Conditions: Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma
Keywords: Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 27
Healthy volunteers: no

Brief summary:
This research study is evaluating a combination of drugs called Ofatumumab and Idelalisib as a possible treatment for Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Leukemia (SLL).

The main purpose of this study is to examine the combination of the two drugs, Ofatumumab and Idelalisib, in participants who have been diagnosed with CLL/SLL and have not previously received treatment but do require treatment. The investigators hope to observe how participants' disease will be impacted by this treatment and whether they will benefit more from combining these drugs together rather than taking them separately. Both of these drugs have been used in treatment for CLL / SLL and information from those research studies suggests that these drugs may help patients with CLL/SLL.

Ofatumumab is an antibody engineered in the lab against CD20, a protein on the surface of CLL cells, which is expressed in CLL. An antibody is a molecule your body creates to identify foreign substances so that it can destroy them. Ofatumumab has been FDA approved for treatment of CLL/SLL that has relapsed or progressed on other therapies. Idelalisib is a drug that blocks one of the signals inside the cells that cause this type of cancer to grow and survive. The investigators hope that combining Ofatumumab with Idelalisib will stop the growth of disease.

In this research study, the investigators are evaluating the side effects of combining these two drugs, gathering information on the CLL/SLL disease process and how the study affects the patient's cells, as well as assessing the outcome of the disease. This combination of drugs has been previously tested, and appeared to be well tolerated.

Detailed description:
Before the research starts (screening): After signing the consent form, the participant will be asked to undergo some screening tests or procedures to find out if they are eligible to be in this research study. Many of these tests and procedures are likely to be part of regular cancer care and may be done even if it turns out that the participant does not take part in the research study. If the participant has had some of these tests or procedures recently, they may or may not have to be repeated.

* A medical history, which includes questions about the participant's health, current medications, and any allergies.
* Physical examination, which includes vital signs, height, weight, and disease assessment by the size of the participant's spleen, liver, and lymph nodes.
* Performance status, which evaluates how the participant is able to carry on with their usual activities.
* An assessment of the patient's tumor by CT (Computerized Tomography) scan, MRI or PET (Positron Emission Tomography) scans,
* Bone marrow aspirate and biopsy: A study tube (plastic cylinder container that contains biopsy material) will be drawn during this biopsy to further assess the participant's disease status.
* Blood tests, a maximum of 24 teaspoons will be collected.
* Urine test.
* A blood pregnancy test
* A Hepatitis B and C test, will require blood sample.

If these tests show that the participant is eligible to participate in the research study, then the participant will be begin will begin the study treatment. If you do not meet the eligibility criteria, the participant will not be able to participate in this research study.

Additional research procedures to be performed at the time of screening:

• Blood tests, including baseline tests so that the investigators can measure any additional effect of the study drug and disease status

After the screening procedures confirm that you are eligible to participate in the research study:

If you take part in this research study, the participant will be given a study drug-dosing diary for each treatment cycle. Each treatment cycle lasts 28 days. The diary will also include special instructions for taking the study drugs.

* Study Drugs: The participant will first be given Idelalisib daily for two cycles of 28 days each. Idelalisib will be given orally. Once the participant completes 2 cycles of Idelalisib, then the participant will start to receive a combination of Ofatumumab and Idelalisib. This regimen will continue weekly to complete 8 weeks (two more cycles). This will be followed by monthly Ofatumumab and Idelalisib to complete 4 additional cycles (eight total). The overall treatment period will therefore be 8 months, comprised of two months of Idelalisib followed by 6 months of Ofatumumab with Idelalisib. After completing the 8-month treatment, the participant will likely continue Idelalisib. Restaging with CT scans will happen after Cycle 2, 4, and a final restage will occur 2 months after the completion of Ofatumumab. There will be a tumor response assessment done during a physical exam after Cycle 8.
* Clinical Exams: During all cycles the participant will have a physical exam and will be asked questions about their general health and specific questions about any problems that they might be having and any medications they may be taking.
* Scans (or Imaging tests): The investigator will assess the participant's tumor by CT scan. Restaging with CT scans will happen after Cycle 2, 4, and a final restage will occur 2 months after the completion of Ofatumumab.
* Bone marrow aspirate and biopsy: will be conducted to see if the bone marrow has tumor cells. A study tube will be drawn during this biopsy to further assess the patient's disease status
* Blood tests

Additional Blood Tests:

Blood Tests will be performed throughout the study so that the Investigator can measure any additional effect of the study drug and disease status. These tests will be taken on the days listed below before the participant receive study drug, on some days additional blood will be drawn after they receive study drug.

Cycle 3 Day 1 Cycle 3 Day 8 Cycle 3 Day 15 Cycle 4 Day 21 (last weekly Ofatumumab dose) Cycle 5 Day 1 (first monthly Ofatumumab dose) Cycle 8 Day 1 (last monthly Ofatumumab dose) 2 months after Ofatumumab therapy completed 6 months after Ofatumumab therapy completed

Planned Follow-up:

Once the participant has completed the study treatment, the participant will be monitored until they start a new type of treatment or are removed from the study. During this time the participant will meet with your research physician every 3 or 6 months.

The investigator would like to keep track of the participant's medical condition for the rest of their life. The investigator would like to do this by calling the participant on the telephone once a year to see how the participant is doing. Keeping in touch with the participant and checking their condition every year helps the investigator look at the long-term effects of the research study.

Arms:
arm 1: Idelalisib will be given orally continuously at 150 mg BID. On day 57, ofatumumab will begin with the 300 mg dose, given after idelalisib is taken. Ofatumumab will then be administered at 1000 mg weekly to complete 8 weeks (days 64, 71, 78, 85, 92, 99, 106) throughout Cycles 3 and 4. This will be followed by monthly ofatumumab on weeks 20, 24, 28, 32 to complete 4 additional cycles (5-8). The overall induction treatment period will then be 8 months, comprised of two months of single agent idelalisib followed by 6 months of ofatumumab with idelalisib. After the completion of the induction treatment, idelalisib will continue indefinitely in arbitrarily defined 28 day cycles in all participants who have not had excessive toxicity and do not have progressive disease.

Interventions: intervention 1: Idelalisib intervention 2: Ofatumumab
Intervention descriptions: intervention 1: 150 mg BID Oral Daily intervention 2: Ofatumumab will then be administered at 1000 mg weekly to complete 8 weeks (days 64, 71, 78, 85, 92, 99, 106) throughout Cycles 3 and 4. This will be followed by monthly ofatumumab on weeks 20, 24, 28, 32 to complete 4 additional cycles (5-8).

Protocol document:
Prot_SAP_000.pdf: 
Status Page 
 
 
 
PROTOCOL 13-309 
 
 
 
 
 
Permanent   
Closed to New Accrual  
 
 
 
 
 
 
 
 
 
 
 
Closure Effective Date: 04/25/2018 
No new subjects may be enrolled in the study as described above.  
Any questions regarding this closure should be directed to the 
study’s Principal Investigator 
 
 
 
 


Page 1 of 1 
Date Submitted:  
Alert Page  
DF/HCC Protocol #:  [13-309] 
 
Revised: 01.08.16 
 
 
Protocol Clarifications (non-drug related e.g. eligibility criteria, study 
assessments) 
 
This study is now closed to enrollment at all sites. 
 
 


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Protocol Version Date:  v. 19  
November 1, 2018 
 
Local Protocol #: 13-309  
 
 
Title:  A Phase II Study of Idelalisib (GS1101, CAL101) + Ofatumumab in Previously 
Untreated CLL/SLL  
 
Overall Principal Investigator:  
Jennifer R Brown MD PhD 
Dana-Farber Cancer Institute 
450 Brookline Avenue 
Boston, MA 02215  
 
Coordinating Center:  DFCI  
  
Co-Investigators:  
Co-Investigators: CLL Research Consortium 
 
Jon E. Arnason, MD  
 
 
 
 
 
 
 
Jeffrey Barnes, MD, PhD 
Instructor, Medicine  
 
 
 
 
 
 
 
Instructor of Medicine 
Division of Hematology Oncology  
 
 
Department of Medicine, Hematology/Oncology 
Beth Israel Deaconess Medicine Center  
Massachusetts General Hospital 
330 Brookline Ave.  
 
 
 
 
 
 
 
55 Fruit St. 
Boston, MA 02215  
 
 
 
 
 
 
 
Boston, MA 02114 
  
Collaborator: 
Amy Johnson, PhD 
Research Assistant Professor 
OSU CCC Room 455C 
410 W 12th Avenue 
The Ohio State University 
Columbus, OH 43210 
 
Statisticians: 
Svitlana Tyekucheva 
 
 
 
 
 
 
 
 
 
 
Biostatistics & Computational Biology 
 
Dana-Farber Cancer Institute  
 
 
 
 
svitlana@jimmy.harvard.edu  
 
 
 
 
Study Coordinator:  
 
Responsible Research Nurse:  
 
Agent(s):  
Idelalisib – Gilead Pharmaceuticals 
Ofatumumab – Novartis  
 


IDELALISIB + Ofa in Untreated CLL/SLL 
 
 
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SCHEMA 
 
 
 
 
 


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TABLE OF CONTENTS 
1. 
OBJECTIVES .................................................................................................................................................... 5 
1.1 
Study Design .............................................................................................................................................. 5 
1.2 
Primary Objectives ..................................................................................................................................... 5 
1.3 
Secondary Objectives ................................................................................................................................. 5 
2. 
BACKGROUND ................................................................................................................................................ 6 
2.1 
Preclinical Characterization of Idelalisib ................................................................................................. 6 
2.2 
Clinical Experience with Idelalisib ........................................................................................................... 9 
2.3 
Ofatumumab ............................................................................................................................................ 14 
2.4 
Chronic Lymphocytic Leukemia ............................................................................................................. 16 
2.5 
Rationale .................................................................................................................................................. 17 
2.6 
Correlative Studies Background and Rationale ..................................................................................... 18 
3. 
Participant SELECTION ................................................................................................................................ 20 
3.1 
Eligibility Criteria .................................................................................................................................... 20 
3.2 
Exclusion Criteria ................................................................................................................................. 22 
3.3 
Inclusion of Women, Minorities and Other Underrepresented Populations ......................................... 23 
4. 
REGISTRATION PROCEDURES ................................................................................................................ 24 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions .................................................................. 24 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions .............................................................. 24 
4.3 
General Guidelines for Other Participating Institutions ................................................................. 25 
4.4 
Registration Process for Other Participating Institutions .................................................................... 25 
5. 
TREATMENT PLAN ...................................................................................................................................... 26 
5.1 
Pre-treatment Criteria ............................................................................................................................ 27 
5.2 
Agent Administration............................................................................................................................... 27 
5.3 
General Concomitant Medication and Supportive Care Guidelines ...................................................... 29 
5.4 
Duration of Therapy ................................................................................................................................. 31 
5.5 
Duration of Follow Up ............................................................................................................................ 32 
5.6 
Criteria for Removal from Study ............................................................................................................. 32 
6. 
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS .................................... 32 
6.1 
Anticipated Toxicities .............................................................................................................................. 33 
6.2 
Toxicity Management .............................................................................................................................. 33 
6.3 
Dose Modifications/Delays ...................................................................................................................... 38 
7. 
DRUG FORMULATION AND ADMINISTRATION ................................................................................. 39 
7.1 
Idelalisib ................................................................................................................................................... 39 


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7.2 
Ofatumumab ............................................................................................................................................ 42 
8. 
CORRELATIVE/SPECIAL STUDIES .......................................................................................................... 46 
8.1 
Pharmacokinetic Studies ......................................................................................................................... 46 
8.2 
Pharmacodynamic Studies ...................................................................................................................... 47 
9. 
STUDY CALENDAR ...................................................................................................................................... 50 
10. 
MEASUREMENT OF EFFECT..................................................................................................................... 56 
10.1 
Antitumor Effect – CLL ........................................................................................................................... 56 
10.2 
Duration of Response .............................................................................................................................. 59 
10.3 
Response Review ...................................................................................................................................... 59 
11. 
ADVERSE EVENT REPORTING REQUIREMENTS ............................................................................... 60 
11.1 
Definitions ................................................................................................................................................ 60 
11.2 
Procedures for AE and SAE Recording and Reporting ......................................................................... 62 
11.3 
Reporting Requirements .......................................................................................................................... 63 
11.4 
Reporting to the Study Sponsor ............................................................................................................... 63 
11.5 
Reporting to the Institutional Review Board (IRB) ................................................................................ 65 
11.6 
Reporting to the Food and Drug Administration (FDA) ........................................................................ 65 
11.7 
Reporting to Hospital Risk Management ................................................................................................ 66 
11.8 
Monitoring of Adverse Events and Period of Observation ..................................................................... 66 
12. 
DATA AND SAFETY MONITORING .......................................................................................................... 66 
12.1 
Data Reporting ......................................................................................................................................... 66 
12.2 
Safety Meetings ........................................................................................................................................ 67 
12.3 
Monitoring ............................................................................................................................................... 67 
13. 
REGULATORY CONSIDERATIONS .......................................................................................................... 68 
13.1 
Protocol Review and Amendments .......................................................................................................... 68 
13.2 
Informed Consent .................................................................................................................................... 68 
13.3 
Study Documentation .............................................................................................................................. 68 
13.4 
Records Retention .................................................................................................................................... 68 
13.5 
Multi-center Guidelines ........................................................................................................................... 69 
14. 
STATISTICAL CONSIDERATIONS ............................................................................................................ 69 
14.1 
Sample Size/Accrual Rate ........................................................................................................................ 69 
14.2 
Analysis of Secondary Endpoints ............................................................................................................ 70 
14.3 
Reporting and Exclusions ....................................................................................................................... 70 
15. 
PUBLICATION PLAN .................................................................................................................................... 70 
16. 
REFERENCES ................................................................................................................................................. 72 


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APPENDICES .................................................................................................................................................. 76 
 
 


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1. OBJECTIVES 
1.1 Study Design 
 
 
This study was designed to enroll 50 subjects with untreated chronic lymphocytic leukemia/small 
lymphocytic lymphoma (CLL/SLL) who meet IWCLL 2008 criteria for initiation of therapy will 
initiate single-agent idelalisib (GS1101), a PI3K delta specific inhibitor, daily for the first two 
months on study, and begin ofatumumab at the start of the 3rd month following a complete 
response evaluation. The duration of combination therapy will be 8 months.  All subjects will 
receive 8 weekly doses of ofatumumab, following which they will undergo another response 
evaluation.  They will then continue with idelalisib during their 4 monthly doses of ofatumumab.  
The final primary endpoint response evaluation will occur two months after completion of 
ofatumumab, at 10 months following start of therapy.  Therapy with idelalisib will continue 
throughout the ofatumumab therapy and after, until development of progressive disease. Once 
participants are receiving single agent idelalisib therapy they will be seen in clinic every 2 
months. After treatment is complete subjects will be followed every 3-6 months at the treating 
investigator’s discretion until initiation of a new therapy or death. Subjects who do not complete 
cycle 2 are not considered evaluable for the study efficacy objectives and may be replaced. Their 
data will be included in all toxicity evaluations. 
  
As of 3/11/2016, Gilead has observed an excess of infectious deaths in three trials, one in upfront 
CLL, and as a result the FDA and Gilead are discontinuing enrollment to upfront CLL trials as 
well as discontinuing the administration of idelalisib to patients previously enrolled on these 
trials.  All patients on this trial however may receive ofatumumab as planned and continue to be 
followed per protocol.  Correlative analyses will continue as previously planned.   
 
1.2 Primary Objectives 
 
To determine the ORR of ofatumumab and idelalisib in previously untreated CLL/SLL 
participants in need of therapy 
 
1.3 Secondary Objectives 
 
To determine the CR rate and PFS of ofatumumab and idelalisib. 
 
To determine the ORR, CR rate and rate of nodal PR with lymphocytosis for idelalisib given 
alone for two months of therapy to previously untreated participants 
 
To determine the rate of lymphocytosis with idelalisib in previously untreated participants 
 
To assess the safety of idelalisib in untreated participants and in combination with ofatumumab. 
 
To determine whether clinical response correlates with known CLL molecular prognostic factors 
including FISH, IGHV, ZAP-70. 
 


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To determine whether the use of CT scans in response assessment improves the predictive power 
of ORR for progression-free survival or time to next treatment. 
 
To determine whether serum ofatumumab and/or idelalisib levels in vivo predict response. 
 
To assess whether initial treatment with idelalisib alters the cell surface marker phenotype of 
circulating CLL cells. 
 
To assess whether in vivo treatment with idelalisib alters CLL cell sensitivity to therapy with 
antibodies or other kinase inhibitors. 
 
To assess pharmacodynamic markers of PI3 kinase inhibition including AKT phosphorylation, 
production of T cell chemokines and response to CXCR 4/5. 
 
To determine whether response or resistance correlates with genetic alterations in PIK3CA or 
PIK3CD or other genes. 
 
To determine the influence of idelalisib treatment on intrinsic innate immune suppression and on 
regulatory T cells. 
 
To identify predictors of response and resistance to idelalisib through biochemical and genetic 
analysis of the PI3K pathway. 
 
To assess the clonal dynamics of CLL in peripheral blood vs bone marrow, and during therapy 
with idelalisib.   
 
2. BACKGROUND 
 
2.1 Preclinical Characterization of Idelalisib 
 
Nonclinical efficacy pharmacology data in enzyme-based and cell-based systems indicate that 
idelalisib is a potent inhibitor of PI3Kδ but that its selectivity spares other PI3K isoforms and 
other kinases.  Testing in nonclinical models of lymphoid neoplasia confirm the importance of 
the PI3Kδ pathway in these tumor types, and document idelalisib activity in suppressing in the 
growth and survival of these malignancies [1, 2]. 
In in vitro assays evaluating PI3K enzymatic activity, idelalisib potently inhibited PI3Kδ, with a 
concentration inducing 50% inhibition (IC50) of 2.5 nM.  By contrast, IC50 values for the effects 
of idelalisib on PI3Kα, PI3Kβ, and PI3Kγ were 820, 565, and 89 nM respectively, indicating a 
selectivity of idelalisib for PI3Kδ that is 40- to 300-fold greater than for other PI3K Class I 
family members.  When assessing IC50 values relative to Class II, III, and IV PI3K enzymes, 
idelalisib showed 400- to 4000-fold greater activity for Class I PI3Kδ inhibition.  In vitro 
selectivity was further demonstrated by evaluation of activity against the comprehensive panel of 


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402 kinases in the Ambit KinomeScan; idelalisib at 10 µM (0.42 µg/mL) inhibited PI3K 
enzymes but showed no activity against other enzymes.   
Potency and selectivity have been confirmed in cell-based in vitro assays.  In human whole 
blood, idelalisib potently inhibited basophil activation via a PI3Kδ-dependent pathway, with an 
EC50 of 62 nM; by contrast, inhibition of basophil activation via a PI3Kγ-dependent pathway 
showed an EC50 of 4,456 nM.  Idelalisib also showed potent in vitro inhibition of 
PI3Kδ-mediated processes in other cell types; activation of human B-cell proliferation via the 
B-cell receptor, neutrophil degranulation in response to bacterial peptide, and stimulation of 
human T-cell proliferation via the T-cell receptor were inhibited with respective EC50 values of 
8 nM, 119 nM, and 932 nM.  By contrast, when examining PI3Kα- or PI3Kβ- mediated 
phosphorylation of AKT in primary mouse fibroblasts, idelalisib showed EC50 values of >20 µM 
and 1900 nM, thus substantiating the lack of idelalisib effect on signaling via these PI3K 
isoforms. 
Consistent with the moderate to high bioavailability seen in nonclinical species, idelalisib shows 
high permeability across human Caco-2 cell monolayers.  At lower concentrations, the reverse 
permeability at low concentration exceeds forward permeability, indicating efflux driven by 
transporters (for e.g., human P-glycoprotein (MDR1) and breast cancer resistance protein 
(BCRP)); idelalisib is a substrate for the efflux transporters MDR1 and BCRP; however, the 
permeability increases in a concentration-dependent manner, resulting in a lower efflux ratio at 
higher, clinically relevant concentrations of idelalisib.  
Idelalisib exhibits moderately high plasma protein binding in mouse, rat, dog, and human.  In 
dog and human plasma, the protein binding is concentration-independent between 1 and 20 µM.  
Protein binding in human plasma is slightly higher than in mouse, rat, and dog plasma, which 
have comparable free fractions.  In human plasma, idelalisib and GS-563117 (a metabolite of 
idelalisib) have an average free fraction of ~16% and ~12%, respectively. 
After oral administration of [14C]idelalisib to rats and dogs, radioactivity is widely distributed, 
but relatively excluded from bone, brain, spinal cord, and eye lens in rats and from brain and 
eyes in dogs.  In rats, the radioactivity declines steadily and most tissues have undetectable levels 
by 72 hours post dose.  In bile duct-cannulated rats and dogs, ≥ 69% of radioactivity is recovered 
in bile and urine, indicating high absorption of idelalisib in vivo. 
In hepatic tissues from nonclinical species, idelalisib is primarily metabolized by aldehyde 
oxidase, CYP3A, and UGT1A4.  In vitro metabolism in dog and human yields 3 primary 
oxidative metabolites and 5 primary glucuronides.  Of these, the oxidative product GS-563117 is 
the predominant metabolite in vitro and in vivo.  In preclinical species, plasma levels of GS-
563117 are below those of idelalisib.  However, in humans GS-563117 plasma levels 
significantly exceed those of idelalisib.  After oral administration of [14C]idelalisib to rats and 
dogs, biliary excretion appears to be the major route of elimination of idelalisib and its 
metabolites as the majority of radioactivity is found in feces or bile and little in urine. 


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Idelalisib is  not a substrate for the renal transporters OCT2, OAT1, and OAT3 or the hepatic 
uptake transporters OATP1B1 and OATP1B3.  GS-563117 is not a substrate for OATP1B1 and 
OATP1B3.   
Idelalisib shows insignificant inhibition of CYP1A, CYP2B6, CYP2C9, and CYP2D6, and 
modest/moderate inhibition of CYP2C8 (IC50 = 13 µM), CYP2C19 (IC50 = 76 µM), and CYP3A 
(IC50 = 44 µM). GS-563117 shows insignificant inhibition of CYP1A, CYP2B6, CYP2C8, 
CYP2C9, CYP2C19, and CYP2D6, and is a moderate inhibitor of CYP3A (IC50 = 3.1 µM). 
Idelalisib shows insignificant inhibition of the transporters BCRP, OCT2, OAT1, and OAT3, and 
modest/moderate inhibition of MDR1 (IC50 = 7.7 µM), OATP1B1 (IC50 = 10.1 µM), 
OATP1B3 (IC50 = 7.0 µM), and the glucuronosyltransferase UGT1A1 (IC50 = 42.0 µM).  GS-
563117 shows insignificant inhibition of MDR1, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, 
and OCT2, and moderate inhibition of UGT1A1 (IC50 = 16.8 µM). 
In support of clinical development in patients with lymphoid cancers, idelalisib has undergone 
toxicological evaluation in conformance with the International Conference on Harmonisation 
(ICH) S9 guidance on nonclinical evaluation for anticancer pharmaceuticals 
2.1.1.1 General Toxicology 
Completed GLP toxicology studies have included 28-day evaluations in both rats and dogs and a 
study evaluating the hematological effects of co-administration of idelalisib and 
cyclophosphamide [3]. These studies have shown idelalisib to be tolerated at exposure levels 
greater than those expected to provide therapeutic activity and have identified signals to be 
monitored in the clinic. Reversible lymphoid depletion in rats and dogs was consistent with 
idelalisib-mediated inhibition of PI3Kδ. In rats, partially reversible inflammation of the tongue 
was noted in idelalisib-treated animals; this may have represented an exaggeration of background 
effects related to gavage-mediated irritation. Mild congestion or hemorrhage in the large 
intestine has been seen in dogs receiving high doses of idelalisib. Rats also showed cardiac and 
hepatic chronic inflammatory infiltrates, although attribution to idelalisib was uncertain because 
background infiltrates of a similar nature were observed in control recovery animals. In dogs, 
evidence of hepatocellular injury and chronic inflammation was accompanied by elevations of 
serum transaminase values (serum alanine aminotransferase [ALT] and serum aspartate 
aminotransferase [AST]). These hepatic effects appeared dose-related, reversible, and 
monitorable using standard serum chemistry laboratory parameters. In both rats and dogs, 
persistent minimal to mild degeneration of the seminiferous tubules and decreased spermatozoa 
were present in male animals receiving idelalisib. When co-administered with cyclophosphamide 
in rats, idelalisib did not worsen cyclophosphamide-mediated changes in hematological 
parameters. 
Data from completed 13-week GLP toxicology studies in rats and dogs are available. These data 
confirm the 28-day toxicology findings. Idelalisib was well tolerated with no notable clinical 
observation or changes in body weight at exposure levels approximating or exceeding those 
observed in subjects at the planned clinical starting dose of 150 mg/dose administered twice per 
day (BID). In both species, dose-dependent lymphoid depletion was observed that was consistent 
with PI3Kδ inhibition by idelalisib. In dogs, expected transient low-level elevations of serum 


