Conditions: Loss of Chromosome 17p Recurrent Chronic Lymphocytic Leukemia Recurrent Small Lymphocytic Lymphoma Refractory Chronic Lymphocytic Leukemia Refractory Small Lymphocytic Lymphoma Richter Syndrome
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 37
Healthy volunteers: no

Brief summary:
This phase II trial studies how well nivolumab and ibrutinib work when given together in treating patients with chronic lymphocytic leukemia, small lymphocytic lymphoma, or Richter transformation that has come back after a period of improvement (relapsed), does not respond to treatment (refractory), or is at high risk of spreading and has not been treated. Immunotherapy with monoclonal antibodies, such as niolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving nivolumab together with ibrutinib may kill more cancer cells.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the efficacy (response rate) of nivolumab in combination with ibrutinib in patients with relapsed/refractory or high-risk untreated chronic lymphocytic leukemia (CLL).

II. Determine the response rate (complete response \[CR\]/complete response with incomplete marrow recovery \[CRi\]) by 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria. (Cohort I) III. Determine the conversion rate from partial response (PR) to CR/CRi by 2008 IWCLL criteria. (Cohort II) IV. Determine the response rate (CR/CRi). (Cohort III)

SECONDARY OBJECTIVES:

I. To determine the safety of nivolumab in combination with ibrutinib in patients with relapsed, refractory or high-risk untreated CLL/Richter transformation (RT).

II. To determine the progression-free survival of patients with relapsed, refractory or high-risk untreated CLL/RT treated with nivolumab in combination with ibrutinib.

III. To determine the overall survival of patients with relapsed, refractory or high-risk untreated CLL/RT treated with nivolumab in combination with ibrutinib.

EXPLORATORY OBJECTIVES:

I. To study immunological and molecular changes in peripheral blood, lymph node, and bone marrow in response to nivolumab and ibrutinib therapy.

OUTLINE: Patients are assigned to 1 of 3 treatment cohorts.

COHORT I (NO CURRENT IBRUTINIB TREATMENT): Patients receive nivolumab intravenously (IV) over 1 hour on days 1 and 15 and ibrutinib orally (PO) once daily (QD) on days 1-28 of courses 2-24. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

COHORT II (IBRUTINIB TREATMENT \> 9 MONTHS): Patients receive nivolumab as in Cohort I and continue previous ibrutinib treatment.

COHORT III (RICHTER TRANSFORMATION): Patients receive nivolumab and ibrutinib as in cohort I. Ibrutinib may be given earlier than course 2 in case of worsening disease after discussion with study principal investigator. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity

\* Note: After 3 cycles of treatment, nivolumab administration may be decreased to once every 4 weeks in all cohorts, in consultation with the study principal investigator.

After completion of study treatment, patients are followed up monthly for 1 year.

Arms:
arm 1: Patients receive nivolumab IV over 1 hour on days 1 and 15 and ibrutinib PO QD on days 1-28 of courses 2-24. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive nivolumab as in Cohort I and continue previous ibrutinib treatment. arm 3: Patients receive nivolumab and ibrutinib as in cohort I. Ibrutinib may be given earlier than course 2 in case of worsening disease after discussion with study principal investigator. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Ibrutinib intervention 2: Laboratory Biomarker Analysis intervention 3: Nivolumab
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies intervention 3: Given IV

Protocol document:
Prot_SAP_000.pdf: 
 
Page 1 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
Nivolumab Combined with Ibrutinib 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 nivolumab in combination with ibrutinib in patients 
with  relapsed/refractory or high-risk untreated CLL by 
a. Cohort 1: determine the response rate (CR/CRi) by 2008 IWCLL criteria 
b. Cohort 2: determine the conversion rate from PR to CR/CRi by 2008 IWCLL criteria 
c. Cohort 3: determine the response rate (CR/CRi) 
 
Secondary Objectives 
1. To determine the safety of nivolumab in combination with ibrutinib in patients with relapsed, 
refractory or high-risk untreated CLL/Richter transformation (RT).  
2. To determine the progression-free survival of patients with relapsed, refractory or high-risk 
untreated CLL/RT treated with nivolumab in combination with ibrutinib.  
3.  To determine the overall survival of patients with relapsed, refractory or high-risk untreated 
CLL/RT treated with nivolumab in combination with ibrutinib.  
 
Exploratory Objectives 
1.  To study immunological and molecular changes in peripheral blood, lymph node, and bone 
marrow in response to nivolumab and ibrutinib 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 established and validated to help in prognostication and 


 
Page 2 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
are routinely used in clinical practice.1 These include β2-microglobulin, cytogenetics, 
immunoglobulin variable heavy chain gene (IGHV) mutational status, zeta chain-associated 
protein 70 (ZAP-70) expression, and CD38 expression. Presence of deletion of the short arm of 
chromosome 17 [del(17p)] (and/or mutated TP53) is associated with the worst 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 Richter 
transformation (RT) represents an aggressive transformation of CLL, and is associated with poor 
prognosis.6,7 Treatment with chemoimmunotherapy, though commonly employed, is not very 
effective.8 Recently, immunotherapy with PD-1 blockade was shown to be effective in patients 
with RT with 4 out of 5 patients responding to pembrolizumab.9 These early results represent a 
major advance for patients with RT.  
 
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)10,11; b) use of lenalidomide12-14; c) adoptive immunotherapy with an allogeneic 
stem cell transplant15; d) use of chimeric antigen receptor (CAR).16 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.11,13,14,17-21 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).13 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.14 
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.18 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.14 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.22-24 PD-
L1 (ligand for PD-1) is also over expressed in the CLL B cells.17 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 Anti-PD1 (Nivolumab, BMS-936558, MDX1106): 
 
2.4.1 Mechanism of Action 
Immune activation is tightly regulated by co-stimulatory (e.g. CD28 and ICOS) and co-inhibitory 
(e.g. CTLA-4 and PD-1) receptors expressed on T cells. Agonistic antibodies against co-
stimulatory T cell receptors and blocking antibodies against co-inhibitory T cell surface receptors 
have both been shown to potentiate T cell activation for tumor cell killing. 
 


 
Page 3 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
PD-1 is mainly expressed by activated CD4+ and CD8+ T cells, as well as APCs. It has two 
ligands, PD-L1 and PD-L2, with distinct expression profiles.25 PD-L1 is expressed not only on 
APCs, but also on non- hematopoietic cells, including tumor cells. Expression of PD-L2 is largely 
restricted to APCs including macrophages and myeloid dendritic cells, as well as mast cells. The 
role of PD-1 as a negative regulator of T cells was best demonstrated by the finding that PD-1 
deficient mice developed significant autoimmunity with high titers of autoantibodies.22,26 
Subsequently, blocking antibodies against PD-1 were shown to activate immune responses that 
resulted in reduction of tumor metastasis and tumor growth in a number of experimental tumor 
models.27,28 Consistent with the immune inhibitory role of PD-1/PD-L1/2 signaling, forced 
expression of PD-L1 in murine tumor cell lines allowed increased tumor growth in vivo, which 
was otherwise kept in check by T cells. The inciting effect of PD-L1 on tumor growth was reversed 
by blocking anti-PD-L1 antibodies.29  
 
Nivolumab (BMS-936558) is a fully human, IgG4 (kappa) isotype, monoclonal antibody that binds 
PD-1. Blockade of the PD-1 pathway by nivolumab was studied using the mixed lymphocyte 
reaction (MLR). PD-1 blockade resulted in a reproducible enhancement of both proliferation and 
IFN-γ release in the MLR. The effect of nivolumab on antigen-specific recall response was 
investigated using a CMV-restimulation assay with human peripheral blood mononuclear cells 
(PBMCs), and was evaluated by ELISA. These data indicated that nivolumab, versus an isotype-
matched control antibody, augmented IFN-γ secretion from CMV-specific memory T cells in a 
dose-dependent manner. PD-1 blockade by nivolumab is therefore considered a promising 
immunotherapeutic strategy. 
 
2.4.2 Summary of Safety Results from Nivolumab Program 
For a complete review of clinical information, please refer to the nivolumab Investigator Brochure. 
 
2.4.2.1 Summary of Safety 
The overall safety experience with nivolumab is based on experience in approximately 1500 
patients as either a monotherapy or in combination with other therapeutics. In general for 
monotherapy, the safety profile is similar across tumor types. The one exception is pulmonary 
inflammation AEs which may be numerically greater in patients with NSCLC possibly because 
in some cases it can be difficult to distinguish between nivolumab-related and unrelated 
causes of pulmonary symptoms and radiographic changes. The most frequently reported 
treatment- related AE is fatigue which is almost always low grade.  
 
The safety profile is generally consistent across completed and ongoing clinical trials with no 
MTD reached at any dose tested up to 10 mg/kg. There was no pattern in the incidence, 
severity, or causality of AEs to nivolumab dose level. Most related AEs are thought to be due 
to the effects of inflammatory cells on specific tissues. Most AEs were low-grade (Grade 1 to 
Grade 2) with relatively few related high-grade (Grade 3 to Grade 4) AEs. Most high-grade 
events were manageable with use of corticosteroids or hormone replacement therapy 
(endocrinopathies).  
 
 
2.4.2.2 Clinical Safety in Advanced Malignancies (Nivolumab Monotherapy)  


 
Page 4 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
A total of 306 patients with treatment-refractory malignancies were treated in a phase 1 
multidose study (MDX1106-03, CA209003). This is an ongoing, phase I dose-escalation study 
of nivolumab monotherapy in patients with advanced solid tumors; 1, 3, or 10 mg/kg nivolumab 
and 0.1 and 0.3 mg/kg (included as part of Amendment 4) administered by IV Q2W; treatment 
up to 2 years. Results were published by Topalian et al. (NEJM 2012).30 The baseline disease 
diagnosis by treatment for MDX1106-03 is provided in Table 2.4.2.2-1.  
 
Table 2.4.2.2-1: Baseline Disease Diagnosis by Treatment - MDX1106-03 
 
No. of Patients  
Nivolumab 
(mg/kg) 
0.1 mg/kg 
0.3 mg/kg 
1 mg/kg 
3 mg/kg 
10 mg/kg TOTAL 
Total N 
17 
18 
86 
54 
131 
306 
NSCLC 
0 
0 
   33  
   37  
   58 
   128 
Melanoma 
    17  
    18  
   35  
   17  
   20 
   107 
RCC 
0 
0 
   18  
0 
   16 
   34  
mCRPC 
0 
0 
0 
0 
   17 
  17 
CRC 
0 
0 
0 
0 
   19 
  19 
Abbreviations: CRC: colorectal adenocarcinoma; mCRPC: metastatic castration-resistant 
prostate cancer; NSCLC: non-small cell lung cancer; RCC: renal cell carcinoma;  
 
2.4.2.3 Adverse Events 
There was no pattern in the incidence, severity, or causality of AEs related to the dose 
of nivolumab, between 1 and 10 mg/kg, in MDX1106-03. Of the 306 treated patients in 
MDX1106-03, 303 (99.0%) patients have at least 1 reported AE regardless of causality (Table 
2.4.2.3-1). The most frequently reported AEs were fatigue (54.9%), decreased appetite 
(35.0%), diarrhea (34.3%), nausea (30.1%), and cough (29.4%). Treatment-related AEs 
were reported in 230 (75.2%) of the 306 patients. The most frequently reported treatment-
related AEs were fatigue (28.1%), rash (14.7%), diarrhea (13.4%), and pruritus (10.5%). Most 
treatment-related AEs were low grade. Treatment-related Grade 3-4 AEs were reported 
in 52 (17.0%) of patients. The most frequently reported treatment-related high grade AE was 
fatigue (6.5%). 
 


 
Page 5 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
Table 2.4.2.3-1: Summary of Adverse Events Reported in ≥15% of All Treated Patients 
 
No. of Patients (%) 
 
Preferred Term 
AEs regardless of causality 
Treatment-related AEs 
 
   Any Grade  
 
          Grade 3-4  
 
   Any Grade 
 
         Grade 3-4 
Any AE 
303 (99) 
127 (42) 
230 (75) 
52 (17) 
Fatigue 
168 (55) 
20 (7) 
86 (28) 
7 (2) 
Decreased appetite 
107 (35) 
3 (1) 
28 (9) 
1(0.3) 
Diarrhea 
105 (34) 
3 (1) 
41 (13) 
3 (1) 
Nausea 
92 (30) 
9 (3) 
27 (9) 
2 (1) 
Cough 
90 (29) 
4 (1) 
11 (4) 
1 (0.3) 
Dyspnea 
80 (26) 
27 (9) 
11 (4) 
0 
Constipation 
78 (26) 
2 (1) 
5 (2) 
0 
Rash 
74 (24) 
0 
45 (15) 
0 
Vomiting 
70 (23) 
7 (2) 
10 (3) 
1 (0.3) 
Back pain 
68 (22) 
7 (2) 
3 (1) 
1 (0.3) 
Arthralgia 
63 (21) 
4 (1) 
15 (5) 
0 
Pyrexia 
61 (20) 
1 (0.3) 
17 (6) 
0 
Headache 
59 (19) 
1 (0.3) 
8 (3) 
0 
Edema peripheral 
59 (19) 
1 (0.3) 
3 (1) 
0 
Dizziness 
56 (18) 
1 (0.3) 
10 (3) 
0 
Pruritus 
56 (18) 
1 (0.3) 
32 (11) 
1 (0.3) 
Weight decreased 
48 (16) 
1 (0.3) 
11 (4) 
0 
 
2.4.2.4 Select Adverse Events 
Select AE categories (events with a potential inflammatory mechanism requiring more frequent 
monitoring and/or unique intervention such as immunosuppressants and/or endocrine 
replacement therapy) include: GI AEs, pulmonary AEs, renal AEs, hepatic AEs, skin AEs, 
and endocrinopathies. In addition, Select AEs include a category for infusion reactions. These 
Select AEs are considered events of interest based on the mechanism of action and were 
previously 
referred 
to 
as 
immune-related 
AEs 
or 
immune-mediated 
AEs.  
The frequencies of these events are summarized in Table 2.4.2.4-1. The 10 mg/kg 
cohort had numerically greater frequency of high-grade select AEs including the 
subcategories of endocrinopathies, GI, pulmonary, and infusion reactions.  
 


