A Phase II Clinical Trial Evaluating Ibrutinib Maintenance Following Intensive Induction for Patients With Previously Untreated Mantle Cell Lymphoma (MCL)
Phase: PHASE2
Conditions: Contiguous Stage II Mantle Cell Lymphoma, Noncontiguous Stage II Mantle Cell Lymphoma, Stage I Mantle Cell Lymphoma, Stage III Mantle Cell Lymphoma, Stage IV Mantle Cell Lymphoma
Sponsor: Northwestern University

Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
1
A Phase II Clinical Trial Evaluating Ibrutinib Maintenance Following Intensive Induction for 
Patients with Previously Untreated Mantle Cell Lymphoma (MCL)
Principal Investigator:
Reem Karmali, MD, MS
Northwestern University Feinberg School of Medicine 
676 North St. Clair Street, Suite 850
Chicago, IL 60611-2927
Phone: (312) 695-0990
Fax: (312) 695-1144
reem.karmali@nothwestern.edu
NU Sub-Investigator(s):
Leo I Gordon, MD 
Jane N Winter, MD 
Shuo Ma, MD, PhD
Valerie Nelson, MD, MBA
Participating Sites:
 Dana Farber d/b/a Massachusetts General Hospital
University of Utah
Jeremy Abramson, MD
Deborah M. Stephens, DO
jabramson@mgh.harvard.edu
deborah.stephens@hci.utah.edu
Biostatistician:
Xinlei Mi, PhD 
xinlei.mi@northwestern.edu
Study Drug:
Ibrutinib
IND Status:
Exempt
Funding Source:
Janssen Scientific Affairs, LLC
Version Date:
August 8, 2022 (Amendment 11)
Sponsor:
Northwestern University
Robert H. Lurie Comprehensive Cancer Center 
Clinical Trials Office
676 N. St. Clair Street, Suite 1200 
Chicago, IL 60611
IRB #: STU00098385-CR0008 Approved by NU IRB for use on or after 3/3/2023 through 3/2/2024.

Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
2
TABLE OF CONTENTS
LIST OF ABBREVIATIONS...............................................................................................3
STUDY SCHEMA...............................................................................................................4
STUDY SUMMARY............................................................................................................4
1.0
BACKGROUND AND RATIONALE........................................................................7
2.0
STUDY OBJECTIVES & ENDPOINTS ................................................................12
3.0
SELECTION OF SUBJECTS...............................................................................13
4.0
TREATMENT PLAN.............................................................................................17
5.0
STUDY PROCEDURES.......................................................................................24
6.0
ENDPOINT ASSESSMENT .................................................................................24
7.0
ADVERSE EVENTS .............................................................................................27
8.0
DRUG INFORMATION.........................................................................................36
9.0
CORRELATIVES/EXPLORATORY STUDIES.....................................................38
10.0
STATISTICAL CONSIDERATIONS.....................................................................39
11.0
STUDY MANAGEMENT........................................................................................41
IRB #: STU00098385-CR0008 Approved by NU IRB for use on or after 3/3/2023 through 3/2/2024.

Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
3
LIST OF ABBREVIATIONS
Examples Include:
AE
Adverse Event
ALT
Alanine Aminotransferase
ALC
Absolute Lymphocyte Count
ALL
Acute Lymphocytic Leukemia
AST
Aspartate Aminotransferase
BUN
Blood Urea Nitrogen
CBC
Complete Blood Count
CMP
Comprehensive Metabolic Panel 
CLL
Chronic Lymphocytic Leukemia
CR
Complete Response
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events 
CTU
Clinical Trials Unit
DLT
Dose Limiting Toxicity
DSMB
Data and Safety Monitoring Board 
ECOG
Eastern Cooperative Oncology Group 
H&P
History & Physical Exam
HRPP
Human Research Protections Program 
IV (or iv)
Intravenously
MCL
Mantle Cell Lymphoma
MTD
Maximum Tolerated Dose
NCI
National Cancer Institute
ORR
Overall Response Rate
OS
Overall Survival
PBMCs
Peripheral Blood Mononuclear Cells 
PCF
Pathcore Facility
PD
Progressive Disease
PFS
Progression Free Survival
p.o.
per os/by mouth/orally
PR
Partial Response
SAE
Serious Adverse Event
SD
Stable Disease
SGOT
Serum Glutamic Oxaloacetic Transaminase 
SPGT
Serum Glutamic Pyruvic Transaminase 
WBC
White Blood Cells
IRB #: STU00098385-CR0008 Approved by NU IRB for use on or after 3/3/2023 through 3/2/2024.

Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
4
Pre-Study
Induction Therapy1
Registration
Treatment
Maintenance therapy with ibrutinib – administered at fixed 
dose of 560 mg PO daily up to 4 years or until progression 
of disease, intolerable toxicity, or patient preference3
Follow-Up/Off Treatment
For patients on treatment 4 years:
Last visit 30 days post-last dose
For patients off treatment prior to 4 years:
Follow up for survival endpoints up to 4 years post-first dose4
STUDY SCHEMA
Screening
Patients with previously-untreated MCL in CR or PR 
post-induction therapy2
1Patients must receive at least 4 cycles of induction chemotherapy with or without auto-SCT, 
including R-CHOP (with or without alternating R-DHAP), R-Hyper-CVAD, or R- 
bendamustine.
2Per Cheson 2007 criteria.
3During treatment, 1 cycle = 28 days. Patients will be evaluated (and drug will be dispensed) 
prior to each cycle for the first 6 months, then every 3 cycles thereafter for the remainder 
of treatment. See section 4.2 for the provision of 6-month visits after 2 years.
4Follow-up schedule for patients off-treatment will be every 3 months up to 2 years post-first 
dose, then every 6 months up to 4 years post-first dose. Date of progression will be 
documented as well.
IRB #: STU00098385-CR0008 Approved by NU IRB for use on or after 3/3/2023 through 3/2/2024.

Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
5
STUDY SUMMARY
Title
A Phase II Clinical Trial Evaluating Ibrutinib Maintenance 
Following Intensive Induction for Patients with Previously 
Untreated Mantle Cell Lymphoma (MCL)
Version Date
August 8, 2022 (Amendment 11)
Phase/Design
Phase II, single-arm, multicenter, open-label study
Study Center(s)
Lead site: Northwestern University
Participating sites:, University of Michigan, University of Utah, and 
Dana Farber d/b/a Massachusetts General Hospital
Objectives
Primary objective:
Determine the 3-year PFS in patients with previously-untreated 
MCL who achieve response to intensive induction therapy and 
then receive maintenance Ibrutinib.
Secondary objectives:

Toxicity

Rates of conversion from PR to CR

Median overall survival at 4 years
Exploratory objectives:
Monitor MRD results by PCR and correlate with PFS and OS.
Sample Size
36 evaluable patients (patients who receive < 1 complete cycle of 
therapy will not be considered evaluable for efficacy endpoints 
and will be replaced; we estimate this to represent 3 or fewer 
subjects)
Diagnosis
and
Main 
Inclusion Criteria
1.
Histologically confirmed MCL.
2.
Disease response (either CR or PR), without known 
progression, to one (1) prior systemic chemotherapy regimen, 
with or without consolidative auto SCT. The options are:
a.
R-CHOP (with or without cytarabine-containing 
cycles, including “Nordic” [1] and MCL-NET 
protocols [2]) with or without auto SCT
b.
R-Hyper-CVAD with or without auto SCT
c.
R-Bendamustine with or without auto SCT
3.
Prior radiotherapy is permissible.
4.
Age ≥ 18 years.
5.
ECOG performance status ≤ 2.
Treatment Plan
Ibrutinib will be given at a fixed dose of 560 mg PO daily 
throughout the study, to patients who have completed at least 4 
cycles of intensive induction chemotherapy (with or without 
ASCT). The dose is based upon safety and efficacy data. For the 
purposes of this study, one cycle will be defined as 28 days. This 
will be continued up to 4 years in the absence of progression of 
disease, intolerable toxicity, or patient preference (including 
withdrawal of consent).
IRB #: STU00098385-CR0008 Approved by NU IRB for use on or after 3/3/2023 through 3/2/2024.

Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
6
Statistical 
Methodology
The primary endpoint is three-year PFS. Our null hypothesis is 
that ibrutinib maintenance will yield no improvement upon the 60% 
three-year PFS observed in studies described above. We 
consider an observed three-year PFS of 80% both feasible and of 
significant clinical improvement. The study will have 10% Type I 
error and 90% power to detect an effective treatment using a one- 
stage design based on the true proportion of patients achieving 3- 
year PFS is at least 80% versus the null hypothesis that the true 
complete response rate is at most 60%. Based upon these 
parameters, our sample size will be 36 evaluable patients. For 
the final analysis, if 25 or fewer patients are alive and without 
progression from among all 36 evaluable patients accrued, we will 
consider this regimen ineffective for this patient population. If, on 
the other hand, 26 or more patients are alive and without 
progression, this will be considered sufficient evidence that this 
treatment may be recommended for further testing in subsequent 
studies, particularly in a randomized setting.
IRB #: STU00098385-CR0008 Approved by NU IRB for use on or after 3/3/2023 through 3/2/2024.

Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
7
1.0
BACKGROUND AND RATIONALE
1.1
Disease Background & Current Therapies
Mantle cell lymphoma (MCL) is an uncommon B-cell non-Hodgkin lymphoma 
(NHL) that carries a poor overall prognosis in spite of high response rates to 
induction chemotherapy [3, 4]. It accounts for about 6% of all NHL cases in the 
Western world. At the molecular level, MCL is uniquely characterized by 
overexpression of the cell cycle regulator protein cyclin D1. This is due to the 
chromosomal translocation t(11;14)(q13;q32), which puts the cyclin D1 gene, B- 
cell leukemia/lymphoma 1 (bcl-1), under the control of the immunoglobulin heavy 
chain enhancer with subsequent overexpression of cyclin D1 [5-7].
Although there is no consensus as to the ideal frontline therapy for MCL, 
aggressive multi-agent chemoimmunotherapy combinations such as R-CHOP 
(rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone) have 
been advocated. More intensive regimens, such as Hyper-CVAD 
(hyperfractionated cyclophosphamide, vincristine, doxorubicin, and 
dexamethasone alternating with methotrexate and cytarabine) or other regimens 
that incorporate high-dose cytarabine [1, 2], may improve outcomes, though this 
has not been clearly shown and toxicity with such regimens is clearly 
increased[8]. Younger patients with good performance status are frequently 
considered for more intensive induction therapy followed by consolidation 
therapy with autologous stem cell transplant (ASCT); however, this degree of 
intensive therapy is not an option for most patients with MCL because of their 
age and comorbidities[9, 10].
Multiple prospective and retrospective trials have demonstrated patterns of 
continuous response over many months and years, suggesting that all patients 
are at risk for eventual relapse [3, 4, 11]. Once the disease has progressed after 
first-line therapy, the prognosis is dismal.
The best estimates of 3-year progression-free survival (PFS) in patients with 
MCL treated with R-Hyper-CVAD (Rituximab-Hyper-CVAD) in multicenter studies 
are 58-64% [11]. Likewise, consolidation with high-dose therapy (HDT) and 
ASCT after R-CHOP also seems to improve depth and duration of responses as 
compared to R-CHOP, but does not clearly improve overall survival. Interestingly, 
an retrospective analysis of patients treated at National Comprehensive Cancer 
Network (NCCN) Centers suggested that patients treated with Hyper-CVAD had 
similar outcomes to those treated with R-CHOP followed by HDT-ASCT, but that 
HDT-ASCT did not improve outcomes when used as consolidation after induction 
with R-Hyper-CVAD [11].
Maintenance strategies have previously been studied in patients with MCL. For 
example, a phase III European study randomized patients with previously 
untreated MCL, who achieved a response to R-CHOP, to maintenance treatment 
of either rituximab or interferon, and showed improved median PFS and OS 
among those on the rituximab arm [12].
Ibrutinib is a selective BTK inhibitor that has demonstrated profound activity in 
patients with relapsed/refractory MCL, with an overall response rate (ORR) of 
68% and median PFS of 13.9 months [13]. Ibrutinib was approved by the Food
IRB #: STU00098385-CR0008 Approved by NU IRB for use on or after 3/3/2023 through 3/2/2024.

Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
8
and Drug Administration (FDA) in November 2013 as single agent treatment for 
patients with MCL who have received at least one prior therapy. It has since 
been approved for CLL/SLL, CLL/SLL with 17p deletion, and Waldenstrӧm’s 
macroglobulinemia. The drug is well tolerated, with neutropenia and 
gastrointestinal disturbances as its chief adverse effects. Ibrutinib is now the 
focus of multiple combination treatment trials. However, there is no reported data 
for the role of ibrutinib as maintenance therapy after response to other treatment.
1.2
Ibrutinib Background and Toxicities
Ibrutinib, an irreversible inhibitor of BTK, has been shown to have potent 
inhibitory and anti-proliferative activity, in cell line as well as in vivo mouse 
xenograft models of B-cell malignancies such as ALL and CLL. Inhibition of BTK 
activity interrupts cellular signaling processes that control cell division in B-cells. 
The pharmacology and toxicology of ibrutinib in animal models are detailed in the 
Investigator’s Brochure.
In an open-label drug-drug interaction study of 18 men, ibrutinib was 
administered alone at a 120 mg dose or in combination with ketoconazole at a 40 
mg dose. Preliminary results demonstrated a mean 25-fold increase in ibrutinib 
area under the plasma concentration-time curve (AUC) and a 29-fold increase in 
Cmax following co-administration with ketoconazole. Terminal half-life was not 
increased. Ibrutinib single-dose administration was well-tolerated. No drug- 
related adverse events were reported. No Grade 3 or 4 toxicities or serious 
adverse events were reported.
1.2.1
Preclinical & pharmacokinetic data
1.2.1.1 Mechanism of Action
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. BTK is a signaling 
molecule of the B-cell antigen receptor (BCR) and cytokine 
receptor pathways. BTK’s role in signaling through the B-cell 
surface receptors results in activation of pathways necessary for 
B-cell trafficking, chemotaxis, and adhesion. Nonclinical studies 
show that ibrutinib inhibits malignant B-cell proliferation and 
survival in vivo as well as cell migration and substrate adhesion in 
vitro.
1.2.1.2 Pharmacodynamics
In patients with recurrent B-cell lymphoma > 90% occupancy of 
the BTK active site in peripheral blood mononuclear cells was 
observed up to 24 hours after ibrutinib doses of ≥2.5 mg/kg/day 
(175 mg/day for average weight of 70 kg).
1.2.1.3 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 observed in patients at 560 mg is
IRB #: STU00098385-CR0008 Approved by NU IRB for use on or after 3/3/2023 through 3/2/2024.

Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
9
(mean ± standard deviation) 953 ± 705 ng/mL. Administration with 
food increases ibrutinib exposure approximately 2-fold compared 
with administration after overnight fasting.
Distribution
Reversible binding of ibrutinib to human plasma protein in vitro 
was 97.3% with no concentration dependence in the range of 50 
to 1000 ng/mL. The apparent volume of distribution at steady state 
(Vd,ss/F) is approximately 10000 L.
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. 
The range of the mean metabolite to parent ratio for PCI-45227 at 
steady-state is 1 to 2.8.
Elimination
Apparent clearance (CL/F) is approximately 1000 L/h. The half-life 
of ibrutinib is 4 to 6 hours. Ibrutinib, mainly in the form of 
metabolites, is eliminated primarily via feces. After a single oral 
administration of radiolabeled [14C]-ibrutinib in healthy subjects, 
approximately 90% of radioactivity was excreted within 168 hours, 
with the majority (80%) excreted in the feces and less than 10% 
accounted for in urine. Unchanged ibrutinib accounted for 
approximately 1% of the radiolabeled excretion product in feces 
and none in urine, with the remainder of the dose being 
metabolites.
1.2.2
Clinical efficacy data
Efficacy results from two separate studies demonstrate that ibrutinib has 
robust activity as a single-agent in the treatment of subjects with relapsed 
or refractory MCL. As of October 2011, 60 subjects with MCL (9 from 
study PCYC-04753 and 51 from study PCYC-1104-CA) had been 
evaluated for response to treatment with ibrutinib; despite the poor-risk 
nature of the MCL population on these 2 studies, the ORR was 70% 
(42/60); this is very favorable in comparison to historical data with 
bortezomib in a less heavily pretreated relapsed MCL population.
In the PCYC-04753 study (a phase I, multicenter, dose escalation study 
of 56 patients with a variety of B-cell malignancies) all 9 subjects with 
MCL were evaluable for response. Of these, 7 achieved an objective 
response by the Revised Response Criteria for Malignant Lymphoma 
[14], including 3 CRs and 4 PRs; in addition there was 1 SD and 1 PD. All 
of the subjects responding to treatment achieved response at the time of 
the first response assessment (after 2 cycles of treatment). Of the 3 
subjects who achieved a CR, 2 subjects did so upon initial response 
assessment and 1 was a PR initially who converted to CR after 8 cycles 
(28-days cycle duration) of therapy. Responses have been durable; 5
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Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
10
subjects who entered a long-term follow-up study and continued to 
receive study treatment achieved duration of response ranging from 10.5 
to 27.5 months from treatment initiation.
The safety and efficacy of ibrutinib in patients with MCL who have 
received at least one prior therapy were evaluated in an open-label, multi- 
center, single-arm trial of 111 previously treated patients. The median age 
was 68 years (range, 40 to 84 years), 77% were male, and 92% were 
Caucasian. At baseline, 89% of patients had a baseline ECOG 
performance status of 0 or 1. The median time since diagnosis was 42 
months, and median number of prior treatments was 3 (range, 1 to 5 
treatments), including 11% with prior stem cell transplant. At baseline, 
39% of subjects had at least one tumor >/= 5 cm, 49% had bone marrow 
involvement, and 54% had extranodal involvement at screening.
Ibrutinib was administered orally at 560 mg once daily until disease 
progression or unacceptable toxicity. Tumor response was assessed 
according to the revised International Working Group (IWG) for non- 
Hodgkin’s lymphoma (NHL) criteria. The primary endpoint in this study 
was investigator-assessed overall response rate (ORR). Efficacy results 
indicated an ORR of 65.8% (95% CI 56.2-74.5; 69% by IRC), including 
CR rate of 17.1% and PR rate of 1548.6%. The median DOR was 17.5 
months, and median time to response 1.9 months.
1.2.3
Toxicity data
The data described below reflect exposure to ibrutinib in a clinical trial 
that included 111 patients with previously treated MCL treated with 560 
mg daily with a median treatment duration of 8.3 months. The following 
risks are discussed in more detail in the full prescribing information:

Hemorrhage (5%)

Infections (25%)

Myelosuppression (41%)

Renal Toxicity (67%)

Second Primary Malignancies (5%)
Because clinical trials are conducted under widely variable conditions, 
adverse event rates observed in clinical trials of a drug cannot be directly 
compared with rates of clinical trials of another drug and may not reflect 
the rates observed in practice.
The most commonly occurring adverse reactions (≥ 20%) were 
thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, 
musculoskeletal pain, peripheral edema, upper respiratory tract infection, 
nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting 
and decreased appetite. The most common Grade 3 or 4 non- 
hematological adverse reactions (≥ 5%) were pneumonia, abdominal 
pain, atrial fibrillation, diarrhea, fatigue, and skin infections.
An evaluation of the safety data across 5 clinical studies (sponsored by 
Pharmacyclics & Janssen Scientific Affairs) including 392 subjects found 
moderate toxicities associated with ibrutinib treatment. The most common 
(> 10%) treatment-emergent adverse events (AEs) were diarrhea
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Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
11
(40.4%), fatigue (32.1%), nausea (24.0%), cough (17.6%), and peripheral 
edema (16.7%). These AEs are classified as grade 1 or 2 in severity and 
were not dose-limiting. Grade 3 or 4 adverse events were noted in about 
45.8% of the patients, which were typically hematologic in nature (anemia 
5.8%, thrombocytopenia 5.1%, and neutropenia 4.5%). Serious adverse 
events (SAEs) were experienced by 35.9% of subjects, which included 
pneumonia (4.5%), febrile neutropenia (3.2%), and atrial fibrillation 
(2.9%).
Hemorrhagic AEs have been reported following ibrutinib treatment, either 
as monotherapy or in combination with other agents. Out of 392 subjects, 
6 (1.5%) experienced subdural hematoma; in 5 of these 6 the event was 
reported as serious, and in 2 it was determined to be possibly related to 
ibrutinib. Additional serious hemorrhagic events have included hematuria 
(2 subjects), cerebrovascular accident with intracerebellar hemorrhage, 
GI hemorrhage, hematoma, and hemorrhagic enterocolitis (1 subject 
each). Non-serious bleeding events have included contusion, 
ecchymosis, petechiae, epistaxis, retinal hemorrhage, hematuria, 
hemoptysis, and hematochezia. These events have generally resolved.
Although in vitro studies have found that ibrutinib can inhibit platelet 
function, the clinical significance of this effect is not clear. An expert 
review of the hemorrhagic SAEs that have occurred in clinical studies 
seemed to conclude that the incidence of subdural hematoma was 
unlikely to be related to the platelet inhibitory activity of ibrutinib. Other 
potential risk factors for subdural hematoma may have included age, any 
history of fall, or concomitant use of anti-coagulants such as warfarin.
Across all ibrutinib studies—monotherapy and combination treatment—32 
(8.2%) of the 392 subjects discontinued treatment due to an AE, including 
12 for reasons related to infection or its complications (e.g., pneumonia, 
sepsis, bacteremia, pyrexia, neutropenia with or without fever, etc.).
Refer to the investigator’s brochure for additional toxicity information.
1.3
Rationale for the Current Study
There is an unmet medical need for developing new therapeutic options to treat 
patients with MCL. Ibrutinib is currently the focus of several mono and 
combination-treatment studies, in a variety of B-cell malignancies. However, the 
role of single-agent ibrutinib in a maintenance therapy setting for previously- 
untreated MCL patients has not been explored. We therefore propose a phase II 
trial to assess the role of ibrutinib as maintenance therapy for MCL patients who 
have achieved response to induction with either R-Hyper-CVAD, R-CHOP (with 
or without cytarabine-containing cycles [1, 2]), or R-Bendamustine, with or 
without auto transplant. The study population would therefore involve patients 
with histologically confirmed MCL who have achieved either CR or PR after 
intensive induction systemic chemotherapy.
Ibrutinib will be given as maintenance therapy at a daily dose of 560 mg taken 
orally (1 cycle = 28 days). In the PCYC-1104-CA study, ibrutinib was 
administered to relapsed/refractory MCL patients as a fixed dosage of 560
IRB #: STU00098385-CR0008 Approved by NU IRB for use on or after 3/3/2023 through 3/2/2024.

Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
12
mg/day; in this study, 96% of the patients retained steady-state ibrutinib AUC 
values >160 ng·h/mL, indicating that the vast majority of patients who received a 
dose of 560 mg/day achieved exposures yielding full BTK active-site occupancy. 
This dose in relapsed or refractory MCL patients showed an acceptable toxicity 
profile. Based on these data, the oral daily 560 mg dose has been selected for 
this study. Treatment will continue up to 4 years in the absence of progression of 
disease or intolerable toxicity, or patient preference. We also plan to collect 
whole blood samples from all patients in order to monitor MRD results by PCR; 
samples will be collected at four time-points: baseline (pre-treatment), after 1 
month and 6 months of treatment, and approximately 18-24 months post-first 
dose of treatment.
2.0
STUDY OBJECTIVES & ENDPOINTS
2.1
Primary Objective & Endpoint
The primary objective will be to determine the progression-free survival (PFS) 
rate after 3 years.
Progression-free survival (PFS) will be defined as the absence of disease 
progression or death from any cause. The rate of PFS will be calculated after 3 
years.
2.2
Secondary Objectives & Endpoints
Secondary objectives will include the following:
2.2.1
Assess toxicity.
Adverse events will be defined according to the National Cancer 
Institute’s Common Terminology Criteria for Adverse Events (NCI 
CTCAE) version 4.03. The occurrence and severity of each will be 
recorded.
2.2.2
Determine rates of conversion from PR to CR.
The rate of conversion from PR to CR will be calculated based on Cheson 
2007 criteria.
2.2.3
Determine median overall survival (OS) after 4 years.
Patients will be evaluated monthly for the first 6 months on treatment, 
then every 3 months thereafter. Patients who go off treatment will continue 
to be followed for survival up to a maximum of 4 years post-first dose. 
Follow-up will occur every 3 months (up to 2 years after the first dose of 
treatment) and then every 6 months thereafter (up to 4 years post-first 
dose). Median OS after 4 years will be calculated.
2.3
Exploratory Objectives & Endpoints
Compare MRD results overtime by PCR and correlate these with PFS and OS.
We will obtain archived tissue (FFPE slides) from a previous biopsy from all 
patients for baseline clone identification; in addition, we will collect peripheral 
whole blood samples at baseline, 1 month after first dose, 6 months after first 
dose, and approximately 18-24 months after first dose. MRD analysis will be
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Study Numbers: NU 14H06 
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Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
13
conducted using PCR methods and results will be compared over time and 
correlated with PFS and OS.
3.0
SELECTION OF SUBJECTS
The target population for this phase II study is patients with histologically confirmed 
(previously untreated) mantle cell lymphoma (MCL) who have achieved response (CR or 
PR) to intensive induction systemic chemotherapy (with or without ASCT). This will be a 
multicenter trial conducted at Northwestern University. Northwestern University will serve 
as the lead site and coordinating center for this study. Participating sites will include 
University of Utah, and Dana Farber d/b/a Massachusetts General Hospital.
A total of 36 evaluable subjects will be needed for this trial (defined as having received ≥ 
1 complete cycle of treatment). Approximately 5 potentially eligible patients are seen per 
month, and it is anticipated that at least 2 per month will be accrued once the protocol is 
open and enrolling at all sites. Potential patients may be referred to the Principal 
Investigator (PI) at Northwestern University or to the local PI at each participating site.
Eligibility will be evaluated by the study team according to the following criteria. Eligibility 
waivers are not permitted. Subjects must meet all of the inclusion and exclusion criteria 
to be registered to the study. Study treatment may not begin until a subject is registered. 
Please refer to Section 11.4 for complete instructions regarding registration procedures.
3.1
Inclusion Criteria
3.1.1
Patients must have histologically confirmed MCL
Please note: Measureable disease is not required, but will be followed if it 
exists.
3.1.2
Patients must have received 4 or more cycles of one of the following prior 
systemic induction chemotherapy regimens:

R-CHOP (with or without cytarabine-containing cycles, including 
“Nordic” and MCL-NET protocols) [1, 2]) with or without auto SCT

R-Hyper-CVAD with or without auto SCT

Bendamustine + rituximab with or without auto SCT
Please note:

Patients are allowed to receive combinations of the above regimens

At the time of registration, patients must be at least 14 days out from 
last dose of cytotoxic chemotherapy, but no more than 120 days. If 
a patient underwent auto SCT, he/she must demonstrate 
engraftment (per treating investigator’s discretion) and meet all 
other hematological requirements as outlined in 3.1.8 below.

Patients who progress during induction therapy are not eligible to 
enroll in this study.
3.1.3
Patients must have achieved a response to induction chemotherapy 
(either CR or PR by Cheson 2007 criteria) and be without known 
progression.
3.1.4
Patients may have received prior radiotherapy.
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Study Numbers: NU 14H06 
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AMD 11: ver. date 08.06.2022 
14
3.1.5
Patients must be age ≥ 18 years.
3.1.6
Patients must exhibit an ECOG performance status ≤ 2.
3.1.7
Patients must demonstrate adequate organ and marrow function (as 
defined below) documented within 14 days of registration:

ANC ≥ 1000/mm3, independent of growth factor support

Platelets ≥ 100,000/mm3, or ≥ 50,000 in cases of ongoing bone 
marrow involvement (In either case, these must be independent of 
transfusion support)

Total bilirubin ≤ 1.5 x upper limit of normal (ULN)

