Conditions: Leukemia Chronic Lymphocytic Leukemia Lymphocytic Leukemia
Keywords: Leukemia Chronic Lymphocytic Leukemia CLL Refractory/Relapsed Untreated with high-risk molecular features Small lymphocytic leukemia SLL Lirilumab Rituximab Rituxan
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 7
Healthy volunteers: no

Brief summary:
The goal of this clinical research study is to learn if lirilumab in combination with rituximab can help to control either CLL or Small lymphocytic lymphoma (SLL). The safety of the drug combination will also be studied.

Detailed description:
Study Treatment:

Each study cycle is 28 days.

You will receive rituximab by vein over about 4-6 hours on Days 1,8, 15, and 22 of Cycle 1. After Cycle 1, you will receive rituximab on Day 1 of Cycles 2-12.

You will also receive lirilumab by vein over about 1 hour on Day 1 of each cycle.

Study Visits:

On Days 1, 8, 15, and 22 of Cycles 1 and 2 and then about every 2 weeks during Cycles 3-6:

* You will have a physical exam. You will not have this exam on Days 8 and 22 of Cycle 2.
* Blood (about 2 tablespoons) will be drawn for routine tests. If the doctor thinks it is needed, more blood may need to be drawn and you may need to have these tests performed more often. The study doctor will tell you if more blood will be drawn or if you will have this blood draw repeated.

On Day 1 of each cycle, if you can become pregnant, blood (about 1 tablespoon) or urine will be collected for a pregnancy test.

On Day 28 of Cycles 3 and 6:

* You will have physical exam.
* Blood (about 2 tablespoons) will be drawn for routine tests. This routine blood draw may include a pregnancy test if you can become pregnant. Urine may also be collected for this pregnancy test.
* You will have a bone marrow aspiration/biopsy to check the status of the disease.
* You will have a computerized tomography (CT) or positron emission tomography (PET) scan.

At least 1 time each month after Cycle 7:

* You will have physical exam.
* Blood (about 2 tablespoons) will be drawn for routine tests.

At least 1 time every 3 months after Cycle 7:

* Urine will be collected for routine tests. This routine urine collection will include a pregnancy test, if you can become pregnant. Blood (about 1 tablespoon) may also be drawn for this pregnancy test.
* You will have a bone marrow aspiration/biopsy to check the status of the disease.
* You will have a CT or PET scan.

Any time that the doctor thinks it is needed while you are on study, you will have blood draws, CT or PET scans, and/or bone marrow aspirations/biopsies to check the status of the disease and/or to monitor your health.

If the doctor thinks it is acceptable, you may be able to have some of these tests, such as routine blood and urine collections, performed at a local lab or clinic closer to your home. The results will be sent to the study doctor for review. Ask the study staff or study doctor about this possibility.

Length of Study:

You may receive up to 12 cycles of rituximab and up to 24 cycles of lirilumab. You will no longer be able to take the study drugs if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

Your participation on the study will be over after about 1 year of follow-up visits.

End-of-Study Visit:

Within 30 days after your last dose of study drug:

* You will have a physical exam.
* Blood (about 2-3 tablespoons) will be drawn for routine tests.
* If the doctor thinks it is needed, you will have a bone marrow aspirate to check the status of the disease.
* If the doctor thinks it is needed, you will have a CT or PET scan.

Follow-Up Visits:

After your end-of-study visit, you will have the following tests and procedures performed.

One (1) time each month for up to 1 year:

* You will have a physical exam.
* Blood (about 2-3 tablespoons) will be drawn for routine tests.

One (1) time every 3-6 months for up to 1 year, if the doctor thinks it is needed:

* You will have a bone marrow aspirate to check the status of the disease.
* You will have a CT scan or a PET scan.

If you start a new type of anticancer treatment during the year after your last dose of study drugs, you will stop having these follow-up visits.

This is an investigational study. Lirilumab is not FDA approved or commercially available. Rituximab is FDA approved and commercially available for the treatment of CLL. The use of these drugs in combination to treat CLL/SLL is considered investigational. The study doctor can explain how the drugs are designed to work.

Up to 48 participants will be enrolled in this study. All will take part at MD Anderson.

Arms:
arm 1: Participants receive Rituximab 375 mg/m2 by vein weekly for the first 4 weeks (Days 1, 8, 15, 22), then with start of each course. Lirilumab 3 mg/kg by vein given on Day 1 of each cycle. Rituximab given for the first 12 cycles and Lirilumab continues for up to 24 cycles. Each cycle is 4 weeks. arm 2: Participants receive Rituximab 375 mg/m2 by vein weekly for the first 4 weeks (Days 1, 8, 15, 22), then with start of each course. Lirilumab 3 mg/kg by vein given on Day 1 of each cycle. Rituximab given for the first 12 cycles and Lirilumab continues for up to 24 cycles. Each cycle is 4 weeks.

Interventions: intervention 1: Lirilumab intervention 2: Rituximab
Intervention descriptions: intervention 1: 3 mg/kg by vein given on Day 1 of each 28 day cycle. intervention 2: 375 mg/m2 by vein weekly for the first 4 weeks on Days 1,8, 15, and 22 of Cycle 1. After Cycle 1, given on Day 1 of Cycles 2 - 12.

Protocol document:
Prot_SAP_000.pdf: 
2014-0933
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Lirilumab (anti-KIR mAb) Combined with Rituximab for Relapsed, Refractory or High-risk 
Untreated Patients with Chronic Lymphocytic Leukemia (CLL)
Nitin Jain, MD, William Wierda, MD, PhD
Department of Leukemia
MD Anderson Cancer Center
1.0 OBJECTIVES
Primary Objectives
1. To determine the efficacy (response rate) of combined lirilumab and rituximab in patients 
with high-risk CLL as follows:
a. Cohort 1: refractory to and/or relapsed after at least one prior therapy OR
b. Cohort 2: untreated patients with high-risk molecular features such as del(17p), mutated 
TP53, del(11q), unmutated IGHV gene, or are >65 years of age
Secondary Objectives
1. To determine the safety of lirilumab combined with rituximab in patients with high-risk CLL. 
2. To determine the progression-free survival of patients with high-risk CLL treated with 
lirilumab combined with rituximab.
3. To determine the overall survival of patients with high-risk CLL treated with lirilumab
combined with rituximab. 
Exploratory Objectives
1. To study immunological and molecular changes in the peripheral blood and bone marrow in 
response to lirilumab and rituximab therapy.
2.0 BACKGROUND
2.1 Chronic lymphocytic leukemia (CLL): CLL is the most common leukemia in the United
States and Western hemisphere.1 It is a disease of the aging population; the median age at
diagnosis is 72 and over two-thirds of patients with CLL are over 60 years of age. Both the
incidence and prevalence of this disease increase with age.
The natural history for 
individuals with this disease is diverse. Generally, patients with early Rai stage (stage 0,
low-risk) have a median expected survival of more than 10 years. Those with evidence of
marrow failure manifested by anemia (stage III) or thrombocytopenia (stage IV) (Rai high-
risk) have an estimated median survival of only 2 years. In patients with intermediate-risk 
disease (Rai stage I and II) the estimated median survival is 7 years. There is remarkable 
clinical diversity in patients with CLL.  Following diagnosis, some patients have smoldering,
asymptomatic disease that may not progress for many years; others are diagnosed with 
advanced stage, or early stage disease that rapidly progresses, causing symptoms and/or
bone marrow failure and require treatment. Various genetic/molecular markers have been 
2014-0933 Lirilumab and Rituximab for Relapsed/Refractory CLL 
Version 2 – November 05, 2015 
Page 1 of 27 