 
 
 
Table 2.4.2.4-1: Treatment-related Select Adverse Events by Treatment - All CTC Grades Reported in at Least 10 
Treated Patients in MDX1106-03 
 
Preferred Term 
0.1 
mg/kg 
n=17 
Any 
Grade 
Grade 
3-4 
0.3 
mg/kg 
n=18 
Any 
Grade 
Grade 
3-4 
1 
mg/kg 
n=86 
Any 
Grade 
Grade 
3-4 
3 
mg/kg 
n=54 
Any 
Grade 
Grade 
3-4 
10 
mg/kg 
n=131 
Any 
Grade 
Grade 
3-4 
Total 
N=30
6 
Any 
Grade 
Grade 
3-4 
Any Select AE 
8 (47) 
1 (5.9) 
9 (50) 
0 
42 (49) 
3 (4) 
23 (43) 
2 (4) 
58 (44) 
13 (10) 
140 (46) 
19 (6) 
Any 
Endocrinopathies 
4 (24) 
0 
2 (11) 
0 
9 (11) 
0 
4 (7) 
0 
10 (8) 
3 (2) 
29 (10) 
3 (1) 
Endocrinopathi
es Thyroid 
3 (18) 
0 
2 (11) 
0 
9 (11) 
0 
4 (7) 
0 
8 (6) 
2 (2) 
26 (9) 
2 (1) 
Blood TSH 
i
d
2 (12) 
0 
1 (6) 
0 
2 (2) 
0 
2 (4) 
0 
4 (3) 
1 (1) 
11 (4) 
1 (0.3) 
Hypothyroidism 
1 (6) 
0 
1 (6) 
0 
5 (6) 
0 
1 (2) 
0 
3 (2) 
1 (1) 
11 (4) 
1 (0.3) 
Any Skin AEs 
3 (18) 
0 
5 (28) 
0 
27 (31) 
0 
12 (22) 
0 
28 (21) 
1 (1) 
75 (25) 
1 (0.3) 
Rash 
3 (18) 
0 
3 (17) 
0 
20 (23) 
0 
5 (9) 
0 
14 (11) 
0 
45 (15) 
0 
Pruritus 
0 
0 
1 (6) 
0 
15 (17) 
0 
3 (6) 
0 
13 (10) 
1 (1) 
32 (11) 
1 (0.3) 
Any GI AE 
1 (6) 
0 
2 (11) 
0 
19 (22) 
0 
7 (13) 
0 
14 (11) 
3 (2) 
43 (14) 
3 (1) 
Diarrhea 
1 (6) 
0 
2 (11) 
0 
19 (22) 
0 
6 (11) 
0 
13 (10) 
3 (2) 
41 (13) 
3 (1) 
Any hepatic AE 
0 
0 
2 (11) 
0 
8 (9) 
0 
3 (6) 
2 (4) 
5 (4) 
2 (2) 
18 (6) 
4 (1) 
ALT increased 
0 
0 
1 (6) 
0 
6 (7) 
0 
1 (2) 
0 
3 (2) 
1 (1) 
11 (4) 
1 (0.3) 
Any Pulmonary AE 
1 (6) 
0 
1 (6) 
0 
6 (7) 
3 (4) 
2 (4) 
0 
7 (5) 
3 (2) 
17 (6) 
6 (2) 
Pneumonitis 
1 (6) 
0 
0 
0 
4 (5) 
2 (2) 
1 (2) 
0 
6 (5) 
2 (2) 
12 (4) 
4 (1) 
Infusion reaction 
0 
0 
1 (6) 
0 
3 (4) 
0 
3 (6) 
0 
8 (6) 
2 (2) 
15 (5) 
2 (1) 
Infusion-
related 
0 
0 
1 (6) 
0 
3 (4) 
0 
3 (6) 
0 
5 (4) 
0 
12 (4) 
0 
Hypersensitivity 
0 
0 
0 
0 
0 
0 
1 (1.9) 
0 
3 (2) 
2 (2) 
4 (1) 
2 (1) 
 
 
 


 
Page 7 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
2.4.2.5 Adverse Events Leading to Discontinuation 
At least 1 treatment-related AE leading to discontinuation was reported in 32 (10.5%) of the 
306 treated patients. Grade 3-4 treatment-related events were reported in 14 (4.6%) patients. The 
frequency of treatment-related AEs leading to discontinuation was not associated with the dose 
of nivolumab. Pneumonitis was the most common treatment-related AE leading to discontinuation 
(8 patients, 2.6%); pneumonitis reported in 3 (1.0%) patients was Grade 3-4.  Treatment-related 
AEs reported in at least 2 patients included pneumonitis (8 patients, 2.6%), colitis (3 patients, 1.0%) 
and myalgia,  hepatitis,  hypersensitivity,  and  infusion-related  reactions  (each  reported  in 2 
patients, 0.7%). One event of Grade 5 sepsis was reported for 1 subject, a 62-year-old male 
treated with 1 mg/kg nivolumab. 
 
2.4.3 Summary of Efficacy (Nivolumab monotherapy) 
The clinical activity data presented below are from MDX1106-03 (nivolumab monotherapy). 
The data from melanoma cohort is shown below.31 
  Table 2.4.3-1: Responses Melanoma Patients -  MDX1106-03 
Dose  (mg/kg) 
 
N 
ORR (%) 
PFS (months) 
OS (months) 
0.1 
17 
35.3 
3.6 
16.2 
0.3 
18 
27.8 
1.9 
12.5 
1.0 
35 
31.4 
9.1 
25.3 
3.0 
17 
41.2 
9.7 
20.3 
10.0 
20 
20.0 
3.7 
11.7 
All doses 
107 
30.8 
3.7 
16.8 
 
2.4.3 Nivolumab monotherapy in Hodgkin’s lymphoma 
Ansell et al recently reported results of nivolumab monotherapy in patients with relapsed or refractory 
Hodgkin’s lymphoma.32 Twenty-three patients were treated (median age 35, range 20-54). A total of 
22 patients had nodular sclerosis subtype of Hodgkin’s lymphoma and one patient had mixed 
cellularity disease. About two-thirds of the patients had received 4 or more prior therapies. 78% had 
failed brentuximab vedotin and a similar number had failed prior autologous stem cell transplantation. 
Nivolumab was administered at 3 mg/kg IV every 2 weeks. Among the 23 patients, Grade 3 or 4 
adverse events occurred in 12 patients (52%). Overall, drug-related adverse events were reported in 
18 patients (78%). The most common were rash (in 22%) and a decreased platelet count (in 17%). 
Drug-related grade 3 adverse events, which were reported in 5 patients (22%), included the 
myelodysplastic 
syndrome, 
pancreatitis, 
pneumonitis, 
stomatitis, 
colitis, 
gastrointestinal 
inflammation, thrombocytopenia, an increased lipase level, a decreased lymphocyte level, and 
leukopenia. There were no drug-related grade 4 or 5 adverse events. Three patients had one serious 
drug-related adverse event each (grade 3 pancreatitis, grade 3 myelodysplastic syndrome, and grade 
2 lymph-node pain). There were no treatment-related deaths. The rate of adverse events was similar 
to that in trials of nivolumab in patients with solid tumors.  
The median number of nivolumab doses that patients received was 16 (range, 6 to 37), administered 
over a median treatment duration of 36 weeks. The response rate was 87%, with a CR occurring in 
4 patients (17%), a PR in 16 patients (70%), and stable disease in 3 patients (13%). Of the 4 patients 


 
Page 8 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
with complete responses, 3 had not received previous treatment with brentuximab. The rate of PFS 
at 24 weeks was 86%. The median duration of follow-up was 40 weeks (range, 0 to 75). 
 
2.5 Ibrutinib 
2.5.1 B cell receptor (BCR) signaling plays a crucial role in the pathogenesis in CLL.33-36 The BCR 
signaling pathway consists of immunoglobulin bound to the cell membrane that attaches to 
heterodimer consisting of CD79a and CD79b.36-38 Binding of a ligand to the membrane 
immunoglobulin leads to recruitment and phosphorylation of spleen tyrosine kinase (SyK) and Src 
family kinase (Lyn), which in turn recruit and phosphorylate many kinases and adapter proteins 
including Bruton tyrosine kinase (BTK). BTK is a non-receptor tyrosine kinase of the Tec kinase family 
and plays a crucial role in BCR signaling.39,40 BTK is expressed in non-T cell hematopoietic cell 
lineages.41,42 The BTK gene is located on chromosome Xq21.33-q22 and mutations in this gene 
results in X-linked agammaglobulinemia, a condition characterized by marked reduction in mature B 
cells, severe hypogammaglobulinemia, and increased susceptibility to infections.43 BTK activates 
downstream molecules such as nuclear-factor-kappa B and MEK/ERK, which are involved in many 
cellular processes including proliferation, survival, differentiation, apoptosis, and metabolism. Gene 
expression profiling has shown that BCR signaling is the most expressed signaling pathway in 
patients with CLL.35 BCR signaling is enhanced in patients with poor prognostic markers such as 
ZAP-70 overexpression and those with unmutated immunoglobulin heavy chain gene (IGHV).44,45 
 
2.5.2 Ibrutinib forms a specific bond with the cysteine-481 of BTK.46 It leads to highly potent BTK 
inhibition with an IC50 of 0.5nM.47 Treatment of CLL cells with ibrutinib induced apoptosis in a dose- 
and time- dependent manner which was independent of baseline cytogenetics, IGHV mutational 
status or baseline BTK protein expression.48 Ibrutinib also induced apoptosis in normal B cells, but 
this was significantly less than that seen in CLL cells, indicating that CLL cells are more sensitive to 
ibrutinib than normal B cells. Ibrutinib treatment of CLL cells inhibited downstream signaling pathways 
including ERK1/2 phosphorylation, CD40L induced AKT phosphorylation and CD40L induced NF-kB 
DNA binding.48 Ponader et al. evaluated the role of the tissue microenvironment of CLL cells and its 
effect on treatment with ibrutinib.49 They reported that ibrutinib treatment significantly inhibited CLL 
cell migration and survival in a nurse-like cells (NLC) co-culture assay. In this model, ibrutinib 
treatment significantly decreased the levels of CCL3 and CCL4 and inhibited chemotaxis towards 
CXCL12 and CXCL13. In an adoptive transfer TCL1 mouse model, ibrutinib treatment delayed CLL 
progression.49 Ibrutinib has impressive monotherapy activity in patients with relapsed CLL. Byrd et al. 
reported an ORR of 71% with ibrutinib in the relapsed setting.50,51 However, most of the responses 
with ibrutinib are partial responses. The 30-month PFS was reported as 68.4%, with median PFS of 
28.1 months in patients with del(17p) (O’Brien et al. ASCO 2014). Ibrutinib is approved by the FDA 
for patients with CLL who received at least one prior therapy and in patients with del(17p). Ibrutinib is 
well tolerated with diarrhea being the most common adverse event (mostly grade 1-2).52 
 
2.6 Rationale for nivolumab and ibrutinib  
 
There is a strong scientific rationale for targeting BTK in CLL and ibrutinib is approved by the FDA for 
treatment of patients with relapsed or refractory CLL and untreated patients with del(17p). There is 
also a strong rationale for targeting immune checkpoint inhibitors in CLL (see section 2.3). Several 
lines of argument support the combination of nivolumab and ibrutinib for patients with CLL. (A) 


 
Page 9 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
Nivolumab and ibrutinib have different mechanisms of action – Nivolumab targets PD1 leading to T 
cell immune responses, whereas ibrutinib targets the BTK which impacts the downstream B cell 
receptor pathway. (B) Early preclinical data indicate that ibrutinib may lead to increased PD-1 
expression on T cells (S. Neelapu, MDACC, unpublished data). Therefore, PD-1 down regulation with 
nivolumab may be synergistic. (C) Ibrutinib is very well tolerated with diarrhea being the most common 
adverse event. Immune side-effects are not known to occur with ibrutinib. Therefore, we do not 
anticipate any excess toxicity with this combination.  
 
 
Richter Transformation Cohort (Cohort 3): RT occurs in 5-10% of patients with CLL (Jain N, 
Keating M. Expert Rev Hematol. 2016 Aug;9(8):793-801). There is no standard of care for patients 
with RT. Majority patients are treated with chemoimmunotherapy such as OFAR, Hyper-CVAD. 
However, the response rate is only 40% (majority PR), and median survival is less than 1 year. There 
is urgent need to develop better therapies for this group of patients. Ding et al. reported 7 patients 
with RT who received pembrolizumab (PD1 monoclonal ab) (ASH 2015). One patient achieved CR, 
2 PR (CR for large cell component), and 3 stable disease. We have treated 4 patients with RT and 1 
patient with accelerated CLL. One is too early for response assessment. Of the remaining 4, 2 have 
achieved PR (ongoing for 7+ and 9+ months). 
 
3.0 STUDY POPULATION 
 
3.1 Inclusion Criteria 
1. Patients will have a diagnosis of CLL or SLL, refractory to and/or relapsed after at least one prior 
standard therapy or untreated with del(17p) by FISH (high-risk cytogenetics) and have an 
indication for treatment by IWCLL 2008 criteria53 (Cohort 1) OR have been on ibrutinib for at least 
9 months with measurable persistent disease (ALC > 4K/uL, any lymph node > 1.5 cm by CT 
scan, or > 30% lymphocytes on bone marrow aspirate differential) (Cohort 2) OR Patients will 
have a diagnosis of RT, refractory to and/or relapsed after at least one prior standard therapy or 
untreated with del(17p) by FISH (high-risk cytogenetics) (Cohort 3) 
2. Age 18 years or older 
3. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2 
4. Patients must have adequate renal and hepatic function 
- 
Total bilirubin ≤1.5 x upper limit of normal (ULN). For patients with Gilbert’s disease, total 
bilirubin up to ≤3 x ULN is allowed provided normal direct bilirubin. 
- 
Serum creatinine ≤1.5 x ULN 
- 
ALT and AST ≤3 x ULN  
5.  Females of childbearing potential must have a negative serum or urine beta human chorionic 
gonadotrophin (β-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 23 weeks 
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. 


