, Neupogen may be substituted at the 
discretion of the treating investigator and administered at 300-480mcg SC 
daily for up to 10 days, until ANC ≥ 1500 for two consecutive days. Neulasta 
and Neupogen will be from commercial supply. 
 
5.4.2 Tumor Lysis Syndrome (TLS) Prophylaxis 
 
Though relatively rare in CLL, 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 FCR chemotherapy, necessitating TLS prophylaxis including 
allopurinol and oral or IV hydration.  
 
The risk of TLS is highest during the first cycle of therapy.  It is recommended 
that allopurinol 300mg PO daily begin at least 3 days before the start of IPI-
145 monotherapy and continue through the end of cycle 1.  Subjects with an 
allopurinol allergy should receive alternative TLS prophylaxis if possible.  All 
subjects should be instructed to maintain adequate hydration and maintain 
urinary output as an additional measure to prevent TLS.  To maintain fluid 
intake, subjects should be instructed to drink 8 to 10 eight ounce glasses of 
water each day for the first 14 days of Cycles 1 and 2. Hydration levels should 
be adjusted according to age and clinical status, and lowered if the subject’s 

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cardiovascular status indicates the possibility of volume overload. Based on 
clinical and laboratory parameters, TLS prophylaxis may be continued or 
restarted as needed at the investigator’s discretion. 
 
All subjects meeting criteria of laboratory TLS or ≥ Grade 1 TLS according to 
the Cairo-Bishop Definition of Tumor Lysis Syndrome (see Appendix F) 
should receive vigorous intravenous hydration and should be considered for 
rasburicase therapy as needed to reduce hyperuricemia, until correction of 
electrolyte abnormalities. See Section 6.2, Dose Modification, for additional 
instructions. 
 
5.4.2.1 Treatment and Dose Modification for Tumor Lysis Syndrome 
 
All subjects meeting criteria of laboratory TLS or ≥ Grade 1 TLS 
according to the Cairo-Bishop Definition of Tumor Lysis Syndrome (see 
Appendix 4) should receive vigorous intravenous hydration and should be 
considered for rasburicase therapy as needed to reduce hyperuricemia, 
until correction of electrolyte abnormalities. See Section 6.2, Dose 
Modification Table, for additional instructions. 
 
5.4.3 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 
study. 
  
5.4.4 CMV Monitoring:   
 
Based on data from the IPI-145 phase I study in CLL, subjects taking IPI-145 
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 
load measurement at study entry and monthly thereafter.   
 
Subjects whose CMV viral load becomes positive will be started on 
valganciclovir 900 mg bid and the CMV viral load checked weekly until it 
becomes undetectable.  At that point, dosing of valganciclovir can be changed 
to the prophylactic dose of 450 mg PO bid for the remainder of the study, but 
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 may be stopped during 
valganciclovir dosing.  
 

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Patients in the maintenance phase of the study can have CMV viral load 
testing performed every 2 months. 
 
5.4.5  Medications that are Substrates of CYP3A4/5 or CYP2C8  
 
In vitro studies in human liver microsomes have demonstrated IPI-145 is an 
inhibitor of cytochrome P450 (CYP) enzymes CYP2C8 (Ki = 1.1 μM) and 
CYP3A4/5 (Ki = 3.4 μM) activity, therefore systemic exposure to medications 
that are substrates for CYP2C8 or CYP3A4/5 may be increased in patients 
receiving IPI-145. The clinical significance of this inhibition is currently 
unknown; therefore, caution should be used if IPI-145 is used concomitantly 
with drugs or foods that are substrates of CYP2C8 and CYP3A4/5.  
Appendix B provides a list of medications known to be substrates of 
CYP3A4/5 or CYP2C8. Please note that Appendix B is not a comprehensive 
list of all medications which may be substrates of CYP3A4/5 or CYP2C8. The 
Principal Investigator should be contacted with any questions regarding 
concomitant use of medications that are CYP3A4/5 or CYP2C8 substrates.  
 
5.4.6 Medications or Food that Inhibit or Induce CYP3A4/5  
 
In vitro data also indicate that oxidative metabolism may play an important 
role in the elimination of IPI-145, with CYP3A4/5 identified as a primary 
contributor to drug metabolism. Draft data from a drug-drug interaction study 
with ketoconazole (a potent CYP3A4/5 inhibitor) indicate exposure to IPI-145 
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 beginning 1 week prior to the 
first dose of IPI-145. Additionally, the use of these drugs and foods are not 
allowed during study treatment.  Appendix C provides a list of medications 
known to be strong or moderate inhibitors or inducers of CYP3A. Please note 
that Appendix C 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. 
 
5.4.7  Medications that are Substrates or Inhibitors of P-glycoprotein 
 
In vitro data indicate that IPI-145 is a substrate for P-glycoprotein (P-gp). 
Concomitant medications that inhibit P-gp may cause the steady state 
concentration of IPI-145 to be reached more quickly than usual. These 
medications may be used as medically indicated but with caution. 
Additionally, in vitro studies demonstrated that IPI-145 has the potential to 
inhibit the active transport of other P-gp substrates.  Appendix D provides a 

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list of medications that are substrates or inhibitors of P-gp. Please note that 
Appendix D is not a comprehensive list of all medications which may be 
substrates of P-gp or may modulate P-gp activity. The Principal Investigator 
should be contacted with any questions regarding concomitant use of 
medications that are thought to modulate P-gp activity. 
 
5.5 Duration of Therapy 
 
Duration of therapy will depend on individual response, evidence of disease 
progression, and tolerance. In the absence of treatment-related adverse events, 
treatment may continue for 6 cycles of combination therapy with iFCR with an 
additional 2 years of IPI-145 maintenance in responders, or until one of the 
following criteria applies: 
 
• Disease progression 
• Intercurrent illness that prevents further administration of treatment 
• Unacceptable adverse event(s) 
• Participant decides to withdraw from the study 
• General or specific changes in the participant's condition render the 
participant unacceptable for further treatment in the opinion of the treating 
investigator. 
 
5.6  Duration of Follow Up 
Participants will be followed until subsequent therapy or until removal from 
study or death, whichever occurs first. 
 
5.7 Criteria for Removal from Study 
 
Participants will be removed from study when any of the criteria listed in 
Section 5.5 applies. The reason for study removal and the date the participant 
was removed must be documented in the study-specific case report form 
(CRF).  Alternative care options will be discussed with the participant. 
 
In the event of unusual or life-threatening complications, participating 
investigators must immediately notify the Principal Investigator, Matthew 
Davids, M.D. at 617-632-3352, DFCI pager # 57215 
 
Management and dose modifications associated with the above adverse events are 
outlined in Section 6 (Expected Toxicities and Dosing Delays/Dose Modifications). 

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6 EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS  
Dose delays and modifications will be made using the following recommendations. 
Fludarabine and cyclophosphamide may be dose-reduced beginning with cycle 1 as per 
standard of care at the discretion of the investigator, if approved by the PI. Dose reductions of 
rituximab are not permitted in cycle 1. Patients who experience a DLT may stay on study with 
IPI-145 dosed at the next lower dose level, as per Table 3. In cycle 2 and beyond, dose 
reductions to fludarabine and/or cyclophosphamide will be made as per standard practices at 
the discretion of the treating investigator, after a discussion with the principal investigator.  
Dose reductions of rituximab will not be permitted.   
Dose reductions of IPI-145 during cycles 2-6 and during the maintenance phase may be made 
as per table 3, after discussion with the principal investigator: 
Table 3. IPI-145 Dose Reduction 
 
Existing Dose (mg) 
New Dose (mg) 
25 mg PO bid 
25 mg PO QD 
25 mg PO QD 
15 mg PO QD 
15 mg PO QD 
IPI-145 must be discontinued 
 
Toxicity assessments will be done using the CTEP Version 4.0 of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) which is identified and located on the 
CTEP website at:  
 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf  
 
If possible, symptoms should be managed symptomatically. In the case of toxicity, 
appropriate medical treatment should be used (including anti-emetics, anti-diarrheals, etc.). 
 
All adverse events experienced by participants will be collected from the time of the first 
dose of study treatment, through the study and until the final study visit. Participants 
continuing to experience toxicity at the off study visit may be contacted for additional 
assessments until the toxicity has resolved or is deemed irreversible. 
  
6.1 Anticipated Toxicities 
  
A list of the adverse events and potential risks associated with the agents administered in this 
study appear below and will determine whether dose delays and modifications will be made 
or whether the event requires expedited reporting in addition to routine reporting. 
  
6.1.2 Adverse Event List for Fludarabine 

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The most common adverse reactions (frequency ≥10%) are edema, fever, fatigue, pain, chills, 
rash, nausea/vomiting, anorexia, diarrhea, gastrointestinal bleeding, urinary tract infection, 
neutropenia, febrile neutropenia, thrombocytopenia, anemia, leukopenia, weakness, myalgia, 
paresthesia, visual disturbance, cough, pneumonia, dyspnea, upper respiratory infection, 
diaphoresis, infection.  Rarely, fludarabine can be associated with autoimmune hemolytic 
anemia and second malignancy, in particular developing cancers such as myelodysplastic 
syndrome (MDS) or acute myelogenous leukemia (AML). Further details may be found in the 
FDA-approved label and Micromedex. 
6.1.3 Adverse Event List for Cyclophosphamide 
 
The most common adverse reactions (frequency ≥10%) are neutropenia, neutropenic fever, 
fever, thrombocytopenia, nausea, anemia, leukopenia, and vomiting.  Other rare, but significant 
adverse events include hemorrhagic cystitis, alopecia, amenorrhea, oligospermia, and gonadal 
suppression.  Further details may be found in the FDA-approved label and Micromedex. 
 
6.1.4 Adverse Event List for Rituximab 
 
Severe infusion reactions/hypersensitivity reactions:  hypotension, angioedema, hypoxia or 
bronchospasm. The most severe manifestations and sequelae include pulmonary infiltrates, 
acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, and 
cardiogenic shock.  Additional AEs include fevers, renal toxicity, rash, neutropenia, infection 
including progressive multifocal leukoencephalopathy, hepatitis B reactivation, 
hypogammaglobulinemia, and tumor lysis syndrome.  Further details may be found in the FDA-
approved label and Micromedex. 
 
6.1.5 Adverse Event List(s) for IPI-145 
 
For a detailed description of the toxicology studies performed in animal models, please see 
section 2.2.2. 
 
Frequently occurring (≥ 20% patients) adverse events observed in relapsed/refractory CLL/SLL 
patients receiving 25 mg BID included neutropenia (40%), diarrhea (32%), rash (combined 
terms) (32%), fatigue (28%), anemia (24%), ALT or AST increased (24%), cough (24%), 
pyrexia (24%), hyperglycemia (20%), nausea (20%) and sinus congestion (20%).  Serious 
adverse events occurring in more than 1 relapsed/refractory CLL/SLL patient at 25 mg BID 
included febrile neutropenia (3 [12%]), disease progression (2 [8%]), and stomatitis (2 [8%]).  
Other notable serious events were infections, including upper respiratory infections and 
pneumonias.   
 
Treatment-Related Lymphocytosis 
 
Similar to other agents targeting B-cell receptor signaling, transient lymphocytosis is a 
pharmacodynamic effect of IPI-145, in which inhibition of PI3K-mediated cellular homing 

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and adhesion results in a mobilization of tumor cells to the peripheral blood.  Upon initiation of 
IPI-145 monotherapy, a rapid, but transient phase of increase in lymphocyte counts (ie, ≥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 treated with IPI-145.  This observed transient lymphocytosis is usually not associated 
with an adverse event and should not be considered progressive disease in the absence of other 
clinical findings. Lymphocytosis occurs typically during the first few weeks of IPI-145 therapy, 
and resolves within a median of 6 months.  In the case of this study, we expect a lymphocytosis 
to occur during the initial week of IPI-145 monotherapy, but this should resolve quickly over 
time as patients are treated with FCR. 
 
Treatment of Overdose 
In the case of overdose, clinic staff should be notified immediately and supportive care is to be 
given as indicated. Patients should be informed to contact their doctor immediately if they have 
taken an overdose and should stop taking IPI-145. 