 
established and validated to help in prognostication and are routinely used in clinical 
practice.1 7KHVH LQFOXGH ȕ-microglobulin, cytogenetics, immunoglobulin variable heavy 
chain gene (IGHV) mutational status, zeta chain-associated protein 70 (ZAP-70) expression, 
and CD38 expression. Presence of deletion 17p (and/or mutated TP53) [del(17p)] or 
deletion 11q [del(11q)] demonstrated by FISH as well as unmutated IGHV are associated 
with inferior clinical outcomes in patients with CLL and considered high-risk disease 
features.2-4 Patients with relapsed/refractory CLL constitute another group of patients with 
poor prognosis.1,5
2.2 Immunotherapy in CLL: Immunotherapy has been an important part of CLL therapeutic 
armamentarium. Several strategies have been employed: a) use of monoclonal antibodies 
(mAb) such as anti-CD20 mAb (rituximab, ofatumumab, obinutuzumab) and anti-CD52 mAb 
(alemtuzumab)6,7; b) use of lenalidomide8-10; c) adoptive immunotherapy with an allogeneic 
stem cell transplant11; d) use of chimeric antigen receptor (CAR).12 These studies highlight 
the fact CLL cells are amenable to immune-based therapies.
2.3 T cell dysfunction in CLL: Several studies have shown that CLL development and 
progression is associated with functional immune-defects in the T cell compartment.7,9,10,13-17
Ramsay et al. showed that T cells isolated from patients with CLL have functional defects in 
F-actin polymerization leading to impaired formation of immunological synapses with antigen 
presenting cells (APCs).9 Riches et al. reported that T cells from patients with CLL exhibit 
features of T cell exhaustion, which results in progressive loss of T cell proliferative and 
cytotoxicity capacity.10 Motta et al. reported increased expression of both surface and 
cytoplasmic cytotoxic T lymphocyte-associated antigen (CTLA-4, also known as CD152) in 
both CD4+ and CD8+ T cells from treatment naïve patients with CLL compared to normal 
donors.14 Riches et al. recently reported increased expression of programmed death-1 (PD-
1, also known as CD279) receptor in T cells of patients with CLL.10 They also reported that 
PD-1 is preferentially expressed on CD3+CD8+CCR7- effector T cells. Unlike CTLA-4 whose 
predominant role is at the time of T cell activation, PD-1 predominantly regulates effector T 
cell function in the peripheral tissues.18-20 PD-L1 (ligand for PD-1) is also over expressed in 
the CLL B cells.13 The increased expression of CTLA-4 and PD-1 on T cells of patients with 
CLL and PD-L1 on the CLL cells contributes to impaired T cell function.
2.4 Natural killer (NK)-cell function in CLL: NK cells constitute 15% of peripheral blood 
lymphocytes and play an important role in the ability of the innate immune system to fight off 
viral infections and also cancer.21 NK cells bind to target cells through multiple receptors and 
binding of ligand to receptor results in activation of the NK cell, release of preformed 
granules containing perforin and granzymes into the target cell, and apoptosis. The 
activation of NK cells is regulated by a variety of activating and inhibitory receptors that are 
expressed by the transformed target cells. Activating receptors include NKp30, NKp44, 
NKp46, NKG2D, and DNAM-1. For effective activation of NK-cells tumor cells must express 
stress or activation ligands for activating receptors. Negative regulators of NK activating 
receptors include killer Ig-like receptor (KIR), CD94/NKG2A, and leukocyte Ig-like receptor-
1, which recognize MHC-class 1 molecules. NK cells have the capability of binding every 
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cell in the body. Binding of normal cells does not result in cytotoxic activity because of the 
ability of NK cells to simultaneously utilize a different set of receptors to bind major 
histocompatibility complex (MHC) class I molecules. Binding to HLA is used as a 
mechanism to distinguish self from non-self, and this recognition controls the activation state 
of NK cells. Thus, KIR/HLA interaction directly impacts NK cell responsiveness. There are
both inhibitory and activating KIR, which is one factor that results in diversity of KIR 
inheritance and expression. KIR is also expressed on NK cells and a small subset of T cells.
Thus, mechanistically, blockade of inhibitory KIR could induce anti-tumor effects by allowing 
for NK cell (and possibly some T cell) activation.
Lack of KIR-HLA class I interactions have been associated with potent NK-mediated 
antitumor efficacy and increased survival in AML patients undergoing haploidentical stem 
cell transplantation from KIR-mismatched donors.22 Romagne et al. developed a monoclonal 
antibody that cross-reacts with KIRDL1, -2 and -3 receptors thereby blocking inhibitory 
signaling via these receptors. This resulted in augmented NK cell mediated lysis of tumor 
cells but did not induce killing of normal peripheral blood mononuclear cells, suggesting a 
preferential NK cell activity against AML cells.23 Intriguingly inoculation of NK cells alone did 
not protect against autologous implanted AML in immunodeficient mice, however 
preadministration with KIR monoclonal antibody induced anti-AML activity with long-term 
survival.
Several studies have reported that the cytotoxic function of NK cells in patients with CLL is 
defective.24-27 Palmer et al. evaluated peripheral blood T cell and NK cell at diagnosis in 166 
consecutive patients with newly diagnosed CLL treated at Mayo clinic.27 They reported at 
45% of the patients with CLL had an increase in the absolute NK cell number (upper limit of 
normal 0.6 x 109/l) at diagnosis. Similarly, 54% of the patients with CLL had an increase in 
the absolute T cell number (upper limit of normal 2.0 x 109/l) at diagnosis. This observational 
cohort study found wide inter-patient variation in size of the normal T cell and NK cell 
compartment at the time of diagnosis. It was found that smaller size of the blood T/NK cell 
compartments relative to the size of the circulating leukemic B-cell clone was associated 
with more advanced stage at diagnosis as well as unmutated IGHV status, raising the 
possibility that CLL patients with greater host immunity may experience a more indolent 
disease course. Both the ratio of NK:MBC (monoclonal B cell) and T:MBC correlated with 
time to first treatment.27 Huergo-Zapico et al. evaluated NK cells in the peripheral blood at 
diagnosis in a group of 99 patients with CLL and 50 healthy matched controls.24  Patients 
with CLL had significantly higher NK cell number than controls. They also reported that 
compared to controls, NK2GD receptor expression on NK cells was markedly decreased in 
patients with CLL.  CD107a degranulation assay showed that NK cells of patients with CLL 
had diminished cytotoxic activity compared with healthy controls.24
2.5 Lirilumab: Lirilumab (BMS-986015, IPH2102) is a fully human IgG4 monoclonal antibody 
(mAb) that is specific for a subset of human KIRs. Lirilumab is a mAb that blocks the 
KIR/HLA interaction, and lowers the threshold for activation of NK cells without directly 
activating NK cells. Lirilumab binds specifically and with high affinity to a subset of KIR, 
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namely KIR2DL-1, 2, and 3 and KIR2DS-1 and 2, thus preventing interaction between KIR 
and HLA-C. Lirilumab also is being developed in combination with the T-cell checkpoint 
inhibitors, ipilimumab and nivolumab. Nonclinical studies combining anti-Ly49 (5E6 F(ab’)2), 
the murine functional homolog of lirilumab, with the mAbs specific for the murine versions of 
either cytotoxic T-lymphocyte antigen 4 (CTLA-4) or programmed cell death 1 (PD-1) 
demonstrated enhanced anti-tumor efficacy. Lirilumab does not bind to NK cells from non-
human primate or other species traditionally used for safety testing. Safety testing was 
performed in mice because Ly49C/I, the murine inhibitory receptors, are functionally 
homologous to human KIR. Mice treated with lirilumab at 10 mg/kg once weekly for 4 weeks, 
or the surrogate anti-Ly49 (5E6 F(ab’)2) at up to 10 mg/kg twice weekly for 13 weeks, 
showed no signs of toxicity.
Lirilumab is being developed for immunotherapy in patients with various hematologic
malignancies and solid tumors. As of the data cut-off for this IB (29-Jul-2014), 293 subjects 
have been treated in 1 concluded and 3 ongoing trials: 1 monotherapy Phase 1 trial, 1 
monotherapy placebo-controlled Phase 2 trial, and 2 combination therapy Phase 1 trials. 
Thirty-seven subjects received lirilumab monotherapy in a Phase 1 trial for patients with 
advanced solid tumors and hematological malignancies (IPH2102-101). One hundred fifty 
subjects received either lirilumab or placebo in a 2:1 ratio in a Phase 2 trial for patients with 
AML (IPH2102-201). IPH2102-201 is a double blind trial; thus, approximately 100 subjects 
received lirilumab. Eighty-eight subjects with advanced solid tumors received lirilumab in 
combination with nivolumab in a Phase 1 trial (CA223001). Eighteen subjects with advanced 
solid tumors received lirilumab in combination with ipilimumab in a Phase 1 trial 
(CA223002). As of 29-Jul-2014, the majority of adverse events (AEs) in these 4 ongoing 
trials were mild or moderate (Grade 1 or 2), self-limiting, and manageable. The most 
common related AEs were asthenia, fatigue, pruritus, infusion-related reaction, chills, and 
headache. 
The first (IPH2102-101) is a monotherapy, dose escalation, Phase 1 trial to determine the 
maximum tolerated dose (MTD). As of the data cut-off date (July 29, 2014) a total of 37 
patients have receive lirilumab on this trial. Of the 20 subjects treated with lirilumab 
monotherapy during the dose escalation period of IPH2102-101, 3 subjects were treated 
with lirilumab 0.015 mg/kg, 3 subjects with 0.3 mg/kg, 4 subjects with 1 mg/kg, 4 subjects 
with 3 mg/kg, 3 subjects with 6 mg/kg, and 3 subjects with 10 mg/kg every 4 weeks. There 
were no DLTs, and the MTD was not reached. Of the 17 subjects treated with lirilumab 
monotherapy during the cohort expansion period of the study, 9 subjects were treated with 
lirilumab at 0.015 mg/kg and 8 subjects at 3 mg/kg every 4 weeks. A total of 245 AEs were 
reported by 36 of 37 (97%) exposed subjects. Overall, most of these AEs were mild (CTCAE 