 
Page 10 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
 
3.2 Exclusion Criteria 
1. History of another primary invasive malignancy that has not been definitively treated or in 
remission for at least 2 years. Patients with non-melanoma skin cancers or with carcinomas in 
situ are eligible regardless of the time from diagnosis (including concomitant diagnoses). 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, cytotoxic chemotherapy, biologic therapy, immunotherapy, 
immunomodulatory drugs, experimental therapy within 4 weeks prior to the first dose of the study 
drugs. Note: Prior therapy with anti CD20 monoclonal antibody, anti CD52 monoclonal antibody, 
and lenalidomide are allowed. For oral targeted therapies (such as idelalisib, venetoclax), a 
washout of 3 days is allowed.     
3. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, 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 month. 
5. Patients who have uncontrolled hypertension (defined as sustained systolic blood pressure ≥ 160 
mmHg or diastolic ≥ 100 mmHg)  
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 30 days before cycle 1 day 1. 
10. Patients with organ allografts (such as renal transplant) are excluded. 
11. History of interstitial lung disease or pneumonitis. 
12. Patients who are on high dose steroids (>10mg daily 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. Malabsorption syndrome or other condition that precludes enteral route of administration. 


 
Page 11 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
18. Concomitant use of warfarin or other Vitamin K antagonists. 
19. Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor (see Appendix 2). 
20. 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.  
 
4.0 TREATMENT PLAN 
 
4.1 Study Design 
This is a phase II open label single-arm study to evaluate the combination of nivolumab and ibrutinib 
in patients with CLL. 
   
COHORT 1 
and 3 
C1D1 
C1D15 
C2D1 
C2D15 
C3D1 and then 
Q2 weeks for a 
total of 96 weeks 
After 96 
weeks 
Nivolumab*  3 mg/kg 
IV 
3 mg/kg 
IV 
3 mg/kg 
IV 
3 mg/kg 
IV 
3 mg/kg 
IV 
__ 
Ibrutinib 
__ 
__ 
Begin 420 mg orally once daily 
COHORT 2 
 
Nivolumab* 
3 mg/kg 
IV 
3 mg/kg 
IV 
3 mg/kg 
IV 
3 mg/kg 
IV 
3 mg/kg IV 
__ 
Ibrutinib 
On ibrutinib stable oral daily dose for >9 months with residual CLL (PR) at 
enrollment, continue at same ibrutinib daily dose 
 
* Note: After 3 cycles of treatment, the frequency of nivolumab administration may be 
decreased to once every 4 weeks, in consultation with the study PI. 
 
Each cycle is 28 days. Nivolumab dosing may be delayed for up to 3 days to accommodate for 
holidays/patient travel. Patients will receive nivolumab (3mg/kg IV over approximately 1 hour) 
monotherapy for the first cycle to assess for monotherapy toxicities of nivolumab. Nivolumab will 
continue for up to 24 cycles (96 weeks; 48 infusions). For Cohort 1 and cohort 3, ibrutinib will be 
initiated from the start of course 2. Treatment with ibrutinib will continue until disease progression, 
study termination, or a patient experiences a toxicity that requires discontinuation of ibrutinib. For 
Cohort 2, patients will have been on ibrutinib for >9 months, and ibrutinib dosing should continue. 
Nivolumab will be initiated after consent is provided, eligibility confirmed, and all pretreatment studies 
are complete.  For patients with RT – ibrutinib may be introduced earlier than start of cycle 2, in case 
of worsening disease, after discussion with study PI. 
 
5.0 STUDY MEDICATIONS 


 
Page 12 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
 
5.1 Nivolumab (Anti-PD1) 
Nivolumab is a fully human, IgG4 (kappa) isotype, monoclonal antibody that binds PD-1. Nivolumab 
will be supplied in vials of 100 mg (10 mg/mL) and packaged in an open-label fashion. See Appendix 
1 for Pharmacy Reference Material. 
 
5.1.1 Preparation and Dispensing of Nivolumab 
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). 
 
Nivolumab vials must be stored at a temperature of 2°C to 8°C and should be protected from light. If 
stored in a glass front refrigerator, vials should be stored in the carton. Recommended safety 
measures for preparation and handling of nivolumab include laboratory coats and gloves. 
 
For details on prepared drug storage and use time of nivolumab under room temperature/light and 
refrigeration, please refer to the Investigator Brochure section for “Recommended Storage and Use 
Conditions”. Care must be taken to assure sterility of the prepared solution as the product does not 
contain any anti-microbial preservative or bacteriostatic agent. No incompatibilities between 
nivolumab and polyolefin bags have been observed. 
 
Nivolumab is to be administered as an IV infusion over approximately 1 hour, using a volumetric pump 
with a 0.2/0.22 micron in-line filter at the protocol-specified dose. The drug can be diluted with 0.9% 
normal saline for delivery but the total drug concentration of the solution cannot be below 1 mg/ml. It 
is not to be administered as an IV push or bolus injection. At the end of the infusion, flush the line 
with a sufficient quantity of normal saline. 
 
Unused or expired nivolumab vials will be disposed per MDACC guidelines. 
 
5.1.2 Administration of Nivolumab 
Patients will receive nivolumab as an IV infusion over approximately 1 hour. Dosing calculations 
should be based on the body weight assessed at the start of each cycle as described above. If the 
subject’s weight on the day of dosing differs by > 10% from the weight used to calculate the original 
dose, the dose must be recalculated. All doses should be rounded to the nearest milligram.  No doses 
of nivolumab may be given within 11 days of another. 
 
5.1.3 Patient Monitoring During Infusion 
For first dose, patient vital signs should be monitored prior to dosing, about 15 minutes after initiation 


 
Page 13 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
of the infusion (then every 15-20 minutes as indicated) and at 30 minutes after completion of the 
infusion, or longer if indicated, until the vital signs normalize or return to baseline. For subsequent 
infusions, vital signs should be collected prior to dosing and every 30 minutes during dosing. 
 
5.1.4 Treatment of Nivolumab Related Infusion Reactions 
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction were to 
occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, arthralgias, hypo- or 
hypertension, bronchospasm, or other symptoms. Infusion reactions should be graded according to 
NCI CTCAE (version 4.0) guidelines. 
 
Treatment recommendations for nivolumab related infusion reactions are provided below and may 
be modified based on MD Anderson treatment standards and guidelines, as appropriate: 
 
For Grade 1 symptoms (Mild reaction; infusion interruption not indicated; intervention not indicated): 
Remain at bedside and monitor subject until recovery from symptoms. The following prophylactic 
premedications are recommended for future infusions: diphenhydramine 50 mg (or equivalent) and/or 
acetaminophen 325 to 1000 mg at least 30 minutes before additional nivolumab administrations. 
 
For Grade 2 symptoms (Moderate reaction requires therapy or infusion interruption but responds 
promptly to symptomatic treatment [e.g. antihistamines, non-steroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic medications indicated for ≤ 24 
hours): 
 
Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the subject with 
diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen 325 to 1000 mg; remain at bedside 
and monitor subject until resolution of symptoms. Corticosteroid or bronchodilator therapy may also 
be administered as appropriate. If the infusion is interrupted, then restart the infusion at 50% of the 
original infusion rate when symptoms resolve; if no further complications ensue after 30 minutes, the 
rate may be increased to 100% of the original infusion rate. Monitor subject closely. If symptoms recur 
then no further nivolumab will be administered at that visit. Administer diphenhydramine 50 mg IV, 
and remain at bedside and monitor the subject until resolution of symptoms. The amount of study 
drug infused must be recorded on the case report form (CRF). The following prophylactic 
premedications are recommended for future infusions: diphenhydramine 50 mg (or equivalent) and/or 
acetaminophen 325 to 1000 mg should be administered at least 30 minutes before additional 
nivolumab administrations. If necessary, corticosteroids (recommended dose: up to 25 mg of IV 
hydrocortisone or equivalent) may be used. 
 
For Grade 3 or Grade 4 symptoms [Severe reaction, Grade 3: prolonged (i.e. not rapidly responsive 
to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following 
initial improvement; hospitalization indicated for other clinical sequelae (e.g. renal impairment, 
pulmonary infiltrates), Grade 4: life- threatening; pressor or ventilatory support indicated]: 
 
Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal saline, and treat the 


 
Page 14 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
subject as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 1:1,000 solution for 
subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution injected slowly for IV 
administration, and/or diphenhydramine 50 mg IV with methylprednisolone 100 mg IV (or equivalent), 
as needed. Subject should be monitored until the investigator is comfortable that the symptoms will 
not recur. Nivolumab will be permanently discontinued. Institutional guidelines will be followed for the 
treatment of anaphylaxis. Remain at bedside and monitor subject until recovery from symptoms. In 
the case of late-occurring hypersensitivity symptoms (e.g. appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (e.g. oral antihistamine 
or corticosteroids). 
 
5.2 Ibrutinib 
Ibrutinib is a small-molecule inhibitor of BTK. Ibrutinib forms a covalent bond with a cysteine residue 
in the BTK active site, leading to inhibition of BTK enzymatic activity. Ibrutinib 420 mg will be 
administered orally once daily. Ibrutinib should be administered with 8 ounces (approximately 240 
mL) of water. The capsules should be swallowed intact and patients should not attempt to open 
capsules or dissolve them in water. Each dose of ibrutinib should be taken approximately 2 hours 
after a meal or at least 30 minutes before the next meal, at approximately the same time each day. If 
a dose of ibrutinib is not taken at the scheduled time, it can be taken as soon as possible on the same 
day with a return to the normal schedule the following day. Extra capsules of ibrutinib should not be 
taken to make up for the missed dose.  
 
Concomitant use of strong CYP3A inhibitors which would be taken chronically (e.g., ritonavir, 
indinavir, nelfinavir, saquinavir, boceprevir, telaprevir, nefazodone) is not recommended. 
Concomitant use of strong CYP3A inducers (e.g., rifampin, rifabutin, phenytoin, carbamazepine, and 
St. John’s Wort) are not recommended. Avoid grapefruit and Seville oranges during ibrutinib 
treatment, as these contain moderate inhibitors of CYP3A. Please see Section 6.2 for more details.   
 
5.2.1 How Supplied 
Supplied as 140mg capsules 
 
5.2.2 Stability 
Store bottles at room temperature 20°C to 25°C 
 
5.2.3 Pharmacokinetics  
Absorption: Ibrutinib is absorbed after oral administration with a median Tmax of 1 to 2 hours. Ibrutinib 
exposure increases with doses up to 840 mg. The steady-state AUC (mean ± standard deviation) in 
patients at 420 mg is 680 ± 517 ng⋅h/mL. Administration with food increased ibrutinib AUC by 
approximately 2-fold.  
Distribution: Reversible binding of ibrutinib to human plasma protein in vitro was 97.3%.   
Metabolism: Metabolism is the main route of elimination for ibrutinib. It is metabolized to several 
metabolites primarily by cytochrome P450, CYP3A, and to a minor extent by CYP2D6. The active 
metabolite, PCI-45227, is a dihydrodiol metabolite with inhibitory activity towards BTK approximately 
15 times lower than that of ibrutinib.   
Elimination: The half-life of ibrutinib is 4 to 6 hours. Ibrutinib, mainly in the form of metabolites, is 


 
Page 15 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
eliminated primarily via feces.   
Renal Impairment: Ibrutinib is not significantly cleared renally; urinary excretion of metabolites is < 
10% of the dose. Creatinine clearance > 25 mL/min had no influence on the exposure to ibrutinib. 
There are no data in patients with severe renal impairment (creatinine clearance < 25 mL/min) or in 
patients on dialysis.  
Hepatic Impairment: Ibrutinib is metabolized in the liver. No clinical trials have been completed in 
patients with impaired hepatic function.  
 
6.0 DOSE DELAYS AND MODIFICATIONS 
Patients who experience Grade 3 or 4 toxicity that can be clearly attributed to either nivolumab or to 
ibrutinib may continue treatment with the other agent while the causative agent is delayed until resolution 
of toxicity to grade ≤1 or baseline. In cases where Grade 3 or 4 toxicity cannot be attributed to a specific 
study drug, both study drugs should be held regardless of attribution of toxicity until the toxicity is resolved 
to grade ≤1 or baseline. Grade 3 or 4 nivolumab immune-related toxicities will generally result in 
discontinuation of nivolumab, leaving ibrutinib monotherapy.  
 
6.1 Dose modification for nivolumab 
Dose reductions or dose escalations are not permitted. 
 
6.1.1 Pulmonary adverse events 
Pulmonary AEs have been observed following treatment with nivolumab and have occurred after a 
single dose and after as many as 48 treatments. The majority of cases reported were Grade 1 or 
Grade 2 and patients presented with either asymptomatic radiographic changes (eg, focal ground 
glass opacities, patchy infiltrates) or with symptoms of dyspnea, cough, or fever. Early recognition 
and treatment of pneumonitis is critical to its management. Patients should be advised to seek 
medical evaluation promptly if they develop new onset dyspnea, cough or fever or if they have 
worsening of these baseline symptoms. As respiratory symptoms are common in patients with CLL, 
it is important that an evaluation/work-up distinguish between non-drug-related causes (eg, infection, 
progression of disease) and a possible drug-related pulmonary toxicity as the management of these 
events is quite different. Rule out non-inflammatory causes. If non-inflammatory cause, treat 
accordingly and continue therapy.  
 