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ALT in 2 animals receiving the highest idelalisib dose were observed at Day 29 of the study; of 
note, animals showed spontaneous recovery during continued idelalisib dosing, with no 
elevations at Day 60 or Day 90. Microscopic review of dog tissues indicated no evidence of 
persistent or residual liver pathology at the conclusion of the study. Consistent with previous 
studies, findings of persistent hypospermatogenesis and decreased testicular weight were 
observed in both species. 
In an investigative study, a further characterization of the pattern of serum transaminase changes 
associated with administration of high-dose of idelalisib to dogs confirmed hepatic adaptation to 
the effect. In this study, mean serum ALT/AST values peaked at approximately Day 24 to Day 
27 and resolved spontaneously as the dogs continued on idelalisib through the end of the study 
on Day 44. 
2.1.1.2 Genotoxicity 
Idelalisib was not genotoxic in a standard battery of assays [3]. In the Ames assay, idelalisib did 
not cause mutagenic effects. In human peripheral blood lymphocytes, the compound induced no 
chromosomal aberrations. In a rat micronucleus study, idelalisib did not show evidence of 
clastogenicity. 
2.1.1.3 Reproductive Toxicology 
A definitive embryo-fetal developmental toxicity study of idelalisib was performed in time-
mated pregnant female rats. Maternal toxicity was demonstrated by dose-dependent decreases in 
the body weight gains of the dams. Dose-dependent developmental findings included decreased 
fetal viability, greater numbers of early and late fetal resorptions, and reduced fetal weights. 
Dose-dependent external malformations included short tail or no tail in multiple fetuses, and 1 
instance each of hydrocephaly and microphthalmia. The results of this study indicate that oral 
administration of idelalisib is embryolethal and teratogenic in rats at maternally toxic doses.   
As noted in Section 2.1.1.1, 28-day and 13-week general toxicology studies in rats and dogs 
indicated dose-dependent reductions in testicular weights, with persistent minimal to mild 
degeneration of the seminiferous tubules and decreased spermatozoa in rats and 
hypospermatogenesis in dogs. The impact of these testicular changes on fertility, if any, has not 
been assessed. 
2.1.1.4 Phototoxicity  
In vitro studies in embryonic murine fibroblasts have yielded equivocal results relating to the 
phototoxicity of idelalisib but suggest that its major oxidative metabolite, GS-563117, may 
enhance cytotoxicity when cells are simultaneously exposed to ultraviolet light. While 
nonclinical findings suggest the hypothetical potential for phototoxicity in humans, available 
clinical data do not reveal a photosafety concern [3]. 
2.2 Clinical Experience with Idelalisib 
Idelalisib has undergone extensive early clinical evaluation in a series of Phase 1 studies in 
healthy volunteers and patients.  Studies in healthy subjects have provided information on drug 
safety; pharmacokinetics; food effects; the potential for drug interactions with CYP3A4 


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inhibitors; and idelalisib absorption, metabolism and excretion[4].  A Phase 1 study in subjects 
with allergic rhinitis has offered additional safety information and confirmed the expected 
immunomodulatory pharmacological effects of the drug.  A Phase 1 study in patients with 
lymphoid malignancies has extended safety and pharmacokinetic observations; documented the 
clinical and pharmacodynamic activity of idelalisib in patients with CLL, iNHL, and MCL; and 
provided dosing information in support of further development[4-6].  Idelalisib was recently 
approved by the FDA for the therapy of relapsed CLL in combination with rituximab, as well as 
for the therapy of relapsed indolent NHL after at least two prior therapies.   
2.2.1 Phase 1 Studies in Healthy Subjects and in Patients with Allergic Rhinitis 
Three studies in healthy subjects (Studies 101-01, 101-04, and 101-05) have provided 
information regarding drug safety, pharmacokinetics, food effects, and the potential for drug 
interactions with CYP3A4 inhibitors [3, 4]. One of these trials also included a preliminary 
evaluation of absorption, metabolism and excretion in healthy volunteers; in this trial, unlabeled 
idelalisib was co-administered with a trace amount of [14C] idelalisib given either orally or 
intravenously and biological samples were assessed by accelerator mass spectrometry. 
Safety results from these studies indicated that idelalisib was well tolerated when administered to 
healthy subjects at single doses through 400 mg (the highest dose level tested) and was also 
generally well tolerated when administered to healthy subjects over 7 days at dose levels through 
200 mg/dose BID (the highest dose level tested). Dosing with 200 mg/dose BID for 7 days 
resulted in a skin rash in 3 out of 6 subjects; histological findings were consistent with a delayed-
type hypersensitivity maculopapular exanthema. Rashes have sometimes occurred in patients 
with hematological malignancies receiving idelalisib, but have not typically proved dose- or 
treatment-limiting. In placebo-controlled single-dose and multiple-dose trials, repeated ECG 
evaluations performed in tandem with pharmacokinetic monitoring showed no evidence of drug-, 
dose-, or exposure-dependent effects on cardiac rhythm or cardiac intervals (eg, QT interval). 
Pharmacokinetic results indicated that plasma idelalisib maximum concentration (Cmax) and area 
under the concentration-time curve (AUC) values were less-than-dose-proportional with 
increasing single- and multiple-dose administration. Consistent with mean half-life (t1/2) values 
in the range of 6 to 10 hours,  steady state was achieved within 7 days of BID dosing and 
accumulation was modest.  
Idelalisib dosing after a high-fat, high-calorie meal delayed median time of maximum 
concentration (Tmax) from 0.75 hours to 3 hours; mean Cmax was unaffected and mean AUC was 
~40% higher. These changes in idelalisib exposures are considered modest/clinically non-
relevant; thus, idelalisib may be given with or without food. 
Idelalisib is metabolized in humans primarily by aldehyde oxidase, with some involvement of 
CYP3A4 and UGT1A4. Accordingly, when idelalisib was administered following 4 days of daily 
dosing with ketoconazole (a potent inhibitor of CYP3A4), modest/moderate increases in mean 
idelalisib Cmax and AUC values of  ~30% and ~80%-higher, respectively, were observed, 
indicating that idelalisib is not a sensitive substrate for CYP3A4. Thus, co-administration of 


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CYP3A4 inhibitors and idelalisib is not contraindicated and does not require special monitoring. 
GS-563117 is formed from idelalisib primarily via aldehyde oxidase. 
The 14C-labeled idelalisib huma mass balance results showed that the drug has moderate to high 
oral bioavailability Idelalisib is eliminated mainly via hepatic metabolism and biliary excretion 
in the feces (~78% of dose); recovery in urine was < 15%. GS-563117, was the primary/only 
circulating metabolite observed in human plasma, and was also observed in urine and feces.  
Pharmacodynamic results showed that an idelalisib dose of 200 mg inhibited ex vivo basophil 
activation via the PI3Kδ-specific, high-affinity immunoglobulin (Ig)E receptor (anti-FCεR1) in 
basophils collected from healthy volunteers. The findings were confirmed when the drug was 
assessed over 7 days in a Phase 1b study in subjects with allergic rhinitis. In this study, idelalisib 
at a dose level of 100 mg/dose BID showed clinical and pharmacodynamic activity (attenuating 
adverse responses to allergenic challenge and decreasing markers of inflammation) and was well 
tolerated. 
2.2.2 Phase 1 Study in Patients with Relapsed or Refractory Hematologic Malignancies 
A Phase 1 dose-ranging study (Study 101-02) of single-agent idelalisib extended safety and 
pharmacokinetic observations; documented the clinical and pharmacodynamic activity of 
idelalisib in subjects with iNHL, MCL, and CLL; and provided dosing information in support of 
further development [7]. In this study, idelalisib was administered in cohorts of subjects across a 
range of dose levels from 50 mg/dose BID to 350 mg/dose BID. Idelalisib administration was 
continued as long as individual subjects were safely benefitting from therapy. Subjects were 
evaluated in 4-week cycles; response and progression assessments were based on standard 
criteria [8]. 
Altogether, 192 subjects were enrolled to the study, including 55 subjects with CLL. As expected 
given the demographics of these diseases, subjects were predominantly male and were often 
elderly, ranging in age to 82 years for the subjects with CLL. The majority (82%) of the subjects 
with CLL had bulky tumors (≥1 lymph node ≥5 cm in diameter) and 31% had the adverse 
prognostic factor of a 17p chromosomal deletion (which commonly confers a p53 mutation in the 
tumors of these subjects). Subjects were heavily pretreated with chemoimmunotherapy; the 
median number of prior therapies by disease was 5 among subjects with CLL, but ranged up to 
15 prior treatments. Among those with CLL, prior rituximab, alkylator, and fludarabine use were 
nearly universal and 33 percent had received prior alemtuzumab. Considering only rituximab use 
after initial therapy, 35% had received single-agent rituximab at least once (some patients up to 3 
times) and a total of 51/54 (94%) had received rituximab given alone or in combination with 
other agents. In the estimation of the investigators, a substantial proportion (72%) of these 
subjects had disease that was refractory to the last prior therapy. In these subjects, therapy was 
administered for a median of 9 cycles, ranging up to 24 cycles (ie, 96 weeks). 
In this single-agent experience, idelalisib was generally well tolerated at dose levels through 
350 mg BID (the highest dose tested). No maximum tolerated dose (MTD) was apparent within 
the tested dose range. Furthermore, subjects typically found the drug tolerable over periods 
extending to >2 years; there was no profile suggestive of bothersome chronic events such as 


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headache, nausea, diarrhea, or fatigue. No subject had tumor lysis syndrome. No overt pattern of 
myelosuppression was associated with idelalisib treatment. The data also did not suggest drug-
related reductions in circulating CD4+ cells or serum Igs. 
Among Grade 3-4 nonhematological adverse events, pneumonia/pneumonitis was observed most 
frequently, occurring in 24% of subjects with CLL. In most instances, these cases were 
considered bacterial in origin, based either on culture results or on response to conventional 
antibiotics. Subjects with CLL have occasionally been diagnosed with Pneumocystis (carinii) 
jiroveci pneumonia; the specific causal role of idelalisib has been difficult to elucidate because 
infection was sometimes present before starting idelalisib or the patients had other pre-existing 
risk factors. Such subjects were not receiving pneumocystis prophylaxis. The rate of pneumonia 
over time (0.045 events/subject/month) with idelalisib was not worse than the expected rate (0.06 
events/patient/month) reported historically in comparable patients with recurrent CLL [9] . 
Monitorable, reversible elevations of hepatic transaminases were observed in some subjects; 
~5% of subjects with previously treated CLL had Grade 3-4 increases in serum ALT or AST. 
The onset of changes was time-dependent; among those with serum ALT/AST abnormalities, 
onset typically occurred 2 to 8 weeks after idelalisib initiation. In subjects with Grade 1-2 events, 
serum ALT/AST elevations resolved despite continued idelalisib dosing. In subjects with Grade 
3-4 events, idelalisib was temporarily interrupted. Upon resolution of serum ALT/AST 
abnormalities, resumption of idelalisib at a reduced dose did not result in recurrence of serum 
transaminase increases in the majority (>70%) of subjects who were rechallenged. This pattern 
suggests an adaptation to the effect similar to that observed in dogs receiving idelalisib. Such an 
adaptive response is commonly observed with other drugs that induce transaminase elevations. 
Idelalisib proved highly active in subjects with CLL, iNHL, and MCL. Among subjects with 
CLL, idelalisib reduced lymphadenopathy in all 51 (100%) of those with ≥1 post-treatment 
tumor assessment. In subjects with CLL tumors having a known 17p chromosomal deletion, 
substantial antitumor activity was observed, although PFS appeared shorter in these subjects 
relative to other trial participants without such a deletion or in whom the 17p chromosomal 
deletion status was unknown. 
The pattern of changes in CLL was particularly notable. Rapid and substantial reductions in 
lymph node size were observed in subjects with CLL with >80% of subjects showing a lymph 
node response (≥50% reductions in index nodal lesions). Among subjects who entered the trial 
with baseline thrombocytopenia or anemia, idelalisib induced sustained increases in mean 
platelet counts and hemoglobin levels. In study participants who entered the study with enlarged 
spleens due to CLL, >70% showed a resolution in splenomegaly. The median PFS was 14 
months, with some subjects having tumor control for durations exceeding 2 years. Antitumor 
activity and tumor control were longest in subjects starting idelalisib at doses of ≥150 mg/dose 
BID. 
A characteristic finding in the single-agent experience was that the majority of subjects had an 
initial increase in peripheral absolute lymphocyte count (ALC) from baseline. The increase was 
maximal during the first 2 cycles and generally decreased thereafter but could be persistent in 


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some subjects or could be seen repeatedly in subjects who had interruption and resumption of 
drug therapy (eg, due to intercurrent illness). The characteristics of this lymphocytosis indicated 
a mobilization of CLL cells from tissues rather than a proliferative event or a disease flair. The 
effect was evident within 4 hours of initiating treatment, was asymptomatic, and was associated 
with quiescence of CLL cells as indicated by reductions in AKT phosphorylation and decreases 
in circulating levels of disease-associated chemokines, CCL3 and CCL4, and the stroma-derived 
chemokine, CXCL13. The lymphocyte mobilization phenomenon is consistent with in vitro data 
showing that idelalisib depresses chemokine-mediated signaling between CLL cells and stromal 
cells [10]. These preclinical data support the concept that drug-mediated PI3Kδ inhibition 
releases CLL cells from sanctuary sites in lymph nodes and bone marrow. This action is not 
unique to idelalisib alone. Drugs that inhibit spleen tyrosine kinase (SYK) [11], Bruton tyrosine 
kinase (BTK) [12], or mTOR [13] cause a CLL cell redistribution from tissue sites to the 
peripheral blood. Because of the occurrence of this type of pattern, investigators working with 
idelalisib or inhibitors of these other pathways now rely upon measures of disease control other 
than peripheral blood lymphocyte count in determining whether a patient’s disease has 
progressed. 
An analysis of steady-state idelalisib plasma concentrations (Day 28 Cmax, AUC0-6h, or Ctrough) 
relative to dose in subjects with both NHL and CLL showed increases in these parameters 
through the dose level of 150 mg/dose BID. At higher doses, flattening of the mean dose-plasma 
exposure curve was observed, resulting in smaller incremental increases in exposure. 
Considering all safety, efficacy, and pharmacokinetic findings together, the data supported 
150 mg/dose BID as an appropriate idelalisib monotherapy starting dose for future studies in 
patients with CLL and other lymphoid malignancies.   
2.2.3 Phase 1 Combination Study in Patients with Hematological Malignancies 
A separate Phase 1 trial (Study 101-07) has evaluated the safety and preliminary activity of 
idelalisib given in combination with ofatumumab to subjects with recurrent CLL [14].  
In this study, idelalisib (150 mg BID) was co-administered with a total of 12 infusions of 
ofatumumab given over 24 weeks (300-mg initial dose followed 1 week later by 1,000 mg 
weekly for 7 doses, followed 4 weeks later by 1,000 mg every 4 weeks for 4 doses). Thereafter, 
subjects continued to receive single-agent idelalisib as long as the subject was safely benefiting 
from therapy. Subjects were evaluated in 4-week cycles; response and progression assessments 
were based on standard criteria [8]. 
At the time of the data analysis, accrual of the cohorts was complete with 21 subjects enrolled 
and evaluable. Median [range] age was 66 [43-79] years. The majority (14/21; 67%) of patients 
had bulky adenopathy (≥1 lymph node ≥5 cm in diameter). The median [range] number of prior 
therapies was 3 [1-6], including prior exposure to alkylating agents (18/21; 86%), rituximab 
(20/21; 95%), purine analogs (16/21; 76%), alemtuzumab (4/21; 19%), and/or ofatumumab 
(3/21; 14%). The median [range] ofatumumab treatment duration was 36+  [0-48+] week.  


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No idelalisib-related dose-limiting toxicities were observed within the tested subject cohorts. 
Ofatumumab infusion reactions were manageable. One patient developed corticosteroid-related 
hyperglycemia and sepsis. No clinically significant myelosuppression was observed. 
Almost all subjects (17/21, 84%) experienced marked and rapid reductions in lymphadenopathy 
within the first 2 cycles. The lymphocyte mobilization that is expected with PI3Kδ inhibition 
was significantly reduced in magnitude and duration and persisted past Cycle 1 in only 1 patient. 
The ORR was 16/21 (76%) with 2/21 (10%) subjects showing evidence of complete response 
(CR), as reported by the investigators. Elevated baseline levels of CCL3, CCL4, CXCL13, and 
TNFα were significantly reduced after 28 days of treatment. At the time of the data analysis, 
overall PFS through 48 weeks was >75% and a median PFS had not yet been observed. 
Collectively, the emerging data from this study support further evaluation of idelalisib together 
with ofatumumab in subjects with CLL and indicate that co-administration of idelalisib with 
ofatumumab is tolerable when using idelalisib at full dose, ie, at a starting dose level of 
150 mg/dose BID. 
 
2.2.4.  Updated Data on Early Treatment Trials, 3/11/16 
 
As of 3/11/16, Gilead terminated enrollment on all upfront trials in CLL.  This was because an 
excess of mortality was observed on the idelalisib containing arms in three trials:  GS-US_312-
0123, A Phase 3 Randomized Double Blind Placebo Controlled Study Evaluating the Efficacy 
and Safety of Idelalisib (GS1101) in Combination with Bendamustine and Rituximab for 
Previously Untreated CLL; GS-US-313-0124, A Phase 3 Randomized Double Blind Placebo 
Controlled Study Evaluating the Efficacy and Safety of Idelalisib (GS-1101) in Combination 
with Rituximab for Previously Treated Indolent NHLs; and GS-US-313-0125, A Phase 3 
Randomized Double-Blind Placebo Controlled Study Evaluating the Efficacy and Safety of 
Idelalisib (GS1101) in Combination with BR for Previously Treated Indolent NHL.  In total, of 
664 patients on idelalisib containing arms, 7.4% had died, compared to 3.5% of 402 patients on 
the control arm.  Most deaths were due to infections including opportunistic infections, and 
prophylaxis had not been mandated. 
2.3 Ofatumumab 
 
Ofatumumab is a human novel anti-CD20 antibody which binds to a different CD20 epitope 
than rituximab, and induces potent complement–dependent cytotoxicity against cells that express 
CD20 dimly, including CLL.  
2.3.1 Nonclinical Pharmacology 
 
Binding of ofatumumab causes clustering of CD20 on the cell surface and cell death through the 
induction of complement mediated cytotoxicity (CDC) and antibody dependent cell mediated 
cytotoxicity (ADCC). In vitro studies showed that ofatumumab is able to kill tumor B cells 
including those with low CD20 expression, such as primary chronic lymphocytic leukaemia 
(CLL) cells, and cells with high expression of complement defense molecules. The anti-tumor 
effects of ofatumumab were confirmed in human B cell tumor xenograft models in mice. 


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Statins were found to reduce the in vitro ability of ofatumumab to induce CDC or ADCC 
mediated cell lysis.  Compared to rituximab, ofatumumab showed potential in nonclinical studies 
to be more potent at inducing CDC, especially in cells with low CD20 expression. Furthermore, 
as a fully human antibody, ofatumumab is predicted to be less immunogenic than rituximab, 
which is a chimeric monoclonal antibody. 
2.3.2 Effects in Humans 
2.3.2.1  
Pharmacokinetics and pharmacodynamics 
 
Pharmacokinetic data are available from four completed studies (Study Hx-CD20-001, Study 
Hx-CD20-402, Study Hx-CD20-403, and Study OMB111148), three concluded studies (Study 
Hx-CD20-405, Study Hx-CD20-407, and Study GEN414/OMS115102 (48-week interim 
analysis completed)), and four ongoing studies (Study Hx-CD20-406, Study Hx-CD20-409, 
Study GEN410/OFA110635 (completed to 24 weeks), and Study OFA110867 (Day 169 analysis 
completed)). Ofatumumab was administered by IV infusion in all studies except Study 
OFA110867, in which it was given by SC injection.  After repeated IV administration, clearance 
and volume of distribution values were low and half-life values were long for ofatumumab, as 
seen with other monoclonal antibodies.  Statistically significant increases in AUC, Cmax, and t½ 
values and decreases in clearance (CL) values were found between the first and last infusions. 
These findings are likely due to the rapid and sustained depletion of CD20+ B cells after first 
infusion, leaving a reduced number of B cells available for the antibody to bind at subsequent 
infusions. Subcutaneous administration of a single dose of ofatumumab ≥30 mg in subjects with 
rheumatoid arthritis similarly resulted in rapid and sustained B-cell depletion. 
2.3.2.2  
Summary of safety data 
 
Infusion reactions in the IV program are common adverse events (AEs) that are generally mild to 
moderate in severity, and have been mitigated by premedication and slower IV administration. 
Severe infusion reactions have been reported, and have occasionally led to temporary 
interruption or withdrawal of ofatumumab. Adverse events in the SC program to date have also 
shown severe reactions, but overall, most AEs have been generally mild to moderate, and have 
been considered as post-injection systemic reactions (PISRs). Infectious events including lower 
respiratory tract infections and cytopenias that include neutropenia, anemia, and 
thrombocytopenia have been observed in oncology trials with ofatumumab, but these events are 
commonly reported with the diseases under study and/or other concomitant therapies. 
Neutropenia and serious infections have also been reported in RA studies, but these generally 
occurred at a similar frequency between the ofatumumab and placebo groups. 
2.3.2.3  
Efficacy in chronic lymphocytic leukemia (CLL) 
 
As of 21 December 2010, efficacy results are available from two completed studies (Study Hx-
CD20-402, Study 148) and 2 concluded studies in CLL (Study 406, Study 407).  In Study 402 
(N=33), ofatumumab treatment in subjects with relapsed or refractory CLL led to a 48% ORR in 
the highest dose group, Group C (n=27; 1st dose: 500 mg; 2nd, 3rd, and 4th dose: 2000 mg) and 


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included 12 (44%) subjects with PR and 1 (4%) subject with nodular partial response (nPR). One 
of the subjects showed all features of an nPR at Week 19 except that residual lymphadenopathy 
was identified by computed tomography (CT). For Group C, the median TTP was 15.6 weeks in 
the full analysis population and 23 weeks in the subgroup of responders. The median duration of 
response was 16 weeks and the median time to next CLL therapy was 52.4 weeks.  In Study 406 
(N=154 as of the interim data cutoff of 19 May 2008 and updated results as of cut off of 15 July 
2010), the results demonstrated that ofatumumab monotherapy is effective in subjects with CLL 
who are either refractory to both fludarabine and alemtuzumab (i.e., double refractory [DR]) or 
who are refractory to fludarabine and considered inappropriate for alemtuzumab treatment due to 
the presence of bulky (>5cm) lymphadenopathy (i.e., bulky fludarabine refractory [BFR]). 
Additionally, ofatumumab showed activity in “Other” subjects who failed fludarabine but were 
enrolled in the study prior to Amendment 3 and did not meet the classification criteria of either 
DR or BFR defined in the amendment. 
 
The interim results of Study 406 were submitted as the basis for a BLA to the FDA for the use of 
ofatumumab for the treatment of CLL refractory to fludarabine and alemtuzumab (DR), or 
refractory to fludararabine but considered inappropriate for alemtuzumab treatment due to bulky 
(>5 cm) lymphadenopathy (BFR). The FDA reviewed the application and subsequently granted 
accelerated approval for ofatumumab for the treatment of subjects with CLL refractory to 
fludarabine and alemtuzumab (DR population). The Arzerra Prescribing Information describes 
the data presented to the FDA for accelerated approval. As of the 15 July 2010 clinical efficacy 
cut-off date, updated results of preliminary data for Study 406 are summarized. The primary 
endpoint analysis in 223 subjects included subjects in the DR (N= 95), BFR (N= 111), and Other 
(N=17) groups. The ORR was 51% (48/95) in the DR group, 44% (49/111) in the BFR group, 
and 59% (10/17) in the Other group. Among the 107 responders, 2 subjects in the BFR group 
achieved CR, 48 subjects in the DR group achieved PR, 47 subjects in the BFR group achieved 
PR, and 9 subjects in the Other group achieved PR. An additional 33 subjects in the DR group, 
49 subjects in the BFR group, and 5 subjects in the Other group achieved SD. The median 
duration of response was 5.7 months, 6.0 months, and 7.4 months in the DR, BFR, and Other 
groups, respectively. The median PFS was 5.5 months in both the DR and BFR groups and 8.9 
months in the Other group. The median Overall survival (OS) was 14.2 months in the DR group, 
17.4 months in the BFR group, and 28.3 months in the Other group. Additional data and analyses 
are ongoing. 
 
In Study 407 (N=61), subjects with previously untreated CLL were randomized to two dose 
levels of ofatumumab in combination with FC (fludarabine and cyclophosphamide): 300 mg of 
ofatumumab (cycle 1) followed by 500 or 1000 mg of ofatumumab (cycles 2-6), in combination 
with FC, every 4 weeks for 6 cycles. The overall response rate in the 500 mg group was 77% and 
in the 1000 mg group was 73%. Complete responses were observed in 32% of subjects (10/31) in 
the 500 mg group and in 50% of subjects (15/30) in the 1000 mg group. Overall, across both 
dose groups 25 subjects had CR, 19 subjects had PR, 2 subjects had nPR, 5 subjects had SD, and 
7 subjects had PD. With the preliminary data, short median follow-up time of 8.2 months did not 
permit analysis of time to event endpoints. 
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Chronic lymphocytic leukemia is the most common leukemia of adults and remains incurable.  
Although a subset of patients have very indolent disease and may never require therapy, others 
have steadily progressive or aggressive disease.  These patients tend to experience shorter and 
shorter remissions, as well as cumulative effects of chemotherapy, which has significant toxicity 
to their normal bone marrow and immune system.  Over time the disease may become more 
aggressive, acquiring adverse prognostic markers including 11q and 17p deletions.  For this 
reason a highly effective novel therapy which does not induce the myelosuppressive and 
immunosuppressive effects of chemoimmunotherapy would be ideal.  Such a therapy which 
patients can remain on indefinitely for maintenance is even better.  The idelalisib ofatumumab 
combination studied here has the potential to be such a therapy.   
 
 
2.5 Rationale  
 
The advent of chemoimmunotherapy has been very effective in the initial treatment of CLL, 
resulting in long remissions.  Increasing evidence suggests however that patients who relapse 
after chemoimmunotherapy often do not respond well to further chemotherapy.  Furthermore, 
there is an increasing awareness of the long term complications of chemoimmunotherapy, 
including delayed infections, pancytopenia and MDS/AML.  Novel agents that do not have these 
side effects, including antibodies and small targeted inhibitors, can be quite effective even in 
refractory disease, and it is of interest to determine their efficacy in previously untreated patients, 
who may be able to attain prolonged remissions without the side effects of 
chemoimmunotherapy.  Ofatumumab has a 51% response rate in patients refractory to 
fludarabine and alemtuzumab, and has been recently approved by the FDA for this indication.  
Ofatumumab clears CLL from peripheral blood very effectively.  Its activity in previously 
untreated CLL has only recently been described, and the ORR is 55%[15].   
 