Grade 1) or moderate (CTCAE Grade 2). For the 18 (48.6%) subjects who discontinued 
prematurely, reasons for discontinuation were disease progression (13 subjects, related AEs 
(3 subjects), subject’s decision (1 subject), and Sponsor’s decision (1 subject). AEs leading 
to discontinuation included urticaria, hypersensitivity, abnormal liver function test (LFT), 
increased gamma-glutamyl transferase (GGT), increased blood bilirubin, and papular rash, 
all considered to be related to study drug by the investigator. 
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The second (IPH2102-201) is a double-blind, placebo-controlled, Phase 2 trial of lirilumab in 
patients with AML who are in complete remission but ineligible for allogeneic transplant. 
One-third of subjects in this study will be receiving placebo. The doses of lirilumab evaluated 
in this maintenance AML trial were 0.1 mg/kg every 12 weeks and 1.0 mg/kg every 4 weeks. 
A total of 100 patients have been treated with lirilumab on this trial as of the data cut-off date 
(July 29, 2014). One hundred one (67%) subjects have treatment ongoing and 50 (33%) 
subjects discontinued prematurely. In these 50 subjects, the main (or only) reason for study 
discontinuation was relapse of disease (43 subjects), AEs of pancytopenia (1 subject) and 
acute febrile neutrophilic dermatosis (1 subject), withdrawal of consent (2 subjects), 
investigator decision (2 subjects), and suspicion of disease progression (2 subjects). An 
independent Data and Safety Monitoring Board completed safety analysis of 86 randomized
subjects enrolled in this trial. On 11-Mar-2014, the members of this committee 
recommended continuation of the study without any modification. Adverse events were 
reported by 121 of 150 (81%) subjects exposed to either lirilumab or placebo. Most of these 
AEs were mild (Grade 1) or moderate (Grade 2). Thirty-three (22%) subjects reported Grade 
3 or Grade 4 AEs (irrespective of causality) including thrombocytopenia in 5 (3%), arthralgia 
in 1 (<1%), neutropenia in 7 (5%), fatigue in 1 (<1%), weight increase in 2 (1%), and urinary 
tract infection in 1 (1%) patients. One subject reported Grade 5 pulmonary embolism, and 1 
subject reported Grade 5 general physical health deterioration (corresponding to disease 
progression). Both of the Grade 5 events were considered by the investigator to be 
unrelated to study drug. Sixty-six of 150 (44%) subjects had AEs considered to be related to 
the study drug (either lirilumab or placebo). Most related AEs were mild or moderate in 
severity. Nine (6%) subjects had related Grade 3 AEs (neutropenia in 3 subjects and acute 
febrile neutrophilic dermatosis, sciatica, myalgia, thrombocytopenia, increased amylase, and 
bronchospasm in 1 subject each). One subject (0.7%) had a related Grade 4 AE of 
neutropenia that occurred on Cycle 1/Day 8. Adverse events evaluated as related to study 
drug and reported in >/= 3% of subjects were asthenia in 15 (10%) subjects, pruritus in 13 
(9%) subjects, chills in 7 (5%) subjects, pyrexia in 6 (4%) subjects, and neutropenia in 5 
(3%) of subjects. Five (3%) subjects reported AEs that led to study discontinuation: 4 
subjects reported single events that were unrelated to study drug (lirilumab or placebo), and 
1 subject reported Grade 3 acute febrile neutrophilic dermatosis that was considered related 
to study drug. Seventeen (11%) subjects reported SAEs during the study. The only Grade 3 
or Grade 4 SAE’a (irrespective of causality) seen in more than 1 subject was urinary tract 
infection in 2 (1%). Only 4 of 20 SAEs were considered to be related to study drug by the 
investigator, including one case each of Grade 4 neutropenia, Grade 3 myalgia, Grade 3 
sciatica, and Grade 3 acute febrile neutrophilic dermatosis. 
The third (CA223001) and fourth (CA223002) are Phase 1 trials of lirilumab in combination 
with either the anti-PD1 antibody nivolumab or the anti-CTLA-4 antibody ipilimumab, 
respectively, to determine if coordinate modulation of the innate and adaptive immune 
systems results in greater clinical benefit. A total of 88 subjects have received combination 
therapy of nivolumab and lirilumab in clinical trial CA223001 as of the data cut-off date (July 
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29, 2014) including 4 with lirilumab 0.1 mg/kg + nivolumab 3 mg/kg (completed), 13 with 
lirilumab 0.3 mg/kg + nivolumab 3 mg/kg (ongoing), 9 with lirilumab 1 mg/kg + nivolumab 3 
mg/kg, and 62 with lirilumab 3 mg/kg + nivolumab 3 mg/kg. The objective of the study is to 
evaluate the safety of lirilumab in combination with nivolumab in subjects with advanced 
refractory solid tumors. Lirilumab 3mg/kg every 4 weeks in combination with nivolumab was 
well tolerated and was the dose administered to the majority of patients (62 of the 88 
patients) on this trial (see lirilumab investigator brochure). As of the data cut-off date (29-Jul-
2014), preliminary data include 18 subjects who have been treated with the combination of 
lirilumab and ipilimumab in clinical trial CA223002. 3 with lirilumab 0.1 mg/kg + ipilimumab 3 
mg/kg (completed), 8 with lirilumab 0.3 mg/kg + ipilimumab 3 mg/kg, 6 with lirilumab 1 mg/kg 
+ ipilimumab 3 mg/kg, and 1 with lirilumab 3 mg/kg + ipilimumab 3 mg/kg (ongoing). Two 
dose levels of ipilimumab (3 mg/kg and 10 mg/kg) and 4 dose levels of lirilumab (0.1, 0.3, 1, 
and 3 mg/kg) are being evaluated in CA223002, with 3 subjects per dose level if there is no
DLT. The 5 dose cohorts are as follows (lirilumab dose + ipilimumab dose): Cohort 1: 0.1 
mg/kg + 3 mg/kg; Cohort 2: 0.3 mg/kg + 3 mg/kg; Cohort 3: 1 mg/kg + 3 mg/kg; Cohort 4: 3 
mg/kg + 3 mg/kg; Cohort 5: 3 mg/kg + 10 mg/kg. Subjects receive lirilumab in combination 
with ipilimumab every 3 weeks for a total of 4 doses (induction) and then every 12 weeks for 
an additional 4 doses starting at Week 24 (maintenance).
Summary of Safety: Mainly safety data are available, efficacy data available only for the 
IPH2102-101 and no responses observed as of the data cutoff date. As the first clinical trials 
with lirilumab are ongoing or recently concluded, data on safety presented herein are 
preliminary and subject to change. Up until 29-Jul-2014, AEs were reported by 36 of 37 
(97%) subjects treated with lirilumab monotherapy (doses ranging from 0.015 mg/kg to 10 
mg/kg); 121 of 150 (81%) subjects treated with blinded therapy (lirilumab or placebo [2:1]); 
63 of 88 (72%) subjects treated with lirilumab 0.1, 0.3, 1, or 3 mg/kg in combination with 
nivolumab 3 mg/kg; and 17 of 18 (94%) subjects treated with lirilumab 0.1 mg/kg or 0.3 
mg/kg in combination with ipilimumab 3 mg/kg. The majority of AEs were mild or moderate 
(Grades 1 or 2). To date, 12 SAEs were considered to be related to study treatment. 
Additional detailed safety data is available in the Lirilumab investigator brochure.
Blockade of inhibitory KIR by lirilumab is thus a promising mechanism to promote killing of
tumor cells by the innate immune system. IPH2101 is the first fully-human anti-KIR 
monoclonal antibody, and lirilumab is the second generation. Both products bind to the 
same KIR subtypes with similar affinities. Functionally and biologically, the 2 antibodies are 
similar with the following exceptions: 1) IPH2101 is a non-recombinant protein that is 
produced by a murine hybridoma cell line; whereas, lirilumab is a recombinant product 
produced in CHO cells. 2) Lirilumab has a single amino acid substitution of a serine to a 
proline in the IgG4 heavy chain, resulting in greater stability of the compound by reducing 
the formation of half antibodies. IPH2101 studies were done prior to lirilumab studies and 
safety, efficacy, PKs, and immunologic correlates of IPH2101 in a phase 1 trial in elderly 
AML in first remission have been published (Vey N, et al., Blood, 2012 Nov 
22;120(22):4317-23).28 Patients received escalating doses (0.0003-3 mg/kg) of IPH2101 
following a 3 + 3 design. The doses that elicited full occupancy were: 1 week = 0.075 mg/kg, 
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2 weeks = 1 mg/kg, and for at least 4 weeks = 3 mg/kg. There was a clear correlation 
between mAb exposure and KIR occupancy. The maximum tolerated dose was not reached, 
although full KIR saturation (> 90%) was sustained for 4 weeks only at the 3 mg/kg. 
Lirilumab dose of 3 mg/kg every 4 weeks is also the highest dose to be tested in BMS study 
of lirilumab in combination with elotuzumab for multiple myeloma: A Phase I Open Label 
Dose Escalation and Randomized Cohort Expansion Study of the Safety and Tolerability of 
Elotuzumab (BMS-901608) Administered in Combination With Either Lirilumab (BMS-
986015) or Urelumab (BMS-663513) in Subjects With Multiple Myeloma” (study identifier: 
NCT02252263). Based on this data and the tolerability of lirilumab in combination with other 
agent (namely nivolumab) in the CA223001 trial we would like to evaluate lirilumab at the 
dose of 3.0 mg/kg every 4 weeks in this study.
For details of lirilumab preclinical studies, clinical studies, toxicities, pharmacokinetics, and 
adverse events please see the Lirilumab Investigator Brochure.
2.6 Rituximab: Rituxan (rituximab) is a genetically engineered chimeric murine/human 
monoclonal IgG1 kappa antibody directed against the CD20 antigen and is used in the 
treatment of B-NHL and CLL.1
2.7 Rationale for Combined Lirilumab and Rituximab
Kohrt et al recently reported the activity of lirilumab in a KIR2DL3 transgenic lymphoma 
model and of anti-Ly49C/I F(ab’)2 in a C57BL/6 syngeneic lymphoma model.29 In both the 
models tested, combination of lirilumab with an anti-CD20 monoclonal antibody significantly 
improved the antitumor efficacy than anti-CD20 monoclonal antibody alone. They reported 
that anti-Ly49C/I F(ab’)2 increased anti-CD20 mAb-mediated NK-cell degranulation and 
cytotoxicity and potentiated the antilymphoma activity of anti-CD20 mAb in vivo. They also 
reported that NK cells are required for the antilymphoma activity of the combination 
treatment. NK-cell depletion, and not macrophage, CD4, or CD8 T-cell depletion, abrogated 
the therapeutic efficacy of anti-CD20 mAb and anti-Ly49C/I F(ab’)2 combination therapy.   