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6.2  Dose Modifications/Delays 
  
Patients will be monitored continuously for toxicity while on study therapy. Non-hematologic 
Toxicity will be assessed using the NCI-CTCAE Version 4.0. Hematologic toxicity will be 
assessed by IWCLL 2008 criteria.  If a patient has an adverse event of particular  
severity (see Table 4) at least possibly related to study drug, then dose modifications will be made 
according to Table 3. Deviations from these guidelines (e.g. drug interruption for Grade 2 
pneumonitis/pneumonia or AST/ALT elevation) may occur only if approved by the principal 
investigator. There should be no attempt to make up for doses omitted due to toxicity. 
 
Patients enrolled in the phase II expansion cohort or on maintenance who have an event which 
meets the DLT definition during any cycle will have IPI-145 withheld until resolution to Grade 1 
or baseline.  Upon resolution of the event, IPI-145 should be restarted at one dose level lower. In 
dose escalation patients, if the same event recurs during the subsequent cycle, the patient should be 
discontinued from the study. All IPI-145 dose reductions should be discussed with the principal 
investigator. 
 
IPI-145 dosing may be withheld up to 28 days (up to 21 days for Cycle 1 only) for toxicity. Doses 
withheld for >28 days (> 21 days for Cycle 1 only) will result in discontinuation from the study. In 
cases where IPI-145 has been held >28 days, IPI-145 may be resumed  after discussion with the 
overall PI in cases where toxicity is thought to be due to a cause other than IPI-145. Any patient 
who requires > 2 dose reductions for the same toxicity will be discontinued from the study.  
Patients who interrupt drug administration during Cycle 1 for a clinically significant drug-related 
AE that does not meet the DLT criteria will be considered to have had a DLT if the AE does not 
resolve to ≤ Grade 1 or baseline within 2 weeks. 
 
For an individual patient, dose reductions and discontinuations may be more conservative than 
indicated in Table 4 and Table 5 (i.e., dose reduce or discontinue at a lower grade of non-
hematologic toxicity) based on the clinical judgment of the investigator after discussion with the 
principal investigator. 
 
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 > 1 treatment cycle 
2. Patient has recovered to baseline levels from the toxicity which caused the dose reduction 
 
Table 4: Dose Modifications for IPI-145-Related Toxicities 
 
IPI-145-related Toxicitiesa, b 
Dose Modification/Recommendation for IPI-145c 
Grade 1  
Continue at current dose level  
Grade 2  
Continue at current dose level. If dose reduction is clinically 
indicated, contact the principal investigator  
Grade 3 Hematologic 
Continue at current dose level. If dose reduction is clinically indicated,  
contact the principal investigator 

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Grade 3 Nonhematologic (non-DLT)d  
First occurrence:  
Withhold until return to Grade 1 or baseline level; re-initiate therapy 
at current dose level.  If dose reduction is clinically indicated,  
contact the principal investigator 
Second occurrence:  
Withhold until return to Grade 1 or baseline level; re-initiate therapy 
at one dose level lower 
Third occurrence:  
Discontinue patient from study drug 
Grade 3 Nonhematologic (DLT)d  
First occurrence:  
Withhold until return to Grade 1 or baseline level; re-initiate therapy 
at one dose level lower.   
Second occurrence:  
Discontinue patient from study drug 
Grade 4 Nonhematologic (other than 
asymptomatic lab abnormalities) 
Discontinue patient from study drug 
Grade 4 Hematologic (non-DLT)  
First occurrence:  
Withhold until return to Grade 1 or baseline level; re-initiate therapy 
at current dose if duration ≤ 7 days.  If duration >7 days, re-initiate 
therapy at one dose level lower.   
Second occurrence:  
Withhold until return to Grade 1 or baseline level; re-initiate therapy 
at one dose level lower. 
Third occurrence:  
Discontinue patient from study drug 
Grade 4 Hematologic (DLT)  
First occurrence:  
Withhold until return to Grade 1 or baseline level; re-initiate therapy 
at current dose if duration ≤ 3 days.  If duration > 3 days, re-initiate 
therapy at one dose level lower. 
Second occurrence:  
Discontinue patient from study drug  
 
a. IPI-145 Related = possible, probable, or definite relationship to IPI-145 as defined in Section 11.1.4. 
b. Toxicity grades are defined per CTCAE Version 4.0. Note if parameter is not defined by CTCAE, then AE grading criteria (Section 11.1) should be 
utilized. 
c. Refer to the beginning of section 6 for IPI-145 dose levels. 
d. Includes Grade 3 diarrhea persisting for 7 days despite optimal antidiarrheal treatment, Grade 3 nausea and vomiting persisting for 7 days despite 
optimal antiemetic treatment, and Grade 3 QTcF prolongation. Grade 3 QTcF prolongation requires triplicate ECGs with the average measurement 
used and the use of Fridericia’s correction method (QTcF). For patients with a right or left BBB, a Grade 3 QTc prolongation is defined as an increase 
in QTcF of >100 ms from the pre-dose ECG to any post-dose ECG as the QRS interval is prolonged at baseline (by approximately 40 ms) in patients 
with a BBB. 
 
Table 5: Recommended IPI-145 Dose Reduction Levels 
 
Dose (mg)  
Reduction Level -1 (mg)  Reduction Level -2 (mg)  
25 BID  
25 QD  
15 QD  
25 QD  
15 QD 
Discontinue 
15 QD 
Discontinue 
N/A 
 
For patients enrolled in the phase II expansion cohort, a dose may be withheld up to 28 days for 
IPI-145-related toxicity. Doses withheld for >28 days due to IPI-145-related toxicity will result in 
discontinuation from the study. Any patient who requires >2 dose reductions due to treatment-
related toxicity will be discontinued from the study. 
 
 

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Management Guidelines for Hepatotoxicity 
 
Subjects who develop Grade 3 transaminase (ALT/AST) elevations with or without clinical symptoms 
should have IPI-145 held until return to baseline.  IPI-145 may be reintroduced after lab values have 
remained at baseline levels for at least one week. Consideration may be given to resuming IPI-145 at a 
one dose level reduction. Additional work-up to evaluate viral infection/re-activation, exposure to 
environmental toxins (e.g., alcohol/con-meds), or other causes is recommended before restarting 
treatment with IPI-145.  
 
If Grade  3 ALT/AST elevations recur upon re-challenge with IPI-145, hold IPI-145 and administer 
corticosteroids. In asymptomatic patients, a reduced dose of IPI-145 may be re-introduced after lab 
values have remained at baseline levels for at least one week.  
 
IPI-145 will be discontinued permanently in subjects who experience Grade  3 ALT/AST elevations 
following 2 dose reductions or in subjects who experience Grade ≥4 ALT/AST elevations at any time. 
However, patients may remain on study and continue to receive FCR and subsequent active follow-up 
visits as outlined in the treatment schedule. 
 
Dose Modification for FCR 
 
Fludarabine and cyclophosphamide may be dose-reduced beginning with cycle 1 as per standard 
of care at the discretion of the investigator, if approved by the PI. Dose reductions due to toxicity 
from FCR will be made according to standard practice.  Patients who meet DLT criteria for 
hematologic toxicity may for example have a 20% dose reduction of fludarabine from 25 mg/m2 to 
20 mg/m2 and cyclophosphamide from 250 mg/m2 to 200 mg/m2.  Further dose reductions may be 
discussed with the PI including further dose reduction to 15 mg/m2 for fludarabine and 150 mg/m2 
for cyclophosphamide.  Dose reductions to rituximab will not be permitted. 
 
For patients with a creatinine of > 1.5, fludarabine should be dose-reduced to 20 mg/m2.  Patients 
whose creatinine improves to ≤ 1.5 may receive full dose fludarabine in future cycles. 
6.3  Stopping Rules 
 
Adverse events will be monitored closely. The monitoring guidelines will serve as a trigger for 
consultation with the DF/HCC Data Safety and Monitoring Committee (DSMC) for additional review of 
potential closure of the study enrollment. The DSMC will automatically review this study every 6 
months, but can review it at a shorter interval on an as needed basis (see section 12.2 for additional 
detail).   
 
General Stopping Rule:  If in the first 10 additional patients enrolled to phase II part, we observe 3 or 
more patients develop DLTs, further accrual to the phase II portion will be halted pending review by the 
DSMC. Depending on the findings of its review, the DSMC may recommend the permanent closure of 
enrollment or continuation of enrollment.   As noted in section 5.3, the DLT observation period will 
include the entire duration of study treatment to capture any unacceptable toxicities that occur. 
 

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Stopping Rule for Hepatotoxicity:  The observation period for hepatotoxicity  will include the entire 
time the patient is on treatment.   If in the first 7 additional patients (of the remaining 15 to be enrolled in 
the phase II portion) we observe 3 or more patients develop grade 3 or higher hepatotoxicity, further 
accrual to the phase II portion will be halted pending review by the DSMC. Depending on the findings of 
its review, the DSMC may recommend the permanent closure of enrollment or continuation of 
enrollment.   
 
 

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7 DRUG FORMULATION AND ADMINISTRATION  
 
7.1 Fludarabine, Cyclophosphamide, Rituximab (FCR) 
 
7.1.1  Fludarabine 
 
Identification and Mechanism of Action – Fludarabine is a nucleoside analog. It is metabolize 
to 2-fluoro-ara-ATP whereby it inhibits DNA synthesis through inhibition of DNA polymerase, 
ribonucleotide reductase, and DNA primase. 
 
Relevant FDA Indications – Upfront and relapsed CLL 
 
Non-FDA Labeled Indications – AML, malignant lymphoma, membranous glomerulonephritis, 
mycosis fungoides, Sezary’s disease. 
 
Dose and Schedule – 25 mg/m2/day, days 1-3, every 28 days. 
 
How Supplied – 50 mg vials of powder (solution is also acceptable) to be diluted in 100 
ml to 125 ml of D5W or NS for intravenous infusion over approximately 30 to 60 minutes.  
Fludarabine will be commercially supplied and is available from various manufacturers. 
 
7.1.2  Cyclophosphamide 
 
Identification and Mechanism of Action – Cyclophosphamide is an alkylating agent that 
prevents cell division by cross-linking DNA strands and decreasing DNA synthesis.  It is a cell 
cycle phase nonspecific agent.  Cyclophosphamide also possesses potent immunosuppressive 
activity.  Cyclophosphamide is a prodrug that must be metabolized to active metabolites in the 
liver. 
 
Relevant FDA Indications – Upfront and relapsed CLL 
 
Non-FDA Labeled Indications – Ewing’s sarcoma, rhabdomyosarcoma, Wilms tumor, ovarian 
germ cell tumors, gestational trophoblastic tumors, small cell lung cancer, testicular cancer, 
pheochromocytoma, hematopoietic stem cell transplant conditioning.. 
 
Dose and Schedule – 250 mg/m2/day, days 1-3, every 28 days. 
 
How Supplied – 500 mg (1 ea), 1 g (1 ea), 2 g (1 ea) solution, reconstituted for intravenous 
infusion over approximately 30 to 60 minutes.  Cyclophosphamide will be commercially 
supplied and is available from various manufacturers. 
 
7.1.3  Rituximab 
 
Rituximab is a sterile, clear, colorless, preservative-free liquid concentrate for 
intravenous (IV) administration. Rituximab is supplied at a concentration of 10 

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mg/mL in either 100 mg (10 mL) or 500 mg (50 mL) single-use vials. The 
product is formulated for intravenous administration in 9.0 mg/mL sodium 
chloride, 7.35 mg/mL sodium citrate dihydrate, 0.7 mg/mL polysorbate 80, and 
Sterile Water for Injection. The pH is adjusted to 6.5. 
 
Reconstitution 
Use appropriate aseptic technique. Withdraw the necessary amount of Rituximab 
and dilute to a final concentration of 1 to 4 mg/mL into an infusion bag containing 
either 0.9% Sodium Chloride USP or 5% Dextrose in Water USP. Gently invert 
the bag to mix the solution. Discard any unused portion left in the vial. Parenteral 
drug products should be inspected visually for particulate matter and discoloration 
prior to administration. Rituximab solutions for infusion are stable at 2° to 8°C 
(36° to 46°F) for 24 hours and at room temperature for an additional 12 hours. No 
incompatibilities between Rituximab and polyvinylchloride or polyethylene bags 
have been observed. 
 
Stability and Storage 
Rituximab vials are stable at 2° to 8°C (36° to 46°F). Do not use beyond 
expiration date stamped on carton. Rituximab vials should be protected from 
direct sunlight. 
 