The investigational drug idelalisib is a specific inhibitor of the delta isoform of PI3 kinase, which 
is expressed in hematopoietic cells and appears to be functionally critical in B cells.  
Approximately 190 patients with hematologic malignancies have been treated on the Phase I 
study of idelalisib.  At IWCLL and ASH 2009 and 2010, response rates of 60% in indolent 
lymphomas were reported.  Interestingly, in CLL, all patients have reductions in 
lymphadenopathy, with 80% of patients reaching >50% reduction, often within 1-2 weeks, and 
apparently independent of high risk 17p or 11q deletions.  However, concomitant with this 
marked decrease in adenopathy is an increase in lymphocytosis.  This lymphocytosis appears to 
represent a redistribution of lymphocytes from lymph nodes and possibly bone marrow to 
peripheral blood.  Because of the response criteria for CLL, however, this lymphocytosis has 
prevented a response from being called, even in a patient with marked improvement in bulky 
lymphadenopathy.  A recent revision to the response criteria supports that this lymphocytosis is 
not progressive disease, and that patients with nodal response with lymphocytosis may be 
considered as PRs with lymphocytosis.  However, this pattern of response suggests that 
combining idelalisib’s activity in nodal disease with another drug which would effectively clear 
the lymphocytosis should result in excellent and frequent clinical responses.  In fact, in 
previously untreated patients this may represent a potential paradigm for achieving excellent 
disease control without the side effects of chemotherapy.  Thus the combination of idelalisib to 


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mobilize CLL from lymph nodes, combined with ofatumumab to clear the disease from 
peripheral blood, should be highly effective in CLL.  We have therefore chosen to combine these 
two drugs in a phase 2 study in which all patients will start idelalisib two months prior to 
ofatumumab.  It is possible that mobilization of cells from sanctuary sites with idelalisib prior to 
initiation of ofatumumab may enhance response to the combination but this is unclear, as is the 
rate of lymphocytosis in previously untreated patients.  This study design will allow us to address 
these questions.  This study will be run as a multicenter study of the CLL Research Consortium.    
 
Rationale for Prior Amendments in 2014-2015 
 
This study activated for enrollment on June 16, 2014, and since then 15 patients have initiated on 
therapy.  Among the first 8 patients to reach cycle 2, two patients developed grade 4 
transaminitis.  Transaminitis is a well-known side effect of idelalisib, and included as a black 
box warning in the FDA approved label.  In these two cases the onset was rapid, and continued 
to increase after discontinuation of the drug.  We have therefore previously amended the protocol 
to significantly increase the frequency of LFT monitoring during the high risk period.  
Additional observation has shown that this transaminitis appears to be inflammatory, based on 
the results of two liver biopsies showing a CD8 T cell infiltrate and the response of these patients 
to steroids and/or mycophenolate mofetil.  We have developed an algorithm for the early 
initiation of steroids with the first signs of transaminitis which together with the frequent 
monitoring has resulted in predictable safety and much shorter drug interruptions.  This 
amendment served to further refine that treatment algorithm.  
 
An amendment was submitted in January 2015 to add correlative studies, in particular 
sequencing analysis of the clonal composition of CLL in PB vs BM at baseline, mid treatment 
and at final restaging.  This analysis will still occur.  
 
Rationale for Current Amendment 3/14/16 
 
This amendment will take all patients off idelalisib, but allow them to receive ofatumumab and 
be followed per protocol assessments.  All patients had discontinued idelalisib as of 3/11/16.  
They will undergo a full disease restaging with correlative samples within 30 days and be 
followed per protocol until further therapy, and after that just for overall survival.   
 
 
2.6 Correlative Studies Background and Rationale 
 
a) Prognostic correlates- Prognosis in CLL is widely variable and well-correlated with several 
key biologic prognostic factors.  We will therefore determine standard CLL prognostic markers 
including FISH, IGHV and ZAP-70 (by flow cytometry and methylation) in all patients in order 
to determine if a particular subgroup shows better response to idelalisib-ofa than others, as well 
as to define the response rate in each subgroup.  We will employ CT scans in order to compare 
response rates determined with and without CT scans, and a bone marrow biopsy will be 
incorporated at the end of single agent lead-in, and combination therapy even for patients not in 
CR, in order to gain information on the effectiveness of bone marrow clearance with these two 
drugs.  The bone marrow biopsy at two months on therapy will allow comparison of the features 


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of CLL cells that redistribute to peripheral blood with the features of those that remain alive in 
the bone marrow.  Serum ofatumumab levels and serum idelalisib levels will be determined by 
Covance, in order to correlate response with drug levels.  It will be of interest to determine how 
long ofatumumab will remain detectable following completion of the course of therapy.  We will 
also assess whether CD20 expression levels are altered with ofatumumab therapy.    
  
b) Activation studies of CLL B cells- CLL cells generally express markers of activation on their 
cell surface.  This may be related to the degree of activation of the BCR pathway, which is 
inhibited by idelalisib.  We will therefore use flow cytometry to determine whether activation 
markers are altered by idelalisib as a single agent or in combination with ofatumumab.  We 
further hypothesize that idelalisib will potently inhibit downstream signaling triggered by the 
BCR and other survival pathways in CLL cells, and we will therefore assess the effects of in vivo 
inhibition of the PI3K delta pathway by idelalisib on those targets.  Other pharmacodynamic 
markers of PI3 kinase inhibition will also be assessed, including for example production of T cell 
chemokines, to see if these correlate with degree of response.       
 
c) CLL B cells and their microenvironment- CLL B-cells are shifted out of the 
microenvironment by idelalisib.  We will compare the biologic features of CLL cells in PB and 
BM at baseline and again on idelalisib therapy, to see if these features shift in the two 
compartments over time.  We will look at markers of activation and proliferation in both 
compartments.  We will look at whether in vivo therapy with idelalisib alters in vitro 
susceptibility to antibody therapy and to therapy with other BCR pathway inhibitors. 
 
d) Predictors of response to idelalisib - Little is known about predictors of response to 
idelalisib, or mechanisms of resistance.  Dr. Amy Johnson will explore the baseline activity of 
the PI3K pathway and the degree of observed inhibition in this regard, and will also look for 
upregulation of alternative signaling pathways in resistant cells.  In addition, we will bank CLL 
cells from prior to all therapy, for assessment of copy number, somatic mutation, gene 
expression and mRNA and miRNA profiling.  Dr Brown has recently completed a large 
integrative analysis in CLL in which she identified amplifications of PIK3CA as associated with 
poor outcome, and found that CLLs with PIK3CA amplification had a higher fraction of PI3K 
activity dependent on alpha vs delta.  We therefore hypothesize that these amplifications may be 
associated with idelalisib resistance, or may be acquired in patients who progress on therapy, and 
we plan to assess for them in patients with persistently elevated white counts, or who develop 
recurrent lymphocytosis on therapy.  Although we have not yet identified a significant rate of 
somatic mutations in PI3K genes in CLL, we have identified somatic RAS, MAPK and mTOR 
mutations which could confer resistance, and we will plan to perform whole exome sequencing 
to assess for such mutations.    
e) Immune suppression correlative studies- CLL progression is associated with 
hypogammaglobulinemia [16-18], expanded T-regs [19, 20], and increased soluble 
immunosuppressive cytokines (TGF-β [21-23], IL-6 [24-26], IL-10 [24, 27-29]) derived from 
the primary tumor cells that can promote both survival of the malignant clone and also potential 
systemic innate immune suppression. Similar to these well-characterized cytokines, expression 
of PD1 and PD1-L1 on activated CLL cells has the potential for suppression of the innate 


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immune system as demonstrated in other types of lymphoma [30, 31] and multiple myeloma 
[32]. The consequence of such innate immune suppression in CLL relative to antibody therapy 
is likely significant as exemplified by data with rituximab. While rituximab has significant 
activity in NHL (reviewed in [33, 34]), success as monotherapy in CLL has been modest 
(reviewed in [35, 36]). Furthermore, unlike NHL and other cancers where specific FcγR SNPs 
predict for increased effectiveness of antibody therapy, work [37, 38] of John Byrd and 
colleagues and confirmed by others [39] showed no such relationship in CLL for rituximab. 
Several groups [40],[41] have documented that one possible reason for innate immune 
dysfunction could be suppressive cytokines released by the tumor. Reversal of tumor 
immunosuppressive properties with respect to cytokine release represents a new potential way 
to augment antibody treatment that has not been approached to this point.  Preliminary data 
from John Byrd’s laboratory demonstrate that idelalisib can diminish expression of many of 
these immunosuppressive cytokines and ligands in vitro. As part of this proposal he will test the 
ability of the BCR signaling antagonist molecule idelalisib to diminish these cytokines and 
improve innate immune therapy. 
f) Autoimmune toxicity:  The early phases of this study have identified a rapid transaminitis 
sometimes with fever or pneumonitis, and a later colitis, in a pattern very reminiscent of that 
seen in mice and humans with genetic defects in T regulatory cells.  In this study we are 
therefore going to investigate the changes in T regulatory cells that occur in patients during 
idelalisib therapy, and attempt to identify findings that correlate with toxicity.  This is still 
possible as samples have already been banked on the patients previously enrolled. 
 
g) CLL subclonal composition and evolution, with outgrowth of resistance.  The last several 
years have seen an explosion of genomic information in CLL, including the identification of 
SF3B1 and NOTCH1 as recurrently mutated in CLL[42-44] and the proposal that subclonal 
driver mutations are associated with shorter time to treatment and shorter overall survival, both 
results from our group at DFCI[45].  Despite these advances, very little is known about the 
subclonal architecture over time in CLL and between compartments, including peripheral blood 
and bone marrow.   In particular, nothing is yet known about whether the redistribution 
lymphocytosis[46-48] associated with BCR inhibitors like idelalisib and ibrutinib changes the 
clonal architecture of the disease in the blood.  Some studies have been initiated with ibrutinib 
but to date no studies have been initiated with idelalisib.  Furthermore, nothing is yet known 
about the genetic characteristics of the residual or persistent disease in blood and bone marrow 
after treatment with BCR inhibitors, and whether this residual disease eventually gives rise to the 
relapse clone.  We will therefore perform exome sequencing on selected patients at baseline and 
after idelalisib therapy in order to assess changes in subclonal architecture, and will subsequently 
collect relapsed samples for comparison purposes. Similarly these studies will still be done as 
samples have already been banked.  
 
3. Participant SELECTION: Study is closed to enrollment 
 
3.1 Eligibility Criteria 


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Participants must meet the following criteria on screening examination to be eligible to 
participate in the study: 
3.1.1 Subjects must have CLL / SLL, as documented by a history at some point in time of an 
absolute peripheral blood B cell count > 5000 / µl, with a monoclonal B cell population co-
expressing CD19, CD5, and CD23, or if CD23 negative, then documentation of the absence of 
t(11;14) or cyclin D1 overexpression.  Alternatively patients with lymphadenopathy in the 
absence of circulating disease will also be eligible for this study if lymph node biopsy or bone 
marrow biopsy establishes the diagnosis of CLL with the above immunophenotype.   
3.1.2 Participants must have measurable disease (lymphocytosis > 5,000 / µl, or palpable or CT 
measurable lymphadenopathy > 1.5 cm, or bone marrow involvement  >30%).  
3.1.3 Subjects must not have received any prior systemic therapy for CLL and currently have an 
indication for treatment as defined by the IWCLL 2008 Guidelines: 
• Massive or progressive splenomegaly; OR 
• Massive lymph nodes, nodal clusters, or progressive lymphadenopathy; OR 
• Grade 2 or 3 fatigue; OR 
• Fever ≥ 100.5°F or night sweats for greater than 2 weeks without documented 
infection; OR 
• Presence of weight loss ≥ 10% over the preceding 6 months; OR 
• Progressive lymphocytosis with an increase of ≥ 50% over a 2-month period or an 
anticipated doubling time of less than 6 months; OR 
• Evidence of progressive marrow failure as manifested by the development of or 
worsening of anemia and or thrombocytopenia. 
 
3.1.4 ECOG performance status <2 (see Appendix A). 
3.1.5 Age ≥ 18 years.  Because no dosing or adverse event data are currently available on the use 
of idelalisib or ofatumumab in participants <18 years of age, children are excluded from this 
study. 
 
3.1.6 Participants must have normal organ and marrow function as defined below: 
• creatinine <2.0 times institutional upper normal limit 
• total bilirubin <1.5 times institutional upper normal limit (unless due to disease 
involvement of liver, hemolysis or a known history of Gilbert’s disease) 
• ALT <institutional upper normal limit  
•alkaline phosphatase <2.5 times institutional upper normal limit (unless due to disease 
involvement of the liver or bone marrow) 
3.1.1 The effects of idelalisib and ofatumumab on the developing human fetus are unknown. For 
this reason, 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. Females of childbearing potential must agree to use a 


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protocol-recommended method of contraception during heterosexual intercourse from the screening 
visit throughout the study and for 30 days from the last dose of idelalisib.  Should a woman become 
pregnant or suspect she is pregnant while participating in this study, she should inform her 
treating physician immediately. 
 
 
 
3.1.2 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 Participants who have had any prior systemic therapy for CLL, or chemotherapy or 
radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) for some other 
indication prior to entering the study or those who have not recovered from adverse 
events due to agents administered more than 4 weeks earlier. 
 
3.2.2 Participants may not be receiving any other study agents. 
 
3.2.3 Participants with known brain metastases should be 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. 
 
3.2.4 History of severe allergic reactions attributed to compounds of similar chemical or biologic 
composition to ofatumumab or idelalisib. 
3.2.5 Subjects who have current active hepatic or biliary disease (with exception of participants 
with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver 
disease per investigator assessment) 
3.2.6 Treatment with any known non-marketed drug substance or experimental therapy within 5 
terminal half lives or 4 weeks prior to enrollment, whichever is longer, or currently 
participating in any other interventional clinical study 
3.2.7 Other past or current malignancy that could interfere with the interpretation of outcome.  
Subjects who have been free of active malignancy for at least 2 years, or have a history of 
completely resected non-melanoma skin cancer or successfully treated in situ carcinoma, or 
whose malignancy will not interfere with the interpretation of study results, are eligible. 
3.2.8 Chronic or current infectious disease requiring systemic antibiotics, antifungal, or antiviral 
treatment such as, but not limited to, chronic renal infection, chronic chest infection with 
bronchiectasis, tuberculosis and active Hepatitis C. 
3.2.9 History of significant cerebrovascular disease in the past 6 months or ongoing event with 
active symptoms or sequelae 


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3.2.10 
Confirmed HIV positive whether or not on antiretroviral therapy.   
3.2.11 
Clinically significant cardiac disease including unstable angina, acute myocardial 
infarction within six months prior to randomization, congestive heart failure (NYHA III-IV), 
and arrhythmia unless controlled by therapy, with the exception of extra systoles or minor 
conduction abnormalities. 
3.2.12 
Significant concurrent, uncontrolled medical condition including, but not limited to, renal, 
hepatic, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease 
which in the opinion of the investigator may represent a risk for the participant. 
3.2.13 
Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In addition, if 
negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HB DNA test will be 
performed and if positive the subject will be excluded.  
*If HBV DNA is negative, subject may be included but must undergo HBV DNA PCR 
testing at least every 2 months from the start of treatment until 12 months post treatment. 
Prophylactic antiviral therapy may be initiated at the discretion of the investigator. 
3.2.14 
Positive serology for hepatitis C (HC) defined as a positive test for HepC Ab, in which 
case reflexively perform an HC RIBA immunoblot assay or hepatitis C viral load to confirm 
the result.  If the confirmatory test is negative the subject will be eligible. 
3.2.15 
Pregnant or lactating women. Women of childbearing potential must have a negative 
pregnancy test at screening. Pregnant women are excluded from this study because idelalisib 
and ofatumumab are anti-neoplastic agents with 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, breastfeeding should be discontinued if the mother is 
treated on this study with idelalisib and ofatumumab.  
3.2.16 
Women of childbearing potential, including women whose last menstrual period was less 
than one year prior to screening, unable or unwilling to use adequate contraception from study 
start to 30 days after the last dose of protocol therapy. Adequate contraception is defined as 
hormonal birth control, intrauterine device, double barrier method or total abstinence. 
3.2.17 
Male subjects unable or unwilling to use adequate contraception methods from study start 
to 30 days after the last dose of protocol therapy. 
3.2.18 
Participants using concomitant corticosteroids are allowed as long as the subject is on the 
equivalent of 20mg/day or less of prednisone and has been on a stable dose for at least two 
weeks prior to initiating therapy. 
3.3 Inclusion of Women, Minorities and Other Underrepresented Populations 
 
CLL is approximately twice as common in men as women, but women have generally been well 
represented on our CLL protocols at DFCI and the CRC.  The eligibility criteria will not have a 


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negative impact on enrollment of women, particularly since most women with CLL are 
postmenopausal.  We will make every effort to enroll minorities on this study although few are 
seen in our clinic. 
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. All subjects should also be 
registered to the CLL Research Consortium tissue bank but this enrollment will be through a 
separate protocol at each institution.  
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
QACT protocol-specific eligibility checklist. Following registration, participants may begin 
protocol treatment. Issues that would cause treatment delays should be discussed with the 
Overall Principal Investigator (PI). If a participant does not receive any protocol therapy 
following registration, the participant’s registration on the study may be canceled. Notify the 
QACT Registrar of registration cancellations 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 QACT protocol-specific eligibility checklist using the eligibility 
assessment documented in the participant’s medical record and/or research chart. To be 
eligible for registration to the protocol, the participant must meet all inclusion and 
exclusion criterion as described in the protocol and reflected 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. 
  


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3. 
Fax the eligibility checklist(s) and all pages of the consent form(s) to the QACT at 617-
632-2295. 
  
4. 
The QACT Registrar will (a) review the eligibility checklist, and (b) register the 
participant on the protocol. 
  
5. 
An email confirmation of the registration will be sent to the Overall PI, study 
coordinator(s) from the Lead Site, treating investigator and registering person 
immediately following the registration. 
  
4.3 General Guidelines for Other Participating Institutions 
 
Eligible participants will be entered on study centrally at the DFCI by the Study 
Coordinator. All sites should call the Study Coordinator to verify treatment availability. 
The required Eligibility Checklist can be found in Appendix B. 
 
Following registration, participants should begin protocol treatment within 5 days. Issues 
that would cause treatment delays should be discussed with the Overall PI. If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study may be canceled. The DFCI study team should be notified of cancellations as soon as 
possible. 
 
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 central email (DFCI13309@partners.org), 
Project Manager and Study Coordinator: 
 
Copy of all screening test results, CT scan, BM report 
 
Signed study consent form 
 
HIPAA authorization form 
 
Signed eligibility checklist 
 
The research nurse or data manager at the participating site will then call the Project 
Manager or email the DFCI central email (DFCI13309@partners.org)  to verify eligibility. 
To complete the registration process, the Project Manager 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 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 DFCI. 


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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 ofatumumab 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. 
 
Idelalisib lead-in followed by ofatumumab 8 wks later 
 
 All therapy with idelalisib has been discontinued.  Patients on drug stopped as of 3/11/16.  
Those currently receiving ofatumumab may complete the planned course and evaluations as 
below.  Those who have not yet reached day 57 may initiate ofatumumab at present.  On day 57, 
ofatumumab will begin with the 300 mg dose. Ofatumumab will then be administered at 1000 
mg weekly to complete 8 weeks (days 64, 71, 78, 85, 92, 99, 106) throughout Cycles 3 and 4. 
Cycle 4 will last 49 days (7 weeks) to accommodate the Ofatumumab dosing schedule. This will 
be followed by monthly ofatumumab on weeks 20, 24, 28, 32 to complete 4 additional cycles (5-
8).   The overall induction treatment period will then be up to 8 months, including whatever 
idelalisib was received prior to March 11, 2016.  Restaging with CT scans will happen after 
Cycle 2, on cycle 4 day 22, and a final restage will occur 2 months after the completion of 
ofatumumab.  There will be a tumor response assessment done via physical exam after Cycle 8.  
Table 1:  Treatment Description 
Agent 
Pre-medications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Idelalisib  
None 
150 mg BID Oral 
Disconti
nued 
28 days 
(4 weeks) 
(Except 
cycle 4- 
49 days, 
7 weeks) 
Ofatumu
mab 
Pre-medication 
before each 
ofatumumab 
infusion must be 
given within 30 
minutes to 2 hours 
prior to the 
treatment: 
Acetaminophen 
1000 mg po 
Benadryl 50 mg IV 
or po 
Methylprednisolon
e 50 mg IV* 
300 mg at 
0.3 mg/ml 
in NS; 
followed 
one week 
later by 
1000 mg at 
1 mg/ml in 
NS 
IV after 
administrati
on of 
Idelalisib and 
premeds 
Weekly 
x 8 
doses, 
then 
monthly 
x 4 
doses 
* If the 2nd infusion has been completed without the subject experiencing any grade = 3 AEs, 
pre-medication with glucocorticoid may be reduced or omitted before the 3rd to Nth infusion at 
the discretion of the investigator. 
 


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5.1 Pre-treatment Criteria 
   
5.1.1 Cycle 1, Day 1       
 
Subjects must continue to meet the laboratory eligibility criteria for creatinine and LFTs. Subjects 
must have initiated infectious prophylaxis; they also must be monitored and/or receive prophylaxis 
against tumor lysis syndrome as needed at the discretion of the treating physician. See section 5.3.2 
and 5.3.6 for additional details. 
 
5.1.2 Subsequent Cycles 
 
Liver function tests, creatinine, and complete blood count with differential must be reviewed prior 
to administration of ofatumumab therapy and managed as below under toxicity management.  
Premedication for ofatumumab during cycles 3-8 must be given as per Table 1 above.  
 
5.2 Agent Administration  
 
5.2.1 Idelalisib will not be given 
 
 
5.2.2 Ofatumumab 
 
The dosing of ofatumumab in CLL should consist of an infusion of 300 mg on Day 1, an 
infusion of 1000 mg weekly for 7 additional doses, and then infusions of 1000 mg monthly for 
up to 4 doses. The monthly ofatumumab doses should be given on Day 1 of the cycles.   
 
First Infusion of 300 mg Ofatumumab (CLL) 
The first dose administered of ofatumumab in CLL should be 300 mg to minimize infusion 
reactions. The initial rate of the first infusion of 300 mg ofatumumab (0.3 mg/mL) should be 12 
mL/h. If no infusion reactions occur the infusion rate should be increased every 30 minutes, to a 
maximum of 400 mL/h, according to Table 2. If this schedule is followed, the infusion duration 
will be approximately 4.6 hours.  If the ofatumumab dose cannot be completed on day 1 in clinic, 
the remaining dose may be completed the following day with the same premedications.  
 
           
    Table 2:  Infusion rate at 1st ofatumumab infusion (300 mg) 
Time 
mL/hour 
0 – 30 minutes 
12 
31 – 60 minutes 
25 
61 – 90 minutes 
50 
91 – 120 minutes 
100 
121 - 150 minutes 
200 
151 - 180 minutes 
300 
181+ minutes 
400 
 


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If an infusion reaction develops, the infusion should be temporarily slowed or interrupted. Upon 
restart, the infusion rate should be half of the infusion rate at the time the infusion was paused. If, 
however, the infusion rate was 12 mL/hour before the pause, the infusion should be restarted at 
12 mL/hour. Thereafter, the infusion rate may be increased according to the judgment of the 
investigator, in the manner described in this section. If the infusion is not completed on day 1, 
the remaining infusion may be completed on day 2 at the starting infusion rate used on day 1. 
 
First Infusion of 1000 mg Ofatumumab 
The initial rate of the first infusion of 1000 mg ofatumumab (1 mg/mL) should be 12 mL/h. If no 
infusion reactions occur the infusion rate should be increased every 30 minutes, to a maximum of 
400 mL/h, according to Table 3. If this schedule is followed, the infusion duration will be 
approximately 4.6 hours.  If the ofatumumab dose cannot be completed on day 1 in clinic, the 
remaining dose may be completed the following day with the same premedications.  
 
                  Table 3: Infusion rate at 1st ofatumumab infusion (1000 mg) 
Time 
mL/hour 
0 – 30 minutes 
12 
31 – 60 minutes 
25 
61 – 90 minutes 
50 
91 – 120 minutes 
100 
121 - 150 minutes 
200 
151 - 180 minutes 
300 
181+ minutes 
400 
 
If an infusion reaction develops, the infusion should be temporarily slowed or interrupted. Upon 
restart, the infusion rate should be half of the infusion rate at the time the infusion was paused. If, 
however, the infusion rate was 12 mL/hour before the pause, the infusion should be restarted at 
12 mL/hour. Thereafter, the infusion rate may be increased according to the judgment of the 
investigator, in the manner described in this section. If the infusion is not completed on day 1, 
the remaining infusion may be completed on day 2 at the starting infusion rate used on day 1. 
 
Subsequent Infusions of 1000 mg Ofatumumab 
If the previous infusion has been completed without grade ≥ 3 infusion-associated AEs, the 
subsequent infusion of the 1000 mg ofatumumab (1 mg/mL) can start at a rate of 25 mL/hour 
and should be doubled every 30 minutes up to a maximum of 400 mL/h, according to Table 4. 
Duration of the infusion will be approximately 4 hours if this schedule is followed. If the 
previous infusion has been completed with grade ≥ 3 infusion-associated AEs, the subsequent 
infusion should start at a rate of 12 mL/hour according to Table 3 for CLL. 
 
                           Table 4: Infusion rate at subsequent ofatumumab infusion 
Time 
mL/hour  
0 – 30 minutes 
25 
31 – 60 minutes 
50 


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61 – 90 minutes 
100 
91 – 120 minutes 
200 
121+ minutes 
400 
 
During infusion the participant should be monitored closely and appropriate measurements 
should be performed whenever judged necessary.  If the ofatumumab dose cannot be completed 
on day 1 in clinic, the remaining dose may be completed the following day with the same 
premedications. If the infusion is not completed on day 1, the remaining infusion may be 
completed on day 2 at the starting infusion rate used on day 1. 
 