Grade of Pneumonitis  
Management  
Follow-up 
Grade 1 (Asymptomatic; clinical or 
diagnostic observations only; 
intervention not indicated) 
 
Consider delay of 
nivolumab 
 
Monitor for symptoms 
every 2-3 days 
 
Consider Pulmonary and 
ID consults 
 
Re-image at least every 3 
weeks.  
If worsens: 
 
Treat as Grade 2 or 3-4 
Grade 2 (Symptomatic; medical 
intervention indicated; limiting 
instrumental ADL) 
 
Delay nivolumab 
 
Pulmonary and ID 
consults 
 
Monitor symptoms daily, 
consider hospitalization 
 
Steroids: 1 mg/kg/day 
 
Re-image every 1-3 days 
If improves: 
 
When symptoms return to 
near baseline, taper steroids 
over at least 1 month and 
then resume nivolumab 


 
Page 16 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
methyl-prednisolone IV 
or oral equivalent 
 
Consider bronchoscopy, 
lung biopsy 
If not improving after 2 weeks or 
worsening: 
 
Treat as Grade 3-4 
Grade 3 (Severe symptoms; limiting 
self-care ADL; oxygen indicated) or  
Grade 4 (Life-threatening respiratory 
compromise; urgent intervention 
indicated [e.g., tracheotomy or 
intubation]) 
 
Discontinue Nivolumab 
 
Hospitalize 
 
Pulmonary and ID 
consults 
 
Steroids: 2-4 mg/kg/day 
methylprednisolone IV or 
IV equivalent 
 
Add prophylactic 
antibiotics for 
opportunistic infections 
 
Consider bronchoscopy, 
lung biopsy 
If improves to baseline: 
 
Taper steroids over at least 6 
weeks 
If not improving after 48 hours or 
worsening: 
 
Add additional 
immunosuppression (e.g. 
infliximab, 
cyclophosphamide, IVIG, or 
mycophenolate mofetil) 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) 
at start of tapering or earlier, once sustained clinical improvement is observed. 
 
6.1.2 Gastrointestinal adverse events 
Gastrointestinal AEs have been observed following treatment with nivolumab. Most cases of 
diarrhea were low grade (Grade 1-2). Colitis occurs less frequently than diarrhea. High grade cases 
of diarrhea and colitis were managed with corticosteroids and in all cases the events resolved. Early 
recognition and treatment of diarrhea and colitis are critical to its management. Patients should 
be advised to seek medical evaluation if they develop new onset diarrhea, blood in stool, or severe 
abdominal pain, or if they have worsening of baseline diarrhea. As GI symptoms are common in 
patients with CLL, it is important that an evaluation/work-up distinguish between non-drug-related 
causes (eg, infection, progression of disease) and a possible drug-related AE as the management 
is quite different. Rule out non-inflammatory causes. If non-inflammatory cause is identified, treat 
accordingly and continue nivolumab therapy. Opiates/narcotics may mask symptoms of perforation. 
NOTE: As diarrhea could occur from the use of ibrutinib, patients with grade 2 diarrhea should have 
their ibrutinib held as well. 
 
Grade of Diarrhea/Colitis   
Management  
Follow-up 
Grade 1  
Diarrhea (Increase of <4 stools per 
day over baseline)  
Colitis (Asymptomatic) 
 
Continue nivolumab 
 
Symptomatic treatment 
 
Close monitoring for 
worsening symptoms  
If worsens: 
 
Treat as Grade 2 or 3-4 
Grade 2 
Diarrhea (Increase of 4 - 6 stools per 
day over baseline) 
Colitis (Abdominal pain; blood in 
stool) 
 
Delay nivolumab 
 
Symptomatic treatment 
If improves to grade 1: 
 
Resume nivolumab 
If persists > 5-7 days or recur: 
 
Steroids: 0.5-1.0 mg/kg/day 
methylprednisolone or oral 
equivalent 
 
When symptoms improve to 
grade 1, taper steroids over 


 
Page 17 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
at least 1 month, consider 
prophylactic antibiotics for 
opportunistic infections, and 
resume nivolumab 
If worsens or persists > 3-5 days 
with oral steroids: 
 
Treat as Grade 3/4 
Grade 3 
Diarrhea (Increase of >=7 stools per 
day over baseline; incontinence; 
hospitalization indicated; interfering 
with ADL) 
Colitis (Severe abdominal pain; 
medical intervention indicated; 
peritoneal signs) 
 
Grade 4  
Diarrhea (Life-threatening 
consequences; urgent 
intervention indicated) 
Colitis (Life-threatening 
consequences; urgent 
intervention indicated; perforation) 
 
Discontinue Nivolumab 
 
Steroids: 1-2 mg/kg/day 
methylprednisolone IV or 
IV equivalent 
 
Add prophylactic 
antibiotics for 
opportunistic infections 
 
Consider sigmoidoscopy 
or colonoscopy 
If improves: 
 
Continue steroids until grade 
1, then taper over at least 1 
month 
If persists >3-5 days, or recurs 
after improvement: 
 
Add infliximab (if no 
contraindication). Note: 
Infliximab should not be used 
in cases of perforation or 
sepsis 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) 
at start of tapering or earlier, once sustained clinical improvement is observed. 
 
6.1.3 Hepatic adverse events 
Hepatic AEs including elevated liver function tests (LFTs) and infrequently hepatitis have been 
observed following treatment with nivolumab. Most cases were low or moderate grade. Higher grade 
hepatic AEs were managed with corticosteroids and in all cases the events resolved. Early recognition 
and treatment of elevated LFTs and hepatitis are critical to its management. Patients should be 
advised to seek medical evaluation if they notice jaundice (yellow appearance of skin or sclera) or if 
they develop bruising, bleeding, or right-sided abdominal pain. Physicians should monitor LFTs prior 
to each nivolumab treatment. As LFT abnormalities are common in patients with CLL, it is important 
that an evaluation/work-up distinguish between non-drug-related causes (eg, infection, progression 
of disease, concomitant medications, alcohol) and a possible drug- related AE as the management 
is quite different. If non-inflammatory cause is identified, treat accordingly and continue nivolumab 
therapy. Consider imaging for obstruction.  
 
Grade of LFT abnormality 
Management  
Follow-up 
Grade 1 
AST or ALT > ULN - 2.5 x ULN 
and/or T. bili > ULN - 1.5 x ULN 
 
Continue nivolumab 
 
Continue LFT monitoring per 
protocol  
If worsens: 
 
Treat as Grade 2 or 3-4 
Grade 2 
AST or ALT > 2.5 to ≤ 5 x ULN  
 
Delay nivolumab (Note: 
Discontinue nivolumab if 
If returns to baseline: 
 
Resume routine monitoring, 


 
Page 18 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
and/or T. bili > 1.5 to ≤ 3 x ULN 
concurrent AST or ALT 
> 3 x ULN and total 
bilirubin > 2 x ULN) 
 
Monitor LFTs at least 
every 3 days  
resume nivolumab 
If elevations persist > 5-7 days or 
worsen: 
 
Steroids: 0.5-1 mg/kg/day 
methylprednisolone or oral 
equivalent and when LFT 
returns to grade 1 or 
baseline, taper steroids over 
at least 1 month, and resume 
nivolumab 
 
consider prophylactic 
antibiotics for opportunistic 
infections 
Grade 3-4 
AST or ALT > 5 x ULN 
and /or T.bili >3 x ULN 
 
Discontinue Nivolumab 
(Note: Nivolumab may 
be delayed rather than 
discontinued if AST/ALT 
≤ 8 x ULN and T.bili ≤ 5 
x ULN) 
 
Monitor LFTs every 1-2 
days 
 
Steroids: 1-2 mg/kg/day 
methylprednisolone IV or 
IV equivalent (Note: Use 
2 mg/kg/day dose for 
Grade 4 LFTs) 
methylprednisolone IV. 
 
Add prophylactic 
antibiotics for 
opportunistic infections 
 
Consult hepatologist or  
gastroenterologist 
If returns to grade 2: 
 
Taper steroids over at least 1 
month 
If does not improve in >3-5 days, 
worsens or rebounds: 
 
Add mycophenolate mofetil 
 
If no response within an 
additional 3-5 days, consider 
other immunosuppressants 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) 
at start of tapering or earlier, once sustained clinical improvement is observed. 
 
6.1.4 Endocrine adverse events 
Endocrinopathies have been observed following treatment with nivolumab. Most cases are low or 
moderate grade. The events have typically been identified through either routine periodic monitoring 
of specific laboratories (eg, TSH) or as part of a work-up for associated symptoms (eg, fatigue). 
Events may occur within weeks of beginning treatment but also have been noted to occur after many 
months (while still on treatment). More than one endocrine organ may be involved. Early recognition 
and treatment of endocrinopathies are critical to its management. Patients should be advised to seek 
medical evaluation if they notice new onset of fatigue, lightheadedness, or difficulty with vision or if 
baseline fatigue worsens. As fatigue is common in patients with CLL, it is important that an 
evaluation/work-up distinguish between non-drug- related causes (eg, progression of disease, 
anemia, concomitant medications, depression) and a possible drug-related AE as the management 
is quite different. The principal management of endocrinopathies is hormone replacement therapy.  


 
Page 19 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
 
Asymptomatic TSH elevation 
 
Continue nivolumab 
 
If TSH < 0.5 x LLN, or TSH > 2 x ULN, or consistently out of 
range in 2 subsequent measurements: consider 
endocrinology consult 
Symptomatic endocrinopathy 
 
Evaluate endocrine 
function 
 
Consider pituitary scan 
Symptomatic with abnormal 
lab/pituitary scan: 
 
Delay nivolumab 
 
Steroids: 1-2 mg/kg/day 
methylprednisolone IV or 
PO equivalent 
 
Initiate appropriate 
hormone therapy 
No abnormal lab/pituitary 
MRI scan but symptoms 
persist: 
 
Repeat labs in 1-3 
weeks / MRI in 1 month 
If improves  (with or without 
hormone replacement): 
 
Taper steroids over at least 1 
month and consider 
prophylactic antibiotics for 
opportunistic infections 
 
Resume nivolumab 
 
Patients with adrenal 
insufficiency may need to 
continue steroids with 
mineralocorticoid component 
 
Suspicion of adrenal crisis (e.g. 
severe dehydration, hypotension, 
shock out of proportion to current 
illness) 
 
Delay or discontinue nivolumab 
 
Rule out sepsis 
 
Stress dose of IV steroids with mineralocorticoid activity 
 
IV fluids 
 
Consult endocrinologist 
 
If adrenal crisis ruled out,  then treat as above for 
symptomatic endocrinopathy 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) 
at start of tapering or earlier, once sustained clinical improvement is observed. 
 
6.1.5 Skin adverse events 
Rash and pruritus are the most common skin AEs observed following treatment with nivolumab. The 
rash is typically focal with a maculopapular appearance occurring on the trunk, back, or extremities. 
Most cases have been low or moderate grade. In some cases, rash and pruritus resolved without 
intervention. Topical corticosteroids have been used for some cases of rash. Anti-histamines have 
been used for some cases of pruritus. More severe cases responded to systemic corticosteroids. 
Patients should be advised to seek medical evaluation if they notice new onset rash. Early 
consultation with a dermatology specialist and a biopsy should be considered if there is uncertainty 
as to the cause of the rash or if there is any unusual appearance or clinical feature associated with it. 
Other drugs which may cause rash should be considered in the differential and if possible 
discontinued.  
 
Grade of Rash   
Management  
Follow-up 
Grade 1-2 
(Covering ≤ 30% of BSA) 
 
Continue nivolumab  
 
Symptomatic therapy 
If persists > 1-2 weeks or recurs: 
 
Consider skin biopsy 


 
Page 20 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
(e.g. antihistamines, 
topical steroids) 
 
 
Delay nivolumab 
 
Steroids: Consider 0.5-1.0 
mg/kg/day 
methylprednisolone IV or oral 
equivalent. Once improving , 
taper steroids over at least 1 
month, consider prophylactic 
antibiotics for opportunistic 
infections, and resume 
nivolumab 
If worsens: 
 
Treat as Grade 2 or 3-4 
Grade 3-4 
(Covering >30% BSA; Life 
threatening consequences)  
 
Delay or discontinue 
nivolumab 
 
Consider skin biopsy 
 
Dermatology consult 
 
Steroids: 1-2 mg/kg/day 
IV methylprednisolone 
 
IV or IV equivalent 
If improves to Grade 1: 
 
Taper steroids over at least 1 
month and add prophylactic 
antibiotics for opportunistic 
infections 
 
Resume nivolumab 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) 
at start of tapering or earlier, once sustained clinical improvement is observed. 
 
6.1.6 Renal adverse events 
Elevated creatinine and biopsy confirmed tubulointerstitial nephritis and allergic nephritis have been 
infrequently observed following treatment with nivolumab. Most cases were Grade 2 or Grade 3 and 
based on creatinine elevation. Events were managed with corticosteroids and in all cases renal 
function partially or fully improved. As creatinine abnormalities are common in patients with CLL and 
other comorbidities, it is important that an evaluation/work-up distinguish between non- drug-related 
causes (eg, dehydration, concomitant medications, hypotension, progression of disease) and a 
possible drug-related AE as the management is quite different. The principal treatment for renal AEs 
is corticosteroids. 
 
Grade of Creatinine Elevation 
Management  
Follow-up 
Grade 1 (Creatinine > ULN and  > 
than baseline but  ≤ 1.5x baseline) 
 
Continue nivolumab 
 
Monitor creatinine 
weekly 
If returns to baseline: 
 
Resume routine creatinine 
monitoring per protocol  
If worsens: 
 
Treat as Grade 2 or 3-4 
Grade 2-3 (Creatinine > 1.5x 
baseline to ≤ 6x ULN) 
 
Delay nivolumab 
 
Monitor creatinine every 
2-3 days 
 
Steroids: 0.5-1 
mg/kg/day methyl-
prednisolone IV or oral 
equivalent 
 
Consider renal biopsy 
If returns to Grade 1: 
 
Taper steroids over at least 1 
month, consider prophylactic 
antibiotics for opportunistic 
infections, and resume 
nivolumab and routine 
creatinine monitoring per 
protocol 


 
Page 21 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
If elevations persist >7 days or 
worsen:  
 
Treat as Grade 4 
Grade 4 (Creatinine > 6x ULN) 
 
Discontinue Nivolumab 
 
Monitor creatinine daily 
 
Steroids: 1-2 mg/kg/day 
methylprednisolone IV or 
IV equivalent 
 
Consult nephrologist 
 
Consider renal biopsy 
If returns to Grade 1:  
 
Taper steroids over at least 1 
month add prophylactic 
antibiotics for opportunistic 
infections 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) 
at start of tapering or earlier, once sustained clinical improvement is observed. 
 