Dosage and Administration 
Rituximab will be administered IV at a dose of 375 mg/m2 on day 1 of cycle 1. 
Patients with ≥ 15,000 circulating malignant cells/ mm3 or at the discretion of the 
treating physician will receive only 50 mg/m2 on day 1 of cycle 1 to reduce the 
incidence of tumor lysis syndrome and infusion reactions, with the remaining 325 
mg/m2 given on day 2 or 3 of cycle 1. If the day 1 infusion cannot be completed 
within 1 day, the patient is allowed to receive the remainder of the infusion the 
following day on day 2. For patients receiving split dose rituximab with cycle 1, 
if the day 2 or 3 infusion cannot be completed within 1 day, the patient is allowed to 
receive the remainder of the infusion the following day. In cycles 2-6, 
rituximab will be escalated to 500 mg/m2 and will be administered on day 1 of 
each cycle. If the day 1 infusion cannot be completed within 1 day, the patient is 
allowed to receive the remainder of the infusion the following day on day 2. 
Rituximab may be administered in an outpatient setting and will be administered according to 
standard clinical practice, roughly described below. 
 
DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS. 
 
Hypersensitivity reactions may occur. Standard premedication, usually consisting 
of acetaminophen 650-1000 mg po x 1, hydrocortisone 100 mg IV x 1 (or any 
equivalent corticosteroid like methylprednisolone or dexamethasone), and 
diphenhydramine 25-50 mg IV or po x 1, should be given before each infusion of 
rituximab. 
 
Rituximab for patients with starting absolute lymphocyte count < 15,000 / μl: 

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First Infusion: The Rituximab solution for infusion should be administered 
intravenously at an initial rate of 50 mg/hr. Rituximab should not be mixed or 
diluted with other drugs. If hypersensitivity or infusion-related events do not 
occur, escalate the infusion rate in 50 mg/hr increments every 30 minutes, to a 
maximum of 400 mg/hr. Variations consistent with standard administration of 
rituximab are acceptable per institutional guidelines. 
 
Rituximab infusion should be interrupted for severe reactions. In most cases, the 
infusion can be resumed at a 50% reduction in rate (e.g., from 100 mg/hr to 50 
mg/hr) when symptoms have completely resolved. Treatment of infusion-related 
symptoms with diphenhydramine and acetaminophen and corticosteroids if 
needed is recommended. Additional treatment with bronchodilators or IV saline 
may be indicated. Most patients who have experienced nonlife-threatening 
infusion-related reactions have been able to complete the full course of rituximab 
therapy. Epinephrine, antihistamines and corticosteroids should be available for 
immediate use in the event of a hypersensitivity reaction to Rituximab (e.g., 
anaphylaxis).  If the day 1 infusion cannot be completed within 1 day, the patient 
is allowed to receive the remainder of the infusion the following day on day 2. 
Subsequent Infusions: Subsequent Rituximab infusions can be administered with 
20 percent of the total dose over 30 minutes, followed by the remaining 80 
percent of the total dose over 60 minutes. 
 
Rituximab for patients with absolute lymphocyte count >15,000 / μl or those 
patients with large tumor burden (at the discretion of the treating physician): 
 
First cycle only: On day 1, patients will receive rituximab 50 mg/m2 
IV over 4 hours without rate escalation, following chemotherapy administration. On day 2 or 3, 
patients may receive rituximab 325 mg/m2 IV starting at 50 mg/hr, escalating by 
50 mg/hr increments every 30 minutes to a maximum rate of 400 mg/hr as 
tolerated, with slight variations permitted according to standard protocol per 
institutional standards. If the day 2 or 3 infusion cannot be completed within 1 day, the 
patient is allowed to receive the remainder of the infusion the following day. 
 
Second and subsequent cycles: Rituximab 500 mg/m2:  IV on day 1 according to 
standard protocol. If the day 1 infusion cannot be completed within 1 day, the 
patient is allowed to receive the remainder of the infusion the following day on 
day 2. 
 
Procurement 
Rituximab is approved by the FDA for treatment of low-grade B cell lymphomas 
and is widely used for the treatment of chronic lymphocytic leukemia. Rituximab 
for this study will be from commercial supply, manufactured by Genentech (South San 
Francisco, CA). 

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7.2 IPI-145 
 
7.2.1 Description 
 
IPI-145 is a potent oral inhibitor of the delta- and gamma-isoforms of PI3K.  In a phase I 
study of 117 patients with relapsed, refractory hematologic malignancies, pharmacokinetics 
studies revealed that IPI-145 is rapidly absorbed, with maximal plasma concentrations 
typically observed 1 hour following dosing (Patel, et al, 2013).  Exposure (AUC) increased 
proportionally with doses through 75 mg PO bid.  The half-life was 4-5 hours, regardless of 
dose.  The mean pre-dose steady state plasma concentration following 25 mg BID was 390 
ng/mL, indicating suppression of PI3K-delta (IC50=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 IPI-145 in CLL cells, as 
well as decreased levels of chemokines such as CCL3 and CCL4, which are important for 
lymphocyte trafficking.  The MTD of IPI-145 as monotherapy for CLL has been determined 
to be 75 mg bid. 
 
7.2.2 Form 
 
IPI-145 drug substance is a white to off-white crystalline powder. The IPI-145 drug product is 
formulated with excipients (diluent/glidant, disintegrant, and lubricant) that are listed in 
FDA’s Inactive Ingredients Database for approved drug products and/or Generally Regarded 
as Safe (GRAS).  IPI-145 drug product is supplied as 5 mg (size 2 Swedish orange) and 25 
mg (size 2 white hard) gelatin capsules for oral delivery. 
 
7.2.3 Storage and Stability 
 
IPI-145 must be stored at room temperature (15 to 30°C) and protected from light. 
  
7.2.4 Compatibility 
 
Not applicable 
7.2.5 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 IPI-145. Pharmacists should follow standard procedures 
for the handling of investigational drugs, including avoidance of eye or skin contact with the 
drug product. If there is exposure to the drug product, provide treatment as necessary for 
physical exposure (skin washing) or inhalation (move to fresh air) and seek medical advice as 
necessary.  
 

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When IPI-145 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 IPI-145 swallows a capsule or inhales 
drug powder from a broken capsule of IPI-145, 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. 
 
7.2.6 Availability 
 
IPI-145 is an investigational agent and will be supplied free-of-charge from Verastem, 
Needham, MA.  
 
7.2.7 Preparation 
 
IPI-145 will be supplied to the clinical trial site as open-label medication.   Capsules are 
packaged in opaque bottles with induction-sealed child-resistant caps or thermoform blister 
cards with peel and push child-resistant lidding. The label attached to each bottle or blister 
card will include, at a minimum, a statement limiting its use for investigational study only. 
 
7.2.8 Administration 
 
IPI-145 is administered orally as a capsule formulation once a day or twice per day in 28 day 
cycles as a fixed dose in mg, and should be administered using the minimal number of 
capsules necessary.  
 
Beginning on Cycle 1, Day -7, IPI-145 will be administered QD or bid at the designated 
cohort dose, and will be administered in 28 day cycles (except for cycle 1, which is 28 days 
plus 7 day lead in).  Doses must be taken within ±3 hours of the scheduled dose. The date, 
time, and quantity of each capsule strength taken will be recorded in a drug self-
administration diary. Patients should record any deviation from taking the full daily dose (e.g., 
vomited doses, missed doses, doses reduced due to missing or lost capsules). An attempt 
should be made to enable each dose to be taken at approximately the same time of day. 
Missed doses outside the windows defined above or vomited doses should not be taken or 
repeated.  At each visit, a sufficient number of doses will be dispensed so that the patient will 
have the required number of doses until the next visit, taking into account the window for the 
next visit.  IPI-145 capsules should be swallowed whole with a glass of water (approximately 
8 ounces or 240 mL) at approximately the same time(s) each day. Patients must avoid 
grapefruit or grapefruit juice. IPI-145 may be administered without regard to meals. IPI-145 
should be taken per the usual schedule on the days of laboratory correlative studies; 
administration should not wait until after procedures are performed.   
 
7.2.9 Ordering 
 
The DF/HCC pharmacy will order IPI-145 directly from Verastem, Needham, MA, who will be 
providing the study drug free of charge. 

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7.2.10 Accountability 
 
The investigator, or a responsible party designated by the investigator, will maintain a 
careful record of the inventory and disposition of IPI-145 using the NCI Drug Accountability 
Record or another comparable drug accountability form. (See the CTEP website at 
http://ctep.cancer.gov/protocolDevelopment  for the “Policy and Guidelines for  Accountability 
and Storage of Investigational Agents” or to obtain a copy of the drug accountability form.) 
 
7.2.11 Destruction and Return 
 
After full drug accountability and reconciliation, the Investigators will return all IPI-145 to 
Verastem, or its designee or, at Verastem’s request, will dispose of the study drug at the 
clinical trial site, according to site procedures.  Destruction will be documented in the Drug 
Accountability Record Form.  If any study drug is lost or damaged, the disposition of the 
study drug should be documented.  
 
Patients should be instructed to bring all unused IPI-145 to each study visit. The study site 
should count all capsules that the patient returns, and should take account for taken doses, 
missed doses, doses reduced due to missing or lost capsules, etc., before dispensing new study 
drug to the 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. 

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8 CORRELATIVE/SPECIAL STUDIES 
All sites will be encouraged to provide the correlative samples for analysis, as feasible. While the 
goal of the biomarkers 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 or strategic 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. 
8.1 Pharmacokinetic Studies 
 
As the pharmacokinetic (PK) properties of IPI-145 have been well-characterized in 
patients with CLL, no additional PK studies are planned for this trial.   
8.2 Pharmacodynamic Studies 
8.2.1 Laboratory Correlative Studies 
8.2.1.1 BH3 Profiling 
 
BH3 profiling is a functional assay we previously developed that detects the proximity of 
CLL cells to the threshold of apoptosis (what we call ‘priming’) through interrogation of 
BCL-2 family members.  To perform a BH3 profile, we add individual BH3-only peptides to 
gently permeabilized malignant cells and use FACS to measure the amount of mitochondrial 
depolarization induced by each peptide, as measured by cytochrome c release.  
 
We hypothesize that patients whose cells undergo significant depolarization to BIM BH3 
peptide (highly primed) will have superior clinical response to iFCR 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.   
 
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 IPI-145 monotherapy on cycle 1 day 1 (prior to receiving chemotherapy), 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 in vivo the short term 
change in apoptotic priming induced by IPI-145 as a single agent.  We will also attempt to 
identify potential resistance mechanisms by looking at whether patients who do not achieve 
an MRD-negative CR have different upfront BH3 profiles from those who do.  Finally, 
anothertube of 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 

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samples to help identify whether a change in anti-apoptotic protein dependence is observed 
as a possible mechanism of resistance. 
 