5.3 General Concomitant Medication and Supportive Care Guidelines 
 
To the extent possible, administration of any prescription or over-the-counter drug products other 
than study medication should be minimized during the study period.  Participants should be 
discouraged from use of recreational drugs, herbal remedies, self-prescribed drugs, tobacco 
products, Tylenol or excessive alcohol at any time during the clinical study.   
If considered necessary for the participant’s well-being, drugs for concomitant medical 
conditions or for symptom management may be given at the discretion of the investigator.  The 
decision to authorize the use of any drug other than study drug should take into account 
participant safety, the medical need, the potential for drug interactions, the possibility for 
masking symptoms of a more significant underlying event, and whether use of the drug will 
compromise the outcome or integrity of the study   
Participants should be instructed about the importance of the need to inform the clinic staff of the 
use of any drugs or remedies (whether prescribed, over-the-counter, or illicit) before and during 
the course of the study.  Any concomitant drugs taken by a participant during the course of the 
study and the reason for use should be recorded on the CRFs.   
Information regarding use or restrictions on specific concomitant medications, dietary measures, 
or other interventions is provided below. 
5.3.1 Antiemetics 
 
Nausea and/or vomiting have not been commonly observed with ofatumumab in prior studies.  
However, participants who experience nausea or vomiting while on study therapy may receive 
antiemetics based on the judgment of the treating physician and local institutional practices.  At 
the occurrence of persistent nausea or vomiting of severity grade ≥ 1, it is suggested that the 
participant receive an oral or transdermal serotonin antagonist (eg, dolasetron, granisetron, 
ondansetron, tropisetron, palonosetron).  The neurokinin receptor antagonist, aprepitant, may be 
considered but is a mild inhibitor of CYP3A4 and so may modestly increase idelalisib plasma 
exposures.  Other classes of antiemetic medications that may be employed include dopamine 
antagonists or benzodiazepines.  If possible, systemic corticosteroids should be avoided other 
than as premedication for ofatumumab.   
5.3.2 Tumor Lysis Prophylaxis 
 


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Subjects initiating each study drug should be given allopurinol 300 mg daily for approximately 10 
days unless contra-indicated, and tumor lysis laboratory testing should be done at the discretion of 
the treating investigator.  Allopurinol therapy should continue through ofatumumab therapy. If 
allopurinol is contra-indicated another uric acid reducing agent may be substituted or alternative 
plans may be discussed with the overall principal investigator. Intravenous fluid prophylaxis may 
also be given at the discretion of the treating investigator and is recommended at the time of 
initiating therapy with both idelalisib and again with ofatumumab initiation at cycle 3 day 1.  
  
5.3.3 Granulocyte Colony-Stimulating Factors and Erythropoietin 
 
Granulocyte-macrophage colony-stimulating factor (GM-CSF) should not be administered given 
the potential for GM-CSF-related inflammatory symptoms.  Granulocyte colony-stimulating 
factor (G-CSF) agents including pegfilgrastim if desired and erythropoietic agents (eg, 
erythropoietin or darbepoetin) may be administered in response to Grade ≥3 neutropenia or 
anemia, respectively.  Such use should be particularly considered if providing hematopoietic 
support might help to maintain idelalisib-ofatumumab therapy.  Reference should be made to the 
American Society of Clinical Oncology guidelines [49, 50]. 
5.3.4 Contraception 
 
In the context of this protocol, a female subject is considered to be of child-bearing potential 
unless she has had a hysterectomy, a bilateral tubal ligation, or a bilateral oophorectomy; has 
medically documented ovarian failure (with serum estradiol and FSH levels within the 
institutional postmenopausal range and a negative serum or urine βHCG); or is menopausal (age 
≥55 years with amenorrhea for ≥6 months). 
 
Sexually active females of child-bearing potential must accept continuous heterosexual 
abstinence as a lifestyle choice or agree to use a protocol-recommended method of contraception 
during heterosexual intercourse throughout the study treatment period and for 30 days from the 
last dose of study drug or 12 months from the last dose of ofatumumab (whichever is later). The 
investigator should counsel subjects on the most effective methods for avoiding pregnancy 
during the trial. Protocol-recommended contraceptive methods are described in table below. 
 
Protocol-Recommended Contraceptive Methods 
Individual Methods 
Combination Methods 
Hormonal Methods 
(One method to be used with a 
barrier method) 
Barrier Methods 
(Both of these methods to be used OR one of these 
methods to be used with a hormonal method) 
IUD  
Estrogen and progesterone 
Diaphragm with spermicide 
Copper T 380A IUD  
Oral contraceptives 
Male condom (with spermicide) 
LNg 20 IUD  
Transdermal patch 
 
Tubal sterilization  
Vaginal ring 
 
Hysterectomy  
Progesterone 
 
 
Injection 
 
 
Implant 
 
Abbreviation: IUD=intrauterine device 
 


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In the context of this protocol, a male subject is considered able to father a child unless he has 
had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy, or is receiving 
ongoing testicular suppression with a depot luteinizing hormone-releasing hormone (LH-RH) 
agonist (eg, goserelin acetate [Zoladex®]), leuprolide acetate [Lupron®]), or triptorelin pamoate 
[Trelstar®]). 
 
Sexually active male subjects who can father a child must accept continuous heterosexual 
abstinence as a lifestyle choice; limit intercourse to female partners who are surgically sterile, 
post-menopausal, or using effective contraception (as noted in table above); or agree to use a 
protocol-recommended method of contraception during heterosexual intercourse throughout the 
study treatment period and for 90 days following discontinuation of idelalisib (as noted in table 
above). 
 
The Gilead Sciences medical monitor should be consulted regarding any questions relating to 
child-bearing status or contraception. 
 
5.3.5 Corticosteroids 
 
Participants may receive topical or inhaled corticosteroids while on study.  The use of systemic 
corticosteroids is discouraged except as needed for prevention or treatment of infusion reactions 
related to ofatumumab, or as needed for therapy of transaminitis.  However, participants who 
develop severe or life-threatening conditions that may be alleviated by systemic corticosteroid 
therapy are permitted to receive such drugs and are not required to discontinue study 
participation. 
 
5.3.6 Prophylactic Antibiotics 
 
Because of the observation of two cases of PCP in this study, PCP prophylaxis is required for all 
participants initiating therapy on study.  At the same time antiviral prophylaxis against HSV and 
VZV is also required, because of the frequency of reactivation of these viruses in CLL participants.  
5.3.7 Immunization 
 
Because of its actions to inhibit PI3Kδ-dependent B-cell function, high doses of idelalisib can 
impair primary or secondary responses to immunization in animals.  The specific clinical 
relevance of these nonclinical findings is unknown.  However, for participants who are at 
substantial risk of an infection (eg, influenza) that may be prevented by immunization, 
consideration should be given to providing the vaccine prior to initiation of treatment with 
idelalisib if at all possible, and if not, then vaccination should be provided during idelalisib 
therapy.   
 
5.4 Duration of Therapy 
The planned duration of induction therapy is 8 months of induction therapy.  For those still in the 
midst of induction, they may complete the planned 6 months of ofatumumab therapy followed by 


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observation.   Protocol follow-up may continue until achievement of CR, or indefinitely, until 
one of the following criteria applies: 
 
Disease progression, 
 
Intercurrent illness that prevents further administration of treatment, 
 
Unacceptable adverse event(s), 
 
Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements 
 
Participant decides to withdraw from the study, or 
 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the opinion of the treating investigator. 
 
5.5 Duration of Follow Up  
 
Once participants have completed study treatment they will be followed until initiation of 
new therapy following removal from study, or until death, whichever occurs first. They will 
be seen every 3 or 6 months in the follow up phase; this will be decided by their treating 
physician. Follow up will continue for up to 10 years. Participants removed from study for 
unacceptable adverse events will be followed until resolution or stabilization of the adverse 
event, and/or until initiation of new therapy for their disease, whichever is longer. 
 
5.6 Criteria for Removal from Study  
 
Participants will be removed from study when any of the criteria listed in Section 5.4 
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 (or Protocol Chair) Jennifer R Brown MD PhD 
at 617-632-4894 or page at 617-632-3352 pager 41344. 
 
6. EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS  
 
Dose delays and modifications will be made using the following recommendations. Toxicity 
assessments for non-hematologic toxicity 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://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  Hematologic 
toxicity will be evaluated according to the IWCLL 2008 guidelines as outlined below and in 
Appendix C.   
 
If possible, symptoms should be managed symptomatically. In the case of toxicity, appropriate 
medical treatment should be used (including anti-emetics, anti-diarrheals, etc.). 
 


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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. 
 
Please note that if one study drug is held, the other will also be held.  If drugs are held for more 
than half a week, then the assessment schedule will also be held until drug resumption.  
  
6.1.1 Adverse Event Lists(s) for Idelalisib 
 
Symptomatic adverse events are infrequent, usually low-grade, and not clearly idelalisib-related.  
Among Grade ≥3 nonhematological adverse events occurring in ≥5% of patients, pneumonia was 
observed most frequently, occurring in 24% of patients with CLL.  In most instances, these cases 
were considered bacterial in origin, based either on culture results or on response to conventional 
antibiotics; 2 patients with CLL have had pneumocystis pneumonia.  The observed rate of 
pneumonia of any type in patients with CLL receiving idelalisib over 360 patient-months of 
observation has been 0.04 pneumonias/patient/month; this rate is modestly less than the rate of 
0.06 pneumonias/patient/month reported in the literature for a comparable population of CLL 
patients [9].  There have however also been a few cases of what appears to be a steroid-
responsive idelalisib-related pneumonitis.  Other nonhematological adverse events in patients 
with CLL have included diarrhea (4%), and fatigue (4%).  Grade ≥ 3 hematological laboratory 
abnormalities include neutropenia (8%), thrombocytopenia (4%), anemia (2%) and neutropenic 
fever (7%).  
 
6.1.2 Adverse Event List(s) for Ofatumumab 
 
The primary adverse event associated with ofatumumab is infusion reactions during drug 
administration.  The management of those is discussed under drug administration.  Other potential 
concerns include LFT abnormalities, hepatitis B reactivation, and PML, which has been observed 
with another CD20 antibody, rituximab.  
 
6.2 Toxicity Management 
 
Patients should be followed closely for adverse events or laboratory abnormalities that might 
indicate idelalisib or ofatumumab-related toxicity.  Recommendations for idelalisib dose 
modification and when to hold and restart drug are provided below.  If a patient experiences a 
idelalisib-related adverse event requiring dose modification during the course of idelalisib 
therapy, then study drug administration should be held, as necessary, until the adverse event 
resolves or stabilizes to an acceptable degree.  Thereafter, idelalisib may be reinstituted, but the 


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dose of idelalisib should be reduced by 1 dose level (except for hematologic toxicity or grade 3 
infections or grade 3 asymptomatic laboratory abnormalities, when dose may potentially be 
maintained at the investigator’s discretion); dose adjustments may be made.  If the patient cannot 
tolerate idelalisib at Dose Level -1 (100 mg/dose BID) then the patient should be discontinued 
from study drug therapy. 
After a dose is reduced, the dose need not be re-escalated, even if there is minimal or no toxicity 
with the reduced dose.  However, if the patient tolerates a reduced dose of idelalisib for 
≥4 weeks then the idelalisib dose may be increased to the next higher dose level, at the discretion 
of the investigator.  Such re-escalation may be particularly warranted if further evaluation reveals 
that the adverse event that led to the dose reduction was not study drug-related.  Successive 
adjustments to progressively higher dose levels can be made at 4-week intervals.  The starting 
dose level (150 mg BID) should not be exceeded.  
Except as specified below for hematologic and liver toxicity, in most cases of adverse events 
both study drugs will be held until resolution. 
                                                                Table 5 
Dose Level 
Idelalisib Dose 
-1 
100 mg BID 
(1 tablet, 100 mg) 
  
 0 
150 mg BID 
(1 tablet, 150 mg) 
 
Management of Hepatic Adverse Events in Patients on or soon after discontinuation of 
Idelalisib 
Based on Phase 1 clinical experience with idelalisib, other adverse events potentially attributable 
to idelalisib have included pneumonias, rash, and colitis/diarrhea.  Hepatic laboratory 
abnormalities deserve particular attention and reversible Grade ≥3 ALT/AST elevations were seen in 
patients and attributed to idelalisib.  Onset has generally occurred 2 to 8 weeks after idelalisib 
initiation and resolution has usually been seen 2 to 6 weeks after idelalisib interruption.  After 
resolution of ALT/AST changes, the majority of the patients who were rechallenged at the same 
or a reduced dose of idelalisib were able to resume treatment without recurrence of transaminase 
elevations.  Only 1 (0.9%) patient has had an elevation in bilirubin to >2 times the upper limit of 
normal; because of a recent history of biliary obstruction requiring endoscopic retrograde 
cholangiopancreatography for biliary and common bile duct stone removal, a causal relationship 
to idelalisib could not be established. 
In the initial phase of this study, grade 1-2 LFT elevations have been seen beginning in week 3.  
Given the rapid rate of rise seen in two patients, a comprehensive metabolic panel (electrolytes, 
BUN, creatinine, glucose, LDH, phosphate, uric acid, LFTs (total bilirubin, direct bilirubin, AST, 
ALT, alkaline phosphatase) will be obtained twice per week starting in week 3 and continuing up 
through week 16 in the absence of LFT abnormalities.  
 


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First Event of Transaminitis  
If a first event of grade 1 AST or ALT elevations are noted (very slight elevation of 1 to 5 points 
above normal may be repeated within 3-4 days prior to initiating management as follows), 
dosing may continue with ongoing at least twice per week monitoring of levels and initiation of 
prednisone 40 mg daily.  Patients whose AST or ALT remain grade 0-1 after initiation of 
steroids will remain on prednisone 40 mg daily until initiation of ofatumumab therapy at which 
time steroids may be tapered slowly over not less than one month.   
If at any point either AST or ALT reaches grade 2 elevation or higher on any test, idelalisib will 
be held and prednisone will either be started or increased to 1 mg/kg daily, rounded up to the 
nearest multiple of 10 mg. If direct or total bilirubin is elevated (grade 2 or higher) and not due to 
an obvious unrelated cause such as hemolysis or gilbert's syndrome, drug should be held.  
Monitoring will continue twice weekly until LFTs trend towards normalizing, at which point labs 
may switch to once weekly, based on conversation between the treating investigator and the 
overall PI. The labs on non-protocol specified treatment days may be obtained locally at the 
discretion of the site-responsible investigator but must be followed up the same day by the study 
site.  For patients with a grade 2-3 transaminitis, following resolution of AST or ALT to normal 
(grade 0), consideration may be given to resuming idelalisib at a one dose level reduction, at 100 
mg BID.  Steroid dose should be held at its prior level for at least one week after idelalisib is 
restarted, following which if AST / ALT remain within normal limits, prednisone may be tapered 
at a recommended rate of 10 mg per week.  LFTs should be checked weekly for at least twelve 
weeks after resuming study drug, even while on prednisone  
Patients whose AST or ALT reach grade 4 but resolve rapidly with steroids may be reinitiated on 
idelalisib while on steroids, as per the above protocol for grade 2-3, at the discretion of the 
treating investigator in consultation with the PI.  Patients whose grade 4 AST or ALT continue to 
rise despite steroids, or fail to improve in 3-5 days after initiation of steroids, should be discussed 
with the overall PI, with consideration given to initiation of mycophenolate mofetil 2000 mg 
BID.  These patients will also be carefully assessed for the suitability of reinitiation of idelalisib, 
in consultation with the overall PI.    Otherwise subjects who reinitiate at 100 mg BID with 
stable normal LFTs and who taper off prednisone may be considered for dose re-escalation to 
150 mg BID, after they reach cycle 5 or beyond. 
Several subjects have had stable minor grade 1 to low grade 2 AST/ALT elevations typically 
developing in cycle 3-4.  If twice weekly monitoring shows stability at this level, , as either an 
initial event or a subsequent event, initiation of prednisone and holding idelalisib will be 
discretionary if LFTs remain less than grade 3, with approval of the overall PI. 
Subsequent Events of Transaminitis During Cycle 1-4 
If AST / ALT go back up to grade 1, idelalisib and prednisone may be continued at current level 
or prednisone may be resumed or increased to 40 mg daily at the discretion of the treating 
investigator and PI, but if they rise to grade 3 or higher, follow above recommendations for grade 
2 or above (i.e. hold idelalisib and increase steroids back to 1 mg/kg).  Monitoring will continue 
twice weekly until LFTs trend towards normalizing, at which point labs may switch to once 
weekly, based on conversation between the treating investigator and the overall PI. These 
additional labs should be continued at least twelve weeks after resuming study drug. The labs on 


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non-protocol specified treatment days may be obtained locally at the discretion of the site-
responsible investigator.   
Alternative management plans for hepatotoxicity may be acceptable with prior approval of the 
overall PI, except in cases of fulminant grade 3/4 events. 
 
Management of Transaminitis Cycle 5 and onward 
Several subjects have had stable minor grade 1 to low grade 2 AST/ALT elevations at this point 
in the study, as either an initial event or a subsequent event.  Therefore initiation of prednisone 
and holding idelalisib will be discretionary if LFTs remain less than grade 3.  On initial 
observation of this finding, LFTs must be repeated twice per week for at least 2 and up to 4 
weeks or an alternative monitoring plan should be discussed with the overall principal 
investigator. Very slight elevations (approximately 1-5 points) may not necessitate repeat labs in 
the absence of clinical symptoms.  If at any point either AST or ALT reaches grade 3, Idelalisib 
must be held and LFTs re-checked within 2-3 days; prednisone may be started at the discretion 
of the treating investigator. If either AST or ALT is greater than 10 times the ULN at any time, 
or if AST or ALT continue to rise after stopping study drug, then Prednisone must be started at 
1mg/kg and LFTs must be checked twice per week until resolution to grade 0, at which time 
Idelalisib may be resumed. If Idelalisib is resumed prednisone should be continued at current 
dose for at least one week prior to beginning taper as described above. All subjects will continue 
with at least weekly LFTs for up to 12 weeks while on stable dose of Idelalisib and off 
prednisone. If at that time LFTs have remained stable grade 1 or within normal limits, the 
frequency of LFT checks may decrease to every 2-4 weeks at the discretion of the treating 
investigator with communication with the overall PI. Some variation in these guidelines may be 
considered upon consultation of the treating investigator with the overall PI.  
Ofatumumab has also been associated with LFT abnormalities.  Of particular concern in this 
context is the possibility of reactivated or new hepatitis.  In particular, patients enrolled on study 
who had HBcAb positive with HBsAg negative may be at (low) risk for reactivation.  For that 
reason, those patients were screened prior to enrollment for HBV DNA and required to be 
negative.  If such a patient develops any even grade 1 LFT elevation, HBV DNA must be 
performed at the time of this occurrence, in addition to the already planned every 2 month HBV 
DNA PCR testing from the start of treatment throughout the treatment course.  Monitoring 
during the on treatment periods is required at least every 2 months and during follow-up at a 
minimum of every 2-3 months up to 12 months after the last dose.  If the subjects’ HBV DNA 
becomes positive during the study, the investigator should manage the clinical situation as per 
the standard of care of that institution, likely including holding drug and instituting antiviral 
therapy. Also, if a subject’s HBV DNA becomes positive during the study, notify Novartis 
(contact information located in 11.4.1). The risks and benefits of continuing or discontinuing 
ofatumumab should be discussed with the overall PI before treatment decisions are made for that 
individual subject.  Subjects initiated on antiviral therapy who achieve suppression of their HBV 
DNA viral load may be eligible to continue on the study at the discretion of the treating 
investigator and the overall PI. 
  


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For those patients with at least grade 2 elevations in ALT/AST and in bilirubin (only if direct), 
drug should be held as noted above, and they should undergo the further workup below as well 
as the monitoring discussed above.  These patients will have ofatumumab held as well as 
idelalisib, until resolution.  Further workup is particularly warranted in patients who first 
experience a serum ALT/AST elevation 12 weeks from the start of idelalisib therapy, who have 
an elevation in serum bilirubin concentration, or who have other characteristics that suggest an 
atypical change in transaminase values.  Further workup may include: obtaining a history of 
recent symptoms/illnesses and of relevant past history (eg, history of hepatitis or of hepatitis A or 
hepatitis B vaccination); obtaining information regarding concomitant drug use (prescription and 
nonprescription medications, dietary supplements, alcohol, illicit drugs, special diets); 
questioning the patient regarding potential exposure to environmental toxins; ruling out viral 
hepatitis A, B, C, D (if hepatitis B is positive), and E, Epstein-Barr virus, cytomegalovirus, 
autoimmune hepatitis, anti-smooth muscle antibody, and Type 1 anti-liver kidney microsomal 
antibodies, alcoholic hepatitis, nonalcoholic steatohepatitis, hypoxic/ischemic hepatopathy, and 
biliary tract disease; obtaining additional tests to evaluate liver function (eg, imaging as 
appropriate, and prothrombin time [PT], activated partial thromboplastin time [aPTT], 
international normalized ratio [INR], albumin); and considering gastroenterology or hepatology 
consultation [FDA 2009] 
PML 
Progressive multifocal leukoencephalopathy (PML) is a viral-induced demyelinating disease of 
the central nervous system usually occurring in the immunocompromised individual. JC virus 
infection resulting in PML and death has been reported in rituximab-treated subjects with 
hematologic malignancies or with systemic lupus erythematosus (SLE), an indication for which 
rituximab has not been approved. In the literature, PML has been reported to occur in 0.52% of 
CLL subjects and in approximately 5% of fludarabine-treated B-CLL subjects. One case of PML 
was reported in a very ill CLL subject treated with ofatumumab, previously treated with 
alemtuzumab and fludarabine and with very low CD4 cell count. 
Investigators and nurses should pay careful attention for signs and symptoms consistent with a 
diagnosis of PML. Signs and symptoms of PML include visual disturbances, ocular movements, 
ataxia, and changes in mental status such as disorientation or confusion.  These symptoms are 
not an exhaustive list and the investigator should exercise judgment in deciding to report signs 
and symptoms to the overall PI and Novartis promptly.  Please see Appendix D for a symptom 
screening questionnaire.  
 
If a subject develops neurological signs or symptoms consistent with PML treatment should be 
halted and the subject referred to a neurologist for evaluation.  The investigator will contact the 
Novartis within 24 hours of being notified of a participant’s potential signs and symptoms of 
PML.  At a minimum, blood JCV PCR and/or MRI will be performed and if either is positive 
perform Cerebrospinal Fluid (CSF) JCV PCR. If blood JCV PCR and MRI are negative, the 
investigator will contact the Novartis for appropriate action to be taken. If blood JCV PCR 
and/or MRI are positive, the subject should proceed to the Follow-Up Period. All such subjects 
will be followed until resolution.  Any subject with a diagnosis of PML will be withdrawn from 
ofatumumab. There are no known tests that can reliably determine who is at increased risk for 


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developing PML. There are no known interventions that can reliably prevent PML or adequately 
treat PML if it occurs. 
Hematologic Toxicities 
While myelosuppression is not a prominent toxicity of idelalisib in previous experience, dose 
modification provisions for patients experiencing neutropenia or thrombocytopenia are provided 
as a precaution.  Recommendations for dose modification based on the type and severity of 
adverse events or laboratory abnormalities are provided below in Table 6.  Whenever possible, 
any dose adjustment of idelalisib should be discussed between the treating investigator and the 
overall Principal Investigator prior to implementation.  Myelosuppression is also not a prominent 
complication of ofatumumab therapy, although neutropenia can occur.  Ofatumumab will 
generally not be held for myelosuppression, but appropriate growth factor and transfusion 
support will be employed as needed.   
Either or both drugs may be held for up to six weeks for resolution of toxicity without removing 
a participant from the study. Longer holds are acceptable in the post-induction phase following 
discussion with the overall principal investigator. 
6.3 Dose Modifications/Delays 
 
No ofatumumab dose modifications are permitted.  