6.1.7 Neurologic adverse events 
Neurologic AEs have been uncommonly observed following treatment with nivolumab. Neurologic 
AEs can manifest as central abnormalities (eg, aseptic meningitis, encephalitis) or peripheral 
sensory/motor neuropathies (eg, Guillain-Barre Syndrome). Early recognition and treatment of 
neurologic AEs is critical to its management. Patients should be advised to seek medical evaluation 
if they notice impairment in motor function (eg, weakness), changes in sensation (eg, numbness), or 
symptoms suggestive of possible central nervous system abnormalities such as new headache or 
mental status changes. As neurologic symptoms can be common in patients with cancer, it is 
important that an evaluation/work-up distinguish between non-drug-related causes (eg, progression 
of disease, concomitant medications, infection) and a possible drug-related AE as the management 
is quite different.  
Grade of Neurological Toxicity  
Management  
Follow-up 
Grade 1 (Asymptomatic or mild 
symptoms; intervention not 
indicated) 
 
Continue nivolumab 
 
 
Continue to monitor patient  
If worsens: 
 
Treat as Grade 2 or 3-4 
Grade 2 (Moderate symptoms; 
limiting instrumental ADL) 
 
Delay nivolumab 
 
Symptomatic treatment 
 
Steroids: 0.5-1 
mg/kg/day methyl-
prednisolone IV or oral 
equivalent 
If improves to baseline: 
 
Resume nivolumab 
If worsens: 
 
Treat as Grade 3-4 
Grade 3-4 (Severe symptoms; 
limiting self-care ADL; life-
threatening) 
 
Discontinue Nivolumab 
 
Neurology consult 
 
Symptomatic treatment 
 
Steroids: 1-2 mg/kg/day 
methylprednisolone IV or 
IV equivalent 
 
Add prophylactic 
antibiotics for 
opportunistic infections 
If improves to Grade 2: 
 
Taper steroids over at least 1 
month 
If worsens or atypical 
presentation: 
 
Consider IVIG or other 
immunosuppressive 
therapies 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) 
at start of tapering or earlier, once sustained clinical improvement is observed. 
 


 
Page 22 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
6.1.8 Lipase/Amylase Elevations 
Asymptomatic elevations in lipase and amylase have been reported. In monotherapy studies of 
nivolumab, lipase and amylase levels were not systematically monitored, so an estimate of the 
frequency of asymptomatic lipase/amylase elevations is unknown. In a study evaluating the safety of 
the nivolumab + ipilimumab combination in melanoma, lipase and amylase levels were systematically 
monitored and the frequency of any grade lipase/amylase AEs was 29% and Grade 3-4 were 18%. 
Very few patients reported associated symptoms (eg, abdominal pain) or radiographic findings (eg, 
stranding) consistent with pancreatitis. Thus, there does not seem to be clinical significance to the 
elevated laboratory values. As lipase/amylase abnormalities are not uncommon in patients with 
cancer, it is important that an evaluation/work-up distinguish between non-drug-related causes (eg, 
progression of disease, concomitant medications, alcohol) and a possible drug-related cause as the 
management is quite different. The recommended management of nivolumab-related elevated 
lipase/amylase values centers around close observation. Physicians should ensure patients have no 
associated symptoms consistent with pancreatitis such as abdominal pain. Corticosteroids do not 
seem to alter the natural history of lipase/amylase elevations. Laboratory values tend to fluctuate day 
to day and eventually return to baseline or low grade over the course of weeks whether or not patients 
receive corticosteroids. Asymptomatic elevations should be monitored approximately weekly. For 
patients with elevated lipase/amylase and symptoms consistent with possible pancreatitis, nivolumab 
should be discontinued and consultation with a gastroenterologist should be considered.  
 
6.1.9 Uveitis and Visual Complaints 
Immune therapies have been uncommonly associated with visual complaints. Inflammation of 
components within the eye (eg, uveitis) is an uncommon but clinically important event. An 
ophthalmologist should evaluate visual complaints. Topical corticosteroids may be used to manage 
low grade events. Low-grade events that do not resolve and high-grade events should be managed 
with systemic corticosteroids.  
 
6.1.10 Nivolumab administration should be delayed for the following: 
 
Any Grade ≥ 2 non-skin, drug-related AE, with the following exceptions: 
 
Grade 2 drug-related fatigue or laboratory abnormalities do not require a treatment 
delay 
 
Any Grade 3 skin, drug-related AE 
 
Any Grade 3 drug-related laboratory abnormality, with the following exceptions for 
lymphopenia, leukopenia, AST, ALT, total bilirubin, or asymptomatic amylase or lipase: 
 
Grade 3 lymphopenia or leukopenia does not require dose delay 
 
If a subject has a baseline AST, ALT, or total bilirubin that is within normal limits, 
delay dosing for drug-related Grade ≥ 2 toxicity 
 
If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity 
range, delay dosing for drug-related Grade ≥ 3 toxicity 
 
Asymptomatic amylase or lipase does not require dose delay 


 
Page 23 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
 
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, warrants delaying the dose of study medication 
 
6.1.11 Criteria to Resume Treatment 
Patients may resume treatment with study drug when the drug-related AE(s) resolve to Grade ≤1 or 
baseline value, with the following exceptions: 
 
Patients may resume treatment in the presence of Grade 2 fatigue  
 
Patients who have not experienced a Grade 3 drug-related skin AE may resume treatment in 
the presence of Grade 2 skin toxicity  
 
Patients with baseline Grade 1 AST/ALT or total bilirubin who require dose delays for reasons 
other than a 2-grade shift in AST/ALT or total bilirubin may resume treatment in the presence 
of Grade 2 AST/ALT OR total bilirubin 
 
Patients with combined Grade 2 AST/ALT AND total bilirubin values meeting discontinuation 
parameters (Discontinuation Section, Section 12.0) should have treatment permanently 
discontinued 
 
Drug-related pulmonary toxicity, diarrhea, or colitis, must have resolved to baseline before 
treatment is resumed 
 
Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment 
If the criteria to resume treatment are met, the subject should restart treatment at the next scheduled 
timepoint per protocol. However, if the treatment is delayed past the next scheduled timepoint per 
protocol, the next scheduled timepoint will be delayed until dosing resumes. 
If treatment is delayed > 6 weeks, the subject must be permanently discontinued from study therapy, 
except as specified in discontinuation section. 
6.2 Dose modifications for ibrutinib 
Interrupt ibrutinib for any Grade 3 or greater non-hematological, Grade 3 or greater neutropenia with 
infection or fever, or Grade 4 hematological toxicities. Once the symptoms of the toxicity have 
resolved to Grade 1 or baseline, reinitiate ibrutinib at the starting dose. If the toxicity reoccurs, reduce 
dose by one capsule (140 mg per day).  
NOTE: As diarrhea could occur from the use of ibrutinib or nivolumab, patients with grade 2 diarrhea 
should have their ibrutinib held. 
 
Recommended dose modifications are described below:  
Toxicity Occurrence 
Dose modification 
Starting Dose = 420 mg daily 
First 
Restart at 420 mg daily 
Second 
Restart at 280 mg daily 
Third 
Restart at 140 mg daily 
Fourth 
Discontinue ibrutinib 


 
Page 24 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
 
Dose Modifications for Use with CYP3A Inhibitors/Inducers: Ibrutinib is metabolized primarily by 
CYP3A. Concomitant use of strong CYP3A inhibitors which would be taken chronically (e.g., ritonavir, 
indinavir, nelfinavir, saquinavir, boceprevir, telaprevir, nefazodone) is not recommended. For strong 
CYP3A inhibitors used short-term (e.g., antifungals and antibiotics for 7 days or less, e.g., 
ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin), consider 
holding ibrutinib therapy during the duration of the inhibitor use. Avoid strong CYP3A inhibitors that 
are needed chronically. If a moderate CYP3A inhibitor must be used (e.g., fluconazole, darunavir, 
erythromycin, diltiazem, atazanavir, aprepitant, amprenavir, fosamprevir, verapamil, grapefruit 
products and ciprofloxacin), reduce ibrutinib dose to 140 mg daily.  
Avoid grapefruit and Seville oranges during ibrutinib treatment, as these contain moderate inhibitors 
of CYP3A. Avoid Star fruit as it contains inhibitors of CYP3A. 
Administration of ibrutinib with strong inducers of CYP3A can decrease ibrutinib plasma  
concentrations. Concomitant use of strong CYP3A inducers (e.g., rifampin, rifabutin, phenytoin, 
carbamazepine, and St. John’s Wort) are not recommended.  
 
A list of common CYP3A inhibitors and inducers is provided in Appendix 2; a comprehensive list of 
inhibitors, inducers, and substrates may be found at  
http://medicine.iupui.edu/clinpharm/ddis/table.aspx. This website is continually revised and should be 
checked frequently for updates. 
 
7.0 CONCOMITANT THERAPY 
7.1 Allowed concomitant therapy 
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)  
 
Radiotherapy (Note: Localized radiotherapy to an area not compromising bone marrow function 
is allowed) 
 
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 for nivolumab, or replacement/stress corticosteroids are permitted. 
 
Strong CYP3A inhibitors which would be taken chronically 
 
Grapefruit, Seville oranges, Star fruit 
 
Strong CYP3A inducers (e.g., rifampin, rifabutin, phenytoin, carbamazepine, and St. John’s Wort) 
are not recommended 
 
8.0 PRETREATMENT EVALUATIONS 
 


 
Page 25 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
1.  Pretreatment evaluation will include a complete history and physical examination including vital signs, 
neurological examination, ECOG performance status, height and weight and recording of concurrent 
medications (within 14 days of the first dose) 
2. Complete blood count (hemoglobin, white blood cell count, platelet count, white blood count 
differential) (within 14 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 acid, LDH, amylase, lipase, β-2 microglobulin, immunoglobulins (within 14 days of the first 
dose) 
4. B, T, NK cell counts and subset analyses on the peripheral blood (within 14 days of the first dose) 
5. PT, aPTT (within 14 days of the first dose) 
6.  Urinalysis (within 14 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 urine β-hCG pregnancy test result 
within 24 hours prior to the first dose. 
10. 12-lead EKG (within 30 days of the first dose) 
11. MUGA or Echocardiogram (within 30 days of the first dose) 
12. Bone marrow aspiration and biopsy (within 60 days of the first dose if no intervening treatment for 
CLL given)   
13. CT scan of the neck (if indicated), chest, abdomen, and pelvis with IV and oral contrast, within 30 
days of the first dose with no intervening treatment for CLL given. 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.  
 
9.0 EVALUATIONS DURING THE STUDY 
 
Cycle 1 Day 1 
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 (Note: Cycle 1 Day 1 labs obtained within 3 days prior to the Day 1 is acceptable) 
2.  Vital signs, history and physical examination including neurological examination (Note: History and 
physical examination within 3 days prior to the Day 1 is acceptable) 
 
Cycle 1 Day 8 (+/- 3 days) 
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 
2.  Vital signs, history and physical examination including neurological examination 
 
Cycle 1 Day 15 (+/- 3 days) 


 
Page 26 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
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, amylase, lipase 
2.   Vital signs, history and physical examination including neurological examination 
3.  Urinalysis  
 
Cycle 1 Day 22 (+/- 3 days) 
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 
2.   Vital signs, history and physical examination including neurological examination 
 
End of Cycle 1 (+/- 3 days) 
1. For COHORT 1 only - 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. Note: This evaluation should be 
done prior to starting ibrutinib in this cohort (i.e. prior to starting cycle 2). 
2. For COHORT 1 only – Bone marrow aspiration with multi-color flow cytometry for MRD evaluation.  
 
Cycle 2 Day 1 (+/- 3 days) 
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, amylase, lipase, quantitative immunoglobulin levels, and B, T, NK cell counts and subset 
analyses on the peripheral blood 
2.   Vital signs, history and physical examination including neurological examination 
3.  TSH, Free T4 
4.  Urinalysis  
 
Cycle 2 Day 8 (+/- 3 days) 
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 
 
Cycle 2 Day 15 (+/- 3 days) 
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, amylase, lipase 
2. Serum or urine β-hCG pregnancy test (for women of childbearing potential) 
3.   Vital signs, history and physical examination including neurological examination 
 
Cycle 2 Day 22 (+/- 3 days) 
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 
 


 
Page 27 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
Cycle 3 Day 1 (+/- 3 days) 
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, amylase, lipase, quantitative immunoglobulin levels and B, T, NK cell counts and subset 
analyses on the peripheral blood 
2.   Vital signs, history and physical examination including neurological examination 
3.  TSH, Free T4 
4.  Urinalysis  
 
Cycle 3 Day 8 (+/- 3 days) 
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 
 
Cycle 3 Day 15 (+/- 3 days) 
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, amylase, lipase 
2.   Vital signs, history and physical examination including neurological examination 
 
Cycle 3 Day 22 (+/- 3 days) 
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 
 
End of Cycle 3 (+/- 1 week) 
1. Bone marrow aspiration and biopsy with multi-color flow cytometry for MRD evaluation. 
2.   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 (+/- 3 days) 
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, amylase, lipase, β-2 microglobulin, quantitative immunoglobulin levels and B, T, NK cell 
counts and subset analyses on the peripheral blood 
2.   Vital signs, history and physical examination including neurological examination 
3.  TSH, Free T4 
4.   Urinalysis  
5. Serum or urine β-hCG pregnancy test (for women of childbearing potential) 
 
Cycle 4 Day 15 (+/- 3 days) 
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, amylase, lipase 


 
Page 28 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
2.   Vital signs, history and physical examination including neurological examination 
 
Cycle 5 Day 1 (+/- 3 days) 
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, amylase, lipase, quantitative immunoglobulin levels and B, T, NK cell counts and subset 
analyses on the peripheral blood 
2.   Vital signs, history and physical examination including neurological examination 
 
Cycle 5 Day 15 (+/- 3 days) 
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, amylase, lipase 
2. Serum or urine β-hCG pregnancy test (for women of childbearing potential) 
3.   Vital signs, history and physical examination including neurological examination 
 
Cycle 6 Day 1 (+/- 3 days) 
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, amylase, lipase, quantitative immunoglobulin levels and B, T, NK cell counts and subset 
analyses on the peripheral blood 
2.   Vital signs, history and physical examination including neurological examination 
 
Cycle 6 Day 15 (+/- 3 days) 
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, amylase, lipase 
2.   Vital signs, history and physical examination including neurological examination 
 
End of Cycle 6 (+/- 1 week) 
1. Bone marrow aspiration and biopsy with multi-color flow cytometry for MRD evaluation. 
2.   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 7 onwards (+/- 3 days) 
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, amylase, lipase (on the day of Nivolumab infusions) 
2.  Complete history and physical examination including vital signs and neurological examination 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. Serum or urine β-hCG pregnancy test (for women of childbearing potential) at least every 6 weeks 
6. TSH, Free T4 every 3 months 


 
Page 29 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
7.   Urinalysis every 3 months 
8. Bone marrow aspiration and biopsy with multi-color flow cytometry for MRD evaluation every 3 
months for the first year of the study, then every 6 months 
9.  CT scan of the neck (if indicated), chest, abdomen, and pelvis with IV and oral contrast every 3 months 
for the first year of the study, then then every 6 months. PET scan may be used instead of the CT 
scan imaging.  
 