All peripheral blood samples will promptly be delivered to the laboratory of Dr. Jennifer 
Brown at room temperature, 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. Anthony Letai, where the BH3 profiling assays will be 
performed (for detailed methods see Ryan et al., 2010). 
8.2.1.2 
Genomic Analysis 
 
We plan to perform whole exome sequencing on CLL cells and normal tissue from patients 
at baseline to evaluate for somatic mutations such as NOTCH1, MYD88 and SF3B1 that may 
confer drug sensitivity and resistance. If the patient does not have significant circulating CLL 
cells, bone marrow aspirate should be obtained as well in patients who require a new bone 
marrow biopsy for screening.In addition, saliva as a source of germline will be collected 
prior to study initiation and may be collected more than once if inadequate specimen is 
obtained.   All of the above samples will promptly be delivered to the laboratory of Dr. 
Jennifer Brown at room temperature, where DNA will be extracted and then sent to the 
Broad Institute (Cambridge, MA) for whole exome sequencing.  In an exploratory analysis, 
we will assess novel mutations as potential predictors of response and progression-free 
survival.  We will also collect a sample from each patient at time of relapse or progression 
for repeat analysis by whole exome sequencing to assess for acquired resistance mutations. 
8.2.1.3 
Pharmacodynamic Markers 
 
Pharmacodynamic markers will also be assessed to determine whether IPI-145 is hitting its 
proposed target in vivo.  Peripheral blood samples will be drawn pretreatment and on cycle 1, 
day 1, at the end of cycle 3, at the end of combination therapy, 6 months after the end of 
combination therapy, and 12 months after the end of combination therapy.  Additional 
peripheral blood samples are requested every subsequent 6 months for up to 5 additional time 
points. These samples will be brought to the laboratory of Dr. Jennifer Brown, where PBMCs 
will be isolated for analysis.  Viably frozen cells will be shipped to Verastem, who will use 
phosphoflow cytometry to determine the levels of phospho-AKT and phospho-ERK 
compared to total AKT and ERK, respectively.  These analyses will be confirmed in a subset 
of patients by Western Blot.  In addition, current work has suggested that reduction in the cell 
proliferation marker Ki-67 in peripheral blood CLL cells occurs rapidly in patients treated 
with BCR pathway antagonists, and this may also be assessed in the Brown lab by 
phosphoflow cytometry in samples from patients on our study. 
8.2.1.4 
Genzyme Minimal Residual Disease 
 
Bone marrow samples will be collected for minimal residual disease analysis by Genzyme 
Genetics by flow cytometry at the end of cycle 3, the re-staging evaluation approximately 2 
months after the end of combination therapy with FCR, and again approximately 12 months 
after combination therapy. Patients who have not already had Zap70, TP53 and IGHV testing 

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45 
will send additional baseline samples to Genzyme/LabCorp. These samples will be shipped 
alongside the Integrated Oncology/LabCorp requisition form ambient priority overnight to: 
 
Genzyme/LabCorp Specialty Testing Group 
521 West 57th Street 
New York, NY 10000 
8.2.1.5 
Sample Collection Schedule 
Sample Time 
Point 
Container1 
Sample Type 
Shipping Method 
Recipient3 
Screening or      
Pre-dose Day -7 
6x 6mL Green Top 
1x6ml Red Top 
1x10ml Purple Top 
Peripheral Blood  
Fridge pack 
overnight  
CLL Center, J. 
Brown lab 
1x6ml Green Top 
1x3ml Purple Top 
Bone Marrow Aspirate 
 
1x Oragene Kit 
Saliva2 
Ambient overnight 
2x10ml Purple Top* 
1x6ml Green Top* 
Peripheral Blood 
Ambient overnight  
Genzyme/LabCorp 
Cycle 1 Day 1 
(Prior to 
chemotherapy) 
6x6mL Green Top 
1x6ml Red Top 
Peripheral blood 
Fridge pack 
overnight 
CLL Center, J. 
Brown lab 
End of Cycle 32 
6x6ml Green Top 
1x6ml Red Top 
Peripheral Blood  
Fridge pack 
overnight  
CLL Center J. Brown 
lab 
1x6ml Green Top 
 
Bone Marrow Aspirate 
1x 6ml Green Top 
 
Bone Marrow Aspirate 
Ambient overnight 
Genzyme/LabCorp 
Re-Staging (2 
months post FCR) 
6x6mL Green Top 
1x6mL Red Top 
1x10ml Purple Top 
Peripheral Blood  
 
Fridge pack 
overnight 
CLL Center, J. 
Brown lab 
1x6ml Green Top 
1x3ml Purple Top  
Bone Marrow Aspirate 
1x 6ml Green Top 
Bone Marrow Aspirate 
Ambient overnight 
Genzyme/LabCorp 
6 months post FCR 
6x6mL Green Top 
1x6ml Red Top 
Peripheral Blood 
Fridge pack 
overnight 
CLL Center, J. 
Brown lab 
12 months post 
FCR 
6x6mL Green Top 
1x6ml Red Top 
Peripheral Blood  
Fridge pack 
overnight 
CLL Center, J. 
Brown lab 
1x6ml Green top  
Bone Marrow Aspirate 
1x6ml Green Top 
Bone Marrow Aspirate 
Ambient overnight 
Genzyme/LabCorp 
Q 6 months 
thereafter for up to 
5 time points 
6x6mL Green Top 
1x6ml Red Top 
Peripheral Blood 
Fridge pack 
overnight 
CLL Center, J. 
Brown lab 
Relapse/Disease 
Progression 
6x6mL Green Top 
1x6mL Red Top 
Peripheral Blood  
 
Fridge pack 
overnight 
CLL Center, J. 
Brown lab 
1x6ml Green Top 
Bone Marrow Aspirate 
1 Green top= sodium heparin tube; Red top= no additive; Purple top: K2EDTA 
2Oragene kits will be provided by the lead site, and requires approximately 2mLs of saliva 
3LabCorp and CLL labs only provides requisition form 
* Samples required for all patients at baseline unless already been tested for Zap70, IGHV and TP53

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9  STUDY CALENDAR 
Baseline evaluations are generally to be conducted within 2 weeks prior to start of protocol 
therapy.  Scans must be done ≤8 weeks prior to the start of therapy. Bone marrow biopsy 
must be done ≤8 weeks prior to the start of therapy unless done within the prior 6 months 
without intervening therapy.  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. 
All assessments must be performed prior to administration of any study medication. All 
study assessments should be performed within +7 days of the protocol-specified date, 
unless otherwise noted.  All study visits should occur within a +4 day window, except 
for visits occurring during the follow-up phase after the completion of the combination 
portion of the study, which may occur within a +14 day window. The two month post 
FCR restaging visit may occur with a +14 day window. 
9.1 Pre-Treatment Evaluations 
 
• Signed informed consent document 
• Vital signs and physical examination 
• Medical history: Detailed documentation of disease and treatment history with 
outcomes 
•  ECOG performance status 
•  Concurrent medical conditions 
•  Concurrent medications 
•  CBC with differential and platelet count 
• Serum chemistries: Electrolytes (sodium, potassium, chloride, and bicarbonate), 
calcium, magnesium, phosphate, blood urea nitrogen (BUN), creatinine, glucose, 
uric acid, lactate dehydrogenase (LDH), and liver function tests (aspartate 
aminotransferase (AST) and alanine aminotransferase (ALT), alkaline phosphatase 
(ALP), total protein, albumin, total bilirubin, direct bilirubin, lipase, amylase, beta-
2 M 
• Coagulation studies including prothrombin time and partial thromboplastin time 
• Thyroid stimulating hormone level (TSH) 
• Urinalysis 
• Quantitative immunoglobulins and serum protein electrophoresis 
• Direct antiglobulin test (Direct Coomb’s test) 
• Reticulocyte count 
• Haptoglobin 
• Bone marrow biopsy, including flow cytometry (lymphoma panel), karyotype, and 
FISH (CLL panel) 
• Peripheral FISH analysis (if not being performed on Bone Marrow) (6 month 
window) 
• CD4 panel (routine T-cell subsets) 

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• NOTCH1, MYD88 (unless already tested and enrolled on DFCI trial i.e: 99-224) 
•  Hepatitis B and C serologies 
• HIV 
• Serum pregnancy test for females of childbearing potential. A female of 
childbearing potential (FCBP) is a sexually mature female who: 1) has not 
undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally 
postmenopausal for at least 24 consecutive months (i.e., has had menses at any time 
in the preceding 24 consecutive months). 
• Saliva Sample 
• Baseline EKG 
• Full body CT scan (neck, chest, abdomen/pelvis) with oral and IV contrast, unless 
contrast is contraindicated. Measurements will be made by the DF/HCC tumor 
imaging metric core (TIMC). 
• Serum IGHV and TP53 mutational analysis (1 purple top 10 cc tube each )and 
ZAP-70 testing (1 green top 6 cc tube) (unless already tested and enrolled on DFCI 
trial i.e: 99-224) 
9.2  Evaluations During Treatment 
 
9.2.1 The following assessments will be performed weekly during the first cycle, every 
2 weeks during the second cycle, and on day 1 of all subsequent cycles: 
 
Physical Examination 
• Recording of AEs (patients and/or family members will be instructed to 
telephone the site with any changes in mental or physical status or with any 
questions regarding treatment) 
• CBC with differential and platelet count 
• Serum chemistries: Electrolytes (sodium, potassium, chloride, and bicarbonate), 
calcium, magnesium, phosphate, blood urea nitrogen (BUN), creatinine, glucose, 
uric acid, lactate dehydrogenase (LDH), and liver function tests (aspartate 
aminotransferase (AST) and alanine aminotransferase (ALT), alkaline 
phosphatase (ALP), total protein, albumin, total bilirubin, direct bilirubin, amylase.  
AST/ALT and total bilirubin will be checked at least weekly in all subjects beginning in 
the third week of IPI-145 treatment and continuing through week 16 of IPI-145 treatment, 
even in the absence of abnormalities.  Local laboratory testing will be acceptable at the 
discretion of the treating investigator, provided that the results can be obtained in a timely 
fashion. 
• MRD performed on peripheral blood at cycle 3 re-stage. 
 
9.2.2 The following assessments will be performed only on day 1 of all cycles: 
• ECOG Performance Status 
• Recording of concomitant medications. 
 
9.2.3 The following objective disease assessments are to be performed within 7 days 
prior to completing cycles 3 and one month after completion of cycle 6 (i.e. 2 months 
after last dose of chemotherapy): 

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• Full body CT scan (neck, chest, abdomen/pelvis) with oral and IV contrast, unless 
contrast is contraindicated. Measurements will be made by the DF/HCC tumor 
imaging metric core (TIMC). 
•  A bone marrow biopsy will be performed to determine MRD status. 
 
9.3 Evaluations after Combination Treatment  
 
9.3.1 One Month Post-FCR Safety Evaluation 
 
After completing FCR, patients will continue on IPI-145 with continuous dosing.  They 
will be seen one month after FCR for a safety evaluation, and if continuing to tolerate IPI-
145 well will continue on IPI-145 monotherapy thereafter. 
 
The following clinical assessments will be performed at this visit: 
• Full physical examination 
• Weight and vital signs (blood pressure, pulse rate, respiratory rate, and 
temperature) 
• ECOG Performance Status 
• Recording of AEs 
• Recording of concomitant medications 
 
The following laboratory assessments will be performed: 
• CBC with differential and platelet count 
• Serum chemistries: Na, K, Cl, HCO3, glucose, blood urea nitrogen (BUN), 
creatinine, calcium, magnesium, phosphate, total bilirubin, AST, ALT, alkaline 
phosphatase, albumin, total protein, and lactate dehydrogenase (LDH), direct 
bilirubin, amylase. 
 
9.3.2 Two Months Post-FCR Re-staging Visit 
 
For patients completing 6 cycles of therapy, restaging assessments should occur about 8 
weeks after last dose of chemotherapy (+14 day window). When a patient discontinues 
treatment prior to completion of cycle 6, end of study assessments are to be performed 
approximately 8 weeks after the last dose of chemotherapy. If the patient is not 
available, the reason for not completing the end of study assessments must be recorded 
in the patient’s source documents. 
 
The following clinical assessments will be performed at this visit: 
• Full physical examination 
• Weight and vital signs (blood pressure, pulse rate, respiratory rate, and 
temperature) 
• ECOG Performance Status 
• Recording of AEs 
• Recording of concomitant medications 

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• Full body CT scan (neck, chest, abdomen/pelvis) with oral and IV contrast, unless 
contrast is contraindicated. Measurements will be made by the DF/HCC tumor 
imaging metric core (TIMC).   
 
The following laboratory assessments will be performed: 
• CBC with differential and platelet count 
• Serum chemistries: Na, K, Cl, HCO3, glucose, blood urea nitrogen (BUN), 
creatinine, calcium, magnesium, phosphate, total bilirubin, AST, ALT, alkaline 
phosphatase, albumin, total protein, and lactate dehydrogenase (LDH), direct 
bilirubin, amylase. 
• Bone Marrow Biopsy including flow cytometry and CLL FISH panel in patients 
completing the chemotherapy portion of the study, for end-of-treatment response 
assessment (to be completed 4 weeks following completion of the final cycle of 
chemotherapy, ie 8 weeks after the last dose of chemotherapy).  
•  Minimal Residual Disease (MRD) assessment will be made by flow cytometry 
both on bone marrow as well as peripheral blood. 
 
9.3.3 IPI-145 Maintenance 
 
Patients who complete 6 cycles of iFCR and have achieved a PR, CRi, or CR will be 
eligible to proceed with IPI-145 monotherapy as maintenance, and will continue at the 
same dose they were previously on during the combination portion of the trial.  Patients 
who complete at least 3 cycles of iFCR but cannot receive additional cycles of 
chemotherapy due to toxicity will also be able to proceed to IPI-145 monotherapy 
maintenance, as long as they have achieved a PR, CRi, or CR. 
  