AST(SGOT)/ALT(SPGT) ≤ 3 x ULN

Creatinine clearance ≥ 25 ml/min (using the Cockcroft-Gault Equation 
– See Appendix III)
Please note: Patients who do not meet the above criteria because of 
Gilbert’s Syndrome are still eligible.
3.1.8
Women of child-bearing potential (WOCBP) and men must agree to use 
adequate contraception (see below ‘NOTE” for details) prior to study entry 
and for the duration of study participation (see timelines below for women 
and men). In addition, men must agree not to donate sperm during and 
after study participation. Should a woman become pregnant or suspect she 
is pregnant while participating in this study, she should inform her treating 
physician immediately.
NOTE: For female patients, these restrictions apply for 1 month after the 
last dose of study drug. For male patients, these restrictions apply for 3 
months after the last dose of study drug.
NOTE: A female of child-bearing potential is any woman (regardless of 
sexual orientation, having undergone a tubal ligation, or remaining 
celibate by choice) who meets the following criteria:

Has not undergone a hysterectomy or bilateral oophorectomy; or

Has not been naturally postmenopausal for at least 12 consecutive 
months (i.e., has had menses at any time in the preceding 12 
consecutive months).
NOTE: ‘Adequate contraception’ is defined as a method that has a low 
failure rate (i.e., less than 1% per year) when used consistently and 
correctly and includes implants, injectables, birth control pills with two 
hormones, some intrauterine devices (IUDs), sexual abstinence (which is 
defined as refraining from all aspects of sexual activity) or a sterilized 
partner. If using hormonal contraceptives, such as birth control pills or 
devices, a second barrier method of contraception (e.g., condoms) must 
be used.
Men must notify the study staff if their partner becomes pregnant while on 
study treatment or within 3 months of last dose. Women must notify the
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15
study staff if they become pregnant while on study treatment or within 1 
month of last dose of ibrutinib, and must immediately stop taking the 
study treatment.
3.1.9
Female patients must have a negative pregnancy test (blood or urine) 
within 14 days prior to registration.
3.1.10 Patients must be willing and able to avoid consuming food and beverages 
containing grapefruit, Star fruit or Seville oranges (as these contain certain 
ingredients that inhibit CYP3A4/5 enzymes) while on ibrutinib study 
therapy.
3.1.11 Patients must have the ability to understand and the willingness to sign a 
written informed consent prior to registration on study.
3.2
Exclusion Criteria
3.2.1
Patients who have received ≥ 7 days of prior ibrutinib or any prior treatment 
with another BTK inhibitor are not eligible.
3.2.2
Patients receiving ongoing treatment with any other investigational 
agents are not eligible.
3.2.3
Patients receiving live/attenuated vaccinations within 4 weeks prior to 
registration are not eligible.
3.2.4
Patients with a known CNS involvement of lymphoma are not eligible 
(CNS staging not required).
3.2.5
Patients who have undergone major surgery within 4 weeks prior to 
registration are not eligible.
3.2.6
Patients who have had a prior allogeneic stem cell transplant are not 
eligible.
NOTE: If a patient underwent auto SCT, he/she must demonstrate 
engraftment (per treating investigator’s discretion) and meet all other 
hematological requirements as outlined in 3.1.8 above.
3.2.7
Patients diagnosed or treated for malignancy other than MCL are not 
eligible unless they meet one of the following exceptions:

Malignancy treated with curative intent and with no known active 
disease present for ≥3 years before registration and felt to be at low risk 
for recurrence by the treating physician.

Adequately treated non-melanoma skin cancer or lentigo maligna 
without evidence of disease.

Adequately treated cervical carcinoma in situ without evidence of 
disease.

Malignancy is not considered life-threatening in the opinion of the 
investigator and does not require treatment (for example, low risk
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AMD 11: ver. date 08.06.2022 
16
prostate
cancer
undergoing
active
surveillance
or
low-risk 
myelodysplastic syndrome not requiring therapy).
3.2.8
Patients with a history of stroke or intracranial hemorrhage within 6 
months prior to registration are not eligible.
3.2.9
Patients who require anticoagulation with warfarin or equivalent vitamin K 
antagonists are not eligible.
3.2.10 Patients who require chronic treatment with strong CYP3A4/5 inhibitors ≤
14 days prior to registration are not eligible.
NOTE: See Appendix I for examples of such medications. Patients who are 
currently on treatment with strong CYP3A4/5 inhibitors may be eligible if 
they are able to be switched to an alternative therapy that is not a strong 
CYP3A4/5 inhibitor prior to registration on study.
3.2.11 Patients with a history of allergic reactions attributed to compounds of 
similar chemical or biologic composition to ibrutinib are not eligible.
3.2.12 Patients with uncontrolled intercurrent illness including, but not limited to, 
any of the following are not eligible:

Ongoing or active systemic infection

Symptomatic congestive heart failure

Myocardial infarction within 6 months prior to registration

Unstable angina pectoris

Uncontrolled or symptomatic cardiac arrhythmias

Any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined 
by the New York Heart Association Functional Classification