Note: Patients who complete all protocol specified nivolumab treatments (or discontinue nivolumab early, 
see Section 12.0) will have the following evaluations until removal from study (These are the patients 
continuing on ibrutinib monotherapy): 
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 for the first 3 months, then every 3 months 
2.  Complete history and physical examination including vital signs and neurological examination at least 
monthly for the first 3 months, then every 3 months. 
3. Quantitative immunoglobulin levels monthly for the first 3 months, then every 3 months 
4.  B, T, NK cell counts and subset analyses on the peripheral blood monthly for the first 3 months, then 
every 3 months 
5. Serum or urine β-hCG pregnancy test (for women of childbearing potential) monthly for 3 times 
6. TSH, Free T4 every 3 months 
7.   Urinalysis every 3 months 
8. Bone marrow aspiration and biopsy with multi-color flow cytometry for MRD evaluation every 3 
months for the first year of the study, then every 6 months 
9.   CT scan of the neck (if indicated), chest, abdomen, and pelvis with IV and oral contrast every 3 
months for the first year of the study, then then every 6 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 +/- 7 days 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 including neurological 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. Note: This post-protocol follow-up period of one year will end early if the 


 
Page 30 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
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.  
 
Adverse Events Monitoring - Adverse events will be assessed continually while on the study, until 30 
days after the last dose of drug 
 
NOTE: All treatments with nivolumab 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 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 3)  
 
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, according to the modified 2008 IWCLL response criteria for CLL. 
OR is defined as a CR or PR (or CR with incomplete marrow recovery) as determined by investigator 
assessment using CLL response criteria.53,54 Patients with missing or no response assessments will be 
classified as non-responders. 
 
Complete Response (CR): Requires all of the following:  
 
Peripheral blood lymphocytes <4000/µL 
 
Absence of significant lymphadenopathy (eg, lymph nodes >1.5 cm in diameter) by physical exam 
and CT (PET may be used in place of CT scan)  


 
Page 31 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
 
No hepatomegaly or splenomegaly by physical exam (and CT/PET scan if assessment was 
abnormal before therapy or if physical exam is inconclusive) 
 
Absence of constitutional symptoms 
 
Blood counts above the following values (without need for growth factors or transfusions): 
neutrophils >1,500/μL, platelets >100,000/μL, hemoglobin >11.0 g/dl 
 
Bone marrow aspirate and biopsy must be normocellular for age with <30% of nucleated cells 
being lymphocytes. Lymphoid nodules should be absent. If the bone marrow is hypocellular, a 
repeat determination should be made in 4 weeks or when peripheral blood counts have 
recovered. Hypocellular marrow should be noted as CR with incomplete marrow recovery 
(CRi).  
Partial Response (PR): Requires one of the following for a period ≥2 months:  
 
≥50% decrease in peripheral lymphocyte count from pretreatment baseline value 
 
≥50% reduction in lymphadenopathy as defined by:  
o ≥50% decrease in lymph node size either in the sum products of up to 6 lymph nodes or 
in the largest diameter of the enlarged lymph node(s) detected before therapy 
o No increase in any lymph node and no new enlarged lymph node (In small lymph nodes 
[<2cm], an increase of <25% is not considered significant) 
 
≥50% reduction in pretreatment enlargement of the spleen or liver, as detected by CT/PET scan 
Additionally, these patients must have at least one of the following for ≥2 months: 
 
Neutrophils >1,500/μL (without need for growth factors) 
 
Platelets >100,000/μL or ≥50% improvement over baseline (without need for growth factors) 
 
Hemoglobin >11.0 g/dl (untransfused) or ≥50% improvement over baseline 
Additionally, patients who fulfill the criteria above for CR but who have the following will be considered a 
PR 
 
Patients with bone marrow nodules (may be noted as nodular PR). Immunohistochemistry should 
be performed to define whether these nodules are composed of primarily T cells or lymphocytes 
other than CLL cells, or CLL cells. 
 
Patients with persistent anemia or thrombocytopenia or neutropenia apparently unrelated to 
disease activity and more likely the consequence of persistent drug toxicity (may be noted as 
CRi). 
 
Progressive Disease (PD): Characterized by ≥1 of the following events:  
 
 
Lymphadenopathy: ≥50% increase in greatest determined diameter of any previous site; 
appearance of any new lesion, such as enlarged lymph nodes (>1.5 cm), splenomegaly, 
hepatomegaly, or other organ infiltrates (NOTE: new lesion or isolated and/or transient increase 
in target lesion(s) in the setting of reduced lymph node size or organomegaly, or improvement in 
hemoglobin/platelets is not considered PD unless persists for >4 weeks (CT/PET scan 
confirmation required) 
 
≥50% increase in the previously noted enlargement of the liver or spleen; de novo appearance of 
hepatomegaly or splenomegaly 


 
Page 32 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
 
≥50% increase in the absolute number of circulating lymphocytes to ≥5,000/μL (NOTE: In the 
absence of other objective evidence of PD,  lymphocytosis alone is not considered progressive 
disease) 
 
Transformation to a more aggressive histology (i.e., Richter’s syndrome) 
 
Occurrence of cytopenia (neutropenia, anemia, or thrombocytopenia) attributable to CLL 
(decrease in hemoglobin ≥2 gm/dL or to <100 g/L; or decrease ≥50% in platelets or to 
<100,000/uL) that occurs ≥3 months after treatment, if the marrow biopsy demonstrates an 
infiltrate of clonal CLL cells. 
Stable Disease (SD): Patients who do not fulfill the criteria for complete or partial response as defined 
above but do not exhibit progressive disease will be considered as having stable disease. 
 
Responses for patients with RT will be assessed by non-Hodgkin’s lymphoma (NHL) criteria.55 
 
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.  
 
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 


 
Page 33 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
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 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 drugs by the PI using the following scale: 
 
Unrelated: The AE is clearly NOT related to the intervention. 
Unlikely: The AE is doubtfully related to the intervention. 
Possible: The AE may be related to the intervention. 
Probable: The AE is likely related to the intervention. 
Definite: The AE is clearly related to the intervention. 
 
11.1.5 All grade 3 and greater non-hematological events that are felt to be related to protocol treatment 
drugs will be documented on the toxicity log and entered into the case report form. The toxicity log and 
case report form data must reflect relationship to the drug the event is felt to be related to. 
 
11.1.6 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:  


 
Page 34 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
 
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": 
 
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 100 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: 


 
Page 35 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project Manager 
IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the protocol 
guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
 
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 
 
All SAEs, whether related or unrelated to nivolumab and all pregnancies must be reported to 
BMS (by the investigator or designee) within 48 hours.  
 
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 nivolumab or to ibrutinib 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. 
 
Additional Discontinuation Criteria for Nivolumab 
Treatment should be permanently discontinued for the following: 
 
Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment  
 
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following exceptions 
for drug-related laboratory abnormalities, uveitis, pneumonitis, bronchospasm, diarrhea, colitis, 
neurologic adverse event, hypersensitivity reactions, and infusion reactions 


 
Page 36 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
o Grade 3 drug-related uveitis, pneumonitis, bronchospasm, diarrhea, colitis, neurologic 
adverse event, hypersensitivity reaction, or infusion reaction of any duration requires 
discontinuation 
o Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except those noted below: 
 
Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation 
 
Any drug-related liver function test (LFT) abnormality that meets the following criteria 
require discontinuation:  
• 
AST or ALT > 8 x ULN  
• 
Total bilirubin > 5 x ULN 
• 
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN 
 
Any Grade 4 drug-related adverse event or laboratory abnormality, except for the following events 
which do not require discontinuation: 
 
Isolated Grade 4 amylase or lipase abnormalities that are not associated with symptoms 
or clinical manifestations of pancreatitis and decrease to < Grade 4 within 1 week of onset.  
 
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72 
hours of their onset 
 
Any dosing interruption lasting > 6 weeks with the following exceptions: 
 
Dosing interruptions to allow for prolonged steroid tapers to manage drug-related adverse 
events are allowed. Prior to re-initiating treatment in a subject with a dosing interruption 
lasting > 6 weeks, the Investigator must be consulted. Tumor assessments should 
continue as per protocol even if dosing is interrupted 
 
Dosing interruptions > 6 weeks that occur for non-drug-related reasons may be allowed if 
approved by the Investigator. Prior to re-initiating treatment in a subject with a dosing 
interruption lasting > 6 weeks, the Investigator must be consulted. Tumor assessments 
should continue as per protocol even if dosing is interrupted 
 
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, presents a substantial clinical risk to the subject with continued nivolumab dosing 
 
13.0 CORRELATIVE STUDIES 
All correlative studies are optional and failure to collect these studies at any of the specified time-points 
is not a protocol deviation. 
 
Correlative Studies relating to immunologic response will be collected on a separate IRB-approved 
Protocol (PA13-0291). 
 
Approximately 30cc of peripheral blood will be collected at the following time-points (pretreatment, C1D1, 


 
Page 37 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
C1D15, C2D1, C3D1, end of C3, C5D1, C6D1, end of C6, C8D1, C9D1, end of C9, C11D1, C12D1, end 
of C12, end of C18, end of C24) and stored in the Leukemia Research Bank. Approximately 6cc of bone 
marrow aspirate will be collected at the following time-points (pretreatment, C2D1 (only for cohort 1), end 
of C3, end of C6, end of C9, end of C12, end of C18, end of C24) and stored in the Leukemia Research 
Bank.  
 
Coevolution of tumor and immune cell heterogeneity following combined ibrutinib and nivolumab therapy 
in CLL (Catherine Wu, MD, Dana-Farber Cancer Institute, Boston, MA) – We propose a correlative study 
to analyze both tumor and immune cells in the marrow and peripheral blood microenvironments of CLL, 
using samples from responders and non-responders, pre- and post-treatment. Using emerging single cell 
profiling tools to deeply monitor the genetic and molecular processes occurring within tumors from 
patients undergoing immune modulation, we hope to derive the co-evolutionary trajectories and principles 
that underlie the success or failure of immunomodulatory therapy. The protocol for freezing whole blood 
and marrow aspirate is in Appendix 4. The research methods and design are detailed in Appendix 5.  
 
14.0 STATISTICAL CONSIDERATIONS 
 
EFFICACY 
A maximum of 72 patients will be enrolled in this Phase II study. Cohort 1 and 3 will enroll up to 24 
patients each who were refractory to or relapsed after at least one prior standard therapy or untreated 
with del(17p) by FISH; Cohort 2 will enroll up to 24 patients who have been on ibrutinib for at least 9 
months and have achieved a partial response.   
 
Note: Statistical analysis and sopping rules, and toxicity assessment for Cohort 3 will be same as Cohort 
1. 
 
In the first cohort, the primary objective is to evaluate best response during the first 12-month of therapy. 
The primary efficacy endpoint, best response (BR), is defined as CR or CRi that occurs during the first 
12 months of treatment.  The optimum two-stage design proposed by Simon will be implemented.56 We 
assume a target BR rate of 20% and a BR rate of 5% or lower will be considered not desirable. With a 
type I error rate of 10% and 80% power, we will enroll 9 patients in the first stage. If no patients achieve 
BR, the trial will be stopped. If 1 or more out of the first 9 patients have BR, accrual will continue until a 
total of 24 patients have been enrolled. We will suspend accrual at the end of the first stage, if all 9 
patients have been enrolled, yet no responder (CR or CRi) has been observed. At the end of the study, 
if 3 or more out of the 24 patients achieve BR, the combination treatment will be considered efficacious 
and is worth further investigation. Under this Simon’s two-stage design, the probability of early termination 
is 63% if the true BR is 5% and the expected sample size is 14.6 patients.  
In the second cohort, the primary objective is to evaluate conversion rate during the first 12-month of 
therapy. The primary efficacy endpoint, conversion rate is defined as the conversion from partial response 
(PR) to complete response (CR/CRi) that occurs during the first 12 months of treatment. Up to 24 patients 
will be enrolled in this cohort. The same Simon’s optimum two-stage design as described above will be 
used here in cohort 2. We assume a target conversion rate of 20% and a conversion rate of 5% or lower 
will be considered not desirable. With a type I error rate of 10% and 80% power, we will enroll 9 patients 
in the first stage. If no patient converts from PR to CR, the trial will be stopped. If 1 or more out of the first 


 
Page 38 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
9 patients achieve conversion, accrual will continue until a total of 24 patients have been enrolled. We 
will suspend accrual at the end of the first stage, if all 9 patients have been enrolled, yet no conversion 
has been observed. At the end of the study, if 3 or more out of the 24 patients achieve conversion, the 
combination treatment will be considered efficacious and is worth further investigation. Under this design, 
the probability of early termination is 63% if the true conversion rate is 5% and the expected sample size 
is 14.6 patients.  
 