All patients who go on to receive IPI-145 maintenance will be followed with visits every 
2 months until time of progression for up to 2 years if there is no progression. 
 
The following clinical assessments will be performed: 
• History 
• Full physical examination 
• Weight and vital signs (blood pressure, pulse rate, respiratory rate, and 
temperature) 
• ECOG Performance Status 
• Recording of AEs 
• Recording of concomitant medications 
•  Re-staging with full body CT is required for patients in partial remission every 6 
months or until complete remission is achieved.  Re-staging scans are also required 
for patients on IPI-145 who are coming off study due to clinical or laboratory 
disease progression.  Routine re-staging CT scan is not required for patients in 
complete remission, and may be performed at the discretion of the treating 
investigator. When employed, the recommended schedule in remission is every 6 
months beginning 6 months following the two month post-FCR CT scan and 
continued until disease progression, or for a minimum of 1 year if the disease 
remains in remission. 

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• For patients in radiographic CR or Cri who have not achieved bone marrow MRD-
negativity, serial bone marrow biopsies to assess MRD status will be performed at 
yearly intervals and MRD status checked on peripheral blood at 6 month intervals 
until MRD-negativity in both compartments is achieved is achieved 
• For patients who have achieved MRD-negativity, serial MRD testing by flow 
cytometry will be performed every 6 months in the peripheral blood 
 
9.3.4    Post-Maintenance Follow-up 
 
Patients completing 2 years of maintenance IPI-145 or those who do not go on to receive 
IPI-145 maintenance will be followed on a schedule at the discretion of their oncologist 
until initiation of new therapy, or death. Patients who complete maintenance will have 
optional bone marrow biopsies yearly to assess for conversion to MRD-positive status. 
 
The following procedures will be completed: 
 
• Recording of AEs (patients and/or family members will be instructed to 
telephone the site with any changes in mental or physical status) for 90 days 
following their last dose of IPI-145 
 
• Restaging with full body CT is not required for patients in complete remission, 
and may be performed at the discretion of the treating investigator. When 
employed, the recommended schedule in remission is every 6 months beginning 6 
months following the end of treatment and continued until disease progression or 
for a minimum of 1 year if the disease remains in remission. 

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51 
Study Calendar 
 
 
Pre- 
Study 
C1D-7 
C1D1 
C1D2 
C1D3 
C1D8 
C1D15 
C1D22 
 
C2D1 
C2D15 
C3-6 D1 
1 month 
post FCR 
2 months post 
FCR (re-staging) 
Maintenancek  
(visits q 2 
months) 
30 day post-
dose follow-
up 
Long Term 
Follow Upn 
Off  
Treatmentd 
IPI-145 
 
X-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X 
 
 
 
FCR 
 
 
X 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
 
 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Con meds 
 
 
 
X---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X 
Physical exam 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Performance 
Status 
X 
X 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
CBC w/diff 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum 
chemistry a 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Descriptive 
Studiesb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CMV viral 
loade 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
B-HCG 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone Marrow 
Biopsyj 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
 
MRD 
assessmenti 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
Xg 
Radiographic 
evaluationf 
X 
 
 
 
 
 
 
 
 
 
Xf 
 
X 
 
X 
X 
 
Correlative 
studiesm 
X 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
Xh 
AE evall 
 
 
X----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X 

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a: Albumin, alkaline phosphatase, direct bilirubin, total bilirubin, BUN, bicarbonate, calcium, chloride, creatinine, glucose, LDH, magnesium, phosphorus, potassium, total  
protein, SGOT  [AST], SGPT [ALT], sodium, uric acid. Lipase, and beta-2 M- only required at pre-study.  AST/ALT and total bilirubin will be checked at least weekly in all 
subjects beginning in the third week of IPI-145 treatment and continuing through week 16 of IPI-145 treatment, even in the absence of abnormalities.  Local laboratory testing will 
be acceptable at the discretion of the treating investigator, provided that the results can be obtained in a timely fashion. 
b: Descriptive studies: Coagulation studies including prothrombin time and partial thromboplastin time; thyroid stimulating hormone level (TSH), urinalysis, quantitative 
immunoglobulins and serum protein electrophoresis, direct antiglobulin test (Direct Coomb’s test), reticulocyte count, haptoglobin,CD4 panel (routine T-cell subsets), 
Hepatitis B and C serologies, NOTCH1, MYD88 and saliva. 
c: Serum pregnancy test (women of childbearing potential). 
d: Off-study evaluation should be conducted at each participating DF/HCC site, except in case of extenuating circumstances. 
e:  CMV viral load testing frequency in patients who develop a positive test will be increased to weekly until testing becomes negative, at which point testing can return to the 
schedule outlined here 
f:  Radiographic evaluations include CT neck/chest/abdomen/pelvis, and will occur at screening, at the conclusion of cycle 3, and at the re-staging visit 2 months after completing 
FCR. 
g:  For patients completing the full maintenance phase or those coming off study for reasons other than disease progression. 
h:  For patients coming off study due to disease progression. 
i:  MRD assessments will be performed by flow cytometry on both bone marrow and blood, just prior to cycle 4, at final re-staging visit, and then on blood only every 6 months 
during maintenance. 
j:  Bone marrow biopsy required pre-treatment, just prior to cycle 4, at 2 month post-FCR re-staging visit, and yearly thereafter in MRD-positive patients continuing on 
maintenance IPI-145 
k:  Please see section 9.3.4 for details on the post-maintenance follow-up schedule 
l: IPI-145 should be taken per the usual schedule on the days of laboratory correlative studies; administration should not wait until after procedures are performed. 
m: See section 8.2.1.5 for complete correlative study sample collection schedule.  
n: Frequency of follow up visits and scans are per MD discretion. Recommended follow up visits for a minimum of one year. Treating physicians will notify lead site their 
preference for FU visits. 

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10   MEASUREMENT OF EFFECT  
 
10.1 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 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.) 
 
10.2 Methods for Evaluation of Measurable Disease 
All lymph node measurements should be taken and recorded in metric notation, using a 
ruler, calipers, or digital measurement tool. All baseline evaluations should be performed 
as closely as possible to the beginning of treatment and not more than 8 weeks before the 
beginning of the 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 and MRI. 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. This applies to tumors of the chest, abdomen, and 
pelvis. Head and neck tumors and those of extremities usually require specific protocols. 
 
10.3 Response Criteria 
 
Response and progression will be evaluated in this study using the 2008 IW-CLL criteria 
for CLL (Hallek et al., 2008) 
 
10.3.1 Complete remission (CR): 
 
CR requires all of the following criteria: 
- Peripheral blood lymphocytes (evaluated by blood and differential count) below 4 x 
109/L (4000/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. 

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- 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. 
 
10.3.2 Complete remission with incomplete marrow recovery (CRi): 
Patients who fulfill all the criteria for a CR but who have a persistent anemia or 
thrombocytopenia or neutropenia felt unrelated to CLL but related to drug toxicity. Bone 
marrow examination must reveal no clonal B-cell population by flow cytometry. 
 
10.3.3 Minimal Residual Disease 
Patients who achieve CR or Cri will be assessed for minimal residual disease (MRD).  
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. 
 
10.3.4 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: 
-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. 
- 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. 
 
10.3.5 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. 
 

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10.3.6 Progressive disease (PD) 
Progressive disease during or after therapy is characterized by at least one of the 
following: 
- Lymphadenopathy. Progression of lymphadenopathy is often discovered by physical 
examination and should be recorded. For CT scans used to 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. 
- 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 IPI-145 
monotherapy or any increase during combination therapy in the setting of improvement 
of lymph nodes or cytopenias will not be considered disease progression) 
- Transformation to a more aggressive histology (eg, Richter syndrome). This diagnosis 
must be established by lymph node biopsy. 
- Occurrence of cytopenia (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. 
 
10.3.7 Stable disease (SD) 
Patients who have not achieved a CR or a PR, and who have not exhibited progressive 
disease, will be considered to have stable disease. 
 
10.3.8 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. 
 
10.3.9 Time to progression, progression-free survival, and overall survival 
Time to progression (TTP) is defined as the time from study entry until objective disease 
progression. Progression-free survival (PFS) is defined as the time from study entry until 
objective disease progression or death. Overall survival is defined as the time from study 
entry until death from any cause. 
 
10.3.10 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. 
 
10.3.11 Refractory disease 
Refractory disease is defined as treatment failure or disease progression within 6 months 
to the last anti-leukemic therapy. 

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10.4 Response Review 
Radiology will be centrally reviewed by the Tumor Imaging Metrics Core (TIMC) 
11 ADVERSE EVENT REPORTING REQUIREMENTS 
11.1 Definitions 
11.1.1 Adverse Event (AE) 
 
An adverse event (AE) is any undesirable sign, symptom or medical condition or 
experience that develops or worsens in severity after starting the first dose of 
study treatment or any procedure specified in the protocol, even if the event is not 
considered to be related to the study.  
 
Abnormal laboratory values or diagnostic test results constitute adverse events 
only if they induce clinical signs or symptoms or require treatment or further 
diagnostic tests.  
11.1.2 Serious adverse event (SAE) 
 
A serious adverse event (SAE) is any adverse event, occurring at any dose and 
regardless of causality that:  
• Results in death 
• Is life-threatening. Life-threatening means that the person was at 
immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction which hypothetically might have caused death had it 
occurred in a more severe form. 
• Requires or prolongs inpatient hospitalization (i.e., the event required at 
least a 24-hour hospitalization or prolonged a hospitalization beyond the 
expected length of stay). Hospitalization admissions and/or surgical 
operations scheduled to occur during the study period, but planned prior to 
study entry are not considered SAEs if the illness or disease existed before 
the person was enrolled in the trial, provided that it did not deteriorate in 
an unexpected manner during the trial (e.g., surgery performed earlier than 
planned). 
• Results in persistent or significant disability/incapacity. Disability is 
defined as a substantial disruption of a person’s ability to conduct normal 
life functions. 
• Is a congenital anomaly or birth defect; or 
• Is an important medical event when, based upon appropriate medical 
judgment, it may jeopardize the participant and require medical or surgical 
intervention to prevent one of the outcomes listed above. Examples of 
such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home; blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 

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Events not considered to be serious adverse events are hospitalizations for: 
• routine treatment or monitoring of the studied indication, not associated 
with any deterioration in condition, or for elective procedures 
• elective or pre-planned treatment for a pre-existing condition that did not 
worsen 
• emergency outpatient treatment for an event not fulfilling the serious 
criteria outlined above and not resulting in inpatient admission 
• respite care 
11.1.3 Expectedness 
 
Adverse events can be 'Expected' or 'Unexpected.'  
11.1.3.1 Expected adverse event 
 
Expected adverse events are those that have been previously identified as 
resulting from administration of the agent. For the purposes of this study, 
an adverse event is considered expected when it appears in the current 
adverse event list, the Investigator’s Brochure, the package insert or is 
included in the informed consent document as a potential risk.   
 
Refer to Section 6.1 for a listing of expected adverse events associated 
with the study agents. 
11.1.3.2 Unexpected adverse event 
 
 
For the purposes of this study, an adverse event is considered unexpected 
when it varies in nature, intensity or frequency from information 
provided in the current adverse event list, the Investigator’s Brochure, 
the package insert or when it is not included in the informed consent 
document as a potential risk.   
11.1.4 Attribution 
 
Attribution is the relationship between an adverse event or serious adverse event 
and the study treatment. Attribution will be assigned as follows: 
 
• Definite – The AE is clearly related to the study treatment. 
• Probable – The AE is likely related to the study treatment. 
• Possible – The AE may be related to the study treatment.  
• Unlikely - The AE is doubtfully related to the study treatment. 
• Unrelated - The AE is clearly NOT related to the study treatment. 
11.2 Procedures for AE and SAE Recording and Reporting 
 

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Participating investigators will assess the occurrence of AEs and SAEs at all participant 
evaluation time points during the study.  
 
All AEs and SAEs whether reported by the participant, discovered during questioning, 
directly observed, or detected by physical examination, laboratory test or other means, 
will be recorded in the participant’s medical record and on the appropriate study-
specific case report forms.  
 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All 
appropriate treatment areas should have access to a copy of the CTCAE version 4.0. 
 