These findings provide rationale for a clinical trial in B cell malignancies investigating this 
novel combination of an anti-KIR mAb to tilt the balance of inhibitory and stimulatory NK 
signals favoring spontaneous cytotoxicity and to further enhance the efficacy of rituximab by
the augmentation of ADCC.
We hypothesize that enhanced CLL cell killing and improved clinical responses will be 
mediated by rituximab by the addition of the anti-KIR monoclonal antibody (lirilumab). The 
rationale for combining anti-KIR antibody and rituximab include 1) Rituximab induces both
NK cell activation (via Fc-FcR engagement). Addition of anti-KIR antibody further enhances 
NK-cell mediated ADCC. The use of rituximab and anti-KIR antibody has been shown to be 
synergistic in vitro and in vivo. 2) Tumor debulking with CD20 monoclonal antibody may 
synergize or augment the activity of anti-KIR monoclonal antibody 3) Lirilumab and rituximab 
have non-overlapping and complimentary mechanisms of action and thus may synergize, 
with no notable increased risk for toxicity. We plan to include patients with relapsed or 
refractory CLL. In addition, untreated patients with high-risk cytogenetic features such as 
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del(17p), mutated TP53, del(11q), unmutated IGHV, or are >65  years will be eligible as they 
have poor outcomes and short progression-free survival with chemoimmunotherapy. 
3.0 STUDY POPULATION
3.1 Inclusion Criteria
1. Patients will have a diagnosis of CLL or SLL who meet one or more criteria for active 
disease as defined by the International Working Group for CLL (IWCLL) and are:
a. Cohort 1: refractory to and/or relapsed after at least one prior therapy OR
b. Cohort 2: untreated patients with high-risk molecular features such as del(17p),
mutated TP53, del(11q), unmutated IGHV gene, or are >65 years of age
2. Age 18 years or older
3. (DVWHUQ&RRSHUDWLYH2QFRORJ\*URXS(&2*3HUIRUPDQFH6WDWXV
4. Patients must have adequate renal and hepatic function
-
6HUXP ELOLUXELQ .5 x upper limit of normal (ULN). For patients with Gilbert’s 
GLVHDVHVHUXPELOLUXELQXSWR[8/1LVDOORZHGSURYLGHGQRUPDOGLUHFWELOLUXELQ
-
6HUXPFUHDWLQLQH[8/1
-
$/7DQG$67[8/1
5. Females of childbearing potential must have a negative serum or urine beta human 
chorionic JRQDGRWURSKLQȕ-hCG) pregnancy test result within 24 hours prior to the first 
dose of treatment and must agree to use an effective contraception method during the 
study and for 12 months following the last dose of the study drugs. Females of non-
childbearing potential are those who are postmenopausal greater than 1 year or who 
have had a bilateral tubal ligation or hysterectomy. Males who have partners of 
childbearing potential must agree to use an effective contraceptive method during the 
study and for 31 weeks following the last dose of study drugs.
6. Patients or their legally authorized representative must provide written informed consent.
3.2 Exclusion Criteria
1. Prior malignancy active within the previous 2 years except for locally curable cancers 
that have been apparently cured, such as basal or squamous cell skin cancer, superficial 
bladder cancer, carcinoma in situ of the cervix or breast, or localized prostate cancer. If 
patients have another malignancy that was treated within the last 2 years, such patients 
may be enrolled if the likelihood of requiring systemic therapy for this other malignancy 
within 2 years is less than 10%, as determined by an expert in that particular malignancy 
at MD Anderson Cancer Center and after consultation with the Principal Investigator.
2. Any major surgery, radiotherapy, chemotherapy, biologic therapy, immunotherapy, 
experimental therapy within 4 weeks prior to the first dose of the study drugs. For oral 
targeted therapies (such as ibrutinib, idelalisib, venetoclax), a washout of 3 days is 
allowed. Note: Prior treatment with anti CD20 monoclonal antibody, anti CD52 
monoclonal antibody and lenalidomide are allowed. Prior treatment with anti-CTLA-4 and 
anti-PD1 therapies is allowed after a wash-out of 5 half-lives.
3. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, 
2014-0933 Lirilumab and Rituximab for Relapsed/Refractory CLL 
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congestive heart failure, or myocardial infarction within 2 months of screening, or any 
Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional 
Classification.
4. History of stroke or cerebral hemorrhage within 2 months.
5. Patients who have uncontrolled hypertension (defined as sustained systolic blood 
SUHVVXUHPP+JRUGLDVWROLFPP+J
6. Known evidence of active cerebral/meningeal CLL. Patients may have history of CNS 
leukemic involvement if definitively treated with prior therapy and no evidence of active 
disease at the time of registration. 
7. Active, uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia 
requiring steroid therapy.
8. Patients with autoimmune diseases are excluded: Patients with a history of Inflammatory 
Bowel Disease (including Crohn’s disease and ulcerative colitis) are excluded from this 
study as are patients with a history of autoimmune disease (e.g., rheumatoid arthritis, 
systemic 
progressive 
sclerosis, 
systemic 
lupus 
erythematosus, 
Wegener’s
granulomatosis).
9. Patients with previous allogeneic stem cell transplant (SCT) within 6 months or with 
active acute or chronic graft-versus host disease are excluded. Patients must be off 
immunosuppression for GVHD for at least 60 days before cycle 1 day 1.
10. Patients with organ allografts (such as renal transplant) are excluded.
11. History of any hepatitis (e.g., alcohol or non-alcohol steatohepatitis (NASH), auto 
immune, or grade 3-4 drug-related hepatitis).
12. Patients who are on high-dose steroids (doses >10mg/day of prednisone or equivalent)
or immune suppression medications. Note: Patients on high-dose steroids (doses 
>10mg/day of prednisone or equivalent) or immune suppression medications are eligible 
provided these drugs are discontinued at least 3 days prior to starting on the study 
drugs.
13. Patients with uncontrolled active infection (viral, bacterial, and fungal) are not eligible. 
14. Current or chronic hepatitis B or C infection, or known seropositivity for HIV. 
15. Patient is pregnant or breast-feeding.
16. Concurrent use of investigational therapeutic agent
17. Patients 
may 
not 
receive 
other 
concurrent 
chemotherapy, 
radiotherapy, 
or 
immunotherapy. Localized radiotherapy to an area not compromising bone marrow 
function does not apply.
18. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality 
that in the opinion of the investigator may increase the risk associated with study 
participation or investigational product administration or may interfere with the 
interpretation of study results and/or would make the patient inappropriate for enrollment 
into this study. 
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4.0 TREATMENT PLAN
4.1 Study Design
This is a phase II open label single-arm study to evaluate combined lirilumab and rituximab 
in patients with CLL. 
C1D1
C1D8
(±2 days)
C1D15
(±2 days)
C1D22
(±2 days)
C2-C12 D1 
(±7 days)
C13-C24 D1 
(±7 days)
Rituximab
375
mg/m2
375
mg/m2
375
mg/m2
375
mg/m2
375
mg/m2
_
Lirilumab
3 mg/kg
_
_
_
3 mg/kg
3 mg/kg
Each cycle is 4 weeks. Patients will receive rituximab (375 mg/m2 IV) weekly for the first 4 
weeks (Days 1, 8, 15, 22), and then with the start of each course. Lirilumab (3 mg/kg IV) will 
be given on day 1 of each cycle. Rituximab will be given for the first 12 cycles and lirilumab 
will continue for up to 24 cycles.  
5.0 STUDY MEDICATIONS
5.1 Lirilumab
5.1.1 Preparation and Dispensing of Lirilumab
The product storage manager should ensure that the study drug is stored in accordance 
with the environmental conditions (temperature, light, and humidity) as determined by the 
Investigator Brochure. If concerns regarding the quality or appearance of the study drug 
arise, do not dispense the study drug and contact the sponsor immediately.
Investigational product documentation must be maintained that includes all processes 
required to ensure drug is accurately administered. This includes documentation of drug 
storage, administration and, as applicable, storage temperatures, reconstitution, and use of 
required processes (e.g. required diluents, administration sets).
Care must be taken to assure sterility of the prepared solution as the product does not 
contain any anti-microbial preservative or bacteriostatic agent. The study drug should be 
administered shortly after preparation in order to avoid exposure of the prepared drug to 
room temperature conditions beyond a recommended 4 hour limit. This 4 hour time limit at 
room temperature includes the time allotted for IV dose administration, which is 60 min. In 
the event that a delay in use of prepared (diluted) study drug is anticipated, prepared bags 
may be refrigerated for a maximum of 20 hours. Study drug is to be administered as IV 
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infusion and not IV push or bolus injection.
Lirilumab must be stored at a temperature of 2°C to 8°C and should be protected from light
and from freezing. For details on prepared drug storage and use time of lirilumab under 
room temperature/ light and refrigeration, please refer to the Investigator Brochure.
Unused or expired lirilumab vials will be disposed per MDACC guidelines.
5.1.2 Administration of Lirilumab
Please refer to the Investigator Brochure
5.2 Rituximab
Rituximab is anti-CD20 monoclonal antibody. Commercial drug supply will be used for this 
study. Rituximab will be administered as per the institutional guidelines. 
6.0 DOSE DELAYS AND MODIFICATIONS
Patients who experience Grade 3 or 4 toxicity that can be clearly attributed to either lirilumab or 
to rituximab may continue treatment with the other agent while the causative agent is delayed
XQWLOUHVROXWLRQRIWR[LFLW\WRJUDGHRUEDVHOLQH,QFDVHVZKHUH*UDGHRUWR[LFLW\FDQQRW
be attributed to a specific study drug, both study drugs should be held regardless of attribution 
RIWR[LFLW\XQWLOWKHWR[LFLW\LVUHVROYHGWRJUDGHRUEaseline.
Rituximab and lirilumab administration should be delayed and increased monitoring of patients
should ensue if any of the following drug-related adverse event(s) occurs:

$Q\*UDGH$/7$67RUtotal bilirubin

$Q\*UDGHQRQODERUDWRU\QRQ-skin drug related adverse event except for fatigue

$Q\*UDGHHQGRFULQHGUXJ-related adverse event

$Q\*UDGHVNLQGUXJUHODWHGDGYHUVHHYHQW

$Q\ *UDGH   GUXJ-related laboratory abnormality (except lymphopenia or any 
electrolyte abnormality without any clinical sequelae that is either spontaneously 
reversible or resolves with clinical management to grade 2 or less within 72 hours)

Any AE, laboratory abnormality or inter-current illness, which in the judgment of the 
investigator, warrants delaying the dose of study medication
Discontinuation of lirilumab will occur in the following situations:

$67$/7RU7%LOL*UDGH

Grade 2 AST or ALT and symptomatic liver inflammation (e.g., right upper quadrant 
tenderness, jaundice) 

AST or ALT > 3 x ULN and concurrent total bilirubin > 2 x ULN in the absence of 
evidence of cholestasis (Hy’s law)
7.0 CONCOMITANT THERAPY
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7.1 Allowed concomitant therapy
All concomitant medications will be documented in the medical record. Patients should receive 
full supportive care during study participation, including hematopoietic growth factors, 
transfusion of blood products, fluid and electrolyte replacement, and antibiotics when 
appropriate. 
7.2 Excluded concomitant therapy
Use of the following therapies is prohibited during the study:

Cytotoxic chemotherapy

Immunotherapy (outside of this study)

Any therapies intended for the treatment of lymphoma/leukemia whether FDA-approved 
or experimental (outside of this study) 