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.57 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) >0.8. 
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 80% 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 14.1 below. The operating characteristics for toxicity monitoring are 
summarized in Table 14.2.  
 
Table 14.1. 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 
 3-6 
12 
 6-12 
18 
 8-18 
24 
 10-24 
30 
 12-30 
36 
 14-36 
42 
 16-42 
 
Table 14.2. Operating characteristics for toxicity monitoring.  
True Toxicity 
Rate 
Early Stopping 
Probability 
Average 
number of 
patients treated 
0.1 
 0.02 
 47.3 
0.2 
 0.12 
 43.4 
0.3 
 0.41 
 33.8 
0.4 
 0.81 
 20.7 
0.5 
 0.98 
 11.7 
 
ANALYSIS PLAN 


 
Page 39 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
Summary statistics will be provided for continuous variables. Frequency tables will be used to summarize 
categorical variables.  The best response rate for cohort 1 and conversion rate for cohort 2 will be 
estimated along with the exact 95% confidence 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.  
 
 
 
15.0 REFERENCES 
1. 
Gribben JG, O'Brien S. Update on therapy of chronic lymphocytic leukemia. J Clin Oncol. 2011;29(5):544-
550. 
2. 
Dohner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic 
leukemia. N Engl J Med. 2000;343(26):1910-1916. 
3. 
Gonzalez D, Martinez P, Wade R, et al. Mutational status of the TP53 gene as a predictor of response 
and survival in patients with chronic lymphocytic leukemia: results from the LRF CLL4 trial. J Clin Oncol. 
2011;29(16):2223-2229. 
4. 
Jain N, O'Brien S. Chronic lymphocytic leukemia with deletion 17p: emerging treatment options. 
Oncology. 2012;26(11):1067, 1070. 
5. 
Badoux XC, Keating MJ, Wang X, et al. Fludarabine, cyclophosphamide, and rituximab 
chemoimmunotherapy is highly effective treatment for relapsed patients with CLL. Blood. 
2011;117(11):3016-3024. 
6. 
Parikh SA, Kay NE, Shanafelt TD. How we treat Richter syndrome. Blood. 2014;123(11):1647-1657. 
7. 
Jain N. New developments in Richter syndrome. Clin Adv Hematol Oncol. 2015;13(4):220-222. 
8. 
Tsimberidou AM, Wierda WG, Wen S, et al. Phase I-II clinical trial of oxaliplatin, fludarabine, cytarabine, 
and rituximab therapy in aggressive relapsed/refractory chronic lymphocytic leukemia or Richter 


 
Page 40 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
syndrome. Clin Lymphoma Myeloma Leuk. 2013;13(5):568-574. 
9. 
Ding W, Dong H, Call TG, et al. PD-1 Blockade with Pembrolizumab (MK-3475) in Relapsed/Refractory 
CLL Including Richter Transformation: An Early Efficacy Report from a Phase 2 Trial (MC1485). Blood. 
2015;126(23):834-834. 
10. 
Kharfan-Dabaja MA, Wierda WG, Cooper LJ. Immunotherapy for chronic lymphocytic leukemia in the era 
of BTK inhibitors. Leukemia : official journal of the Leukemia Society of America, Leukemia Research 
Fund, U.K. 2013. 
11. 
Riches JC, Ramsay AG, Gribben JG. Immune dysfunction in chronic lymphocytic leukemia: the role for 
immunotherapy. Current pharmaceutical design. 2012;18(23):3389-3398. 
12. 
Shanafelt TD, Ramsay AG, Zent CS, et al. Long-term repair of T-cell synapse activity in a phase II trial of 
chemoimmunotherapy followed by lenalidomide consolidation in previously untreated chronic 
lymphocytic leukemia (CLL). Blood. 2013;121(20):4137-4141. 
13. 
Ramsay AG, Johnson AJ, Lee AM, et al. Chronic lymphocytic leukemia T cells show impaired 
immunological synapse formation that can be reversed with an immunomodulating drug. The Journal of 
clinical investigation. 2008;118(7):2427-2437. 
14. 
Riches JC, Davies JK, McClanahan F, et al. T cells from CLL patients exhibit features of T-cell exhaustion 
but retain capacity for cytokine production. Blood. 2013;121(9):1612-1621. 
15. 
Dreger P, European Group for B, Marrow T. The evolving role of stem cell transplantation in chronic 
lymphocytic leukemia. Hematology/oncology clinics of North America. 2013;27(2):355-369. 
16. 
Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic 
lymphoid leukemia. N Engl J Med. 2011;365(8):725-733. 
17. 
Brusa D, Serra S, Coscia M, et al. The PD-1/PD-L1 axis contributes to T-cell dysfunction in chronic 
lymphocytic leukemia. Haematologica. 2013;98(6):953-963. 
18. 
Motta M, Rassenti L, Shelvin BJ, et al. Increased expression of CD152 (CTLA-4) by normal T lymphocytes 
in untreated patients with B-cell chronic lymphocytic leukemia. Leukemia : official journal of the 
Leukemia Society of America, Leukemia Research Fund, U.K. 2005;19(10):1788-1793. 
19. 
Nunes C, Wong R, Mason M, Fegan C, Man S, Pepper C. Expansion of a CD8(+)PD-1(+) replicative 
senescence phenotype in early stage CLL patients is associated with inverted CD4:CD8 ratios and disease 
progression. Clinical cancer research : an official journal of the American Association for Cancer 
Research. 2012;18(3):678-687. 
20. 
Scrivener S, Goddard RV, Kaminski ER, Prentice AG. Abnormal T-cell function in B-cell chronic 
lymphocytic leukaemia. Leukemia & lymphoma. 2003;44(3):383-389. 
21. 
Scrivener S, Kaminski ER, Demaine A, Prentice AG. Analysis of the expression of critical 
activation/interaction markers on peripheral blood T cells in B-cell chronic lymphocytic leukaemia: 
evidence of immune dysregulation. British journal of haematology. 2001;112(4):959-964. 
22. 
Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by 
disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. 
1999;11(2):141-151. 
23. 
Keir ME, Liang SC, Guleria I, et al. Tissue expression of PD-L1 mediates peripheral T cell tolerance. The 
Journal of experimental medicine. 2006;203(4):883-895. 
24. 
Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 
family member leads to negative regulation of lymphocyte activation. The Journal of experimental 
medicine. 2000;192(7):1027-1034. 
25. 
Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annual 
review of immunology. 2008;26:677-704. 
26. 
Nishimura H, Okazaki T, Tanaka Y, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient 
mice. Science. 2001;291(5502):319-322. 


 
Page 41 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
27. 
Nomi T, Sho M, Akahori T, et al. Clinical significance and therapeutic potential of the programmed 
death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clinical cancer research : an 
official journal of the American Association for Cancer Research. 2007;13(7):2151-2157. 
28. 
Iwai Y, Terawaki S, Honjo T. PD-1 blockade inhibits hematogenous spread of poorly immunogenic tumor 
cells by enhanced recruitment of effector T cells. International immunology. 2005;17(2):133-144. 
29. 
Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the 
escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proceedings of the 
National Academy of Sciences of the United States of America. 2002;99(19):12293-12297. 
30. 
Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in 
cancer. N Engl J Med. 2012;366(26):2443-2454. 
31. 
Topalian SL, Sznol M, McDermott DF, et al. Survival, durable tumor remission, and long-term safety in 
patients with advanced melanoma receiving nivolumab. J Clin Oncol. 2014;32(10):1020-1030. 
32. 
Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory 
Hodgkin's lymphoma. N Engl J Med. 2015;372(4):311-319. 
33. 
Chiorazzi N, Ferrarini M. B cell chronic lymphocytic leukemia: lessons learned from studies of the B cell 
antigen receptor. Annual review of immunology. 2003;21:841-894. 
34. 
Stevenson FK, Caligaris-Cappio F. Chronic lymphocytic leukemia: revelations from the B-cell receptor. 
Blood. 2004;103(12):4389-4395. 
35. 
Herishanu Y, Perez-Galan P, Liu D, et al. The lymph node microenvironment promotes B-cell receptor 
signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood. 
2011;117(2):563-574. 
36. 
Burger JA. Nurture versus nature: the microenvironment in chronic lymphocytic leukemia. Hematology / 
the Education Program of the American Society of Hematology. American Society of Hematology. 
Education Program. 2011;2011:96-103. 
37. 
Woyach JA, Johnson AJ, Byrd JC. The B-cell receptor signaling pathway as a therapeutic target in CLL. 
Blood. 2012;120(6):1175-1184. 
38. 
Wiestner A. Emerging role of kinase targeted strategies in chronic lymphocytic leukemia. Blood. 2012. 
39. 
Khan WN. Regulation of B lymphocyte development and activation by Bruton's tyrosine kinase. 
Immunologic research. 2001;23(2-3):147-156. 
40. 
Satterthwaite AB, Witte ON. The role of Bruton's tyrosine kinase in B-cell development and function: a 
genetic perspective. Immunological reviews. 2000;175:120-127. 
41. 
Smith CI, Baskin B, Humire-Greiff P, et al. Expression of Bruton's agammaglobulinemia tyrosine kinase 
gene, BTK, is selectively down-regulated in T lymphocytes and plasma cells. Journal of immunology. 
1994;152(2):557-565. 
42. 
Genevier HC, Hinshelwood S, Gaspar HB, et al. Expression of Bruton's tyrosine kinase protein within the 
B cell lineage. European journal of immunology. 1994;24(12):3100-3105. 
43. 
Conley ME, Dobbs AK, Farmer DM, et al. Primary B cell immunodeficiencies: comparisons and contrasts. 
Annual review of immunology. 2009;27:199-227. 
44. 
Chen L, Widhopf G, Huynh L, et al. Expression of ZAP-70 is associated with increased B-cell receptor 
signaling in chronic lymphocytic leukemia. Blood. 2002;100(13):4609-4614. 
45. 
Rosenwald A, Alizadeh AA, Widhopf G, et al. Relation of gene expression phenotype to immunoglobulin 
mutation genotype in B cell chronic lymphocytic leukemia. The Journal of experimental medicine. 
2001;194(11):1639-1647. 
46. 
Pan Z, Scheerens H, Li SJ, et al. Discovery of selective irreversible inhibitors for Bruton's tyrosine kinase. 
ChemMedChem. 2007;2(1):58-61. 
47. 
Honigberg LA, Smith AM, Sirisawad M, et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell 
activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proceedings of the 


 
Page 42 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
National Academy of Sciences of the United States of America. 2010;107(29):13075-13080. 
48. 
Herman SE, Gordon AL, Hertlein E, et al. Bruton tyrosine kinase represents a promising therapeutic 
target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood. 
2011;117(23):6287-6296. 
49. 
Ponader S, Chen SS, Buggy JJ, et al. The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic 
lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood. 2012;119(5):1182-1189. 
50. 
Byrd JC, Brown JR, O'Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid 
leukemia. N Engl J Med. 2014;371(3):213-223. 
51. 
Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic 
leukemia. N Engl J Med. 2013;369(1):32-42. 
52. 
O'Brien S, Furman RR, Coutre SE, et al. Ibrutinib as initial therapy for elderly patients with chronic 
lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. 
Lancet Oncol. 2014;15(1):48-58. 
53. 
Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic 
lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia 
updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111(12):5446-5456. 
54. 
Cheson BD, Byrd JC, Rai KR, et al. Novel targeted agents and the need to refine clinical end points in 
chronic lymphocytic leukemia. J Clin Oncol. 2012;30(23):2820-2822. 
55. 
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response 
assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 
2014;32(27):3059-3068. 
56. 
Simon R. Optimal two-stage designs for phase II clinical trials. Controlled clinical trials. 1989;10(1):1-10. 
57. 
Thall PF, Simon RM, Estey EH. Bayesian sequential monitoring designs for single-arm clinical trials with 
multiple outcomes. Statistics in medicine. 1995;14(4):357-379. 
 
 
 


 
Page 43 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
APPENDIX 1: SAMPLE OF DRUG ORDERING AND PHARMACY REFERENCE MATERIAL 
Nivolumab (BMS-936558) Pharmacy Reference Material 
 
Nivolumab has a concentration of 10mg/mL and is provided in a 10mL vial.  Ten or five vials are 
provided in a carton. 
 
Initial Orders  
 
Following submission and approval of the required regulatory documents, a supply of nivolumab may 
be ordered from by completing a Drug Request Form provided by BMS for this specific trial. The first 
request may take place upon screening of the first patient  
 
The initial order should be limited to 20 vials. Allow 5 business days for shipment of drug from BMS 
receipt of the Drug Request Form. Drug is protocol specific, but not patient specific. All drug product 
will be shipped by courier in a temperature-controlled container. It is possible that sites may have 
more than one nivolumab clinical study ongoing at the same time. It is imperative that only drug 
product designated for this protocol number be used for this study. 
 
Pharmacy supplies not provided by BMS:  Empty IV bags/containers, approved diluents,  In-line filters 
and infusion tubing 
Re-Supply 
 
Drug re-supply request form should be submitted electronically business days before the expected 
delivery date.  Deliveries will be made Tuesday through Friday. 
 
When assessing need for resupply, institutions should keep in mind the number of vials used per 
treatment dose, and that shipments may take 14 business days from receipt of request. Drug is not 
patient-specific. Be sure to check with your pharmacy regarding existing investigational stock to 
assure optimal use of drug on hand. 
Drug Excursions 
 
Drug  excursions should be reported immediately to BMS on the form provided with the study-specific 
drug order form 
 
 


 
Page 44 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
Please refer to the most recent version of the Investigator Brochure for additional information. 
Storage Conditions & Handling: 
 
Store at 2-8°C (36-46°F), protect from light, freezing, and shaking. 
 