A copy of the CTCAE version 4.0 can be downloaded from the CTEP website at: 
 
 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf  
 
  
11.3  Reporting Requirements 
 
The study must be conducted in compliance with FDA regulations, local safety 
reporting requirements, and reporting requirements of the principal investigator.  
 
It is the responsibility of each participating investigator to report serious adverse events 
to the study sponsor and/or others as described below.  
11.4 Reporting to the Study Sponsor 
11.4.1 Serious Adverse Event Reporting 
 
All serious adverse events that occur after the initial dose of study treatment, 
during treatment, or within 30 days of the last dose of treatment must be reported 
to the DF/HCC Overall Principal Investigator on the institutional SAE form. This 
includes events meeting the criteria outlined in Section 11.1.2, as well as the 
following: 
 
• Grade 2 (moderate) and Grade 3 (severe) Events – Only events that are 
unexpected and possibly, probably or definitely related/associated with the 
intervention. 
 
• All Grade 4 (life-threatening or disabling) Events – Unless expected AND 
specifically listed in the protocol as not requiring reporting. 
 

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• All Grade 5 (fatal) Events – When the participant is enrolled and actively 
participating in the trial OR when the event occurs within 30 days of the 
last study intervention.  
 
Note: If the participant is in long term follow up, report the death at the time 
of continuing review.  
 
For purposes of this protocol, grade 4 lymphopenia is considered an 
expected adverse event associated with study drugs. Such events will be 
recorded but not reported to the Principal Investigator or IRB. 
 
Participating investigators must report each serious adverse event to the DF/HCC 
Overall Principal Investigator within 1 business day of learning of the occurrence. 
In the event that the participating investigator does not become aware of the 
serious adverse event immediately (e.g., participant sought treatment elsewhere), 
the participating investigator is to report the event within 1 business day after 
learning of it and document the time of his or her first awareness of the adverse 
event. Report serious adverse events by telephone, email or facsimile to: 
 
Matthew Davids, MD 
617-632-6331 (phone) 
Matthew_Davids@dfci.harvard.edu 
617-582-9104 (fax) 
 
Within the following 24-48 hours, the participating investigator must provide 
follow-up information on the serious adverse event. Follow-up information should 
describe whether the event has resolved or continues, if and how the event was 
treated, and whether the participant will continue or discontinue study 
participation. 
 
11.4.2 Pregnancy Reporting 
 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female subject occurring while the subject is on study or within 30 days of the 
subject’s last dose of study drug are considered immediately reportable events. IPI-145 is to be 
discontinued immediately. The pregnancy, suspected pregnancy, or positive pregnancy test must 
be reported to the DF/HCC Overall Principal Investigator within 24 hours of learning of the 
occurrence by facsimile or email.. The female subject should be referred to an obstetrician-
gynecologist, preferably one experienced in reproductive toxicity for further evaluation and 
counseling. 
 
The Investigator will follow the female subject until completion of the pregnancy, and the 
DF/HCC Overall Principal Investigator or designee must notify Verastem or designee 
immediately about the outcome of the pregnancy (either normal or abnormal outcome).  If the 
outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic abortion), the 

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Investigator should report the abnormal outcome as an AE. If the abnormal outcome meets any 
of the serious criteria, it must be reported as an SAE to Verastem or designee immediately by 
facsimile, or other appropriate method, within 1 business day of the Investigator’s knowledge of 
the event using the SAE Report Form. 
 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the IP should also be reported to Verastem or designee 
immediately by facsimile, or other appropriate method, within 1 business day of the 
Investigator’s knowledge of the event using the SAE Report Form. 
 
If a female partner of a male subject taking investigational product becomes pregnant, the male 
subject taking study drug should notify the Investigator, and the pregnant female partner should 
be advised to call their healthcare provider immediately. 
11.4.3 Non-Serious Adverse Event Reporting  
Non-serious adverse events will be reported to the DF/HCC Overall Principal Investigator 
on the toxicity Case Report Forms.  
11.5  Reporting to Verastem 
 
In parallel to reporting SAEs to the DF/HCC Overall Principal Investigator site-specific 
investigators must inform Verastem (or Verastem designee) in writing using  a MEDWATCH 
3500A form of any SAE within 1 business day of being aware of the event.  The written report 
must be completed and supplied to Infinity by facsimile within 1 business day.  Serious AEs 
should be communicated on the appropriate form as follows:  
• fax number:  888-529-3580 (USA & Canada) 
 
• email: rtpsafety@ppdi.com 
 
• Hotline (Phone): 888-483-7729 (USA)  
 
The initial report must be as complete as possible, including an assessment of the causal 
relationship between the event and the investigational product(s).  Information not available at 
the time of the initial report (e.g., an end date for the adverse event or laboratory values received 
after the report) must be documented on a follow-up report.  These updates and clarifications in 
follow-up reports will also be reported in parallel to the DF/HCC Overall Principal Investigator 
and Infinity.  Event specific queries as well as monthly SAE listings to confirm receipt of all 
SAEs be sent directly from Infinity to the site specific PI, and the DF/HCC Overall Principal 
Investigator should be included on all such correspondence.  A final report to document 
resolution of the SAE is required.  At any time after completion of the AE reporting period (i.e., 
28 days post-treatment), if an Investigator becomes aware of an SAE that is suspected by the 
Investigator to be related to IPI-145, the event must be reported as described above.  A copy of 

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the fax transmission confirmation of all SAE reports to Infinity should be attached to the SAE 
and retained with the patient records. 
 
11.6 Reporting to the Institutional Review Board (IRB) 
 
Investigative sites will report all serious adverse events directly to the DF/HCC Office 
for Human Research Studies (OHRS). 
11.7 Reporting to the Food and Drug Administration (FDA) 
 
The Study Sponsor, as holder of the IND, will be responsible for all communication 
with the FDA. The Study Sponsor will report to the FDA, regardless of the site of 
occurrence, any adverse event that is serious, unexpected and reasonably related (i.e., 
possible, probable, definite) to the study treatment. 
 
Unexpected fatal or life-threatening experiences associated with the use of the study 
treatment will be reported to FDA as soon as possible but in no event later than 7 
calendar days after initial receipt of the information. 
 
All other serious unexpected experiences associated with the use of the study treatment 
will be reported to FDA as soon as possible but in no event later than 15 calendar days 
after initial receipt of the information. 
 
  
Events will be reported to the FDA according to FDA reporting requirements using 
Form FDA 3500A (Mandatory Reporting Form for investigational agents). Forms are 
available at http://www.fda.gov/medwatch/getforms.htm.  
11.8 Reporting to the NIH Office of Biotechnology Activities (OBA) 
 
 
N/A 
11.9 Reporting to the Institutional Biosafety Committee (IBC) 
 
N/A 
11.10  Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any subject 
safety reports or sentinel events that require reporting according to institutional policy. 
11.11 Monitoring of Adverse Events and Period of Observation 
 
All adverse events, both serious and non-serious, and deaths that are encountered from 
initiation of study intervention, throughout the study, and within 30 days of the last 
study intervention should be followed to their resolution, or until the participating 

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investigator assesses them as stable, or the participating investigator determines the 
event to be irreversible, or the participant is lost to follow-up. The presence and 
resolution of AEs and SAEs (with dates) should be documented on the appropriate case 
report form and recorded in the participant’s medical record to facilitate source data 
verification.  
 
For some SAEs, the study sponsor or designee may follow-up by telephone, fax, and/or 
monitoring visit to obtain additional case details deemed necessary to appropriately 
evaluate the SAE report (e.g., hospital discharge summary, consultant report, or 
autopsy report).  
 
Participants should be instructed to report any serious post-study event(s) that might 
reasonably be related to participation in this study. Participating investigators should 
notify the DF/HCC Overall Principal Investigator and the IRB of any unanticipated 
death or adverse event occurring after a participant has discontinued or terminated 
study participation that may reasonably be related to the study.   

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12 DATA AND SAFETY MONITORING 
12.1 Data Reporting 
12.1.1 Method  
The QACT will collect, manage, and monitor data for this study.  
12.1.2 Data Submission  
The schedule for completion and submission of case report forms (paper or 
electronic) to the QACT is as follows: 
 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration with QACT 
On Study Form 
Within 14 days of registration 
Baseline Assessment Form 
Within 14 days of registration 
Treatment Form 
Within 10 days of the last day of the cycle 
Adverse Event Report Form 
Within 10 days of the last day of the cycle 
Response Assessment Form 
Within 10 days of the completion of the cycle 
required for response evaluation 
Off Treatment/Off Study Form Within 14 days of completing treatment or 
being taken off study for any reason 
Follow up/Survival Form 
Within 14 days of the protocol defined follow 
up visit date or call 
12.2 Safety Meetings 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor 
toxicity and accrual data from this trial. 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 Principal Investigator and study team. 
 
The DSMC will meet every 6 months 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 

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higher unexpected adverse events that have been reported; summary of all deaths 
occurring within 30 days for Phase I or II protocols; for gene transfer 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 Monitoring  
 
Involvement in this study as a participating investigator implies acceptance of 
potential audits or inspections, including source data verification, by representatives 
designated by the DF/HCC Overall Principal Investigator (or Protocol Chair) or 
DF/HCC. The purpose of these audits or inspections is to examine study-related 
activities and documents to determine whether these activities were conducted and 
data were recorded, analyzed, and accurately reported in accordance with the protocol, 
institutional policy, Good Clinical Practice (GCP), and any applicable regulatory 
requirements.  
 
All data will be monitored for timeliness of submission, completeness, and adherence 
to protocol requirements. Monitoring will begin at the time of participant registration 
and will continue during protocol performance and completion.  

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13 REGULATORY CONSIDERATIONS 
13.1 Protocol Review and Amendments 
This protocol, the proposed informed consent and all forms of participant 
information related to the study (e.g., advertisements used to recruit participants) and 
any other necessary documents must be submitted, reviewed and approved by the 
DF/HCC IRB. 
Any changes made to the protocol must be submitted as amendments and must be 
approved by the IRB prior to implementation. Any changes in study conduct must be 
reported to the IRB. The DF/HCC Overall Principal Investigator (or Protocol Chair) 
will disseminate protocol amendment information to all participating investigators.  
All decisions of the IRB concerning the conduct of the study must be made in 
writing. 
13.2 Informed Consent 
 
All participants must be provided a consent form describing this study and providing 
sufficient information for participants to make an informed decision about their 
participation in this study. The formal consent of a participant, using the IRB approved 
consent form, must be obtained before the participant is involved in any study-related 
procedure. The consent form must be signed and dated by the participant or the 
participant’s legally authorized representative, and by the person obtaining the consent. 
The participant must be given a copy of the signed and dated consent document. The 
original signed copy of the consent document must be retained in the medical record or 
research file.  
13.3 Ethics and Good Clinical Practice (GCP) 
This study is to be conducted according to the following considerations, which 
represent good and sound research practice: 
• 
US Code of Federal Regulations (CFR) governing clinical study conduct and 
ethical principles that have their origin in the Declaration of Helsinki 
o Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html  
o Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html  
o Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html  

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o Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html  
• 
State laws 
• 
DF/HCC research policies and procedures        
http://www.dfhcc.harvard.edu/clinical-research-support/clinical-research-unit-
cru/policies-and-procedures/  
It is understood that deviations from the protocol should be avoided, except when 
necessary to eliminate an immediate hazard to a research participant. In such case, 
the deviation must be reported to the IRB according to the local reporting policy.  
13.4 Study Documentation 
 
The investigator must prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each 
research participant. This information enables the study to be fully documented and the 
study data to be subsequently verified. 
 
Original source documents supporting entries in the case report forms include but are 
not limited to hospital records, clinical charts, laboratory and pharmacy records, 
recorded data from automated instruments, microfiches, photographic negatives, 
microfilm or magnetic media, and/or x-rays.  
13.5  Records Retention 
 
All study-related documents must be retained for the maximum period required by 
applicable federal regulations and guidelines or institutional policies.  