Steroid therapy for anti-neoplastic intent. Inhaled steroids for asthma, topical steroids, 
steroids as part of premedication, or replacement/stress corticosteroids are permitted.
8.0 PRETREATMENT EVALUATIONS
1. Pretreatment evaluation will include a complete history and physical examination including 
vital signs ECOG performance status, height and weight and recording of concurrent 
medications (within 7 days of the first dose)
2. Complete blood count (hemoglobin, white blood cell count, platelet count, white blood count 
differential) (within 7 days of the first dose)
3. Clinical laboratory evaluation will include serum sodium, potassium, calcium, BUN, 
creatinine, glucose, phosphorous, magnesium, albumin, total protein, alkaline phosphatase, 
total bilirubin, ALT, AST, uric DFLG/'+ȕ-2 microglobulin, serum immunoglobulins, lipase, 
amylase (within 7 days of the first dose)
4. B, T, NK cell counts and subset analyses on the peripheral blood (within 7 days of the first 
dose)
5. PT, aPTT (within 7 days of the first dose)
6. Urinalysis (within 7 days of the first dose)
7. HIV Ab, Hepatitis C ab, HBsAg, anti-HBcAb (within 30 days of the first dose)
8. TSH, Free T4 (within 30 days of the first dose)  
9. Women of childbearing potential must have a negative serum or XULQHȕ-hCG pregnancy test 
result within 24 hours prior to the first dose of study drugs.
10. 12-lead EKG (within 30 days of the first dose)
11. Bone marrow aspiration and biopsy (within 60 days of the first dose if no intervening 
treatment for CLL given)
12. CT scan of the neck (if indicated), chest, abdomen, and pelvis with IV and oral contrast, 
within 30 days of the first dose. Patients with palpable cervical lymphadenopathy noted at 
screening physical examinations should have imaging of the neck included in their 
screening imaging studies and at subsequent time points for response assessment. Note: 
PET scan may be used instead of the CT scan imaging. 
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9.0 EVALUATIONS DURING THE STUDY
Cycle 1 Day 1 (Rituximab and Lirilumab)
1. CBC, platelet count and differential, sodium, potassium, calcium, BUN, creatinine, glucose, 
phosphorous, magnesium, albumin, total protein, alkaline phosphatase, total bilirubin, ALT,
AST, uric acid, LDH
2. Vital signs, history and physical examination (Note: history and physical examination within 
3 days prior to the Day 1 is acceptable)
Cycle 1 Day 8 (Rituximab) (+/- 2 day)
1. CBC, platelet count and differential, sodium, potassium, calcium, BUN, creatinine, glucose, 
phosphorous, magnesium, albumin, total protein, alkaline phosphatase, total bilirubin, ALT,
AST, uric acid, LDH
2.   Vital signs, history and physical examination
Cycle 1 Day 15 (Rituximab) (+/- 2 day)
1. CBC, platelet count and differential, sodium, potassium, calcium, BUN, creatinine, glucose, 
phosphorous, magnesium, albumin, total protein, alkaline phosphatase, total bilirubin, ALT,
AST, uric acid, LDH
2.   Vital signs, history and physical examination
Cycle 1 Day 22 (Rituximab) (+/- 2 day)
1. CBC, platelet count and differential, sodium, potassium, calcium, BUN, creatinine, glucose, 
phosphorous, magnesium, albumin, total protein, alkaline phosphatase, total bilirubin, ALT,
AST, uric acid, LDH
2. Vital signs, history and physical examination
Cycle 2 Day 1 (Rituximab and Lirilumab) (+/- 1 week)
1. CBC, platelet count and differential, sodium, potassium, calcium, BUN, creatinine, glucose, 
phosphorous, magnesium, albumin, total protein, alkaline phosphatase, total bilirubin, ALT, 
AST, uric acid, LDH, serum immunoglobulins, TSH, Free T4
2. B, T, NK cell counts and subset analyses on the peripheral blood
3. 6HUXPRUXULQHȕ-hCG pregnancy test (for women of childbearing potential)
4. Vital signs, history and physical examination
Cycle 2 Day 8 (no mAb) (+/- 2 day)
1. CBC, platelet count and differential, sodium, potassium, calcium, BUN, creatinine, glucose, 
phosphorous, magnesium, albumin, total protein, alkaline phosphatase, total bilirubin, ALT, 
AST, uric acid, LDH
Cycle 2 Day 15 (no mAb) (+/- 2 day)
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1. CBC, platelet count and differential, sodium, potassium, calcium, BUN, creatinine, glucose, 
phosphorous, magnesium, albumin, total protein, alkaline phosphatase, total bilirubin, ALT, 
AST, uric acid, LDH
2.   Vital signs, history and physical examination
Cycle 2 Day 22 (no mAb) (+/- 2 day)
1. CBC, platelet count and differential, sodium, potassium, calcium, BUN, creatinine, glucose, 
phosphorous, magnesium, albumin, total protein, alkaline phosphatase, total bilirubin, ALT, 
AST, uric acid, LDH
Cycle 3 Day 1 (Rituximab and Lirilumab) (+/- 1 week)
1. CBC, platelet count and differential, sodium, potassium, calcium, BUN, creatinine, glucose, 
phosphorous, magnesium, albumin, total protein, alkaline phosphatase, total bilirubin, ALT, 
AST, uric acid, LDH, serum immunoglobulins, TSH, Free T4
2. B, T, NK cell counts and subset analyses on the peripheral blood
3. 6HUXPRUXULQHȕ-hCG pregnancy test (for women of childbearing potential)
4. Vital signs, history and physical examination
Cycle 3 Day 15 (no mAb) (+/- 3 day)
1. CBC, platelet count and differential, sodium, potassium, calcium, BUN, creatinine, glucose, 
phosphorous, magnesium, albumin, total protein, alkaline phosphatase, total bilirubin, ALT,
AST, uric acid, LDH
2.   Vital signs, history and physical examination
End of Cycle 3 (response assessment) (+/- 1 week)
1. CBC, platelet count and differential, sodium, potassium, calcium, BUN, creatinine, glucose, 
phosphorous, magnesium, albumin, total protein, alkaline phosphatase, total bilirubin, ALT, 
AST, uric acid, LDHȕ-2 microglobulin, serum immunoglobulins
2. Vital signs, History and Physical Examination
3. B, T, NK cell counts and subset analyses on the peripheral blood
4. TSH, Free T4
5. 6HUXPRUXULQHȕ-hCG pregnancy test (for women of childbearing potential)
6. Bone marrow aspiration and biopsy with multi-color flow cytometry for MRD evaluation
7. CT scan of the neck (if indicated), chest, abdomen, and pelvis with IV and oral contrast. PET 
scan may be used instead of the CT scan imaging. 
Cycle 4 Day 1 (Rituximab and Lirilumab) (+/- 1 week)
1. CBC, platelet count and differential, sodium, potassium, calcium, BUN, creatinine, glucose, 
phosphorous, magnesium, albumin, total protein, alkaline phosphatase, total bilirubin, ALT, 
AST, uric acid, LDH 
2. 6HUXPRUXULQHȕ-hCG pregnancy test (for women of childbearing potential)
3. Vital signs, history and physical examination
Cycle 4 Day 15 (no mAb) (+/- 3 day)
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1. CBC, platelet count and differential, sodium, potassium, calcium, BUN, creatinine, glucose, 
phosphorous, magnesium, albumin, total protein, alkaline phosphatase, total bilirubin, ALT, 
AST, uric acid, LDH
2.   Vital signs, history and physical examination
Cycle 5 Day 1 (Rituximab and Lirilumab) (+/- 1 week)
1. CBC, platelet count and differential, sodium, potassium, calcium, BUN, creatinine, glucose, 
phosphorous, magnesium, albumin, total protein, alkaline phosphatase, total bilirubin, ALT, 
AST, uric acid, LDH, serum immunoglobulins, TSH, Free T4
2. B, T, NK cell counts and subset analyses on the peripheral blood
3. 6HUXPRUXULQHȕ-hCG pregnancy test (for women of childbearing potential)
4. Vital signs, history and physical examination
Cycle 5 Day 15 (no mAb) (+/- 3 day)
1. CBC, platelet count and differential, sodium, potassium, calcium, BUN, creatinine, glucose, 
phosphorous, magnesium, albumin, total protein, alkaline phosphatase, total bilirubin, ALT, 
AST, uric acid, LDH
2.   Vital signs, history and physical examination
Cycle 6 Day 1 (Rituximab and Lirilumab) (+/- 1 week)
1. CBC, platelet count and differential, sodium, potassium, calcium, BUN, creatinine, glucose, 
phosphorous, magnesium, albumin, total protein, alkaline phosphatase, total bilirubin, ALT, 
AST, uric acid, LDH, serum immunoglobulins, TSH, Free T4
2. B, T, NK cell counts and subset analyses on the peripheral blood
3. 6HUXPRUXULQHȕ-hCG pregnancy test (for women of childbearing potential)
4. Vital signs, history and physical examination
Cycle 6 Day 15 (no mAb) (+/- 3 day)
1. CBC, platelet count and differential, sodium, potassium, calcium, BUN, creatinine, glucose, 
phosphorous, magnesium, albumin, total protein, alkaline phosphatase, total bilirubin, ALT, 
AST, uric acid, LDH
2.   Vital signs, history and physical examination
End of Cycle 6 (response assessment) (+/- 1 week)
1. CBC, platelet count and differential, sodium, potassium, calcium, BUN, creatinine, glucose,
phosphorous, magnesium, albumin, total protein, alkaline phosphatase, total bilirubin, ALT, 
$67XULFDFLG/'+ȕ-2 microglobulin, serum immunoglobulins
2. Vital signs, History and Physical Examination
3. B, T, NK cell counts and subset analyses on the peripheral blood
4. TSH, Free T4
5. 6HUXPRUXULQHȕ-hCG pregnancy test (for women of childbearing potential)
6. Bone marrow aspiration and biopsy with multi-color flow cytometry for MRD evaluation
7. CT scan of the neck (if indicated), chest, abdomen, and pelvis with IV and oral contrast. PET 
scan may be used instead of the CT scan imaging. 
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Cycle 7 onwards (All evaluations can be +/- 1 week) (Rituximab on day 1 of cycles 7-12; 
Lirilumab on day 1 of cycles 7-24)
1.  CBC, platelet count and differential; serum sodium, potassium, calcium, BUN, creatinine, 
glucose, phosphorous, magnesium, albumin, total protein, alkaline phosphatase, total 
bilirubin, ALT, AST, uric acid, LDH at least monthly.
2. Complete history and physical examination including vital signs at least monthly.
3. Quantitative immunoglobulin levels every month
4. B, T, NK cell counts and subset analyses on the peripheral blood every 3 months
5. TSH, Free T4 every 3 months
6. 6HUXPRUXULQHȕ-hCG pregnancy test (for women of childbearing potential) before dose of 
lirilumab
7.  Urinalysis every 3 months
8. Bone marrow aspiration and biopsy with multi-color flow cytometry for MRD evaluation every 
3 months
9. CT scan of the neck (if indicated), chest, abdomen, and pelvis with IV and oral contrast
every 3 months. PET scan may be used instead of the CT scan imaging.
End of Study Visit – Patients, who are taken off study for any reason, will have an end of study 
visit. The end of study visit will occur 30 days (+/- 1 week) after the last dose of the study drugs. 
At this visit, the patient will have labs (CBC, platelet count and differential, sodium, potassium, 
calcium, BUN, creatinine, glucose, phosphorous, magnesium, albumin, total protein, alkaline 
phosphatase, total bilirubin, ALT, AST, uric acid, LDH), history and physical examination, serum 
immunoglobulins, B, T, NK cell counts and subset analyses on the peripheral blood, bone 
marrow aspiration and biopsy with multi-color flow cytometry for MRD evaluation (if the previous 
bone marrow evaluation was >3 months ago), and CT or PET imaging (if the previous CT or 
PET imaging was >3 months ago). 
After completion of all protocol related treatments, patients will be followed for at least one year 
with at least monthly labs (CBC, platelet count and differential, sodium, potassium, calcium, 
BUN, creatinine, glucose, phosphorous, magnesium, albumin, total protein, alkaline 
phosphatase, total bilirubin, ALT, AST, uric acid, LDH), at least monthly history and physical 
examination, serum immunoglobulins every 3 months, B, T, NK cell counts and subset analyses 
on the peripheral blood every 3 months, bone marrow aspiration and biopsy with multi-color flow 
cytometry for MRD evaluation every 3-6 months, and CT or PET imaging every 3-6 months. All 
evaluations can be +/- 1 week. Note: This post-protocol follow-up period of one year will end 
early if the patient starts another treatment for their CLL/SLL. Inability to comply with these post-
protocol follow-up evaluations will not be considered a protocol-deviation.
NOTE: All treatments with lirilumab and rituximab must be administered at the MDACC. 
During the first cycle all laboratory evaluations will be done at MDACC. Subsequently, the 
patient may have laboratory work and physical examination done at a local clinic and the results 
reported to the research nurse for the study. The laboratory work done at a local clinic will be 
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forwarded to the patient’s attending physician at MDACC, or PI of the study, who will sign off on 
the labs to verify that the results have been reviewed.
Outside Physician Participation During Treatment
1. MDACC Physician communication with the outside physician is required prior to the patient 
returning to the local physician. This will be documented in the patient record
2. A letter to the local physician outlining the patient's participation in a clinical trial will request 
local physician agreement to supervise the patient's care (Appendix D)
3. Protocol required evaluations outside MDACC will be documented by fax. Faxed evaluations
will be dated and signed by the MDACC physician/investigator indicating that they have 
reviewed it. 
4. A copy of the informed consent, protocol abstract, treatment schema and evaluation during 
treatment will be provided to the local physician.
5. Documentation to be provided by the local physician will include progress notes, reports of 
protocol required laboratory and diagnostic studies and documentation of any hospitalizations.
6. The home physician will be requested to report to the MDACC physician/investigator all life 
threatening events within 24 hours of documented occurrence.
10.0 CRITERIA FOR RESPONSE
Response will be assessed by the investigator, based on physical examinations, CT scans, 
laboratory results, and bone marrow examinations, based on the 2008 IWCLL criteria for 
response for CLL. Overall response (OR) includes complete remission (CR), CR with 
incomplete marrow recovery (CRi) or partial remission (PR) as determined by investigator 
assessment using CLL response criteria.30 Minimal residual disease (MRD) will be assessed in 
bone marrow by multi-color flow cytometry. Patients with missing or no response assessments 
will be classified as non-responders by intent to treat analysis.
11.0 ADVERSE EVENT REPORTING
11.1 Leukemia-specific Adverse Event Recording and Reporting Guidelines
These guidelines serve to bring the Department of Leukemia in compliance with the institutional 
policy on Reporting of Serious Adverse Events.
Adverse event is any untoward medical occurrence that may present during treatment with a 
pharmaceutical product but which does not necessarily have a causal relationship with this 
treatment. Adverse drug reaction is a response to a drug which is noxious and unintended and 
which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or 
for the modification of physiologic function. 
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Assessing causal connections between agents and disease is fundamental to the understanding 
of adverse drug reactions. In general, a drug may be considered a contributory cause of an 
adverse event if, had the drug not been administered, 1) the event would not have happened at 
all, 2) the event would have occurred later than it actually did, or 3) the event would have been 
less severe.
The Investigator or physician designee is responsible for verifying and providing source 
documentation for all adverse events and assigning the attribution for each event for all patients
enrolled on the trial.
11.1.1 PDMS/CORe will be used as the electronic case report form for this protocol.  Adverse 
events will be documented in the medical record and entered into PDMS/CORe.
11.1.2 These guidelines will be followed for the recording and reporting of adverse and serious 
adverse events.
a. Baseline events will be recorded in the medical history section of the case report 
form and will include the terminology event name, grade, and start date of the 
event.
i.
Baseline events are any medical condition, symptom, or clinically 
significant lab abnormality present before the informed consent is signed
a. Hematologic laboratory abnormalities will not be recorded 
as baseline events for patients with acute leukemia,  
myelodysplastic syndrome, chronic lymphocytic leukemia, 
or chronic myeloid leukemia in blast phase.
b. If exact start date is unknown, month and year or year may 
be used as the start date of the baseline event.
b. The maximum grade of the adverse event will be captured per course or protocol
defined visit date.
c.
These adverse events will be recorded in the case report form:
i.
Any grade adverse event that is possibly, probably, or definitely related to 
the study drug(s).
ii.
All serious adverse events regardless of attribution to the study drug(s).
iii.
Any grade adverse event regardless of attribution to the study drug(s) that 
results in any dose modification.
d. Hematologic adverse events will not be recorded or reported for studies in 
patients with acute leukemia,  myelodysplastic syndrome, chronic lymphocytic 
leukemia, or chronic myeloid leukemia in blast phase except for:
i.
Prolonged myelosuppression as defined by the NCI-CTCAE criteria 
specific for leukemia, e.g. marrow hypocellularity on day 42 or later (6 
weeks) from start of therapy without evidence of leukemia (< 5% blasts), 
or that results in dose modifications, interruptions or meets the protocol 
definition of DLT or SAE.
e. Serious adverse events will be reported according to institutional policy.
f.
Protocol specific language regarding the recording and reporting of adverse and 
serious adverse events will be followed in the event of discordance between the 
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protocol and Leukemia-specific adverse event recording and reporting 
guidelines.
11.1.3 Abnormal hematologic values will not be recorded on the case report form.  For 
abnormal chemical values, the apogee or nadir (whichever is appropriate) will be reported per 
course on the case report form.
11.1.4 All events that are not listed as expected in section 11.1.2 will be collected for the 
purpose of grading, and determining attribution to study drug by the PI.
11.1.5 Serious Adverse Event Reporting (SAE)
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or the sponsor, it results in any of the following outcomes: 