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7.  DRUG FORMULATION AND ADMINISTRATION  
 
7.1 Idelalisib 
7.1.1 Drug Substance and Formulation 
Idelalisib is a fluorinated quinazolinone with 1 stereogenic center.  Idelalisib is the S enantiomer.  
The compound has no known structural similarity to existing drugs.  The drug substance is a 
white to off-white, crystalline powder with a chemical formula of C22H18FN7O, a molecular 
weight of ~415 Daltons, and low aqueous solubility.  Idelalisib is orally bioavailable.  
Table 6.  Recommendations for Dose Modification of Study Drug(s) Based on  
Type and Severity of Adverse Event or Laboratory Abnormality 
 
Non-Hepatic and Non-Hematological Study Drug-Related Event  
CTCAE Grade 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Idelalisib  and Ofa 
Dosing 
Recommendation 
Maintain dose level 
Maintain dose level 
Withhold drugs until toxicity is Grade ≤1.   
May resume idelalisib only at next lower dose level 
for most toxicities, but may resume at current dose 
level in the case of grade 3 infections, grade 3 
nausea/vomiting/diarrhea that can be 
symptomatically managed, grade 3 asymptomatic 
laboratory abnormalities or grade 3 infusion 
reactions. 
Hepatic Study Drug-Related Event (Elevation in ALT, AST, or Bilirubin) 
CTCAE Grade 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
ALT/AST 
>ULN-3 x ULN 
>3-5 x ULN 
>5-20 ULN 
>20 x ULN 
Bilirubin 
>ULN-1.5 x ULN 
>1.5-3 x ULN 
>3-10 x ULN 
>10 x ULN 
Idelalisib  and Ofa 
Dosing 
Recommendation 
See Section 6.2: Management of Hepatic Events. 
Hematological  Idelalisib -Related Event 
IWCLL Grade  
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Neutropenia 
(ANC x 109/µL) 
ANC <LLN-1.5 
ANC <1.5-1.0 
ANC <1.0-0.5 
ANC <0.5 
Thrombocytopenia 
(platelets x 109/µL) 
Platelets 11-24% 
below baseline 
Platelets 25-49% 
below baseline 
Platelets 50-74% 
below baseline 
Platelets ≥75% below 
baseline or <=25K 
Idelalisib  Dosing 
Recommendation  
Maintain dose level 
Maintain dose level 
Maintain dose level; 
support with g-csf 
growth factors at 
investigator discretion 
During combination therapy 
period, consider G-CSF 
support and maintain current 
study drug dose level and 
schedule. During initial and 
continuing single-agent 
study drug therapy period, 
consider G-CSF support and 
continue study drug at initial 
or lower dose level at 
investigator discretion. 
**Note: In any case where Idelalisib is held, ofatumumab should also be held. The assessment schedule is also held in cases 
where study drug is held for greater than half a week.  
Abbreviations:   ALP, alkalkine phosphatase; ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate 
aminotransferase; CTCAE, Common Terminology Criteria for Adverse Events; LLN, lower limit of normal; ULN, upper limit 
of normal 


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7.1.2 Description 
Idelalisib is manufactured according to cGMP.  The study drug is provided in tablets intended for 
oral administration.  Each tablet contains  100, or 150 mg of the active study drug substance.  
Inactive excipients present in the formulation are microcrystalline cellulose, hydroxypropyl 
cellulose, croscarmellose sodium, sodium starch glycolate, and magnesium stearate.  The   100-
mg tablets are orange, and the 150-mg tablets are pink.  The yellow coating contains yellow iron 
oxide, polyethylene glycol, talc, polyvinyl alcohol polymer, and titanium dioxide.  The orange 
coating contains Food Drug & Cosmetic Yellow #6/Sunset Yellow Food Cosmetic Formulary 
Aluminum Lake, polyethylene glycol, talc, polyvinyl alcohol polymer, and titanium dioxide.  
The pink coating contains red iron oxide, polyethylene glycol, talc, polyvinyl alcohol polymer, 
and titanium oxide.   
7.1.3 Packaging 
Idelalisib will be packaged in bottles containing 60 tablets.  A label will be affixed to each bottle 
and will contain the following information in English:  
 Manufacturer name and address 
 Protocol identifier 
 Description of contents, including dose strength and fill count 
 Caution statement (includes “keep out of reach of children” statement) 
 Storage conditions 
 Manufacture date  
 Lot number 
7.1.4 Source 
Idelalisib will be supplied free of charge by Gilead Sciences. Biologics has been selected for the 
provision of supply procurement and distribution services to each investigative site.  Any 
questions or concerns regarding study drug supply should be referred to DFCI team and 
Biologics for routing to Gilead  Sciences clinical project manager.   
7.1.5 Storage and Stability 
Bottles containing tablets of idelalisib will be stored at controlled room temperature (~15 to 
30°C).  While stability of tablets stored at controlled room temperature has been confirmed, brief 
excursions to temperatures up to 40°C or down to 5°C will not adversely affect the drug.  
Freezing must be avoided.  Stability data at the start of study will support the use of the drug 
product for ≥12 months.  The clinical site will be updated as more stability data become 
available. 
7.1.6 Dispensing 
The clinic pharmacist or an alternative qualified person will be responsible for dispensing study 
medication.  It is planned that drug will be dispensed at 4-week intervals through the first 
24 weeks of treatment and at 12-week intervals thereafter.  A modest overage will be supplied 
such that patients have sufficient drug in case of loss, spillage, or necessary deviations in 
scheduling clinic returns (eg, due to inclement weather, holidays, etc).  Tablets should be kept in 
the original bottles provided. However, it is permissible to re-package the quantity of study 


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medication into standard amber prescription bottles in the case the need arises (e.g. participant requires a 
lesser quantity of medication due to dose reductions). 
7.1.7 Return 
Patients should return all unused study medication to the study site at each applicable study visit.   
7.1.8 Accountability 
The disposition of all idelalisib study drug should be documented from the time of receipt at the 
site through patient dispensing and return.   
Study personnel must ensure that all study drug is kept in a secure locked area with access 
limited to authorized personnel.  The study drug must not be used outside the context of this 
protocol.  Under no circumstances should the investigator or site personnel supply study drug to 
other investigators or clinics, or allow the study drug to be used other than as directed by this 
protocol. 
The investigator and/or the responsible site personnel must maintain accurate records of the 
receipt of all study drug shipped by Gilead Pharmaceuticals or its designee, including, but not 
limited to, the date received, lot number, amount received, and the disposition of all study drug.  
Study drug accountability records must also be maintained that include the patient number to 
whom the study drug was dispensed and the date, quantity and lot number of the study drug 
dispensed. 
The study drug supply should be retrieved from patients at the end of each dosing interval.  The 
quantity of study drug and the date returned by the patient should be recorded in the study drug 
accountability records.   
Remaining unused study drug supply will be destroyed at the clinical site, standard institutional 
policy should be followed.  Records documenting the date of study drug destruction, relevant lot 
numbers, and destroyed should be maintained.   
7.1.9 Overdose Precautions 
For this protocol, an overdose is defined as administration of >700 mg of idelalisib in a single 
day.  In a patient who experiences an overdose of this magnitude, idelalisib administration 
should be temporarily interrupted.  If the overdose ingestion is recent and substantial, and if there 
are no medical contraindications, use of gastric lavage or induction of emesis may be considered.  
Observation for any symptomatic side effects should be instituted, and vital signs and 
biochemical and hematological parameters should be followed closely (consistent with the 
protocol or more frequently, as needed).  Appropriate supportive management to mitigate 
adverse effects should be initiated.   
The Gilead  Sciences  medical expert should be contacted if an overdose occurs.  Under 
applicable regulations, overdosing may result in a serious adverse event and may require 
reporting accordingly (see Section 11 below). 
7.1.10 
Inadvertent Exposure and Spill Precautions 
Based on available data from nonclinical studies, idelalisib does not appear to be acutely toxic, 
genotoxic, or irritative at levels that are likely to result from inadvertent exposure to the contents 


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42 
 
of broken capsules or tablets.  Personnel handling the drug should use reasonable precautions to 
avoid eye contact, skin contact, inhalation, or ingestion of the study drug product.  For further 
information regarding inadvertent exposure and spill precautions, please consult the idelalisib 
investigator brochure. 
7.2 Ofatumumab 
7.2.1 Medication 
 
GlaxoSmithKline will supply commercial ofatumumab free of charge. Biologics has been 
selected for the provision of supply procurement and distribution services to each investigative 
site as content-labeled Ofatumumab vials presented as either 100 mg – acetate formulation, 20 
mg/mL, 5 mL fill vials; or 1000 mg – acetate formulation, 20 mg/mL, 50 mL fill vials.  
 
The medical product, ofatumumab, is a liquid concentrate for solution for infusion presented in 
glass vials. Ofatumumab will be infused intravenously as specified above in Section 5.2.2. 
 
The ofatumumab infusions will be prepared in 1000 mL NaCl sterile, pyrogen free 0.9% NaCl to 
yield a 0.3 mg/mL or 1 mg/mL ofatumumab concentration for infusions of 300 mg or 1000 mg, 
respectively.  
 
Ofatumumab vials must be stored at 2-8°C. Protect from light and do not freeze. No special 
packaging components, other than the outer white cardboard carton in which the vials are placed, 
will be used to afford light protection.  
 
Ofatumumab open-labeled product will be for intravenous infusion. The site is responsible for 
labeling individual vials for investigational use.  
 
All items required for administration of study medication (e.g., infusion bags, etc.) are to be 
provided by the site.  Filters will be supplied with commercial drug. 
7.2.2 Composition of Ofatumumab Injection 20 mg/mL 
 
The quantitative composition of acetate formulation 20 mg/mL.  This is available in two fill 
volumes, 5 mL / vial (100 mg/vial) and 50 mL/vial (1000 mg/vial). 
 
Ingredient  
Quantity/ mL 
Ofatumumab 
20.0 mg 
Sodium Acetate, Trihydrate 
6.80 mg 
Edetate Disodium, 
Dihydrate (EDTA) 
0.019 mg 
Polysorbate 80 
0.20 mg 
L-Arginine 
10.0 mg 
Sodium Chloride 
2.98 mg 


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Hydrochloric Acid 
to give pH 5.5 
Water for Injection 
q.s. to 1.0 mL 
 
7.2.3 Preparation of Ofatumumab Infusion 
 
Ofatumumab will be prepared as 1000 mL dilution of ofatumumab in sterile, pyrogen-free 0.9% 
NaCl. The expiration time which is calculated based on the exact dilution time into the 0.9% 
NaCl must be written on the label of the infusion bag. 
 
Once diluted into saline, the product is stable for up to 24 hours at ambient temperature. 
However, the product contains no preservative and should be used as soon as possible after 
dilution.   
 
Preparation of drug solution for intravenous injection by the site pharmacist or designee will be 
done in accordance with the protocol, and in these dilution instructions. Ofatumumab 
intravenous solution will be prepared using standard dilution methods and following general 
aseptic practice standard to preparation of IV medications. Eyes and hands should be protected 
when handling ofatumumab.  
 
For intravenous administration, compatibility of the following components for ofatumumab in 
clinical studies (i.e., not for commercial product) has been established: 
                      Table 7: Dosing Components for Ofatumumab in Clinical Studies 
Dosing component 
Material of construction 
Suggested Vendor 
1L Saline Bags 
Polyvinyl Chloride (PVC) 
Baxter 
 
Polyolefin [polyethylene* 
(PE)/polypropylene (PP)] 
Baxter, B. Braun 
Administration Set 
PVC 
Baxter 
 
PVC lined with Polyethylene B. Braun 
 
Preparation of the 1000 mL infusion bags should be done on the day of planned infusion.  
* polyethylene (IUPAC name: polyethene) 
 
7.2.3.1 Materials for Preparation and Administration of Infusion 
 
The following materials are needed when preparing and administering the infusion: 
 


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 1000 mL sterile pyrogen free 0.9% saline (NaCl) infusion bag(s).  The solution can be 
kept at ambient temperature for a maximum of 24 hours after preparation; however, the 
product does not contain a preservative and dosing should begin as soon as possible after 
dose preparation.  
 Ofatumumab 100 mg and 1000 mg vials (supplied by Novartis) 
 Needles and syringes (50 mL sterile syringe) not supplied by Novartis 
 Intravenous (IV) cannula (not required if subject has central venous access) [not supplied 
by Novartis] 
 Infusion pump (not supplied by Novartis) and infusion tubing set (supplied by Novartis) 
7.2.3.2 Dilution of Ofatumumab  
 
 Ensure the correct container number is used. 
 Take a 1000 mL infusion bag (sterile pyrogen free 0.9%  saline), remove and dispose of 
the appropriate amount of saline according to Table 8 or Table 9 below 
 Draw the required amount of ofatumumab according to Table 2 (100 mg vials) or Table 3 
(1000 mg vials) below 
 Inject ofatumumab into the saline bag 
 Invert the infusion bag slowly 3 times, avoiding formation of any foam 
 Label the infusion bag with the completed label 
                      Table 8:  
Preparation of Ofatumumab Infusion:  100 mg vials  
Dose of 
Ofatumumab 
Infusion bag 
size 
Volume of NaCl to 
be removed from 
infusion bag 
Volume ofatumumab  
(number of ofatumumab 
vials) 
300 mg 
1000 mL 
15 mL 
15 mL 
(3 vials, 5 mL/vial) 
1000 mg 
1000 mL 
50 mL 
50 mL  
(10 vials, 5 mL/vial)  
 
                      Table 9:  
Preparation of Ofatumumab Infusion:  1000 mg vials 
Dose of 
Ofatumumab 
Infusion bag 
size 
Volume of NaCl to 
be removed from 
infusion bag 
Volume ofatumumab  
(number of ofatumumab 
vials) 
1000 mg 
1000 mL 
50 mL 
50 mL  
(1 vial, 50 mL/vial)  
 


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7.2.4 Ofatumumab Infusion Set up 
 
Ofatumumab must be administered by IV infusion through an in-line filter and through a well-
functioning IV catheter (IV cannula) into a vein in the arm (or other venous access) by an 
infusion pump.   
 
Please Note:   It is mandatory to use an in-line low protein binding 0.2 micron polyether sulfone 
filter for all IV dosing of ofatumumab drug product. 
 
DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS. 
Ofatumumab should not be mixed with any other medication.  The intravenous line should 
be flushed with normal saline before and after completion of each infusion.  
 
Please note that the infusion site can be used for blood sampling only if there is no risk of 
contamination of the infusion needle with the saline, infusion solutions, or any other 
fluid(s).  Only a newly inserted needle can be used for the predose blood samples.   
 
 
Check subject ID against the label on the infusion bag and ensure the expiry of the 
solution. The solution must be administered in its entirety to the subject within 24 hours 
from time of preparation.   
 
Attach the 1000mL infusion bag to the infusion set (if not done at the pharmacy). 
 
Attach the in-line filter to the infusion set (closest to the subject; see    Figure 1). Note: 
The in-line filter must be used during the entire infusion. 
 
Prime the infusion set and filter with ofatumumab (if not done at the pharmacy). 
 
In case of a problem with the filter (i.e. clogging/blockage), please change, re-prime the 
new filter, and continue the infusion. 
 
In case of problem with infusion set, follow local procedures. 
 
Collect the pre-dose blood samples, if required. 
 
Check the backflow from the IV cannula according to routine practice at site 
 
Set the pump at the initial infusion rate 12mL/hr for the first infusion and 25mL/hr for the 
subsequent infusions (if no grade ≥ 3 infusion-associated AEs were observed in the 
previous infusion)  
 
Start the infusion using the infusion rates and directions above in section 5.2.2. 
No ofatumumab dose modifications are permitted. 
 


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   Figure 1:   Infusion Set-Up Schematic 
 
8. CORRELATIVE/SPECIAL STUDIES  
8.1 Pharmacokinetic Studies 
 
Ofatumumab concentrations are determined in EDTA plasma (i.e., one lavender-topped 
Vacutainer).  Samples must be processed in a refrigerated centrifuge (4°C) at 1600g for 15 
minutes and frozen at -20°C within 4 hours of collection.  The ofatumumab PK samples may be 
batched at participating sites and/or sent directly to Novartis.  The shipping information will be 
enclosed with the study kits.  
 
Pharmacokinetic sampling for ofatumumab will be as follows: 
 
Cycle 3 Day 1 – Predose, EOI 
Cycle 3 Day 8 – Predose 
Cycle 3 Day 15 – Predose 
Cycle 4 Day 22 (last weekly Ofatumumab dose) – Predose, EOI 
Cycle 5 Day 1 (first monthly Ofatumumab dose) – Predose, EOI 
Cycle 8 Day 1 (last monthly Ofatumumab dose) – Predose, EOI 
2 months after Ofatumumab therapy completed – Predose 
6 months after Ofatumumab therapy completed - Predose 
 
Samples will also be obtained for idelalisib pharmacokinetics.  These will be determined in K2 
EDTA plasma (i.e., one lavender-topped Vacutainer), obtained pre-dose (trough) and 1.5 hours 
post-dose (peak) with a +/- 10 minute window for post-dose. After drawing invert the tube at 
ofatumumab infusion bag  
infusion pump 
infusion set 
In-line filter 
i.v. cannula 
subject 


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least 8 to 10 times.  Keep sample in wet ice prior to centrifugation.  It is preferred the sample be 
centrifuged within 30 minutes and must be centrifuged within 2 hours of blood collection. 
Centrifuge at a miniumum of 1500 to 2000 x g for 15 minutes until cells and plasma are well 
separated. Use pipette provided to transfer the plasma equally into four appropriately labeled 
tubes. Samples will be processed on-site, stored at -70°C, then batched and shipped 
approximately every 6 months.   If your site can only store in a -20 °C freezer, please send the 
PK sample shipments monthly. The idelalisib PK samples may be batched at participating sites 
then sent after freezing. Please ship frozen samples on dry ice to Covance Laboratory Inc. at the 
following address: 
 
Attention:  Ujjana Nandihalli 
Bioanalytical Principal Investigator 
Sample Management—Bioanalytical (Rm 1S 160)  
Covance Laboratory Inc.  
3301 Kinsman Boulevard  
Madison, WI 53704-2523  
 
Pharmacokinetic sampling for idelalisib will be as follows: 
 
Staggered:   
Cycle 1 Day 1 
Cycle 2 Day 1 
Cycle 3 Day 1 (first weekly dose of Ofatumumab) 
Cycle 4 Day 22 (last weekly dose of Ofatumumab) 
Cycle 8 Day 1 (last monthly dose of Ofatumumab) 
2 and 6 months after end of ofatumumab therapy. 
8.2 Pharmacodynamic Studies 
8.2.1 Biological Features of the CLLs 
FISH will be determined on either peripheral blood or bone marrow for the common CLL probes 
(17p, 11q, +12, 13q and t(11;14) to rule out mantle cell lymphoma) at the local institutions prior to 
enrollment, and this report will be supplied to the Coordinating Center at the time of Registration.  
IGHV, CD38 and ZAP70 will be determined by the CLL Research Consortium central tissue bank.  
All participating CLL Research Consortium sites are required to enroll participants on the above 
tissue bank, using the dedicated consent form for that study at each institution.  Patients already 
enrolled in the CLL Research Consortium central tissue bank need to provide the results of these 
tests to the Coordinating Center at the time of registration.   
At screening for this study three additional sodium heparin green top tubes of peripheral blood will 
be submitted to the Tissue Bank for banking if a patient is already enrolled in the CLL Research 
Consortium  
 


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If a site is not participating in a CLL Research Consortium tissue bank study, the participant will 
be required to provide three sodium heparin green top tubes of peripheral blood at screening, 
cycle 3 day 1 and progressive disease or off study due to toxicity.  These samples will then be 
shipped overnight to Dr. Laura Rassenti at the above CRC address in Section 8.1. In the case of 
closures of the CRC, a temporary covering or local lab may be designated. Guidance will be 
provided by correspondence in such cases. 
     
In addition, a saliva sample will be collected at screening using Oragene collection device and 
shipped to:  
Dana Farber Cancer Institute 
CLL Center, J. Brown Lab 
ATTN: Stacey Fernandes 
77 Avenue de Louis Pasteur  
HIM 421 (Ref. 13-309) 
Boston, MA 02115 
 
CD38 will be determined at screening at the CLL Research Consortium tissue bank.  
 
8.2.2 DFCI  Studies: Genomic Profiling 
Four 10 cc sodium heparin (green top) tubes of peripheral blood will be drawn at screening, and 
saliva will be collected using Oragene collection devices.  Heparinized bone marrow aspirate (5-10 
cc) should be sent in addition.   
At the time that patients come off study for toxicity or progressive disease, four 10 cc sodium 
heparin (green top) tubes of peripheral blood should again be drawn and shipped overnight at 
ambient as below.  If a patient coming off study due to  progressive disease or toxicity is 
undergoing a bone marrow biopsy, and in particular if they do not have significant circulating 
disease, please also send heparinized bone marrow aspirate (5-10 cc).    
These samples will then be shipped overnight to Dr. Laura Rassenti at the above CRC 
address in Section 8.1. 
 
 
From the blood samples, PBMCs or CLL B-cells will be isolated and viably frozen, for 
subsequent use in SNP array, gene expression, miRNA profiling and whole exome sequencing.  
Saliva will be isolated and stored according to the kit directions until DNA is prepared. 
8.2.3 DFCI Studies:  Elucidation of subclonal architecture of CLL treated with idelalisib 
 
The goal of this correlative study is to elucidate the dynamics of CLL subclones during therapy 
with idelalisib, in particular by comparing blood and bone marrow prior to therapy and after two 
months of single agent idelalisib.  We will also look at the acute alteration in the subclonal 
architecture in blood after several weeks of idelalisib, in order to explore the effect of 
redistribution lymphocytosis on the clones present in blood.  We will then compare these results 


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to the features of persistent subclones present in blood and bone marrow at time of final 
restaging.  Eventually, at time of relapse, samples will be banked for comparison to the earlier 
data on clonal architecture, in order to identify the subclone that has led to relapse and to place it 
in context of the prior data.  We expect that these data will greatly enhance our understanding of 
the relationship of CLL cells in blood and bone marrow and how that changes with idelalisib 
therapy, as well as giving us critical information on both primary and acquired resistance to 
idelalisib. 
 
Experimental Procedures:   We propose to perform serial exome sequencing (WES) on a 
selection of patients from this trial, selected to represent the range of CLL prognostic factors and 
a range of initial idelalisib responses.  We will include roughly half IGHV mutated and 
unmutated patients, and half those who had stable disease (SD) after 2 months of single agent 
idelalisib vs those with partial response (PR) or partial response with lymphocytosis (PRL) after 
two months of therapy.   Relatively few patients on this study have high risk del 11q or del 17p 
cytogenetics but we will prioritize those patients for analysis (n=3).  The plan will be to perform 
WES on baseline blood, bone marrow and germline (saliva) samples, on blood and bone marrow 
from end of single agent cycle 2 restaging, and on blood and bone marrow from final restaging at 
cycle 10.  These samples will allow determination of the relative distribution of clones in blood 
and bone marrow at the same timepoint, how this is altered by idelalisib, and ultimately which 
clone(s) persist at the time of low level residual disease.  In addition we will sequence peripheral 
blood at one additional timepoint, week 2-4 on single agent idelalisib, with the goal of assessing 
the alteration of clonal architecture of CLL in the blood during idelalisib-mediated redistribution.  
We will study 8 samples for each of 10-15 patients initially, and then follow these patients 
serially over time and bank them again at relapse, at which time we will sequence them again, 
for comparison to the initial and residual disease subclones. These studies will continue as 
sufficient samples have already been banked. 
8.2.4 Flow cytometry for activation markers, adhesion molecules and CD20 levels 
Flow cytometry analysis for cell surface adhesion molecules and activation markers including 
CXCR4, CXCR5, PD-1, PD-1L, CD38, CD40, CD80, CD86, CD154 and Ki67 will be performed. 
T cell subsets and immunomodulatory effects on T cells may also be analyzed on these samples.  
Plasma will be collected for analysis of cytokine levels including CCL3 and CCL4 at the same 
timepoints.     
At the following time points, collect two 10cc sodium heparin green top tubes: 
Screening 
Cycle 1 Day 8 
Cycle 1 Day 15 
Cycle 2 Day 1 
Cycle 2 Day 22 (two month restaging) 
Cycle 3 Day 8 
Cycle 3 Day 15 
Cycle 4 Day 22 
Cycle 10 Day 1 (final restaging) 


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In addition, the same markers will be assessed on bone marrow aspirates (5-10cc) at the following 
time points: 
Screening 
Cycle 2 Day 22 (two month restaging) 
Cycle 10 Day 1 (final restaging) 
All samples should be sent to Laura Rassenti at the CLL Research Consortium address above in 
Section 8.1.  
8.2.5 OSU Studies: Assessments of intrinsic innate immune suppression  
These correlative studies propose to confirm that idelalisib can decrease immunosuppressive 
cytokines (IL-6, IL-10, TGF-β1, and TGF-β2) in vivo in CLL patients from pre-treatment to day 
29.  Additionally, we will demonstrate by ex vivo evoked stimuli studies from pre-treatment and 
day 29 that CLL cells treated with idelalisib have less production of IL-6, IL-10 and also 
expression of CD279 and CD274.  Finally, we will  assess screening and day 29 monocyte TNF-α 
production using ofatumumab; NK cell production of IFN-γ  and CD107a expression following 
exposure to immobilized ofatumumab and ofatumumab mediated ADCC against RAJI target cells; 
MDSC ex vivo  and inhibition of T-cell proliferation.  We expect this work to demonstrate that 
idelalisib treatment will inhibit evoked activation of IL-6, IL-10, CD279 and CD274 with innate 
immune function at day 29 of therapy as compared to pre-treatment. Collectively, this will provide 
support for idelalisib priming prior to administration of therapeutic antibodies.  
For these studies, three 8.5mL ACD (yellow top) tubes and one sodium heparin (green top) tube of 
peripheral blood should be collected at screening, Cycle 1 Day 1, Cycle 2 Day 1 and cycle 3 day 1 
of therapy (prior to ofatumumab)  
 
These blood tubes will be shipped overnight (ambient) to Laura Rassenti at the CLL Research 
Consortium address above.  
8.2.6 OSU Studies: Effects of in vivo inhibition of the PI3K delta pathway on CLL cell 
signaling 
 
Detailed baseline profiling of tumor cells will be done for expression of PI3K isoforms and 
activity of downstream B-cell relevant specific kinases targeted by PI3K. In vivo response to 
PI3K inhibition will be evaluated by measuring phosphorylation of AKT and Novartis 3-beta in 
CLL cells isolated from two pre-dose 8.5mL ACD (yellow top) tubes of peripheral blood at cycle 
1 day 1, day 15, cycle 2 day 1 and two month restaging on  idelalisib treatment.  During 
 
treatment ex vivo response to chemoimmunotherapy will be evaluated by measuring apoptosis 
(Annexin V/PI staining and flow cytometry) at the same intervals.  
 
These tubes should be sent to the CLL Research Consortium Tissue Bank at the above address, 
overnight  
8.2.7 Mayo Clinic Microvesicle Studies 


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For these studies, a 10 cc sodium heparin green top tube and bone marrow aspirate (a couple ccs if 
a bone marrow is being performed otherwise) will be drawn at screening (only marrow at 
screening), cycle 2 day 22(end of single agent idelalisib therapy), cycle 10 day 1(final restaging), 
every 6 months for the first year in follow-up (if a bone marrow is being performed for clinical 
reasons) and when a patient comes off study due to  progressive disease or toxicity.  These samples 
will be shipped overnight ambient to Laura Rassenti at the above address.  On arrival they will be 
spun in a 15 cc conical tube 3 x 2500g for 20 min at room temperature, and the platelet-free plasma 
will be carefully decanted into a fresh tube without disturbing the pellet.  They can then be 
aliqouted in 1 ml aliquots in eppendorf tubes and frozen at -80C. 
9. STUDY CALENDAR 
Screening evaluations are to be conducted within 14 days prior to start of protocol therapy. 
Scans and Bone Marrow Biopsies must be done <4 weeks prior to the start of 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 and medications should be administered within + 3 days of the 
protocol-specified date during the induction phase and + 7 days of the protocol-specified 
date in the post-induction phase, unless otherwise noted. 
 