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13.6 Multi-center Guidelines 
N/A 
13.7 Cooperative Research and Development Agreement (CRADA)/Clinical Trials 
Agreement (CTA)  
 
    N/A

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14 STATISTICAL CONSIDERATIONS  
14.1 Study Design/Endpoints 
Study Design 
An open-label, phase I/II study of IPI-145 in combination with fludarabine, cyclophosphamide, 
rituximab (iFCR) will be performed.  The phase I part is a standard 3+3 design with three dose 
levels. Patients will start on day -7 with one week of IPI-145 monotherapy, which will allow 
time for mobilization of CLL cells from lymph nodes and marrow and will also allow for 
collection of patient samples for correlative studies.  FCR will subsequently be introduced on 
day 1, and administered at standard dosing for 6 cycles, with dose reductions permitted (see 
Section 6.2).  Patients achieving either a PR or CR will be allowed to continue on IPI-145 
maintenance for up to 2 years after completing chemotherapy.  Conversion to MRD negativity 
and 2 year progression-free survival will be assessed for these patients. 
 
 
Primary Endpoint: 
•   Safety of IPI-145 in combination with FCR in previously untreated younger patients with 
CLL  
• Rate of minimal residual disease negative complete response (MRD-negative CR) in the 
bone marrow at 2 months post last cycle of FCR 
 
Secondary Endpoints: 
• Clinical response, including overall response rate, complete and partial response rates, 
progression-free survival,  overall survival, and duration of remission as determined by 
2008 IW-CLL criteria 
• Rate of minimal residual disease (MRD) in the peripheral blood 
• Rates of treatment-related adverse effects 
• Association of established CLL prognostic factors (e.g. FISH cytogenetics, IGHV status, 
ZAP70 status) with clinical response 
 
Exploratory Endpoints: 
• BH3 profiling  
• Change in pharmacodynamic markers such as p-AKT, p-ERK, and Ki-67 
• Mutation status of SF3B1, TP53, NOTCH1, MYD88 and the BCR/NFKB pathway 
Phase I Design 
 
Three doses of IPI-145 will be considered to determine MTD of IPI-145 in combination of FCR: 
15 mg QD (dose level -1), 25 mg QD (dose level 1, starting dose), 25 mg bid (dose level 2). Dose 
limiting toxicities (DLTs) and the observation period are defined in section 5.3.  
A cohort of 3 patients will enter at a dose level, starting dose level 1. If no DLT is seen in the first 
3 patients, then a dose escalation will take place. If 2 or more of the first 3 patients experience 

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DLT at dose level 1 or 2, then the next cohort of 3 patients will be treated at the next lower dose 
level, unless 6 patients have already been treated at that dose level. If 2 or more of the first 3 
patients experience DLT at dose level -1, then the study will be terminated early. If 1 of the 3 
patients at a dose level experiences a DLT, then 3 additional patients will be treated at that dose 
level. If there is no DLT in the 3 additional patients then dose escalation will take place. If this is 
dose level 2 or -1, then this dose level will be the MTD. If 1 or more of the 3 additional patients 
experience(s) DLT then the MTD is considered to have been exceeded, and 3 more patients will 
be treated at the next lower dose, unless 6 patients have already been treated at that dose level. If 
this is does level -1, then the study will be terminated early. A minimum of six patients must be 
entered at the MTD, and fewer than 2 patients in 6 should experience DLT. If 0 in 6 patients 
experience DLT at dose level 2, this dose level will be the RP2D (recommended Phase II dose). 
 
Table 1 shows the probability of escalation under various true DLT rates. With this   design, 
there is 91% probability of escalation if the true but unknown rate of DLT is 10% and 17% 
probability of escalation if the rate is 50%. 
 
Table 1. Probability of dose escalation 
True but Unknown Rate of DLT 
10% 
20% 
30% 
40% 
50% 
60% 
Prob. of Escalation 
0.91 
0.71 
0.49 
0.31 
0.17 
0.08 
 
Phase II Design 
 
The phase II part of the study is a single arm study which consists of determining the MRD-
negative CR rate in the bone marrow at 2 months post IPI-145 + FCR in previously untreated 
CLL patients.  An exact one sample binomial test is used to compute the sample size.  Twenty 
additional patients will be enrolled and analyzed in conjunction with the 6 patients from the 
phase I portion treated at the MTD/RP2D for a total of 26 patients.  Twenty-six patients are 
needed in order to detect a 45% MRD-negative CR rate, assuming the MRD-negative CR rate 
for the null hypothesis is 20% (Boettcher et al., 2012) and 90% power and 6% one-sided type I 
error.  The null hypothesis will be rejected if 9 or more MRD-negative CRs are observed. Table 
2 presents the operating characteristics of this design. 
 
Table 2. Operating Characteristics 
  
True but Unknown Response Rate  
20% 
25% 
30% 
35% 
40% 
45% 
Prob(≥9 responses) 
0.06 
0.18 
0.37 
0.59 
0.77 
0.90 
 
14.2  Toxicity Monitoring.  
 
Adverse events will be continuously monitored in the Phase II part of the study. The monitoring 
guidelines will serve as a trigger for consultation with the DF/HCC Data Safety and Monitoring 
Committee (DSMC) for additional review of potential closure of the study enrollment. 
 
General Stopping Rule: If in the first 10 additional patients enrolled to phase II part, we observe 3 or 
more patients develop DLTs, further accrual to the phase II portion will be halted pending review by the 

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DSMC.  Depending on the findings of its review, the DSMC may recommend the permanent closure of 
enrollment or continuation of enrollment. With this design, the probability of halting enrollment in the 
phase II portion is 0.07 if the true but unknown DLT is 10%, 0.62 if the rate is 30%, and 0.95 if the rate is 
50%. 
 
Stopping Rule for Hepatotoxicity: As of August 2015, grade 3/4 LFT elevations have been seen in 
4/17 (24%): 1/6 at the dose level 1 and 3/11 at the dose level 2 (RP2D).  If in the first 7 additional 
patients enrolled to phase II part, we observe 3 or more patients develop grade 3 or higher hepatotoxicity, 
further accrual to the phase II portion will be halted pending review by the DSMC. Depending on the 
findings of its review, the DSMC may recommend the permanent closure of enrollment or continuation of 
enrollment.  With this design, the probability of halting enrollment after the additional 7 patients is 0.026 
if the true but unknown grade 3/4 hepatotoxicity rate is 10%, 0.35 if the rate is 30%, 0.58 if the rate is 
40%, and 0.77 if the rate is 50%.  
14.3 Sample Size/Accrual Rate 
Planned Sample Size:  Minimum:  4,  Maximum:  32 
Estimated Monthly Accrual:  2-3 
Follow-up:  Patients completing 2 years of maintenance IPI-145 or those who do not go on to 
receive IPI-145 maintenance will be followed until initiation of new therapy, or death.  
14.4  Stratification Factors 
 
There will be no stratification of patients on this study. 
14.5 Analysis of Secondary Endpoints 
 
Clinical response, including overall response rate, complete and partial response rates 
determined by IW-CLL criteria as well as rate of MRD negativity in the peripheral blood will be 
summarized as percentages and 90% CI will be calculated using exact binomial test.  The Kaplan 
Meier method will be used to summarize progression-free survival and overall survival 
descriptively.  Association of established CLL prognostic factors (e.g. FISH cytogenetics, IGHV 
status, ZAP70 status) and clinical response will be assessed using Fisher’s exact test for 
categorical variables and Wilcoxon’s rank sum test for continuous variables.  In addition, a 
correlation analysis between peripheral blood and bone marrow MRD negativity will be 
performed.  Toxicity will be reported descriptively. Association between clinical outcome and 
exploratory endpoints will beevaluated. Exploratory endpoints include BH3 profiling, change in 
pharmacodynamic markers such as p-AKT, p-ERK, and Ki-67, and Genomic analysis with 
mutation status of SF3B1, TP53, NOTCH1, MYD88 and the BCR/NFKB pathway.   
Reporting and Exclusions 
Subjects who never start protocol therapy will be excluded from all analyses.  
14.5.1 Evaluation of toxicity.  All participants will be evaluable for toxicity from the time of 
their first treatment. 
14.5.2 Evaluation of response.  All participants included in the study must be assessed for 
response to treatment, even if there are major protocol treatment deviations or if they are 

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ineligible. Each participant will be assigned one of the following categories: 1) complete 
response, 2) partial response, 3) stable disease, 4) progressive disease, 5) early death 
from malignant disease, 6) early death from toxicity, 7) early death because of other 
cause, or 9) unknown (not assessable, insufficient data). By arbitrary convention, 
category 9 usually designates the "unknown" status of any type of data in a clinical 
database. 
        

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15  PUBLICATION PLAN 
 
The initial results of this study will be made public within 24 months of the end of data 
collection. Study results will be published in a peer-reviewed journal, but the initial release may 
be an abstract that meets the requirements of the International Committee of Medical Journal 
Editors. A full report of the outcomes will be made public no later than three (3) years after the 
end of data collection. 

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16 REFERENCES  
 
Barrientos JC, Furman RR, Leonard J, et al.  Update on a phase I study of the selective PI3K-
delta inhibitor idelalisib (GS-1101) in combination with rituximab and/or bendamustine in 
patients with relapsed or refractory CLL.  J Clin Oncol 31, 2013 (suppl; abstr 7017). 
 
Boettcher, S, Ritgen, M, Fischer, K, et al.  Minimal residual disease quantification is an 
independent predictor of progression-free and overall survival in chronic lymphocytic leukemia: 
a multivariate analysis from the randomized GCLLSG CLL8 trial.  J Clin Oncol, 2012, 
30(9);980-8. 
 
Brown, JR, Byrd, JC, Coutre, SE et al., Idelalisib, an inhibitor of phosphatidylinositol 3 kinase 
p110-delta, for relapsed/refractory chronic lymphocytic leukemia.  Blood, 2014, Mar 10 [Epub 
ahead of print] 
 
Byrd JC, Rai K, Peterson BL, Appelbaum FR, et al.  Addition of rituximab to fludarabine may 
prolong progression-free survival and overall survival in patients with previously untreated 
chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 
and CALGB 9011. Blood. 2005 Jan 1;105(1):49-53. Epub 2004 May 11. 
 
Ciraolo, E.; Morello, F.; Hirsch, E., Present and future of PI3K pathway inhibition in cancer: 
perspectives and limitations. Curr Med Chem 2011, 18 (18), 2674-85. 
 
Davids MS, Brown JR.  Phosphoinositide 3'-kinase inhibition in chronic lymphocytic leukemia. 
Hematol Oncol Clin North Am. 2013 Apr;27(2):329-39. doi: 10.1016/j.hoc.2012.12.002. 
 
Davids, MS, Deng, J, Wiestner, A, et al. Decreased mitochondrial apoptotic priming underlies 
stroma-mediated treatment resistance in chronic lymphocytic leukemia, Blood, 2012, Oct 
25;120(17):3501-9. 
 
Flinn, IW, Patel, M, Kahl, BS, et al.  Preliminary Safety and Efficacy of IPI-145, a Potent 
Inhibitor of Phosphoinositide-3-Kinase-δ,γ, in Patients with Chronic Lymphocytic Leukemia.  
ASH Annual Meeting, 2013, abstract 677. 
 
Furman, R. R., Byrd, J.C., Brown, J.R., Coutre, S.E., Benson, D.M., et al., CAL-101, An 
Isoform-Selective Inhibitor of Phosphatidylinositol 3-Kinase P110d Demonstrates Clinical 
Activity and Pharmacodynamic Effects in Patients with Relapsed or Refractory Chronic 
Lymphocytic Leukemia.  ASH Annual Meeting, 2010. 
 
Hainsworth JD, Litchy S, Barton JH, et al., Single-agent rituximab as first-line and maintenance 
treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a 
phase II trial of the Minnie Pearl Cancer Research Network.  J Clin Oncol. 2003 May 
1;21(9):1746-51 
 

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Hallek, M, Cheson, BD, Catovsky, D, et al.  Guidelines for the diagnosis and treatment of 
chronic lymphocytic leukemia: a report from the International Workshop on Chronic 
Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines.  
Blood, 2008, Jun 15;111(12):5446-56. 
 
Hallek M, Fischer, K, Fingerle-Rowson, G, et al. Addition of rituximab to fludarabine and 
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phase 3 trial.  Lancet, 2010, Oct 2;376(9747):1164-74. 
 
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lymphocytic leukemia. Blood 2011, 118 (13), 3603-12. 
 