Psychiatric illness/social situations that would limit compliance with 
study requirements.
3.2.13 Patients who have any life-threatening illness, medical condition, or organ 
system dysfunction which, in the investigator’s opinion, could compromise 
the subject’s safety, interfere with the absorption or metabolism of ibrutinib 
capsules, or put the study outcomes at risk are not eligible.
3.2.14 Patients with a known HIV infection are not eligible (HIV testing not 
required).
3.2.15 Patients with a known JC virus infection and/or progressive multifocal 
leukoencephalopathy (PML) are not eligible.
3.2.16 Patients with clinically active hepatitis A, B, or C infections are not eligible. 
Note: Patients with a history of hepatitis may be eligible if they have a 
normal titer. Such cases should be approved by the study PI.
3.2.17 Female patients who are pregnant and/or lactating are not eligible.
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Study Numbers: NU 14H06 
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AMD 11: ver. date 08.06.2022 
17
NOTE: It is not known whether ibrutinib or its metabolites are excreted in 
human milk. Because many drugs are excreted in human milk and 
because of the potential for serious adverse reactions in nursing infants 
from ibrutinib, breastfeeding should be discontinued during ibrutinib 
treatment.
4.0
TREATMENT PLAN
4.1
Overview
Induction therapy will not be part of the protocol-specified treatment. Patients 
must have received four (4) or more cycles of R-CHOP (with or without 
alternating R-DHAP), R-Hyper-CVAD, or bendamustine + rituximab (all with or 
without auto SCT), with documented PR or CR by Cheson 2007 criteria. Within 
14 days of study registration, patients will begin treatment with ibrutinib at a fixed 
dose of 560 mg PO daily. One cycle will be defined as 28 days. Patients may 
continue to receive cycles of ibrutinib therapy up to 4 years in the absence of 
progression of disease or intolerable toxicity, or patient preference (including 
withdrawal of consent).
4.2
Administration
Ibrutinib will be administered orally at a dose of 560 mg daily. Patients will be 
instructed to take 4 140mg capsules for a dose of 560 mg. Ibrutinib is to be taken 
in the morning (around the same time each day) with approximately 8 ounces 
(240 mL) of water. All 4 capsules should be taken at the same time and the 
capsules should remain intact. Subjects should not attempt to open capsules or 
dissolve them in water.
Subjects should avoid consuming food and beverages containing grapefruit, Star 
fruit, or Seville oranges for the duration of the study due to CYP 3A4/5 inhibition. 
The study drug should be taken at roughly the same time each day. If a dose is 
missed, it can be taken anytime later that same day, with a return to the normal 
schedule the following day. In general, vomited doses should not be made up, 
however patients should contact their physician to discuss such cases.
Subjects will be given a study calendar on which to record all taken, missed, or 
skipped doses for the first 6 cycles of study treatment. The calendar will be 
returned for review with a member of the study team at scheduled visits to 
assess compliance in addition to pill counts. During the first 6 cycles, ibrutinib will 
be dispensed at the beginning of each 28-day cycle. Subjects will be provided 
with 2 days overage (30 days’ worth total) each time study drug is dispensed to 
allow for delays in scheduling of return visits. After the initial 6 cycles of 
treatment, visits will be conducted every 3 months and a sufficient drug supply 
will be dispensed at each visit to last until the next visit. If after 2 years a patient 
is clinically stable without significant adverse events and lives far from the study 
site, he or she may elect to be seen by the study investigator every 6 cycles with 
local clinic visits every 3 cycles in between. In such cases, a 6-month drug supply 
may be dispensed, however this supply should be given in moderation only for 
patients who live far away or are otherwise inconvenienced by quarterly study 
visits. Patients will continue maintaining a study calendar/pill diary for the 
duration of treatment.
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Study Numbers: NU 14H06 
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AMD 11: ver. date 08.06.2022 
18
Study staff will instruct subjects on how to store ibrutinib for at-home use as 
indicated for this protocol (e.g. in a secure location, away from children).
4.3
Toxicity Management & Dosing Holds/Dose Modifications
4.3.1
Dose Holds
At each study visit (see section 5.0 for schedule), the subject will be 
evaluated for possible drug toxicities. All previously established or new 
toxicities observed at any time are to be recorded in the appropriate 
electronic case report form (eCRF) and managed as described below. 
The lead principal investigator and QAM should be contacted regarding 
any unmanageable toxicity.
Study drug may be held for a maximum of 28 consecutive days. Once the 
ibrutinib dose is reduced, it cannot be re-escalated. When a dose is 
missed or held, it will not be made up, regardless of duration.
Observations and scheduled assessments will continue regardless of 
amount of drug the patient has had and should always be based on time 
from C1D1. (For example, if a patient is held on C2D14 for a week, the 
day they re-start will be C2D21, and the patient will still have scheduled 
assessments as planned on C3D1) Please contact QA if you have any 
questions on timing of holds or study assessments.
See section 4.4.3 for subjects requiring the initiation of anticoagulants 
while receiving study drug and for instructions on dose modifications or 
temporary hold during concomitant administration of CYP3A4/5 inhibitors 
or inducers. For guidance on dose hold during the perioperative period for 
subjects who require surgical intervention or an invasive procedure while 
receiving study drug please see section 4.4.4.
4.3.2
Dose Modifications
The actions described below should be followed for the indicated drug- related 
toxicities per Table 4-1:

Grade 3 (ANC <1000/mm3) or Grade 4 neutropenia (ANC <500/mm3)

Grade 3 thrombocytopenia (platelets <50,000/mm3) in the presence of 
significant bleeding

Grade 4 thrombocytopenia (platelets <25,000/mm3)

Grade 3 or 4 neutropenia with infection or fever

All other Grade 4 hematological toxicities

Grade 3 or Grade 4 non-hematological toxicities including nausea, 
vomiting or diarrhea (if persistent despite optimal antiemetic or 
antidiarrheal therapy), exceptions noted below for cardiac related 
toxicities (see Sections 4.3.2.1 & Section 4.3.2.1.1)

Grade 2 cardiac failure

Any unmanageable Grade 2 or Grade 3 drug-related toxicities. The PI 
should be contacted in these cases.
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Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
19
Table 4-1 Dose Modification Actions 
Occurrence
Action1
First
Hold ibrutinib until recovery to ≤ Grade 1 or baseline; 
restart at 420 mg dose
Second
Hold ibrutinib until recovery to ≤ Grade 1 or baseline; 
restart at 280 mg dose
Third
Discontinue ibrutinib
1 When ibrutinib doses are held they will not be made up – study assessments 
will continue as originally scheduled. Ibrutinib may be held for a maximum 
of 28 consecutive days at a time. Study treatment should be permanently 
discontinued in the event of a toxicity lasting >28 days. Once the ibrutinib 
is reduced it cannot be re-escalated.
4.3.2.1 Dose Modifications for Grade 3 Cardiac Arrhythmias
The actions described below should be followed for the indicated following drug- 
related toxicities (Table 4-2):