 
 
 
 
 
Table 10 
Procedures Screen 
Treatment Phase 
 
Post Induction 
Phase 
Long Term 
Follow-up 
Survival 
Follow-up 
 
 
Cycle 1-2 
Idelalisib 
only 
(Days 1-
56) 
Cycle 3 & 
4 
Weekly 
Ofa + 
Idelalisib15 
 
Cycle 5-8 
Monthly 
Ofa + 
Idelalisib 
Restage 
Cycle 4 
day 22  
 
 
Cycle 2 day 
22 (Restage 
end of cycle 
2), Cycle 10 
day 1 (Final 
Restage 
2 months after 
end of ofa 
therapy) and 
off treatment 
prior to cycle 
10 
Cycle 
9 Day 
1 
Every 2 
mos while 
on study 
drug 
beginning 
Cycle 10 
Every 3 or 6 
months11 
Yearly 


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Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
Medical 
History 
X 
 
 
 
 
 
 
 
 
 
Bone marrow 
biopsy 
X1 
 
 
 
X1 
 
X1 
 
 
Flow 
Cytometry by 
Marrow or 
blood16 
X 
 
 
 
X 
X 
 
 
 
 
MRD on bone 
marrow 
 
 
 
 
 
X 
 
 
 
 
CT (Chest 
Abdomen 
Pelvis) 
X2 
 
 
 
X2 
X2 
 
X2 
X2 
 
Tumor 
Assessment by 
PE 
X 
 
 
 
X 
X 
X 
X 
X 
 
CLL FISH 
panel (on bone 
marrow) 
X 
 
 
 
 
X (ON 
BONE 
MARROW) 
 
 
 
 
Banking at 
CRC, with 
Flow 
Cytometry3 
X 
C1 DAY 8 
&15, C2 
DAY 1  
C3 D8 & 
15, C4 
D22 
 
 
X 
 
 
 
 
DFCI Studies: 
Genomic 
Profiling4  
X 
 
 
 
 
 
 
End of 
therapy4 
 
 
Banking at 
Clinical 
Research 
Consortium for 
Sites 
participating in 
a CRC study17  
X 
 
 
 
 
 
 
 
 
Procedures 
Screen 
Treatment Phase 
 
Post Induction 
Phase  
Long Term 
Follow-up 
Survival 
Follow-up 
 
 
Cycle 1-2 
Idelalisib 
only 
(Days 1-
56) 
Cycle 3 & 
4 
Weekly 
Ofa + 
Idelalisib15 
 
Cycle 5-8 
Monthly 
Ofa + 
Idelalisib 
Restage 
Cycle 4 
day 22  
 
Cycle 2 day 
22 (Restage 
end of cycle 
2), Cycle 10 
day 1 (Final 
Restage 
2 months after 
end of ofa 
therapy) and 
off treatment 
prior to cycle 
10 
Cycle 
9 Day 
1 
Every 2 
mos while 
on study 
drug 
beginning 
Cycle 10 
Every 3 or 6 
months11 
Yearly 


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Banking at 
Clinical 
Research 
Consortium for 
Sites  not 
participating in 
a CRC study18 
X 
 
C 3 D1 
 
 
 
 
X 
 
PK samples, 
ofatumumab5 
 
 
C3 D1, 8, 
15; C4 D 
22 
CYCLE 5 
D 1 & 
CYCLE 8 
D 1 
 
FINAL 
ONLY 
 
6 MOS  
 
 
PK samples, 
idelalisib 5 
 
DAY 1 
EACH 
CYCLE 
CYCLE 3 
DAY 1, 
CYCLE 4 
DAY 22 
CYCLE 8 
DAY 1 
 
FINAL 
ONLY 
 
6 MOS 
 
 
OSU Studies6 
X 
CYCLE 1 
DAY 1, 
15; 
CYCLE 2 
DAY 1 
CYCLE 3 
DAY 1 
 
 
TWO 
MONTH 
ONLY  
 
 
 
 
Mayo Studies7  
X 
 
CYCLE 3 
DAY 1 
 
 
FINAL 
ONLY 
 
 
EVERY 6 
MONTHS 
FOR 
FIRST 
YEAR; & 
AT PD 
 
Physical Exam 
X 
WEEKL
Y 
CYCLE 3 
DAY 1, 8, 
15, 
CYCLE 4 
DAY 1, 15 
MONTH
LY 
X 
X 
X 
X 
X 
 
ECOG 
X 
WEEKL
Y 
WITH PE WITH PE 
X 
X 
X 
X 
 
 
Height 
X 
 
 
 
 
 
X 
 
 
 
Weight 
X 
 
X 
X 
X 
X 
X 
X 
 
 
Vital Signs12  
X 
WEEKL
Y 
WEEKLY MONTH
LY 
X 
X 
X 
X 
X 
 
12-lead ECG  
X 
 
 
 
 
 
 
 
 
 
Procedures 
Screen 
Treatment Phase 
 
Post Induction 
Phase 
Long Term 
Follow-up 
Survival 
Follow-up 
 
Cycle 1-2 
Idelalisib 
only 
(Days 1-
56) 
Cycle 3 & 
4 
Weekly 
Ofa + 
Idelalisib15 
 
Cycle 5-8 
Monthly 
Ofa + 
Idelalisib 
Restage 
Cycle 4 
day 22  
 
 
Cycle 2 day 
22 (Restage 
end of cycle 
2), Cycle 10 
day 1 (Final 
Restage 
2 months after 
end of ofa 
therapy) and 
off treatment 
prior to cycle 
10 
Cycle 
9 Day 
1 
Every 2 
mos while 
on study 
drug 
beginning 
Cycle 10 
Every 3 or 
6 months11 
Yearly 


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Adverse Events 
X 
WEEKL
Y 
WITH PE WITH PE 
X 
X 
X 
X 
X8 
 
Concomitant 
Therapy 
X 
WEEKL
Y 
 WITH 
PE 
WITH PE 
X 
X 
X 
X 
 
 
Chemistry13  
X 
WEEKL
Y13 
WEEKLY 
THROUG
H C4 D 
2213 
MONTH
LY 
X 
X 
X 
X 
X 
 
Hematology14  
X 
WEEKL
Y 
WEEKLY 
THROUG
H C4 D 22 
MONTH
LY 
X 
X 
X 
X 
X 
 
Beta-2-
microglobulin 
X 
 
 
 
X 
X 
 
EVERY 6 
MOS 
EVERY 6 
MOS 
 
Immunoglobuli
ns (IgG, IgM, 
IgA) 
X 
 
 
 
X 
X 
 
EVERY 6 
MOS  
EVERY 6 
MOS 
 
Serum protein 
electrophoresis 
X 
 
 
 
X 
X 
 
EVERY 6 
MOS 
EVERY 6 
MOS 
 
CD4 count 
X 
 
 
 
X 
X 
 
EVERY 6 
MOS 
EVERY 6 
MOS 
 
Direct Coombs 
test 
X 
 
 
 
 
 
 
 
 
 
Serum 
Pregnancy 
Test9 
X 
 
MONTHL
Y 
X 
 
X 
 
ONCE 5 
MONTHS 
POST 
OFA 
 
 
Hepatitis B 
surface antigen  
and antibody10, 
Hepatitis C 
antibody, HIV 
X 
 
 
 
 
 
 
 
 
 
Survival follow-
up by telephone 
or clinic visit 
note 
 
 
 
 
 
 
 
 
 
X 
1.  Bone marrow biopsies are required at screening, cycle 2 day 22 (end of cycle 2 restaging) and cycle 10 day 1 
(final restaging).  Those patients in clinical CR at any bone marrow restaging should have 4 color MRD flow 
cytometry performed at the time of their bone marrow evaluation.  Bone marrow biopsy can also be done at any 
subsequent point to confirm a suspected CR.  In addition to standard clinical testing, 15 cc bone marrow 
aspirate will be obtained at each bone marrow biopsy, for flow cytometry immunophenotyping and comparison 
to PB, as well as studies at OSU and Mayo Clinic.  These heparinized aspirate samples will be sent to the CRC 
for processing and storage. In cases where it is unsafe or not feasible to obtain the appropriate quantity of 
aspirate, the performing clinician should indicate this in his/her note. 
2.  CT scan required at screening, cycle 2 day 22 (end of cycle 2), cycle 4 day 22, and cycle 10 day 1 (final 
restaging).  In subsequent follow-up only if clinically indicated at investigator discretion and when a patient 
comes off treatment due to disease progression or toxicity. A CT scan of the chest, abdomen, pelvis and any 
other known sites of disease should be completed. Any regions captured at screening such as the neck must be 
followed by CT throughout subject’s participation. All CT scans will be centrally reviewed. These scans should 
be burned onto CD and sent via FedEx to the Project Manager at DFCI, ATTN: (Project Manager), 450 
Brookline Avenue, LG100, Boston, MA 02215.  The scan will then be reviewed at the Tumor Imaging Metrics 
Core at DFCI. 


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3.  Two sodium heparinized tubes (green tops) at screening and at subsequent times. Sodium heparinized bone 
marrow aspirate (5-10 cc, green top) at screening and cycle 2 day 22 (end of cycle 2 restaging) and cycle 10 day 
1 (final restaging).  
4. Four sodium heparinized tubes (green tops) and saliva. Sodium heparinized bone marrow aspirate (5-10 cc, 
green top). Patients who come off treatment for toxicity or progressive disease, four 10 cc sodium heparin 
(green top) tubes of peripheral blood.  If a patient coming off treatment due to   progressive disease or toxicity is 
undergoing a bone marrow biopsy, and does not have significant circulating disease, send sodium heparinized 
bone marrow aspirate (5-10 cc, green top) 
5.  For ofatumumab, 2 lavender top tubes.  Predose and end of infusion on cycle 3 day 1, cycle 3 day 8, cycle 3 day 
15 and cycle 4 day 22 (end of weekly ofa), and cycles 5 and 8 day 1. Note: Predose only for cycle 3 days 8 and 
15; and 2 and 6 mos post therapy, no end of infusion. 
For idelalisib, one lavender top predose and one lavender top 1.5 hours post-dose, on Cycles 1-3 Day 1, Cycle 4 
Day 22, Cycle 8 Day 1 (last monthly dose of Ofatumumab) and 2 and 6 months after end of ofatumumab.  
6.  OSU:  3 ACD (yellow top) tubes, 8.5 cc each, + one sodium heparin (green top) tube at screen;  5 ACDs and 
one heparin on day 1 prior to therapy, 2 ACDs on cycle 1 day 15, 5 ACDs and one heparin on cycle 2 day 1, 3 
ACDs and 1 sodium heparin (green top) tube at two month restage, and 2 ACDs on cycle 3 day 1.   
7.  Mayo Clinic:  1 sodium heparinized (10 cc green top) tube.  Bone marrow aspirate (a couple ccs) will be 
obtained at each timepoint. At screening only aspirate should be collected.      
8.  SAEs and deaths for six months after completion of all therapy. 
9.  Only in women of childbearing potential  
10.  For those patients who are hepatitis B core antibody positive but surface antigen and HBV DNA negative, 
monitoring of HBV DNA or viral load is required during the on treatment period at least every 2 months and 
during follow-up at a minimum of every 2-3 months up to 12 months after the last dose.  This testing is also 
required in the event of development of grade 1 or more elevation in LFTs. 
11.  Subjects who discontinue therapy due to an adverse event, but have demonstrated a response of SD or better 
will enter the follow-up period and be followed every 3 or 6 months until documented relapse or PD, initiation 
of a new therapy, or for a total of 12 months of follow-up, whichever occurs first. 
12.  Vitals Signs include: heart rate, respiratory rate, temperature, blood pressure and oxygen saturation. 
13.  Chemistry:  Electrolytes, BUN, creatinine, glucose, LDH, phosphate, uric acid, LFTs (total bilirubin, AST, 
ALT, alkaline phosphatase).  Beginning C1D15 through C4D28 a comprehensive metabolic panel (electrolytes, 
BUN, creatinine, glucose, LDH, phosphate, uric acid, LFTs (total bilirubin, AST, ALT, alkaline phosphatase) 
will be obtained twice per week.  If grade 1 or higher AST, ALT, or bilirubin elevations are noted please see 
Section 6.2 “Management of Hepatic AEs.” 
14. Hematology:  CBC, manual differential 
15. Weekly Ofatumumab proceeds through Cycle 4 Day 22.  
16. Flow Cytometry should assess at minimum the following markers: CD5+CD19+, CD19+, CD 20+, 
CD19+CD23+, CD19+CD38+, kappa and lambda surface immunoglobulins.  
 
Footnotes 16 & 17 outline the sample collection for sites that are or are not participating in the CLL Research 
Consortium tissue bank study, (for more information-Section8.2.1):  
17. Sites participating in a CLL Research Consortium tissue bank study (Section 8.2.1) provide 3 sodium 
heparinized (green top) tubes of peripheral blood at screening. 
18. Sites not participating in a CLL Research Consortium (CRC) tissue bank study (Section 8.2.1) provide 3 
sodium heparinized (green top) tubes of peripheral blood at screening, cycle 3 day 1 and coming off study due 
to  disease progression or toxicity.  In addition, collect a saliva sample at screening.  
 
Off-Treatment Evaluations 
If at all possible, patients going off study should have:  hematology, chemistry, beta-2-
microglobulin, CD4 count, IgG, IgM, IgA, serum protein electrophoresis, full tumor assessment 
by CT, bone marrow biopsy and samples for correlative studies. Please obtain the following 
samples described under genomic and Mayo Microvesicle for correlative studies. If prior to 
cycle 2 day 22 please obtain any additional studies required for that visit.  


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10. MEASUREMENT OF EFFECT  
10.1 Antitumor Effect – CLL 
Definition of response, relapse, and refractory disease 
Assessment of response should include a careful physical examination and evaluation of the 
blood and marrow.  CT scanning will be performed as indicated in the table of assessments 
(required at screening, and at key response assessments).   
 
It is important to note that idelalisib may result in increasing lymphocytosis at the start of the 
study, which will not be considered evidence of progressive disease.  In fact, an isolated increase 
in lymphocytosis, in the absence of other signs of disease progression including worsening 
lymphadenopathy, neutropenia, anemia or thrombocytopenia or disease symptoms, will not in 
this study be sufficient to define progressive disease.  This modification to the standard criteria is 
needed because idelalisib can cause redistribution of CLL lymphocytes from sanctuary sites into 
peripheral blood, in the absence of progressive disease.    
10.1.1 
Complete remission (CR) 
CR requires all of the following criteria present at one time point and still present when re-
assessed at least 2 months after initial documentation: 
 Peripheral blood lymphocytes (evaluated by blood and differential count) below 4 × 
109/L (4000/μL).  
 Absence of significant lymphadenopathy (eg, lymph nodes >1.5 cm in diameter) by 
physical examination.  A CT scan of the chest, abdomen, pelvis will be used to confirm 
complete response if previously abnormal, and on that CT, lymph nodes should not be 
larger than 1.5 cm in long axis diameter.  
 No hepatomegaly or splenomegaly by physical examination.   
 Absence of constitutional symptoms. 
 Blood counts above the following values: 
 
Neutrophils more than 1500/μL without need for exogenous growth factors.  
 
Platelets more than 100 000/μL without need for exogenous growth factors.  
 
Hemoglobin more than 11.0 g/dL without red blood cell transfusion or need for 
 
exogenous erythropoietin. 
 For patients on this study meeting the above criteria for CR, a marrow aspirate and 
biopsy must confirm CR.   To define a CR, the marrow sample must be at least 
normocellular for age, with less than 30% of nucleated cells being lymphocytes. 
Lymphoid nodules should be absent.  In some cases, lymphoid nodules can be found, 
which often reflect residual disease.55,56 These nodules should be recorded as “nodular 
PR.” Moreover, immunohistochemistry should be performed to define whether these 
nodules are composed primarily of T cells or lymphocytes other than CLL cells or of 
CLL cells. If the marrow is hypocellular, a repeat determination should be performed 
after 4 weeks, or not until peripheral blood counts have recovered. However, this time 
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interval should not exceed 6 months after the last treatment. A marrow biopsy should be 
compared with that of pretreatment marrow and the quality of the CR should be assessed 
for MRD by flow cytometry.  
Patients who fulfill all the criteria for a CR (including the marrow examinations described 
above) but who have a persistent anemia or thrombocytopenia or neutropenia apparently 
unrelated to CLL but related to drug toxicity will be considered CR with incomplete 
marrow recovery (CRi). For the definition of this category, CRi, the marrow evaluation should 
be performed with scrutiny and not show  any clonal infiltrate.  
10.1.2 
Partial remission (PR) 
PR is defined by the criteria described below if abnormal before therapy, as well as one or more 
of the blood count requirements. To define a PR, these parameters need to be  documented for a 
minimal duration of 2 months. 
 
 A decrease in the number of blood lymphocytes by 50% or more from the value 
before therapy. 
 Reduction in lymphadenopathy (by CT scans or by physical exam) as defined by the 
following:  (1)  A decrease in lymph node size by 50% or more either in the sum of the 
bidimensional products of up to 6 lymph nodes, or in the largest diameter of the enlarged 
lymph node(s) detected prior to therapy AND (2)  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 on physical examination.  
 The blood count should show one of the following results:  (1) Neutrophils more than 
1.5 × 109/L (1500/μL) without need for exogenous growth factors.  (2)  Platelet counts 
greater than 100 × 109/L (100 000/μL) or 50% improvement over baseline without need 
for exogenous growth factors.   (3)  Hemoglobin greater than 110 g/L (11.0 g/dL) or 50% 
improvement over baseline without requiring red blood cell transfusions or exogenous 
erythropoietin.  
10.1.3 
Progressive disease 
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. In CLL, the use of CT scans usually does not add 
much information for the detection of progression or relapse. Therefore, the use of 
imaging methods to follow CLL progression is at the discretion of the treating physician.  
 Disease progression occurs if one of the following events is observed:  (1) Appearance of 
any new lesion, such as enlarged lymph nodes (>1.5 cm),  splenomegaly, hepatomegaly, 
or other organ infiltrates. (2)  An increase by 50% or more in greatest determined 
diameter of any previous site. (3) An increase in  the previously noted enlargement of the 
liver or spleen by 50% or more or the de novo appearance of hepatomegaly or 
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 Transformation to a more aggressive histology (eg, Richter syndrome). Whenever 
possible, this diagnosis should be established by lymph node biopsy.  
 Occurrence of cytopenia (neutropenia, anemia, or thrombocytopenia) attributable 
to CLL. 
 
 During therapy.  Cytopenias may occur as a side effect of many therapies and should 
 
be assessed according to Appendix C.  
 
 After treatment.  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 × 109/L (100 000/μL), which occurs at least 3 months after treatment, 
 
defines disease progression, if the marrow biopsy demonstrates an infiltrate of clonal 
 
CLL cells and there is no evidence for an autoimmune process.  
10.1.4 
Nodal Partial Response with Lymphocytosis 
In this study, patients who achieve PR criteria for lymphadenopathy and/or splenomegaly, but 
have a lymphocyte count which is elevated and/or does not meet PR criteria (and may be 
significantly above baseline), will be considered to have nodal PR with lymphocytosis. 
10.1.5 
Stable disease 
Patients who have not achieved CR, PR, or nodal PR with lymphocytosis, and who have not 
exhibited progressive disease, will be considered to have stable disease (which is equivalent to a 
nonresponse).   
10.1.6 
Treatment failure 
Responses that should be considered clinically beneficial include CR, PR and nodal PR with 
lymphocytosis; all others (eg, stable disease, nonresponse, progressive disease, or death from any 
cause) should be rated as a treatment failure.  
10.1.7 
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 (see above).  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, and is measured in the intent-to-treat population.  
10.1.8 
Relapse 
Relapse is defined as a patient who has previously achieved the above criteria of a CR or PR or 
nodal response with lymphocytosis, but after a period of 6 or more months, demonstrates 
evidence of disease progression as described above.  
10.1.9 
Refractory disease 


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Refractory disease is defined as treatment failure or disease progression within 6 months to the 
last antileukemic therapy.  
10.1.10 Minimal residual disease 
 
The complete eradication of the leukemia is an obvious desired endpoint. New detection 
technologies, such as multicolor flow cytometry and real-time quantitative PCR, have 
determined that many patients who achieved a CR by the 1996 NCI-WG guidelines have 
detectable MRD. Either 4-color flow cytometry (MRD flow) or allele-specific oligonucleotide 
PCR is reliably sensitive down to a level of approximately one CLL cell in 10,000 leukocytes. 
As such, patients will be defined as having a clinical remission in the absence of MRD when 
they have blood or marrow with less than one CLL cell per 10,000 leukocytes.   
 
 
Those patients undergoing bone marrow biopsy for evaluation of CR should have a  sample sent 
for 4 color MRD flow.   
10.2 Duration of Response 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrence or PD is objectively documented, taking as reference for PD the smallest 
measurements recorded since the treatment started. 
Duration of clinical benefit: The duration of clinical benefit is measured from the time 
measurement criteria are first met for CR, PR or nodal PR with lymphocytosis, until the 
first date that recurrent disease is objectively documented.  
Duration of overall complete response: The duration of overall CR is measured from the time 
measurement criteria are first met for CR until the first date that recurrent disease is 
objectively documented. 
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since 
the treatment started 
10.3 Response Review 
10.3.1 
Central review of the CT scans is required for all scans ( screening, cycle 2 day 22, cycle 
4 day 22, cycle 10 day 1 (final restaging), and at disease progression).  These scans should be 
burned onto CD and sent via FedEx to the Project Manager at DFCI, ATTN: (Project 
Manager), 450 Brookline Avenue, LG 100, Boston, MA 02215.  The scan will then be 
reviewed at the Tumor Imaging Metrics Core at DFCI.  
 


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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. 
 
Laboratory and Other Safety Assessment Abnormalities Reported as AEs and SAEs 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECGs, radiological scans, vital signs measurements), 
including those that worsen from baseline, and felt to be clinically significant in the 
medical and scientific judgment of the investigator are to be recorded as AEs or SAEs. 


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 Grade 4 uncomplicated hematologic toxicities that are common in this patient population 
do NOT need to be reported as SAEs or reported to the DFCI IRB, unless resulting in 
hospital admission or if the treating investigator deems it appropriate to report.   
 All events requiring patients to come off study due to liver toxicity must be recorded as 
an SAE.  
 However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the subject’s condition, are not to be reported as AEs or SAEs. 
 B cell depletion, lymphopenia, IgG below LLN, low CD19+ count, and 
hypogammaglobulinemia due to treatment with ofatumumab are not to be reported as 
AEs or SAEs. 
 Infusion related AEs may lead to a prolonged infusion time. Overnight stay at the 
hospital due to slow infusion rate is not to be reported as a SAE.   
 Pregnancy complications and elective terminations for medical reasons must be reported 
as an AE or SAE.  Spontaneous abortions must be reported as a SAE.  Any SAE 
occurring in association with a pregnancy, brought to the investigator’s attention after the 
subject has completed the study and considered by the investigator as possibly related to 
the investigational product, must be promptly reported to Novartis 
 
Not included as SAEs:  
 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 
 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as SAEs 
An event which is part of the natural course of the disease under study (i.e., disease progression) 
does not need to be reported as a SAE.  However, if the progression of the underlying disease is 
greater than that which would normally be expected for the subject, ends in death, or if the 
investigator considers that there was a causal relationship between treatment with investigational 
product or protocol design/procedures and the disease progression, then this must be reported as 
an SAE. 
 
Pregnancy 
Any pregnancy that occurs during study participation must be reported to the overall Principal 
Investigator and to Novartis.   To ensure subject safety, each pregnancy must be reported to 
Novartis within 2 weeks of learning of its occurrence.  The pregnancy must be followed up to 
determine outcome (including premature termination) and status of mother and child.  Pregnancy 
complications and elective terminations for medical reasons must be reported as an AE or SAE.  
Spontaneous abortions must be reported as an SAE. 
 


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Any SAE occurring in association with a pregnancy, brought to the investigator’s attention after 
the subject has completed the study and considered by the investigator as possibly related to the 
investigational product, must be promptly reported to Novartis. 
 
In addition, the investigator must attempt to collect pregnancy information on any female 
partners of male study subjects who become pregnant while the subject is enrolled in the study. 
Pregnancy information must be reported to Novartis as described above. 
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 the most common expected adverse events associated with 
the study agent(s). 
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 
 
Participating investigators will assess the occurrence of AEs and SAEs at all participant 
evaluation time points during the study.  
 


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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, with the exception of 
hematologic toxicity, which will be graded according to Appendix C. 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://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
11.3 Reporting Requirements 
 
For multi-site trials where a DF/HCC investigator is serving as the principal investigator, each 
participating investigator is required to abide by the reporting requirements set by the DF/HCC. 
The study must be conducted in compliance with FDA regulations, local safety reporting 
requirements, and reporting requirements of the principal investigator.  
 
Each investigative site will be responsible to report SAEs that occur at that institution to their 
respective IRB. It is the responsibility of each participating investigator to report serious adverse 
events to the overall PI Dr. Brown and to Novartis and to Gilead as described below.  
11.4 Reporting to the Study Sponsor 
11.4.1 
Serious Adverse Event Reporting to DF/HCC 
 
All serious adverse events that occur after the initial dose of study treatment, during treatment, or 
within 6 months of the last dose of treatment must be reported to the DF/HCC Overall Principal 
Investigator on a MedWatch 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. 
 Grade 4 (life-threatening or disabling) Events – Unless expected AND specifically listed in 
the protocol as not requiring reporting. See Section 11.1.2 for grade 4 hematological 
toxicities.  
 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.  


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Participating investigators must report each serious adverse event to the DF/HCC Overall 
Principal Investigator Dr. Brown 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 email to investigator, 
Project Manager, and study coordinator (contact information on study contact list): 
 
 
 
PI: Jennifer R Brown, MD, PhD 
 
 
Email: jbrown2@partners.org 
 
Within the following 1-2 business days, 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 
Reporting to Gilead 
 
In addition to reporting SAEs to the overall principal investigator, SAEs also must be reported to 
Gilead as follows: 
Serious 
Within 15 calendar days 
Fax or email relevant CRFs (eg, adverse event form, medical history 
form, concomitant drug/therapy form) and source documentsb (eg, 
progress notes, nurses’ notes, laboratory and diagnostic test results, 
discharge summaries) to Gilead Sciences, Inc.a 
a. The Gilead fax number is 650-522-5477 and email address is Safety_FC@gilead.com. All documents sent to 
Gilead should have their internal study number included. Gilead internal study number: IN-US-312-1237. 
b.  Patient name, address, and other personal identifiers should be obscured. 
Abbreviations: CRF, case report form; IRB/IEC, Institutional Review Board/Independent Ethics Committee 
 
 
 
 
 
 
All SAEs which are reported to Gilead a copy of the report must also be reported to the overall 
principal investigator, Project Manager and study coordinator (contact information on study 
contact list):  
PI: Jennifer Brown, MD PhD,  
Email: jbrown2@partners.org 
 
Gilead SAE reporting criteria: See definition of SAE in 11.1.2 
 
All SAEs regardless of relationship to investigational product will be collected from the first 
dose of investigational product up to 1 month after the last dose of investigational product. SAEs 
are no longer required to be reported if a  subject begins treatment with another therapy.  
 