Improgo, MR, Kiezun, A, Wang, Y, et al.  Functional Somatic and Germline Variants in the NF-
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Landau, DA, Carter, SL, Stojanov, P, et al.  Evolution and Impact of Subclonal Mutations in 
Chronic Lymphocytic Leukemia.  Cell, 2013, 152:714-726. 
 
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combination regimen in chronic lymphocytic leukemia.  J Clin Oncol. 2001 Mar 1;19(5):1414-
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Patel M, Kahl B, Horwitz, SM, et al.  Preliminary Safety and Efficacy of IPI-145, a Potent 
Inhibitor of Phosphoinositide-3-Kinase-δ,γ, in Patients with Relapsed/Refractory CLL.  ASCO 
Annual Meeting, 2013, abstract 7070. 
 
Rai KR, Peterson BL, Appelbaum FR, et al.  Fludarabine compared with chlorambucil as 
primary therapy for chronic lymphocytic leukemia. N Engl J Med. 2000 Dec 14;343(24):1750-7. 
 
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international harmonised approach for flow cytometric residual disease monitoring in CLL.  
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Subramaniam PS, Whye DW, Efimenko E, et al.  Targeting nonclassical oncogenes for therapy 
in T-ALL.  Cancer Cell. 2012 Apr 17;21(4):459-72. 
Wang L, Lawrence, MS, Wan, Y, et al.  SF3B1 and other novel cancer genes in chronic 
lymphocytic leukemia.  N Engl J Med, 2011, Dec 29;365(26):2497-506. 

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75 
 
17 APPENDICES  
Appendix A: Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Description 
Percent 
Description 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
In bed < 50% of the time. 
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities. Up and about more 
than 50% of waking hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, 
hospitalization indicated. Death 
not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or 
chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly.  
5 
Dead. 
0 
Dead. 
 

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Appendix B: Known CYP3A4 or CYP2C8 Substrates  
The following lists provide known sensitive CYP3A4 substrates, CYP3A substrates with a 
narrow therapeutic range, and CYP2C8 substrates.  
Additional information can be found at: 
http://www.medicine.iupui.edu/clinpharm/ddis/ClinicalTable.asp and 
http://www.pharmacytimes.com/issue/pharmacy/2008/2008-09/2008-09-8687 
Sensitive CYP3A Substrates   
budesonide  
buspirone  
eplerenone  
eletriptan  
felodipine  
fluticasone  
lovastatin  
midazolam  
saquinavir 
sildenafil 
simvastatin 
triazolam 
vardenafil  
CYP3A Substrates with a Narrow Therapeutic Range  
alfentanil  
astemizole 
cisapride 
cyclosporine 
diergotamine 
ergotamine  
fentanyl 
pimozide 
quinidine 
sirolimus 
tacrolimus 
terfenadine  
CYP2C8 Substrates  
paclitaxel 
torsemide 
amodiaquine  
cervistatin  
repaglinide  
rosiglitazone 
pioglitazone  
 

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Appendix C: Medications or Foods Known to Inhibit or Induce CYP3A4  
 
The following list provides medications known to induce or inhibit CYP3A activity. Note that 
this is not a comprehensive list of all medications which may modulate CYP3A activity.  
 
Additional information can be found at: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm080499.htm and 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionsla
beling/ucm093664.htm#4 
  
Classification of In Vivo 
Inhibitors of CYP3A Strong 
Inhibitors(1) ≥ 5-fold 
increase in AUC or > 80% 
decrease in CL  
Moderate inhibitors(2) ≥ 2 
but < 5-fold increase in 
AUC or 50-80% decrease in 
CL  
Weak inhibitors(3) ≥ 1.25 
but < 2-fold increase in 
AUC or 20-50% decrease in 
CL  
Boceprevir, clarithromycin, 
conivaptan, grapefruit 
juice,(5) indinavir, 
itraconazole, ketoconazole, 
lopinavir/ritonavir, 
mibefradil, (6) nefazodone, 
nelfinavir, posaconazole, 
ritonavir, saquinavir, 
telaprevir, telithromycin, 
voriconazole  
Amprenavir, aprepitant, 
atazanavir, ciprofloxacin, 
darunavir/ritonavir, diltiazem, 
erythromycin, fluconazole, 
fosamprenavir, grapefruit 
juice, (5) imatinib, verapamil  
Alprazolam, amiodarone, 
amlodipine, atorvastatin, 
bicalutamide, cilostazol, 
cimetidine, cyclosporine, 
fluoxetine, fluvoxamine, 
ginkgo, (4) goldenseal,(4) 
isoniazid, nilotinib, oral 
contraceptives, ranitidine, 
ranolazine, 
tipranavir/ritonavir, zileuton  
 
1. A strong inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a substrate for that CYP 
by equal or more than 5-fold.  
2. A moderate inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate 
for that CYP by less than 5-fold but equal to or more than 2-fold.  
3. A weak inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate for 
that CYP by less than 2-fold but equal to or more than 5-fold.  
4. Herbal product.  
5. The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-dependent. 
Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain preparation was used 
(e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when another preparation was used (e.g., low 
dose, single strength).  
6. Withdrawn from the United States market because of safety reasons.  
 

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

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Appendix D: P-gp Substrates and Medications that are Inhibitors of P-gp  
The following list provides medications that are substrates or inhibitors of P-gp. This is not a 
complete list of all medications which may be substrates of P-gp or may modulate P-gp activity.  
 
P-gp Substrates  
Amitriptyline  
Amiodarone  
Atorvastatin  
Cefoperazone  
Chlorpromazine  
Cimetidine  
Ciprofloxacin  
Clarithromycin  
Colchicine  
Cyclosporine  
Dexamethasone  
Digoxin  
Diltiazem  
Erythromycin  
Estradiol  
Fentanyl  
Fexofenadine  
Hydrocortisone  
Itraconazole  
Lansoprazole  
Levofloxacin  
Lidocaine  
Loperamide  
Losartan  
Lovastatin  
Methadone  
Methotrexate  
Methylprednisolone  
Morphine  
Nadolol  
Norfloxacin  
Nortriptyline  
Ondansetron  
Omeprazole  
Pantoprazole  
Phenytoin  
Pravastatin  
Propranolol  
Quinidine  
Ranitidine  
Sirolimus  
Tacrolimus  
Timolol  
Trimethoprim  
Verapamil  
P-gp Inhibitors  
Amiodarone  
Amitriptyline  
Carvedilol  
Chlorpromazine  
Clarithromycin  
Cortisol  
Cyclosporine  
Desimpramine  
Diltiazem  
Dipyridamole  
Doxepin  
Erythromycin  
Felodipine  
Fluphenazine  
Grapefruit juice  
Haloperidal  
Itraconazole  
Ketoconazole  
Lovastatin  
Mefloquine  
Nicardipine  
Nifedipine  
Ofloxacin  
Omeprazole  
Pantoprazole  
Progesterone  
Propafenone  
Propranolol  
Quinidine  
Rifampicin (Rifampin)  
Saquinavir  
Simvastatin  
Sirolimus  
Tacrolimus  
Testosterone  
Verapamil  
Source: Atkinson AJ et al. Principles of Clinical Pharmacology, 2nd ed. cademic Press, Massachusetts, 2007.  

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Appendix E: Drugs Known to Prolong the QTc  
It has been recognized for a number of years that certain prescription medications can prolong the 
QT/QTc interval. Medications that prolong the QT interval and/or have a risk of inducing Torsade de 
Pointes (TdP) are listed below. They are divided into two groups based on their known or perceived 
risk of causing TdP.  
 
Additional information can be found at: http://www.azcert.org/medical-pros/drug-
lists/bycategory.cfm 
  
Group 1. Drugs that are Generally Accepted by Authorities to have a Risk of Causing Torsades 
de Pointes  
 
Group 1 Drugs   
Amiodarone  
Arsenic trioxide  
Bepridil  
Chlorpromazine  
Chloroquine  
Cisapride  
Disopyramide  
Dofetilide  
Domperidone  
Droperidol  
Erythromycin  
Halofantrine  
Haloperidol  
Ibutilide  
Levomethadyl  
Mesoridazine  
Methadone  
Moxifloxacin  
Pentamidine  
Pimozide  
Probucol  
Procainamide  
Quinidine  
Sotalol  
Sparfloxacin  
Thioridazine  
Vandetanib  
 
Group 2. Drugs That in Some Reports May be Associated With QT Prolongation and/or 
Torsades de Pointes But at This Time Lack Substantial Evidence of Causing Torsades de 
Pointes 
 
Group 2 Drugs 
Alfuzocin 
Amantadine 
Atazanavir 
Azithromycin 
Chloral hydrate 
Clozapine 
Dolasetron 
Dronedapone 
Escitalopram 
Felbamate 
Flecainide 
Foscarnet 
Fosphenytoin 
Gatifloxacin 
Gemifloxacin 
Granisetron 
Nicardipine 
Nilotinib 
Octreotide 
Ofloxacin 
Ondansetron 
Oxycontin 
Paliperidone 
Quetiapine 
Ranolazine 
Risperidone 
Roxithromycin 
Sertindole 
Sunitinib 
Tacrolimus 
Tamoxifen 
Telithromycin 

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Indapamide 
Isradipine 
Lapatinib 
Levofloxacin 
Lithium 
Moexipril/HCTZ 
Tizanidine 
Vardenafil 
Venlafaxine 
Voriconazole 
Ziprasidone 
 

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 Appendix F:  Cairo-Bishop Tumor Lysis Syndrome Criteria 
 
Cairo-Bishop Definition of Tumor Lysis Syndrome (Cairo MS et al., 2004) 
 
Laboratory Tumor Lysis Syndrome (LTLS): 
 
Uric Acid ≥ 476 μmol/l (≥ 8.0 mg/dl) or 25% increase from baseline 
Potassium ≥ 6.0 mmol/l (≥ 6.0 mEq/l) or 25% increase from baseline 
Phosphorous ≥1.45 mmol/l (≥ 4.5 mg/dl) or 25 % increase from baseline 
Calcium ≤ 1.75 mmol/l (≤ 7.0 mg/dl) or 25% decrease from baseline 
 
Laboratory tumor lysis syndrome (LTLS) is defined as either a 25% change or level above or 
below normal, as defined above, for any two or more serum values of uric acid, potassium, 
phosphate, and calcium within 3 days before or 7 days after the initiation of chemotherapy. This 
assessment assumes that a patient has or will receive adequate hydration (± alkalinization) and a 
hypouricaemic agent(s). 
 
 
Clinical Tumor Lysis Syndrome (CTLS): 
 
The presence of laboratory TLS and one or more of the following criteria: 
1. Creatinine: ≥ 1.5 ULN (age > 12 years or age adjusted) 
2. Cardiac arrhythmia / sudden death 
3. Seizure* 
 
ULN, Upper limit of normal 
*Not directly attributable to a therapeutic agent 
 

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Cairo-Bishop Grading System for TLS 
Grade LTLS Creatinine 
Cardiac Arrhythmia 
Seizure 
0 
- 
0 - ≤ 1.5 x ULN 
None 
None 
1 
+ 
1.5 x ULN 
Intervention not indicated None 
2 
+ 
> 1.5 – 3.0 x ULN 
Non-urgent medical 
intervention indicated 
One brief generalized 
seizure; seizure(s) well 
controlled or infrequent; 
focal motor seizures not 
interfering with ADL 
 
3 
+ 
> 3.0 – 6.0 x ULN 
Symptomatic and 
incompletely controlled 
medically or controlled 
with device.   
Seizure in which 
consciousness is altered; 
poorly controlled seizure 
disorder; break through 
generalized seizures despite 
medical intervention 
4 
+ 
> 6.0 x ULN 
Life-Threatening 
Seizures of any kind that are 
prolonged, repetitive, or 
difficult to control 
 
5 
+ 
Death* 
Death* 
Death* 
 
ULN, upper limit of normal; ADL, activities of daily living 
 
*Probably or definitely attributable to clinical TLS 

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Appendix G NCI CTC Version 4.0 
 
Toxicity will be scored using NCI CTC Version 4.0 for toxicity and adverse event reporting. A 
copy of the NCI CTC Version 4.0 can be downloaded from the CTEP homepage: 
(http://ctep.info.nih.gov). All appropriate treatment areas have access to a copy of the CTC 
Version.