Death

A life-threatening adverse drug experience – any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience that, had it 
occurred in a more severe form, might have caused death.

Inpatient hospitalization or prolongation of existing hospitalization.

A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions.

A congenital anomaly/birth defect.
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse (21 CFR 312.32).
Pregnancy, drug overdose, and secondary malignancy will be handled as SAE.

Important medical events as defined above, may also be considered serious adverse 
events.  Any important medical event can and should be reported as an SAE if deemed 
appropriate by the Principal Investigator or the IND Sponsor, IND Office.

All events occurring during the conduct of a protocol and meeting the definition of a SAE 
must be reported to the IRB in accordance with the timeframes and procedures outlined 
in “The University of Texas M. D. Anderson Cancer Center Institutional Review Board 
Policy for Investigators on Reporting Unanticipated Adverse Events for Drugs and 
Devices”.  Unless stated otherwise in the protocol, all SAEs, expected or unexpected, 
must be reported to the IND Office, regardless of attribution (within 5 working days of 
knowledge of the event).
"Serious Adverse Event Reporting (SAE) for M. D. Anderson-Sponsored IND Protocols":
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
All life-threatening or fatal events, that are unexpected, and related to the study drug, 
must have a written report submitted within 24 hours (next working day) of knowledge of 
the event to the Safety Project Manager in the IND Office.  

Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety 
reporting to the IND Office and MDACC IRB. 

Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug, unless the participant withdraws 
consent. Serious adverse events must be followed until clinical recovery is complete and 
laboratory tests have returned to baseline, progression of the event has stabilized, or 
there has been acceptable resolution of the event.

Additionally, any serious adverse events that occur after the 30 day time period that are 
related to the study treatment must be reported to the IND Office. This may include the 
development of a secondary malignancy.
Reporting to FDA:

Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project 
Manager IND Office) according to 21 CFR 312.32.
Investigator Communication with Supporting Companies:

Any individual expedited SAE reports required by the FDA will be reported to BMS.

All Serious Adverse Events must be reported to BMS Worldwide Safety
x
All SAEs, whether related or unrelated to lirilumab and all pregnancies must be 
reported to BMS (by the investigator or designee) within 24 hours. 
x
All SAEs should be reported via confirmed facsimile (fax) transmission, or scanned 
and reported via electronic mail to: 
SAE Email Address: Worldwide.Safety@BMS.com
SAE Fax Number: 609-818-3804
12.0 DISCONTINUATION OF STUDY TREATMENT
A patient’s treatment with study drugs may be discontinued for any of the following reasons:

Clinically significant progressive disease

Adverse events that are not manageable with dose adjustments and/or optimal medical 
management, or that, in the opinion of the investigator, pose an unacceptable risk for the 
patient. 

Investigator decision

Patient decision (e.g., withdrawal of consent)