If any temperature excursions are encountered during storage, please report these to BMS for 
assessment via the Temperature Excursion Response Form.    
 
As with all injectable drugs, care should be taken when handling and preparing nivolumab. Whenever 
possible, nivolumab should be prepared in a laminar flow hood or safety cabinet using standard 
precautions for the safe handling of intravenous agents applying aseptic technique.  
 
Partially used vials should be disposed at the site following procedures for the disposal of anticancer 
drugs.  
After final drug reconciliation, unused nivolumab vials should be disposed at the site following procedures 
for the disposal of anticancer drugs. For further information, please either discuss with your BMS CSR&O 
protocol manager or refer to your site IP Destruction policies and procedures  
 
Use Time/Stability: Please refer to section 3.2.3 of the current Investigator Brochure. Due to parameters 
surrounding the use time of Nivolumab, the time of preparation should be noted in the Pharmacy Source 
documents [accountability logs] or in study files as required for investigator sponsored research [FDA 
and GCP] 
The administration of BMS-936558-01 injection prepared for dosing nivolumab infusion must be 
completed within 24 hours of preparation. If not used immediately, the infusion solution may be stored 
up to 20 hours in a refrigerator at under refrigeration conditions (2°-°-8°C (, 36°-46°F) and used within 
4for up to 24 hours, and a maximum of 4 hours of the total 24 hours can be at room temperature (20°-
25°C, 68°-77°F) and under room light. The maximum 4-hour period under room temperature and room 
light conditions for undiluted and diluted solutions of BMS-936558-01 injection in the IV bag should be 
inclusive of the includes the product administration period. 
Preparation and Administration: 
1. Visually inspect the drug product solution for particulate matter and discoloration prior to 
administration.  Discard if solution is cloudy, if there is pronounced discoloration (solution may have a 
pale-yellow color), or if there is foreign paticulate matter other than a few translucent-to-white, 
amorphous particles. 
Note: Mix by gently inverting several times.  Do not shake. 
2. Aseptically withdraw the required volume of nivolumab solution into a syringe, and dispense into an 
IV. bag.  If multiple vials are needed for a subject, it is important to use a separate sterile syringe and 
needle for each vial to prevent problems such as dulling of needle tip, stopper coring, repeated friction 
of plunger against syringe barrel wall. Do not enter into each vial more than once.  Do not administer 
study drug as an IV push or bolus injection 
3. Add the appropriate volume of 0.9% Sodium Chloride Injection solution or 5% Dextrose Injection  
solution. It is acceptable to add nivolumab solution from the vials into an appropriate pre-filled bag of 
diluent. 
Note: Nivolumab infusion concentration must be at or above the minimum allowable 
concentration of 1 mg/mL.  
Note: It is not recommended that so-called “channel” or tube systems are used to transport prepared 
infusions of nivolumab. 
4. Attach the IV bag containing the nivolumab solution to the infusion set and filter. 
5. At the end of the infusion period, flush the line with a sufficient quantity of approved diluents. 
 


 
Page 45 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
Example Dose Calculation [at 3mg/kg] 
Total dose should be calculated as follows (assuming total dose volume of 210 mL, 70 kg pt, 
dose of 3 mg/kg):  
 
 
Subject body weight in kg x 3 mg (for the 3 mg/kg cohort) = total dose (mg) 
70 kg x 3 mg/kg = 210 mg  
 
Total dose (mg) ÷ 10 mg/mL = Amount of solution to be withdrawn from vials 
210 mg ÷ 10 mg/mL = 21 mL 
 
Example of Total volume of solution to infuse (mL) for a minimum conc solution. – Volume of 10 
mg/mL solution (mL) = Volume of Diluent (mL) to add 
                210 mL – 21 mL = 189 mL 
 
Please note it is perfectly acceptable to dose Nivolumab at a higher drug concentrations, as long as 
the total volume of diluted solution is at or above the minimum  allowable concentration of 1 
mg/mL, below is the calculation based on the above example. Please double check. 
Total dose in mg ÷ Total volume to infuse in mL = Overall drug concentration, mg/mL 
210 mg ÷  210mL = 1 mg/mL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Page 46 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
 
Appendix 2: 
Inhibitors and Inducers of CYP3A4/5 
Inhibitors of CYP3A4/5 are defined as follows. A comprehensive list of inhibitors can be found at 
the following website: http://medicine.iupui.edu/clinpharm/ddis/table.aspx.  The general 
categorization into strong, moderate, and weak inhibitors according to the website is displayed 
below. Refer to Section 6.2 on instructions for concomitant use of CYP3A4/5 inhibitors or inducers 
with ibrutinib. 
Inhibitors of CYP3A4/5 
Inducers of CYP3A4/5 
Strong inhibitors: 
INDINAVIR  
NELFINAVIR  
RITONAVIR 
CLARITHROMYCIN 
ITRACONAZOLE 
KETOCONAZOLE 
NEFAZODONE 
SAQUINAVIR  
SUBOXONE 
TELITHROMYCIN 
Moderate inhibitors: 
aprepitant  
erythromycin  
diltiazem    
fluconazole   
grapefruit juice  
Seville orange juice 
verapamil 
Weak inhibitors: 
cimetidine 
All other inhibitors: 
amiodarone    
NOT 
azithromycin 
chloramphenicol 
boceprevir 
ciprofloxacin 
delaviridine 
Carbamazepine 
Efavirenz 
Nevirapine 
Barbiturates 
Glucocorticoids 
Modafinil 
Oxcarbarzepine 
Phenobarbital 
Phenytoin 
Pioglitazone 
Rifabutin 
Rifampin 
St. John’s 
Wort 
Troglitazone 
fluvoxamine  
gestodene  
mibefradil  
mifepristone  
norfloxacin  
norfluoxetine  
star fruit  
telaprevir 
voriconazole 
Source:  http://medicine.iupui.edu/clinpharm/ddis/table.aspx 


 
Page 47 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
APPENDIX 3:  Outside Physician Letter 
 
 
[DATE] 
 
Dear Doctor  [_______], 
_______________________ (name) is a mutual patient of ours with _______. We have placed him/her 
on a protocol: “Nivolumab Combined with Ibrutinib for Relapsed, Refractory or High-risk Untreated 
Patients with Chronic Lymphocytic Leukemia (CLL)” that is being conducted at M.D. Anderson. A 
copy of the abstract, treatment schedule and consent form will be sent to you for your reference.  
(Name) started treatment on [DATE]. Nivolumab is given on day 1 and 15 of each course (courses 1-
24). Each course is 28 days. Ibrutinib is given orally once daily. The principal investigator on this study 
is Dr. Nitin Jain, and (name)’s treating physician is Dr. [NAME]. 
 
In order to allow the patient to spend as much time as possible at home, we request your cooperation in 
the following.   
 
While at home the patient will need the following: 
 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. These tests will be required at least weekly during the first 3 cycles, and 
then every 2 weeks, until he/she returns to M.D. Anderson. 
 Physical examination is required weekly during the first cycle 1, and then every 2 weeks.  
 Please fax all clinic notes, progress notes, labs, imaging and pathology studies to the attention of 
[RESEARCH NURSE] at [PHONE] as soon as they become available.  
 Please notify [RESEARCH NURSE] of hospitalizations for any reason, or any other serious 
adverse events at telephone number [_____] or pager number [_____]. 
 
Please contact Dr. [NAME] or myself before adding any new medications as concurrent medications are 
strictly regulated and must be documented on this protocol.  
 
By signing below, you indicate: 
1) Confirmation of your willingness to perform the physical exam, vital signs, ECOG performance 
status, hematologic and biochemical profiles, and toxicity notation on the dates indicated below;   
 
2)  Fax a copy of all patient’s visit note as required by the protocol and you deem necessary, (receipt of 
this documentation will enable us to meet NCI requirements related to the submission of specific 
paperwork) and allow us to adjust the dose per protocol; 
 
 
3)  Fax a copy of your lab’s CLIA certification.  
 
4)  All protocol-specific decisions must be made by the MD Anderson investigator/physician. 
 
If you agree with these requests, please sign and return this letter as confirmation that we will receive by 


 
Page 48 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
fax a copy of all labs, and a copy of the dictated or handwritten clinic visit notes regarding assessments 
for the following dates: _______________________________ 
 
 
Signature: ______________________________, Date _______ Tel: ______________, Email 
____________ 
A follow up visit at MDACC, for evaluation of response and additional testing is scheduled for: 
________________ [date]                                                                                                                                              
 
For any questions please do not hesitate to contact the research nurse or the Principal Investigator for 
this study – contact details below. 
 
Sincerely, 
 
 
Nitin Jain, MD 
Principal Investigator 
Office:  713-7745-6080; Pager:  713-404-5209; Fax:  713-794-4297 
UT MD Anderson Cancer Center 
PO Box 301402 
Houston, TX  77230-1402 
 
___________________________________ 
[RESEARCH NURSE] RN 
Leukemia Research Nurse  
 
 
 
 
Office:  [___]; Pager:  [___]; Fax:  [___] 
UT MD Anderson Cancer Center 
PO Box 301402 
Houston, TX  77230-1402 
 
 


 
Page 49 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
 
 
 
APPENDIX 4:  PROTOCOL FOR FREEZING WHOLE BLOOD 
1. Collect blood in a heparin tube (green top) and put tube in ice until freezing.  
2. Preparation of freezing buffer: 20% DMSO 80% heat-inactivated FBS (preparation volume 
accordingly to the number of samples need to be frozen). Keep the freezing buffer cold - it should be 
cold before adding it to the cell suspension.  
3. Blood and freezing buffer should be added in a 1:1 ratio. If different volumes of whole blood are 
required, adjust the volume of the blood to the volume of the freezing buffer by keeping a 1:1 ratio 
all the time. Please write on the tube the volume of the blood that you added. Example: Put 750μl of 
whole blood into a freezing tube (we use Nunc cryotube vials Cat-363401) and ad 750μl of freezing 
buffer to the blood. Mix well (do not vortex) until you get a homogenized solution and then put 
tube in ice. 
4. After preparation of all the freezing tubes containing the cells in freezing buffer, put the tubes in a 
Mr. Frosty box and put the box in a -80°C freezer. After 48h or more, you can transfer the tubes to 
liquid nitrogen or you can store them for up to 1 year in -80°C.  
Reagents: 
DMSO- SIGMA, D8418-100ML 
FBS- SIGMA F2442-500ML 
Cryotubes- Nunc 363401 
Mr Frosty- Thermo Scientific 5100-0001. 
 
 


 
Page 50 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016 
 
 
APPENDIX 5:  COEVOLUTION OF TUMOR AND IMMUNE CELL HETEROGENEITY 
FOLLOWING COMBINED IBRUTINIB AND NIVOLUMAB THERAPY IN CLL 
 
We propose a correlative study to analyze both tumor and immune cells in the marrow and peripheral 
blood microenvironments of CLL, using samples from responders and non-responders, pre- and post-
treatment. Using emerging single cell profiling tools to deeply monitor the genetic and molecular 
processes occurring within tumors from patients undergoing immune modulation, we hope to derive the 
co-evolutionary trajectories and principles that underlie the success or failure of immunomodulatory 
therapy. 
 
Research Design and Methods:  
Aim 1) To define genetic evolution of malignant cells in response to BTK/ITK and PD-1 
antagonism. We will study the genetic evolution of cancer somatic alterations through analysis of whole 
exome sequencing data (WES) pre-/post-therapy (i.e. pre/post ibrutinib, pre/post nivolumab, and pre/post 
combined ibrutinib/nivolumab) using both germline (saliva) and cancer (either peripheral blood or 
marrow) from patients at the aforementioned timepoints. Paired RNA-sequencing will be used to validate 
mutational calls and identify unique transcriptional signatures. From these data, we will estimate tumor 
purity, then identify somatic point mutations, insertions/deletions, copy number alterations and 
neoantigens, quantifying their clonal frequencies from pre- and post-treatment samples. 
 
Aim 2) To map distinct molecular states of marrow-infiltrating immune cells at the single cell level, 
pre- and post-therapy. Using marrow aspirates from the timepoints mentioned in Aim 1, we will utilize 
a novel, droplet-based high-throughput single cell mRNA sequencing technology to define distinct 
molecular states of marrow-infiltrating immune cells that associate with therapeutic response or 
resistance. Thousands of single cells will be encapsulated into droplets with lysis buffer, reverse-
transcription mix, and hydrogel microspheres carrying barcoded primers. During reverse-transcription 
each cDNA is tagged with a unique cellular barcode; droplets are subsequently broken, and all material 
is linearly amplified before sequencing. Depending on sample availability, multiparameter flow cytometric 
and multiplexed immunohistochemical analysis of cryopreserved and formalin-fixed paraffin-embedded 
samples, respectively, will be performed to validate single cell transcriptional signatures and immune 
populations. 
 
Aim 3) To track tumor specific infiltrating T cell clones by single cell sequencing of paired T cell 
receptor (TCR) chains. From the peripheral blood, we will sequence paired TCR and  genes at the 
single cell level, encoding a fully functioning TCR, in order to identify and monitor T cell clones after 
therapy that associate with outcome. Over the past year, our group has collaborated extensively with the 
Broad Technology Labs to develop a high-throughput system for amplifying and sequencing paired TCR 
and  genes in single cells, then transfecting the cloned TCR chains into a TCR-deficient T cell line for 
screening against a library of candidate neoantigens (identified from above) that are used to pulse, and 
be presented by, patient blood-derived B cells. Monitoring individual T cell clones and the tumor-specific 
antigens they recognize is critical to understanding coevolution of tumor-T cell responses; recent studies 
signify the clinical potency of neoantigen-specific TCRs. 


 
Page 51 of 51 
2014-0931 Nivolumab and Ibrutinib for CLL 
Version 4 – 01OCT2016