From the time a subject consents to participate in and completes the study all SAEs assessed as 
related to study participation (e.g., protocol-mandated procedures, invasive tests, or change in 
existing therapy), will be reported promptly to Gilead. 
 


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Any SAE brought to the investigator’s attention after the subject has completed the study and 
considered by the investigator as possibly related to investigational product must be reported to 
Gilead. 
11.4.3 
Reporting to Novartis 
 
All Serious Adverse Events including life-threatening events resulting in required 
hospitalization, disability, congenital anomaly, death, or progression of the disease being greater 
than expected. In the event that the investigator identifies an SAE according to protocol 
definitions, the SAE will be reported to Novartis within 24 hours of identification of the SAE. 
SAEs should be reported to Novartis by fax to: U.S. Drug Safety & Epidemiology at fax number: 
887-778-9739. . Please use the Novartis SAE Report Fax Coversheet and reference to the 
Novartis study code provided by the DFCI study team.  
 
All SAEs which are reported to Novartis a copy of the report must also be reported to the overall 
principal investigator, Project Manager and study coordinator (contact information on study 
contact list):  
 
PI: Jennifer Brown, MD PhD,  
Email: jbrown2@partners.org 
11.4.4 
Non-Serious Adverse Event Reporting to DF/HCC 
 
Non-serious adverse events will be reported to the DF/HCC Overall Principal Investigator on the 
toxicity Case Report Forms.   
11.5 Reporting to the Institutional Review Board (IRB) 
 
Investigative sites within DF/HCC will report all serious adverse events directly to the DFCI 
Office for Human Research Studies (OHRS). 
Other investigative sites should report serious adverse events to their respective IRB according to 
the local IRB’s policies and procedures in reporting adverse events. A copy of the submitted 
institutional SAE form should be forwarded to: 
 
 
 
Jennifer R Brown MD PhD 
 
 
Tel 617-632-4564 
 
 
 
 
Fax 617-582-7909 
 
 
Email jbrown2@partners.org 
 
The DF/HCC Principal Investigator Dr. Brown will submit SAE reports from outside institutions 
to the DFCI Office for Human Research Studies (OHRS) according to DFCI IRB policies and 
procedures in reporting adverse events.  
11.6 Reporting to the Food and Drug Administration (FDA) 
 


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The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA. Please refer to appendix E for FDA reporting guidelines. 
11.7 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. 
11.8 Monitoring of Adverse Events and Period of Observation 
 
All adverse events 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 investigator assesses them as stable, or the participating investigator 
determines the event to be irreversible, or the participant is lost to follow-up. SAEs and death 
should be reported for 6 months after the last day of study intervention. 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 their respective 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.   
12. DATA AND SAFETY MONITORING 
12.1 Data Reporting 
12.1.1 
Method  
The QACT will collect, manage, and perform quality checks on the 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 


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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 review each protocol up to four times a year or more often if required to review 
toxicity and accrual data.  Information to be provided to the committee may include:  up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring within 30 
days; 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 a properly constituted IRB 
governing each study location.  
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 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. 
13.4 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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13.5 Multi-center Guidelines 
 
This protocol will adhere to the policies and requirements of the Dana-Farber/Harvard 
Cancer Center. The specific responsibilities of the DF/HCC Overall Principal Investigator 
(or Protocol Chair), Coordinating Center, and Participating Institutions are presented in the 
Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan (see 
Appendix D). 
 The DF/HCC Overall Principal Investigator/Coordinating Center is responsible for 
distributing all IND Action Letters or Safety Reports to all participating institutions for 
submission to their individual IRBs for action as required. 
 Mechanisms will be in place to ensure quality assurance, protocol compliance, and 
adverse event reporting at each site.  
 Except in very unusual circumstances, each participating institution will order the 
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 to the Coordinating 
Center.  
14. STATISTICAL CONSIDERATIONS  
14.1 Sample Size/Accrual Rate 
 
Primary Objective: 
 
The primary objective for this phase II study is to estimate the overall response rate or ORR 
(CR+PR) of ofatumumab and idelalisib in previously untreated CLL/SLL.   
 
Hypothesis: 
Null: 0.55 ORR 
Alternative: 0.75 ORR 
 
Sample size and power calculation: 
 
A two stage design is used to compute the sample size.  A total number of 50 eligible 
patients is needed in order to detect a 75% response rate, assuming the ORR for the null 
hypothesis is 55%, with 90% power and 4% type I error.  31 patients will be enrolled 
initially into the study.  The study will stop early if only 17 or fewer responses out of 31 
patients are observed and the drug will not be declared promising if less than 34 responses 
are seen in the total 50 patients.  The probability of stopping at the first stage is 0.56 if the 
null hypothesis is true.  For the purposes of the two-stage design and in order to avoid 
potential closure to enrollment, we will use the four month response evaluation to decide 
about moving to the second stage.     
 
Primary Analysis: 
 
The overall response rate and a 90% confidence interval will also be calculated, using the 


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method of Atkinson and Brown for a two stage study.  Patients’ baseline characteristics will 
be summarized using descriptive statistics (median, interquartile range, proportions).   
 
Enrollment was discontinued at 27 patients and ORR will be estimated based on the data, with 
90% confidence interval. 
14.2 Analysis of Secondary Endpoints 
 
Other Secondary Objectives: 
 
 To determine the CR rate and PFS of ofatumumab and idelalisib. 
 To determine the ORR, CR and rate of nodal PR with lymphocytosis for idelalisib given 
alone for 2 months.   
 To assess the safety of ofatumumab and idelalisib in combination. 
 To determine whether clinical response correlates with known CLL molecular prognostic 
factors. 
 To determine whether the use of CT scans in response assessment improves the predictive 
power of ORR for progression-free or overall survival. 
 To determine whether serum ofatumumab levels in vivo predict response. 
 To assess whether idelalisib alters the flow cytometric phenotype of circulating CLL cells. 
 To assess whether in vivo treatment with idelalisib alters CLL cell sensitivity to therapy 
with antibodies or other kinase inhibitors 
 To assess pharmacodynamic markers of PI3 kinase inhibition including AKT 
phosphorylation, production of T cell chemokines and response to CXCR 4/5 
 To determine whether response or resistance correlates with genetic alterations in PIK3CA 
or PIK3CD or other genes 
 To assess the clonal dynamics of CLL in peripheral blood vs bone marrow, and during 
therapy with idelalisib.   
 
Secondary Analysis: 
  
The CR rate of combination therapy, ORR rate, and rate of nodal PR with lymphocytosis for 
idelalisib given alone for 2 months will be summarized as numbers and percentages. The 
Kaplan Meier method will be used to estimate the median progression free survival. The 
number and percent of patients who experience toxicities on combination therapy after at 
least one dose of treatment will also be summarized. Associations of clinical response rate 
and known prognostic factors will be assessed using Fisher’s exact test. 
14.3 Reporting and Exclusions 
14.3.1 
Evaluation of toxicity. All participants who receive one dose of study therapy will be 
evaluable for toxicity from the time of their first treatment. 


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14.3.2 
Evaluation of response.  All participants included in the study and who actually receive 
at least one dose of study therapy will be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are ineligible. Each participant should be 
assigned one of the following categories: 1) complete response, 2) partial response, 3) stable 
disease, 4) nodal response with lymphocytosis; 5) progressive disease, 6) early death from 
malignant disease, 7) early death from toxicity, 8) 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. 
15. PUBLICATION PLAN 
 
The overall Principal Investigator Dr Jennifer Brown will have the responsibility for collecting 
and analyzing the study data and preparing the manuscript for publication.  The data may be 
presented at a national or international meeting prior to full publication.  The manuscript will be 
written within 6 months of study completion and submitted to Gilead and Novartis for their 
review prior to journal submission. 


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response to rituximab in B-cell chronic lymphocytic leukemia. Blood, 2004. 103(4): p. 
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50. 
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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   IWCLL MODIFIED CRITERIA FOR 
HEMATOLOGIC TOXICITY  
 
Modified Grading Scale for Hematological Toxicity in CLL Studies 
 
Grade 
Decrease in Plts from Lower Limit of 
Normal or Pre-Tx Value, whichever is 
Lower (%)1 
ANC/µl (nadir)2 
Hemoglobin3 
0 
No change to 10% 
≥2000  
No change to 10% 
1 
11 - 24% 
≥1500 and <2000 
11 - 24% 
2 
25 – 49% 
≥1000 and <1500 
25 – 49% 
3 
50 – 74% 
≥500 and <1000 
50 – 74% 
4 
≥ 75% 
<500 
≥ 75% 
1Starting platelet counts must be below 100,000/mm3 to use this chart.  If at any level of decrease 
the platelet count is ≤20,000/mm3 this will be considered grade 4 toxicity, unless the patient’s 
starting platelet count was ≤20,000/mm3.  In that case, the individual is considered not evaluable for 
platelet toxicity and will receive study therapy supported with transfusions as needed. 
2 If baseline ANC is <1,000/µL OR chronically dependent on myeloid growth factors, then 
neutrophil toxicity cannot be evaluated and the patient will be treated on study regardless of 
neutrophil count and supported by myeloid growth factors as needed. 
3 Hb levels must be below 10 gm/dL to use this table.  Baseline and subsequent Hb determinations 
must be performed before any transfusions. 
 
 
 
 


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APPENDIX C  PML SCREENING QUESTIONNAIRE 
 
 
YES 
NO 
1. 
Does the subject report any new weakness? 
 
 
2. 
Does the subject report any new difficulty 
with coordination or walking? 
 
 
3. 
Does the subject report any new signs of 
confusion, impaired memory or attention? 
 
 
4. 
Does the subject appear apathetic compared 
to previous contacts? 
 
 
5. 
Does the subject report any new visual 
disturbances? 
 
 
6. 
Has the subject had any new trouble 
speaking, either slurring speech, difficulty 
getting out words, difficulty understanding 
words, or difficulty comprehending spoken 
language: 
 
 
7. 
Does the subject have any other new 
neurological symptoms, including but not 
limited to: 
New onset seizure 
New sensory loss 
New emotional liability 
 
 
 
 
If any of the above are answered “Yes” at any visit, the investigator will contact the overall 
PI and the Novartis medical monitor and the patient will be referred to a neurologist. 
 


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DFCI IRB Protocol #: 13-309 
 
 
 
 
 
APPENDIX D 
 
Dana-Farber/Harvard Cancer Center 
Multi-Center Data and Safety Monitoring Plan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
 
1. 
INTRODUCTION ............................................................................................................................................ 81 
1.1 
Purpose .................................................................................................................................................... 81 
1.2 
Multi-Center Data and Safety Monitoring Plan Definitions.................................................................. 81 
2. 
GENERAL ROLES AND RESPONSIBILITIES ......................................................................................... 82 
2.1 
DF/HCC Sponsor .................................................................................................................................... 82 
2.2 
Coordinating Center (Lead Institution DFCI) ....................................................................................... 83 
2.3 
DF/HCC Quality Assurance Office for Clinical Trials (QACT) ............................................................ 83 
2.4 
Participating Institution .......................................................................................................................... 84 
3. 
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS ....................................................... 84 
3.1 
Protocol Distribution ............................................................................................................................... 84 
3.2 
Protocol Revisions and Closures ............................................................................................................. 85 
3.3 
Informed Consent Requirements ............................................................................................................ 85 
3.4 
IRB Documentation ................................................................................................................................. 85 
3.5 
IRB Re-Approval ..................................................................................................................................... 86 
3.6 
Participant Confidentiality and Authorization Statement ...................................................................... 86 
3.7 
DF/HCC Multi-Center Protocol Registration Policy ............................................................................. 87 
3.8 
DF/HCC Protocol Case Number ............................................................................................................. 87 
3.9 
Protocol Deviations, Exceptions and Violations ..................................................................................... 87 
3.10 
Safety Assessments and Toxicity Monitoring ......................................................................................... 89 
3.11 
Data Management ................................................................................................................................... 89 
4. 
Requisitioning Investigational Drug ............................................................................................................... 90 
5. 
MONITORING: QUALITY CONTROL ...................................................................................................... 90 
5.1 
Ongoing Monitoring of Protocol Compliance ........................................................................................ 91 
5.2 
Evaluation of Participating Institution Performance ............................................................................. 92 
6. 
AUDITING: QUALITY ASSURANCE ......................................................................................................... 92 
6.1 
DF/HCC Sponsored Trials ...................................................................................................................... 92 
6.2 
Participating Institution .......................................................................................................................... 92 
6.3 
DF/HCC Sponsor and Coordinating Center .......................................................................................... 93 
6.4 
Sub-Standard Performance ..................................................................................................................... 93 
 
 


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1.   
INTRODUCTION 
 
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan 
(DF/HCC DSMP) outlines the procedures for a DF/HCC Multi-Center research protocol. The 
DF/HCC DSMP should serve as a reference for any sites external to DF/HCC that will be 
participating in the research protocol. 
 
1.1 Purpose 
 
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center (DF/HCC) 
Multi-center protocol will comply with Federal regulations, Health Insurance Portability and 
Accountability Act (HIPAA) requirements and applicable DF/HCC Standard Operating 
Procedures.        
 
1.2 Multi-Center Data and Safety Monitoring Plan Definitions 
 
The Multi-Center Data and Safety Monitoring Plan includes the following components: 
 
DF/HCC Multi-center Protocol:  A research protocol in which one or more outside institutions 
collaborating with Dana-Farber/Harvard Cancer Center where a DF/HCC investigator is the 
sponsor. DF/HCC includes Dana-Farber/Partners Cancer Care (DF/PCC) Network Clinical Trial 
Affiliates. 
 
Lead Institution: One of the Dana-Farber/Harvard Cancer Center consortium members (Dana-
Farber Cancer Institute (DFCI), Massachusetts General Hospital (MGH), Beth Israel Deaconess 
Medical Center (BIDMC), Children’s Hospital Boston (CHB), Brigham and Women’s Hospital 
(BWH)) responsible for the coordination, development, submission, and approval of a protocol 
as well as its subsequent amendments per the DFCI IRB and applicable regulatory guidelines 
(Food and Drug Administration (FDA), Office of Biotechnology Activities (OBA) etc.).  The 
Lead Institution is typically the home of the DF/HCC Sponsor. The Lead Institution also 
typically serves as the Coordinating Center for the DF/HCC Multi-Center Protocol.   
 
DF/HCC Sponsor:  The person sponsoring the submitted Multi-Center protocol.  Within 
DF/HCC, this person is the Overall Principal Investigator who takes responsibility for initiation, 
management and conduct of the protocol at all research locations. In applicable protocols, the 
DF/HCC Sponsor will serve as the single liaison with any regulatory agencies (FDA). The 
DF/HCC Protocol Chair has ultimate authority over the protocol and is responsible for the 
conduct of the study at DF/HCC and all Participating Institutions. In most cases the DF/HCC 
Protocol Chair is the same person as the DF/HCC Principal Investigator; however, both roles can 
be filled by two different people. 
 
Participating Institution:  An institution that is outside the DF/HCC and DF/PCC consortium 
that is collaborating with DF/HCC on a protocol where the sponsor is a DF/HCC Investigator.  


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The participating institution acknowledges the DF/HCC Sponsor as having the ultimate authority 
and responsibility for the overall conduct of the study.    
 
Coordinating Center: The entity (i.e. Lead Institution, Medical Monitor, Contract Research 
Organization (CRO), etc) that provides the administrative support to the DF/HCC Sponsor in 
order that he/she may fulfill the responsibilities outlined in the protocol document and DSMP, 
and as specified in applicable regulatory guidelines (i.e. CTEP Multi-Center Guidelines). In 
general, the Lead Institution is the Coordinating Center for the DF/HCC Multi-Center Protocol. 
Should the DF/HCC Sponsor decide to use a CRO, the CRO will be deemed the Coordinating 
Center. 
 
DF/HCC Quality Assurance Office for Clinical Trials: A unit within DF/HCC developed to 
computerize and manage data, and to provide a Quality Control and Quality Assurance function 
for DF/HCC trials.   
 
2. GENERAL ROLES AND RESPONSIBILITIES 
 
For DF/HCC Multi-Center Protocols, the DF/HCC Sponsor, the Coordinating Center, and the 
Participating Institutions are expected to adhere to the following general responsibilities: 
 
2.1 DF/HCC Sponsor 
 
The DF/HCC Sponsor, Jennifer R Brown MD, PhD, will accept responsibility for all aspects of 
conducting a DF/HCC Multi-Center protocol which includes but is not limited to:  
 Oversee the coordination, development, submission, and approval of the protocol as well as 
subsequent amendments.  
 Ensure that the investigators, study team members, and Participating Institutions are 
qualified and appropriately resourced to conduct the protocol.   
 Submit the Multi-Center Data and Safety Monitoring Plan as an appendix to the protocol. 
 Assure all Participating Institutions are using the correct version of the protocol. 
 Ensure that each participating investigator and study team receives adequate protocol 
training and/or a Site Initiation Visit prior to enrolling participants and throughout trial’s 
conduct as needed. 
 Ensure the protocol will be provided to each participating site in a language understandable 
to all site personnel when English is not the primary language.  
 Monitor progress and overall conduct of the study at all Participating Institutions.  
 Ensure all DFCI Institutional Review Board (IRB), DF/HCC and other applicable (i.e. 
FDA) reporting requirements are met.  
 Review data and maintain timely submission of data for study analysis.  
 Act as the single liaison with FDA (investigator-held IND trials) or OBA (gene therapy 
trials), as applicable. For this study, Dr. Brown will hold the IND and will be responsible 
for all FDA correspondence. 


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 Ensure compliance with all requirements as set forth in the Code of Federal Regulations, 
applicable DF/HCC requirements, HIPAA requirements, and the approved protocol. 
 Commit to the provision that the protocol will not be rewritten or modified by anyone other 
than the DF/HCC Sponsor. 
 Identify and qualify Participating Institutions and obtain accrual commitments prior to 
extending the protocol to that site. 
 Monitor accrual and address Participating Institutions that are not meeting their accrual 
requirements.  
 
2.2     Coordinating Center (Lead Institution DFCI) 
 
The Coordinating Center will assume the following general responsibilities: 
 Assist in protocol development 
 Maintain copies of Federal Wide Assurance and Institutional Review Board (IRB) 
approvals from all participating institutions. 
 MaintainFDA correspondence, as applicable. 
 Maintain updated roster of participants.  
 Verify eligibility. 
 Verify response. 
 Oversee the data collection process from Participating Institutions. 
 Maintain documentation of Serious Adverse Event (SAE) reports submitted by 
Participating Institutions and submit to DF/HCC Sponsor for timely review.   
 Distribute adverse events reported to the DF/HCC Sponsor that fall under the DFCI IRB 
Adverse Event Reporting Policy to all participating investigators. 
 Provide Participating Institutions with information regarding DF/HCC requirements that 
they will be expected to comply with.  
 
 Monitor Participating Institutions either by on-site or virtual monitoring.  
 Maintain Regulatory documents of all Participating Institutions.  
 Conduct regular communications with all Participating Institutions (conference calls, 
emails, etc).  
 Maintain documentation of all communications. 
 Ensure that each Participating Institution has the appropriate assurance on file with the 
Office of Human Research Protection (OHRP). 
 
2.3 DF/HCC Quality Assurance Office for Clinical Trials (QACT) 
 
In addition to the Coordinating Center, the DF/HCC QACT provides the following support 
services to assist the DF/HCC Sponsor: 
 Develop protocol specific case report forms (CRF/eCRFS). 
 QA/QC data of protocol specific CRFs.  
 Provide Central Participant Registration, which includes review of consent and eligibility 


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 Provide auditing services (funding and QACT approval required). 
 
2.4 Participating Institution 
 
Each Participating Institution is expected to comply with all applicable Federal Regulations and 
DF/HCC requirements, the protocol and HIPAA requirements. All Participating Institutions will 
provide a list of personnel assigned to the role for oversight of data management at their site to 
the Coordinating Center.  
 
The general responsibilities for each participating institution are as follows: 
 Commit to the accrual of participants to the protocol. 
 Submit protocol and/or amendments to their local IRB. 
 Maintain a regulatory binder in accordance with DF/HCC requirements. 
 Provide the Coordinating Center with regulatory documents as requested. 
 Participate in protocol training prior to enrolling participants and throughout the trial as 
needed (i.e. teleconferences). 
 Update Coordinating Center with research staff changes on a timely basis. 
 Register participants through the Coordinating Center.  
 Submit source documents, research records, and CRFs per protocol specific submission 
guidelines to the Coordinating Center. 
 Submit Serious Adverse Event (SAE) reports to local IRB per local requirements, and to 
the Coordinating Center, in accordance with DF/HCC requirements as well as to Gilead 
Pharmaceuticals.  
 Submit protocol deviations and violations to local IRB per local requirements and to the 
DF/HCC Sponsor in accordance with DF/HCC requirements. 
 Secure and store investigational agents and/or other protocol mandated drugs per federal 
guidelines and protocol requirements. 
 Have office space, office equipment, and internet access that meet HIPAA standards. 
 For protocols using investigational agents, the Participating Institution will order their own 
investigational agents regardless of the supplier (Novartis and Gilead in this case). 
 
3. DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS 
 
The following section will clarify DF/HCC Requirements and further detail the expectations for 
participating in a DF/HCC Multi-Center protocol.  
 
3.1 Protocol Distribution 
 
The Coordinating Center will distribute the final DFCI IRB approved protocol and any 
subsequent amended protocols to all Participating Institutions.    
 


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3.2 Protocol Revisions and Closures 
 
The Participating Institutions will receive notification of protocol revisions and closures from the 
Coordinating Center.  It is the individual Participating Institution’s responsibility to notify its 
IRB of these revisions. 
 
 Non life-threatening revisions: Participating Institutions will receive written notification 
of protocol revisions regarding non life-threatening events from the Coordinating Center. 
Non-life-threatening protocol revisions must be IRB approved and implemented within 90 
days from receipt of the notification. 
 Revisions for life-threatening causes: Participating Institutions will receive immediate 
notification from the Coordinating Center concerning protocol revisions required to protect 
lives with follow-up by fax, mail, e-mail, etc.  Life-threatening protocol revisions will be 
implemented immediately followed by IRB request for approval. 
 Protocol closures and temporary holds: Participating Institutions will receive notification 
of protocol closures and temporary holds from the Coordinating Center. Closures and holds 
will be effective immediately.  In addition, the Coordinating Center, will update the 
Participating Institutions on an ongoing basis about protocol accrual data so that they will 
be aware of imminent protocol closures. 
 
3.3 Informed Consent Requirements 
 
The DF/HCC approved informed consent document will serve as a template for the informed 
consent for Participating Institutions. The Participating Institution consent form must follow the 
consent template as closely as possible and should adhere to specifications outlined in the 
DF/HCC Guidance Document on Model Consent Language for PI-Initiated Multi-Center 
Protocols.  This document will be provided separately to each Participating Institution. 
 
Participating Institutions are to send their version of the informed consent document and HIPAA 
authorization, if a separate document, to the Coordinating Center for review and approval prior 
to submission to their local IRB. The approved consent form must also be submitted to the 
Coordinating Center after approval by the local IRB. 
 
The Principal Investigator (PI) at each Participating Institution will identify the physician 
members of the study team who will be obtaining consent and signing the consent form for 
therapeutic protocols. Participating institutions must follow the DF/HCC requirement that only 
attending physicians obtain informed consent and re-consent to interventional trials (i.e. drug 
and/or device trials).   
 
3.4 IRB Documentation 
 
The following must be on file with the Coordinating Center: 


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 Approval letter of the Participating Institution's IRB  
 Copy of the Informed Consent Form approved by the Participating Institution’s IRB  
 Participating IRB’s approval for all amendments 
 
It is the Participating Institution's responsibility to notify its IRB of protocol amendments.  
Participating Institutions will have 90 days from receipt to provide the Coordinating Center their 
IRB approval for amendments to a protocol.    
 
3.5 IRB Re-Approval 
 
Verification of IRB re-approval from the Participating Institutions is required in order to 
continue research activities.  There is no grace period for continuing approvals. 
 
The Coordinating Center will not register participants if a re-approval letter is not received from 
the Participating Institution on or before the anniversary of the previous approval date.   
 
3.6 Participant Confidentiality and Authorization Statement 
 
In 1996, congress passed the first federal law covering the privacy of health information known 
as the Health Insurance Portability and Accountability Act (HIPAA). Any information, related to 
the physical or mental health of an individual is called Protected Health Information (PHI). 
HIPAA outlines how and under what circumstances PHI can be used or disclosed.  
 
In order for covered entities to use or disclose protected health information during the course of a 
study, the study participant must sign an Authorization.  This Authorization may or may not be 
separate from the informed consent document.  The Coordinating Center, with the approval from 
the DFCI IRB, will provide a consent template, which covered entities (Participating Institutions) 
must use.  
 
The DF/HCC Sponsor will use all efforts to limit its use of protected health information in its 
trials.  However, because of the nature of these trials, certain protected health information must 
be collected per NCI requirements. These are the primary reasons why DF/HCC has chosen to 
use Authorizations, signed by the participant in the trial, rather than limited data sets with data 
use agreements. 
 
3.6.1  DF/HCC Multi-Center Protocol Confidentiality 
 
All documents, investigative reports, or information relating to the participant are strictly 
confidential. Whenever reasonably feasible, any participant specific reports (i.e. Pathology 
Reports, MRI Reports, Operative Reports, etc.) submitted to the Coordinating Center must have 
the participant’s full name & social security number “blacked out” and the assigned DF/HCC 
QACT case number (as described below) and DF/HCC protocol number written in (with the 


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exception of the signed informed consent document). Participant initials may only be included or 
retained for cross verification of identification 
 
3.7 DF/HCC Multi-Center Protocol Registration Policy 
 
3.7.1 Participant Registration  
 
Please see protocol section 4.4.  
3.7.2 Initiation of Therapy 
 
Participants must be registered with the DF/HCC QACT before receiving treatment.  Treatment 
may not be initiated until the Participating Institution receives a faxed or e-mailed copy of the 
participant’s registration confirmation memo from the Coordinating Center. Therapy must be 
initiated per protocol guidelines.  The DF/HCC Sponsor and DFCI IRB must be notified of any 
exceptions to this policy. 
 