Study termination by Sponsor
Patients who experience toxicity that can be clearly attributed to either lirilumab or rituximab 
may continue treatment with the other agent. If toxicity cannot be clearly attributed to a single 
agent, treatment with both agents should be discontinued. Patients who discontinue treatment 
for reasons other than progressive disease should remain on study and continue to have 
disease assessments per protocol.
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13.0 CORRELATIVE STUDIES
Correlative studies relating to immunologic response will be collected on a separate IRB-
approved Protocol (PA13-0291).
Approximately 20cc of peripheral blood will be collected at the following time-points 
(pretreatment, C1D1, C1D8, C2-24D1) and stored in the Leukemia Research Bank. This testing 
is optional and failure to collect these studies at any of the specified time-points is not a protocol 
deviation. Approximately 3cc of bone marrow aspirate will be collected at the following time-
points (pretreatment, after C3, after C6, after C9, after C12, after C15, after C18, after C21, after 
C24) and stored in the Leukemia Research Bank. This testing is optional and failure to collect 
these studies at any of the specified time-points is not a protocol deviation.
Immune Function Studies (Katy Rezvani MD, PhD, MDACC) – This testing is optional and 
failure to collect these studies at any of the specified time-points is not a protocol deviation. We 
use 14 color multiparameter flow cytometry to comprehensively analyze NK cell frequencies, 
phenotype, function (both KIR-ligand mediated and ADCC), homing to sites of tumor (bone 
marrow and lymph node where available) using the assays described below and in table below.
PBMC will be collected on Day 1 (prior to the study drugs) and Day 2 of each cycle (cycles 1-
12). In addition, PBMC will be collected on day 8 of cycle 1. Approximately 3cc of bone marrow 
aspirate will be collected at the following time-points (pretreatment, after C3, after C6, after C9, 
after C12). To determine whether treatment with a combination of rituximab and lirilumab will 
enhance CD16 mediated ADCC, NK cells will be stimulated with antibodies against CD20 
(Rituximab) to trigger ADCC responses against CD20+ cell lines (Raji and Daudi), in the 
presence or absence of lirilumab. Function will be assessed using a combination of 
degranulation (CD107a), effector cytokine production (IFN-Ȗ DQG 71)-Į DQG FKURPLXP
release.  Each patient will be used as his / her own control and the effect of rituximab and 
lirilumab combination therapy on NK cell frequency, phenotype and function will be assessed 
longitudinally. A total of 25 samples will be analyzed per patient. Samples will be sent to the 
laboratory of Dr. Katy Rezvani, MDACC.
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Table 13.1. Flow cytometric parameters that will be used to evaluate the impact of rituximab + 
lirilumab on NK cell phonotype and function 
Cell type
Markers & transcription factors
Effector 
molecules
NK cells 
NK subsets (may be 
+ or –)
NK activation 
markers
KIR receptors
Adhesion / migration
Costimulatory 
molecules
CD45+ CD56+ CD3– NKp46+ IL-2RD+/– IL-12Rȕ + IL-15RE+/–
IL-18R+ T-bet+ or – Eomes+ or –
CD16, CD27, CD57, CD94, CD141, CD161, KLRG-1, 2B4, 
4-1BB, NKG2A, -C, -D, DNAM-1, NKp30, NKp44, KIRs, 
CD132
CD25, CD69, down-regulation of CD27 & KLRG-1, Ki67, 
Lag3, CD107a
KIR2DL1 (clone 143211, KIR2DS1 (clone 11PB6), KIR2DL3 
(clone REA147), KIR2DSL2/3 (clone GL183), KIR3DL1 
(clone DX9), KIR3DSL11 (CLONE z27.3.7)
&;&5&&5Įȕ&'/&&5&&5&;&5
CLA 
PD1, PDL1, PDL2, Lag 3 (to assess exhaustion)
Perforin, 
Granzymes, 
71)Į
INFJ
Cytotoxicity
CD107a
14.0 STATISTICAL CONSIDERATIONS
A maximum of 48 patients will be enrolled in this Phase II study. Cohort 1 will enroll up to 24 
CLL patients who are refractory to or have relapsed after at least one prior therapy; cohort 2 will 
enroll up to 24 untreated CLL patients with high-risk molecular features such as del(17p), 
mutated TP53, del(11q), unmutated IGHV gene, or are >65 years of age. The primary objective 
is to evaluate overall response (OR) during the first 6 months of therapy. The primary efficacy 
endpoint, overall response (OR), is defined as CR, CRi or PR that occurs during the first 6 
months of therapy. 
EFFICACY
For cohort 1, the target overall response rate is 30%. The Bayesian approach of Thall, Simon, 
Estey will be implemented for the futility monitoring.31 The following futility stopping rule will be 
applied in cohort size of 3, starting from the 9th patient: prob{p(OR)> 0.3) < 0.05, where p(OR) 
denotes the overall response rate. That is, the trial will be stopped early due to futility, if during 
the study we determine that there is less than 5% chance that the OR is more than 30%.  
Assuming that the prior distribution of p(OR) is beta (0.6, 1.4), the stopping boundaries 
corresponding to this futility monitoring rule are shown below in Table 14.1. The operating 
characteristics (OCs) for this futility stopping rule are summarized in Table 14.2.
Table 14.1. Futility stopping boundaries for cohort 1, in cohort size of 3. 
Number of patients 
Stop the trial if there are this 
many patients achieving OR
9
0
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12-15
0-1
18
0-2
21
0-3
Table 14.2. Operating characteristics for the monitoring of OR rate in cohort 1. 
True OR Rate
Early Stopping 
Probability
Average 
number of 
patients treated
0.1
0.88
13.8
0.2
0.45
19.4
0.3
0.14
22.6
0.4
0.03
23.7
0.5
0.005
23.9
For cohort 2, the OR rate is ~30% with Rituximab and we target to reach an OR rate of 50% 
with the combination therapy. The same Bayesian approach of Thall, Simon, Estey will be 
implemented for the futility monitoring.31 The following futility stopping rule will be applied in 
cohort size of 3, starting from the 9th patient: prob{p(OR)> 0.3+delta) < 0.05, where p(OR) 
denotes the response rate and delta=0.2. That is, the trial will be stopped early due to futility, if 
during the study we determine that there is less than 5% chance that the OR rate with the 
combination therapy will improve from 30% (Rituximab alone) to 50%.  Assuming that the prior 
distribution of p(OR) is beta (0.6, 1.4), the stopping boundaries corresponding to this futility 
monitoring rule are shown below in Table 14.3. The operating characteristics (OCs) for this 
futility stopping rule are summarized in Table 14.4.
Table 14.3. Futility stopping boundaries, in cohort size of 3, for cohort 2. 
Number of patients 
Stop the trial if there are this 
many patients achieving OR
9
0-2
12
0-3
15
0-4
18
0-5
21
0-7
Table 14.4. Operating characteristics for monitoring of OR rate in cohort 2. 
True OR Rate
Early Stopping 
Probability
Average 
number of 
patients treated
0.2
0.97
11.0
0.3
0.78
14.8
0.4
0.44
19.1
0.5
0.16
22.2
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0.6
0.04
23.5
0.7
0.005
23.9
TOXICITY
The Bayesian approach of Thall, Simon, Estey will be implemented for toxicity monitoring for 
patients enrolled in cohorts 1 and 2, where toxicity is defined as any grade 3 or higher non-
hematological toxicity which is at least possibly related to the treatment.31 The toxicity, denoted 
as TOX will be monitored by the Bayesian stopping boundaries calculated based on beta-
binomial distributions. We assume as a priori, p(TOX) ~ beta (0.6, 1.4).  The study will be 
stopped for toxicity if Pr(p(TOX)> 0.30 | data)  >0.92. That is, we will stop the trial for new 
patient enrollment if at any time during the study we determine that there is more than 92% 
chance that the toxicity rate is more than 30%. The toxicity monitoring rule will be applied 
starting from the 6th patient, and then in cohort size of 6. The toxicity will be considered 
continuously throughout the study treatment duration.  Stopping boundaries corresponding to 
this toxicity monitoring rule are shown in Table 14.5 below. The operating characteristics for 
toxicity monitoring are summarized in Table 14.6. 
Table 14.5. Toxicity stopping boundaries in cohort size of 6 for patients enrolled in cohorts 1 and 
2. 
Number of patients 
Stop the trial if there are this 
many patients having toxicity
6
4-6
12
7-12
18
9-18
24
11-24
30
13-30
36
15-36
42
18-42
Table 14.6. Operating characteristics for toxicity monitoring. 
True Toxicity 
Rate
Early Stopping 
Probability
Average 
number of 
patients treated
0.1
0.001
47.9
0.2
0.02
47.1
0.3
0.19
42.3
0.4
0.61
30.5
0.5
0.93
18.2
ANALYSIS PLAN
Summary statistics will be provided for continuous variables.  Frequency tables will be used to 
summarize categorical variables.  The overall response (OR) rate will be estimated along with 
2014-0933 Lirilumab and Rituximab for Relapsed/Refractory CLL 
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the 95% credible interval. 
Data from all patients who receive any study drug will be included in the safety analyses. 
Patients who entered the study and did not take any of the study drugs and had this confirmed 
will not be evaluated for safety. The severity of the toxicities will be graded according to the NCI 
CTCAE v4.0 whenever possible. We will follow standard reporting guidelines for adverse 
events. Safety data will be summarized by category, severity and frequency. The proportion of 
patients with AEs will be estimated, along with the Bayesian 95% credible interval. Kaplan-Meier 
method will be used to assess the overall survival (OS) and progression-free survival (PFS) 
probabilities. The change of biomarkers over time will be assessed through fitting linear or non-
linear mixed effect models. 
This study will be conducted as described in this protocol, except for an emergency situation in 
which the protection, safety, and wellbeing of the patient requires immediate intervention, based 
on the judgment of the investigator or his/her designee. In the event of a significant deviation 
from the protocol, the investigator will notify the MDACC surveillance committee following the 
institutional guidelines.
Statistical Language for the correlative studies:  Descriptive statistics including plots, mean, 
median and standard deviations will be used to summarize data. For continuous outcomes, t-
test and ANOVA will be used to compare outcome measures across patient characteristics. 
Dunnett’s and Tukey’s test that properly adjust for multiplicity in multiple tests will be 
implemented. Pair-wise comparisons will be performed using pre- and post-therapy samples 
from each patient. The chi-square (c2) test or Fisher’s exact test will be used to test the 
association between two categorical variables such as disease state and performance status. 
Both univariate and multivariate logistic regressions will be performed to model prognostic 
factors. 
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2014-0933 Lirilumab and Rituximab for Relapsed/Refractory CLL 
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