3.7.3 Eligibility Exceptions 
 
The DF/HCC QACT will make no exceptions to the eligibility requirements for a protocol 
without DFCI IRB approval. The DF/HCC QACT requires each institution to fully comply with 
this requirement. 
 
3.7.4 Verification of Registration, Dose Levels, and Arm Designation 
 
A registration confirmation memo for participants registered to DF/HCC Multi-Center Protocol 
will be faxed or emailed to the registering institution within one business day of the registration. 
Treatment may not be initiated until the site receives a faxed or e-mailed copy of the registration 
confirmation memo. 
 
3.8 DF/HCC Protocol Case Number 
 
Once eligibility has been established and the participant successfully registered, the participant is 
assigned a five digit protocol case number.  This number is unique to the participant on this trial 
and must be used for QACT CRF/eCRF completion and written on all data and QACT 
correspondence for the participant. 
 
3.9 Protocol Deviations, Exceptions and Violations 
 


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Federal Regulations require an IRB to review proposed changes in a research activity to ensure 
that researchers do not initiate changes in approved research without IRB review and approval, 
except when necessary to eliminate apparent immediate hazards to the participant. DF/HCC 
requires all departures from the defined procedures set forth in the IRB approved protocol to be 
reported to the DF/HCC Sponsor, who in turn is responsible for reporting to the DFCI IRB. 
 
 
For reporting purposes, DF/HCC uses the terms “violation”, “deviation” and “exception” to 
describe derivations from a protocol. All Participating Institutions must adhere to these 
requirements for reporting to the DF/HCC Sponsor and will follow their institutional policy for 
reporting to their local IRB. 
 
3.9.1 Definitions 
 
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-approved 
protocol which is prospectively approved prior to its implementation. 
 
Protocol Exception:  Any protocol deviation that relates to the eligibility criteria, e.g. 
enrollment of a participant who does not meet all inclusion/exclusion criteria. 
 
  
Protocol Violation: Any protocol deviation that was not prospectively approved by the IRB prior 
to its initiation or implementation.   
 
3.9.2  Reporting Procedures 
 
DF/HCC Sponsor: is responsible for ensuring that clear documentation is available in the 
medical record and/or regulatory documents to describe all protocol exceptions, deviations and 
violations. The DF/HCC Sponsor will also be responsible for ensuring that all protocol 
violations/deviations are promptly reported per DFCI IRB guidelines.  
 
Participating Institutions: Protocol deviations require prospective approval from the DFCI IRB. 
The Participating Institution must submit the deviation request to the Coordinating Center who 
will then submit the deviation request to the DFCI IRB. Upon DFCI IRB approval the deviation 
is submitted to the Participating Institution IRB, per institutional policy. A copy of the 
Participating Institution’s IRB report and determination will be forwarded to the Coordinating 
Center within 10 business days after the original submission.  
 
All protocol violations must be sent to the Coordinating Center in a timely manner.  
 
Coordinating Center:  Upon receipt of the violation/deviation report from the Participating 
Institution, the Coordinating Center will submit the report to the DF/HCC Sponsor for review. 
Subsequently, the Participating Institution’s IRB violation/deviation report will be submitted to 
the DFCI IRB for review per DFCI IRB reporting guidelines.  
  
 


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3.10 Safety Assessments and Toxicity Monitoring 
 
The study teams at all participating institutions are responsible for protecting the safety, rights 
and well-being of study participants. Recording and reporting of adverse events that occur during 
the course of a study help ensure the continuing safety of study participants.  
 
All participants receiving investigational agents and/or other protocol mandated treatment will be 
evaluated for safety. The safety parameters include all laboratory tests and hematological 
abnormalities, physical examination findings, and spontaneous reports of adverse events reported 
by participants.  All toxicities encountered during the study will be evaluated according to the 
NCI criteria specified in the protocol. Life-threatening toxicities must be reported immediately to 
the DF/HCC Sponsor via the Coordinating Center.  
 
Additional safety assessments and toxicity monitoring will be outlined in the protocol. 
 
3.10.1 
Guidelines for Reporting Serious Adverse Events  
 
Guidelines for reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) are detailed 
in protocol section 11.4. 
 
Participating Institutions must report the AEs to the DF/HCC Sponsor and the Coordinating 
Center following the DFCI IRB SAE Reporting Requirements.  
 
The Coordinating Center will maintain documentation of all Participating Institution Adverse 
Event reports and be responsible for communicating to all participating investigators, any 
observations reportable under the DFCI IRB Reporting Requirements.  Participating 
Investigators will review any distributed AE reports, send a copy to their IRB according to their 
local IRB’s policies and procedures, and file a copy with their regulatory documents. 
 
3.10.2 
Guidelines for Processing IND Safety Reports  
 
FDA regulations require sponsors of clinical studies to notify the FDA and all participating 
investigators of any adverse experience associated with the use of the investigational agent that is 
both serious and unexpected. The DF/HCC Sponsor will review all IND Safety Reports and 
ensure that all IND Safety Reports are distributed to the Participating Institutions.  The 
Participating Institutions willreview and submit to their IRB according to their institutional 
policies and procedures. 
 
3.11 Data Management 
 


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The DF/HCC QACT develops a set of either paper or electronic case report forms (CRF/eCRFs), 
for use with the protocol.  These forms are designed to collect data for each study. The DF/HCC 
QACT provides a web based training for eCRF users. 
 
Notations concerning adverse events will address relationship to protocol treatment for each 
adverse event grade.  All adverse events encountered during the study will be evaluated 
according to the NCI Common Toxicity Criteria and CLL specific hematologic criteria in 
Appendix C, and all adverse events must be noted on the participant's Adverse Event (Toxicity) 
Forms. 
   
3.11.1 
Data Forms Review 
 
When data forms arrive at the DF/HCC QACT, they are reviewed for completeness, protocol 
treatment compliance, adverse events (toxicities) and response. Data submissions are monitored 
for timeliness and completeness of submission. Participating Institutions are notified of their data 
submission delinquencies in accordance with the following: 
 
Incomplete or Questionable Data 
If study forms are received with missing or questionable data, the submitting institution will 
receive a written or electronic query from the DF/HCC QACT Data Analyst or study monitor.  
Responses to all queries should be completed and submitted within 14 calendar days.  Responses 
may be returned on the written query or on an amended paper case report form, or in the case of 
electronic queries, within the electronic data capture (eDC) system. In the case of a written query 
for data submitted on a paper case report form, the query must be attached to the specific data 
being re-submitted in response.   
 
Missing Forms 
If study forms are not submitted on schedule, the Participating Institution will receive a Missing 
Form Report from the Coordinating Center noting the missing forms.  These reports are 
compiled by the DF/HCC QACT and distributed a minimum of four times a year.  
 
 
4. REQUISITIONING INVESTIGATIONAL DRUG 
 
See main protocol Section 7.   
 
5. MONITORING: QUALITY CONTROL 
  
The quality control process for a clinical trial requires verification of protocol compliance and 
data accuracy. The Coordinating Center, with the aid of the QACT provides quality control 
oversight for the protocol. 
 


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5.1 Ongoing Monitoring of Protocol Compliance 
 
The Participating Institutions will be required to submit participant source documents to the 
Coordinating Center for monitoring. Participating Institution may also be subject to on-site 
monitoring conducted by the Coordinating Center.  
 
The Coordinating Center will implement ongoing monitoring activities to ensure that 
Participating Institutions are complying with regulatory and protocol requirements, data quality, 
and participant safety. Monitoring will occur before the clinical phase of the protocol begins, 
continue during protocol performance and through study completion.  
 
The participating institutions in this study are experienced CLL Centers who work together in the 
CLL Research Consortium, which has conference calls every two weeks and a couple meetings 
per year.  The investigators are therefore in close contact on a frequent basis.  Furthermore, these 
are all tertiary care oncology centers with internal audit mechanisms.  We therefore anticipate 
that monitoring will be primarily performed through the submission of source documents to 
DFCI for review (virtual monitoring) at critical points in the therapy.   
 
At a minimum, the Coordinating Center, or designee, will monitor each participating site once a 
year while patients are receiving treatment. Should a Participating Institution be monitored once 
and then not accrue any additional patients, additional monitoring visits may not be necessary.  
 
Virtual Monitoring: Participating Institutions will be required to forward copies of participants’ 
medical record and source documents to the Coordinating Center upon request for remote 
monitoring purposes. Virtual monitoring may include, but is not limited to, review of the 
following: 
1. Eligibility and registration (diagnostic flow cytometry and when available CT scans, 
bone marrow biopsy and FISH results) 
2. Restaging evaluations (end of cycle 2 (idelalisib alone), end of cycle 4 (weekly ofa)) 
3. Final restaging evaluation in both arms (two months after monthly ofa, including 
bone marrow biopsy with MRD analysis and CT scan) 
4. At time of off study for progressive disease  
 
If any issues are identified in the course of virtual monitoring, the participating institution may 
be subject to on-site monitoring conducted by the Coordinating Center or designee. 
 
On-Site Monitoring: On-site monitoring visits will be conducted at the discretion of the 
sponsor-investigator. The need for on-site monitoring will depend on participant accrual, data 
compliance, virtual monitoring findings, and other factors. Participating Institutions will be 
required to provide access to participants’ complete medical records and source documents for 
verification during any on-site monitoring visits. In addition, Participating Institutions should 
provide access to regulatory documents, pharmacy records, local policies related to the conduct 
of research, and any other trial-related documentation maintained by the participating site.  
 
 


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5.2 Evaluation of Participating Institution Performance 
 
5.2.1 Monitoring Reports 
 
The DF/HCC Sponsor will review all monitoring reports for on-site and virtual monitoring of 
Participating Institutions to ensure protocol compliance and ability to fulfill responsibilities of 
participating in the study. The DF/HCC Sponsor may increase the monitoring activities at 
Participating Institutions that are unable to comply with the protocol, DF/HCC Sponsor 
requirements or federal and local regulations. Participating Institutions may also be subject to an 
audit as determined by the DF/HCC Sponsor. 
5.3 Accrual Monitoring 
 
Prior to extending a protocol to an external site, the DF/HCC Sponsor will establish accrual 
requirements for each participating institution. Accrual will be monitored for each participating 
institution by the DF/HCC Sponsor or designee. Sites that are not meeting their accrual 
expectations may be subject to termination. 
 
The minimum accrual requirements are 3-5 patients per site/annually. 
 
6. AUDITING: QUALITY ASSURANCE 
 
Auditing is a method of Quality Assurance. Its main focus is to measure whether standards and 
procedures were followed. Auditing is the systematic and independent examination of all trial 
related activities and documents.  Audits determine if evaluated activities were appropriately 
conducted and whether data was generated, recorded and analyzed, and accurately reported per 
the protocol, Standard Operating Procedures (SOPs), and the Code of Federal Regulations 
(CFR). 
 
6.1 DF/HCC Sponsored Trials 
 
Participating institutions will be eligible for one on-site audit, to be scheduled by the QACT, 
after at least three participants have been treated on protocol at the site. Approximately 3-4 
participants would be audited at the site over a 2 day period.  If violations which impact 
participant safety or the integrity of the study are found, more participant records may be 
audited.  
 
6.2 Participating Institution 
 
It is the Participating Institution’s responsibility to notify the Coordinating Center of all 
scheduled audit dates and re-audit dates (if applicable), which involve this protocol. All 


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institutions will forward a copy of final audit and/or re-audit reports and corrective action plans 
(if applicable) to the Coordinating Center, within 12 weeks after the audit date.  
 
6.3 DF/HCC Sponsor and Coordinating Center  
 
The DF/HCC Sponsor will review all final audit reports and corrective action plans if applicable. 
The Coordinating Center, must forward these reports to the DF/HCC QACT per DF/HCC policy 
for review by the DF/HCC Audit Committee. Based upon the audit assessments the DF/HCC 
Audit Committee could accept or conditionally accept the audit rating and final report. 
Conditional approval could require the DF/HCC Sponsor to implement recommendations or 
require further follow-up.  For unacceptable audits, the DF/HCC Audit Committee would 
forward the final audit report and corrective action plan to the DFCI IRB as applicable. 
 
6.4 Sub-Standard Performance 
 
The DF/HCC Sponsor, DFCI IRB, is charged with considering the totality of an institution’s 
performance in considering institutional participation in the protocol. 
 
6.4.1 Corrective Actions 
 
Participating Institutions that fail to meet the performance goals of accrual, submission of timely 
accurate data, adherence to protocol requirements, and compliance with state and federal 
regulations, will be recommended for a six-month probation period. Such institutions must 
respond with a corrective action plan and must demonstrate during the probation period that 
deficiencies have been corrected, as evidenced by the improved performance measures. 
Participating Institutions that fail to demonstrate significant improvement will be considered by 
the DF/HCC Sponsor for revocation of participation.  


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Guidelines for Dana-Farber use ONLY 
Other sites should NOT make any submissions to the FDA for this trial 
 
Appendix E: 
 
FDA guidelines for Dana-Farber outlined on Study May Proceed Letter  
 
IND Responsibilities: 
The responsibilities of the sponsor-investigator include: 
-Reporting any unexpected fatal-life threatening suspected adverse reactions to the FDA no later 
than 7 days after initial receipt of the information. 
-Reporting any 
1. serious, unexpected suspected adverse reactions 
2. findings from other clinical, animal, or in-vitro studies that suggest significant human risk, 
and  
3. a clinically important increase in the rate of a serious suspected adverse reaction to this 
Division and to all investigators no later than 15 calendar days after determining that the 
information qualifies for reporting. If your IND is not in eCTD format, you may submit 15-
day reports in paper format. 
- Submitting annual progress reports within 60 days of the anniversary of the date that the IND 
became active (the date clinical studies were permitted to begin). 
 
Submission Requirements 
 
Cite the IND number listed above at the top of the first page of any communications concerning 
this application. Each submission to this IND must be provided in triplicate (original plus two 
copies). Please include three originals of all illustrations that do not reproduce well. Send all 
submissions, electronic or paper, including those sent by overnight mail or courier, to the 
following address: 
 
Food and Drug Administration 
Center for Drug Evaluation and Research 
Division of Hematology Products 
Attn: Janet Higgins 
5901-B Ammendale Road 
Beltsville, MD 20705-1266 
Phone Number: (240) 402-0330 
 
All regulatory documents submitted in paper should be three-hole punched on the left side of the 
page and bound. The left margin should be at least three-fourths of an inch to assure text is not 
obscured in the fastened area. Standard paper size (8-1/2 by 11 inches) should be used; however, 
it may occasionally be necessary to use individual pages larger than standard paper size. Non-
standard, large pages should be folded and mounted to allow the page to be opened for review 
without disassembling the jacket and refolded without damage when the volume is shelved. 


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Shipping unbound documents may result in the loss of portions of the submission or an 
unnecessary delay in processing which could have an adverse impact on the review of the 
submission. For additional information, see 
http:/ /wvvw.fda.govDrugs/DevelopmentApprovalProcess/FormsSubmissionReguirements/Drug 
MasterFilesDMFs/ucm073080.htm. 
 


Protocol #.13-309 D: 7/12/2013 KAJ; F: 9/19/2013 KF; R: 8/27/2014 (AM#8) KAJ; Rev (AM#9)MRH 
 
DANA-FARBER CANCER INSTITUTE 
Nursing Protocol Education Sheet 
Protocol Number: 
13-309 
Protocol Name: 
A Phase II Study of Idelalisib (GS1101, CAL101) + Ofatumumab in Previously Untreated 
CLL/SLL 
DFCI Site PI: 
Jennifer Brown, MD, PhD 
DFCI Research Nurse: 
Karen Francoeur RN, Karen Polinski  RN, Kathleen McDermott, RN 
Page the DFCI research nurse or DFCI site PI if there are any questions/concerns about the protocol.   
Please also refer to ONC 15: Oncology Nursing Protocol Education Policy 
*** Remember to check the ALERT PAGE*** 
              SPECIAL NURSING CONSIDERATIONS UNIQUE TO THIS PROTOCOL 
Study Design 
 
Phosphatidylinositol 3-kinases (PI3Ks) are enzymes that regulate several cellular functions including motility, 
proliferations and survival.  PI3K signaling is mediated by 4 catalytic isoforms of the p110 subunit of the enzyme – 
α, β, γ and δ.  PI3Kδ shows an expression pattern that is particularly prominent in cells of hematopoietic origin.  
Idelalisib can selectively inhibit PI3Kδ function.  Ofatumumab ia an anti-CD20 antibody that induces potent 
complement-dependent cytotoxicity against cells tha express CD20 dimly, including CLL.  Study Design – Section 
1.1; Study Rationale – Section 2.5.  A cycle is 28 days – Section 5, Table 1. 
Dose 
Calc. 
 
 
Idelalisib and Ofatumumab are both fixed dosing in mg – Section 5, Table 1 
 
Study Drug  
Administration 
Idelalisib Administration Guidelines are found in Section 5.0 through 5.2,1  including Table 1 
 
Dosing will start on Cycle 1, Day 1 
 
Always administered BEFORE Ofatumumab when given on the same day 
 
Oral, taken twice per day approximately 12 hours apart.  
 
 May be taken with or without food; Note:  Food consumption should be recorded on PK days – Section 5.2.1 
 
Tablets must be swallowed whole with 100 – 200 mL of water.  Participants must be instructed not to bite or 
chew the tablets.  In case of breakage of tablets in the oral cavity, additional water should be taken as a rinse. 
 
Missed doses may be taken within 6 hours of the scheduled dosing time. 
 
Vomited doses can only be retaken if the tablet is visible in the vomitus. 
  
Ofatumumab Administration Guidelines are found in Sections 5.0 through 5.1; 5.2.2 and 7.2 
 
Dosing will start on Cycle 3, Day 1 and continue once weekly for 8 weeks (Cycles 3 and 4).  This will be 
followed by monthly dosing for four additional cycles (Cycles 5, 6, 7 and 8) 
 
Administered IV through infusion tubing set supplied by Sponsor. 
 
Please note than infusion time can be up to 4.6 hours. 
 
Do NOT mix with any other meds.  IV line must be flushed with NS before and after completion of infusion. 
 
Premedication regimen – See Table 1 in Section 5.0 
 
Please review Section 5.2.2 and Tables 2 through 4 for specific instructions on the rate of infusion 
 
Infusion reactions are an expected risk – monitor patient closely – Section 6.1.2 
 
Please review 7.2.4 and Figure 1 for detailed instructions on the infusion set up for Ofatumumab, 
including the use of a 0.2 micron polyether sulfone in-line filter. 
 
NOTE:  Criteria to treat is found in Section 5.1 
 
Dose Mods 
 & Toxicity 
Dose Modifications/Dosing Delay for Toxicity are outlined in Section 6 
 
This protocol uses NCI CTCAE criteria, version 4.0 – Section 6 
 
Participants must be monitored for s/sx consistent with PML and for Hepatic Adverse Events – see 
Table 6 and Section 6.2 for a description of the signs and symptoms.  See also Appendix D for a symptom 
screening questionnaire. 
 
See Section 6.3 and Table 6 for dose modifications and delays. 
Con 
Meds 
Concomitant Therapy Guidelines are in Section 5.3 
 
Please review the cited sections for permitted, prohibited, and “use with caution” medications/therapies/foods 
 
See Section 5.3.2 for required tumor lysis prophylaxis and recommendation for hydration 
 
See Section 5.3.6 for recommended prophylactic antibiotics and antivirals. 
 
Tylenol use is discouraged – Section 5.3 


Protocol #.13-309 D: 7/12/2013 KAJ; F: 9/19/2013 KF; R: 8/27/2014 (AM#8) KAJ; Rev (AM#9)MRH 
 
Required  
Data  
Study Calendar and Assessment Required data are outlined in Sections 8 and 9 
 
PKs and Pharmacodynamics:  Please see Section 8 for time points 
 
Study calendar is in Section 9 
Charting 
Tips 
All study drugs require documentation of exact administration time. 
Please be sure to DOCUMENT study medication actual UP/DOWN times in medical record (e.g. LMR, eMAR, 
nursing notes). Edit eMAR as needed to match the exact time given. 
 If there is a discrepancy in the infusion time, delay in administration, or infusion takes longer than is permitted 
by the guidelines of the protocol, please document the reason for the discrepancy in the medical record. 
Please be sure to also DOCUMENT any additional V/S, routes of administration, and exact time of PK collections. 
 


OTHER MEDICATIONS TAKEN
Study Participant
Self-Administration
If you take a daily medication (prescribed or otherwise), please use one
Study Drug Diary
line per drug and indicate the start and stop dates under the "Date(s) 
Dana-Farber/Harvard Cancer Center
Taken" section (i.e., 6/2/09 - 6/5/09). 
Dose
Dates Taken
Reason Taken
Participant Identifier: ____________________
Protocol # : 13-309
Your MD ____________________ Phone ____________________
Your RN _____________________ Phone ____________________
STUDY DRUG INSTRUCTIONS:
Study Drug: Idelalisib
How Much:  150 mg
How Often: You will take each dose twice daily.
When: You should take your dose at about the same time
each day, ideally 12 hours apart.
Study Participant Initials __________
Date _________
SPECIAL INSTRUCTIONS:
Swallow each dose whole with about 4-8oz. of water.
Do not bite or chew tablets.
FOR STUDY TEAM USE ONLY
If tablet breaks, additional water should be taken as a rinse.
Drug can be taken with or without food.
Staff Initials:
Missed doses can be taken up to 6 hours after scheduled
Date Dispensed:
Date Returned:
dose.
# pills/caps/tabs dispensed:
# pills/caps/tabs returned:
Vomited doses should be retaken only if the tablet is
visible in the vomitus.
# pills/caps/tabs that should have been taken:
Please bring an unused study drug, all empty containers,
Discrepancy Notes:
and diary to the next clinic visit.
Drug Name


DOSING LOG
SYMPTOMS/SIDE EFFECTS
Idelalisib
Cycle: ___
For each AM dose take: 1 tablet
Please record any side effects experienced during this cycle.
For each PM dose take: 1 tablet
Include the date the particular symptom started and when it
ended. Please evaluate the severity of the symptom according to
Please indicate the date, time, amount taken and any comments. 
the following scale:
Mild: Awareness of sign or symptom; easily tolerated and did 
AM dose
PM dose
not affect ability to perform normal daily activities. Symptom 
Ex:
6/1/2009
8 am - 1
7:30 pm - 1
vomited PM pill
did not require medication or therapeutic intervention.
Day 1
Day 2
Moderate: Significant  discomfort which interfered with ability 
Day 3
to perform normal daily activities. Symptom was easily resolved  
Day 4
with at home medication or simple therapeutic intervention.
Day 5
Day 6
Severe: Marked discomfort with an inability to carry out 
Day 7
normal daily activities. Symptom required new medication 
Day 8
and/or therapeutic intervention in order to resolve.
Day 9
Day 10
Please Note: The severity should reflect the most severe level 
Day 11
experienced during the time period. 
Day 12
Day 13
Symptom
Start Date End Date Severity
Day 14
Day 15
Day 16
Day 17
Day 18
Day 19
Day 20
Day 21
Day 22
Day 23
Day 24
Day 25
Day 26
Day 27
Day 28
Amount Taken
Date
Comments


Protocol #.13-309 D: 7/12/2013 KAJ; F: 9/19/2013 KF 
 
Charting 
Tips 
All study drugs require documentation of exact administration time. 
Please be sure to DOCUMENT study medication actual UP/DOWN times in medical record (e.g. LMR, eMAR, 
nursing notes). Edit eMAR as needed to match the exact time given. 
 If there is a discrepancy in the infusion time, delay in administration, or infusion takes longer than is permitted 
by the guidelines of the protocol, please document the reason for the discrepancy in the medical record. 
Please be sure to also DOCUMENT any additional V/S, routes of administration, and exact time of PK collections. 
 


DFCI Protocol: 13-309 
PI: Jennifer R. Brown, MD, PhD 
 
Acceptable Methods of Contraception 
 
Sexually active women of childbearing potential and sexually active men who are able to 
father a child must choose from the methods of birth control listed below: 
 
 
Individual Methods  
Combination Methods  
Hormone Methods 
(choose one and use with a 
barrier method)  
Barrier Methods  
(use both OR choose one with a 
hormone method)  
IUD 
Estrogen and Progesterone 
Diaphragm with spermicide 
    Copper T 380A IUD 
     Oral contraceptives  
Male condom (with spermicide)
 
 
    LNg 20 IUD  
     Transdermal patch  
Tubal Sterilization 
     Vaginal ring  
Hysterectomy 
Progesterone 
     Injection  
     Implant 
Abbreviation: IUD = intrauterine device 
 
Women who could become pregnant should always use barrier contraception in 
combination with other oral or hormonal methods of contraception since it is possible 
that the study drug might make some oral or hormonal contraceptives less effective. If 
your partner had a vasectomy you must use a hormone or barrier method as well. 
 
Your study doctor or personal health care provider can discuss the benefits and 
disadvantages of these birth control options with you. 


DFCI Protocol: 13-309 
PI: Jennifer R. Brown, MD, PhD 
 
Idelalisib possible interactions with other medications 
 
Idelalisib is a strong inhibitor of CYP3A. Accordingly, coadministration of CYP3A 
substrates with idelalisib may result in an increase in their systemic exposures (eg, 
certain antiarrhythmics, calcium channel blockers, benzodiazepines, HMG-CoA 
reductase inhibitors, phosphodiesterase-5 [PDE5] inhibitors, and warfarin). Particular 
caution is recommended during coadministration of idelalisib with drugs that are highly 
dependent on CYP3A for clearance and for which elevated plasma concentrations are 
associated with serious and/or life-threatening events, including narrow therapeutic 
index CYP3A substrates (eg, alfentanil, cyclosporine, sirolimus, tacrolimus, cisapride, 
pimozide, fentanyl, quinidine, ergotamine, dihydroergotamine, astemizole, and 
terfenadine). 
When coadministered with rifampin, a highly potent inducer of CYP3A, idelalisib 
exposures are approximately 75% lower. Coadministration of potent inducers of CYP3A 
(rifampin, carbamazepine, phenytoin, and St. John’s wort) with idelalisib should be 
avoided.