Grade 3 cardiac arrhythmias
Table 4-2  Dose Modification Actions for Grade 3 Cardiac Arrhythmias
Occurrence
Action1
First
Hold ibrutinib until recovery to ≤ Grade 1 or baseline; 
restart at 420 mg dose
Second
Discontinue ibrutinib
1 When ibrutinib doses are held they will not be made up – study assessments 
will continue as originally scheduled. Ibrutinib may be held for a maximum 
of 28 consecutive days at a time. Study treatment should be permanently 
discontinued in the event of a toxicity lasting >28 days. Once the ibrutinib 
is reduced it cannot be re-escalated.
4.3.2.1.1 Dose Modifications for Grade 3 and higher Cardiac Failure & 
Grade 4 Cardiac Arrhythmias
Ibrutinib is to be discontinued if the following drug related toxicities occur:

Grade 3 or 4 cardiac failure

Grade 4 cardiac arrhythmias
4.3.3
Lymphocytosis
Upon initiation of ibrutinib, a temporary increase in lymphocyte counts 
(i.e., ≥ 50% increase from baseline and above absolute count 5,000/mcL) 
occurred in 33% of relapsed/refractory MCL treated with ibrutinib in the 
MCL registration trial (PCYC1104). This onset of isolated lymphocytosis 
occurs during the first few weeks of ibrutinib therapy and resolves by a 
median of 8 weeks. Patients with MCL who develop lymphocytosis 
greater than 400,000/mcL have developed intracranial hemorrhage, 
lethargy, gait instability and headache. However, some of these cases 
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AMD 11: ver. date 08.06.2022 
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were in the setting of disease progression.
4.4
Concomitant Medications/Treatments
All concomitant therapies must be recorded in the appropriate eCRF and source 
documents throughout the study, beginning with the time of written informed 
consent up to 30 days after the last dose of study drug.
4.4.1
Permitted Concomitant Medications/Treatments

Standard supportive care therapies (e.g., antiemetics, loperamide) 
needed for the management of symptoms are permitted, as clinically 
indicated.

Hematopoietic growth factors may be administered according to 
institutional guidelines

Hormonal birth control is permitted.
4.4.2
Prohibited Concomitant Medications/Treatments
The following medications are prohibited during the study:

Any chemotherapy

Anticancer immunotherapy

Chronic use of systemic corticosteroids above prednisone 10mg p.o. 
daily (or equivalent dose of other corticosteroid)

Experimental therapy

Radiotherapy
4.4.3
Concomitant Medications/Treatments Requiring Special Precautions
4.4.3.1 CYP3A4/5 Inhibitors/Inducers
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AMD 11: ver. date 08.06.2022 
21
Ibrutinib is metabolized primarily by CYP3A4/5. The clinical 
significance of the potential drug-drug interaction with strong 
CYP3A4/5 inhibitors in oncology subjects is currently not known. 
Due to this potential increase in ibrutinib exposure, concomitant 
use of strong CYP3A4/5 inhibitors (such as, indinavir, nelfinavir, 
ritonavir, saquinavir, clarithromycin, telithromycin, ketoconazole, 
itraconazole, and nefazodone; see Appendix I for a 
comprehensive list of such medications) should be avoided while 
the subject is receiving treatment and at least 14 days prior to 
registration. Moderate CYP3A4/5 inhibitors (aprepitant, 
erythromycin, fluconazole, verapamil, and diltiazem) should be 
used with caution. Grapefruit juices, Star fruit, and Seville oranges 
may also increase ibrutinib plasma concentrations and should be 
avoided for the duration of ibrutinib treatment.
If use of a strong CYP3A inhibitor is indicated, selection of an 
alternate concomitant medication with less potent enzyme 
inhibition potential is strongly recommended. If ibrutinib
must be administered with a strong or moderate CYP3A inhibitor, 
refer to Table 4-3 for recommended dose modifications for 
ibrutinib, and notify the PI and NU Quality Assurance Monitor 
(QAM). Subjects should be monitored closely for potential 
treatment-related toxicities. After discontinuation of the CYP3A 
inhibitor, the same dose of ibrutinib that was administered prior to 
the temporary hold may be given upon reinitiation of ibrutinib.
Table 4-3: Dose Modifications for Use with CYP3A Inhibitors
Patient Population
Coadministered Drug
Recommended Ibrutinib Dose

Moderate CYP3A inhibitor
280 mg once daily
Modify dose as recommended per 
Table 4-1, Table 4-2 and Section 
4.3.2.1.1.

Voriconazole 200 mg twice daily

Posaconazole suspension 100 mg 
once daily, 100 mg twice daily, or 
200 mg twice daily
140 mg once daily
Modify dose as recommended per 
Table 4-1, Table 4-2 and Section 
4.3.2.1.1.

Posaconazole suspension 200 mg 
three times daily or 400 mg twice 
daily

Posaconazole IV injection 300 mg 
once daily

Posaconazole delayed-release 
tablets 300 mg once daily
70 mg once daily
Interrupt dose as recommended per 
Table 4-1, Table 4-2 and Section 
4.3.2.1.1..
B-Cell Malignancies

Other strong CYP3A inhibitors
Avoid concomitant use.
If these inhibitors will be used short- 
term (such as anti-infectives for seven 
days or less), interrupt ibrutinib.
Chronic Graft versus 
Host Disease

Moderate CYP3A inhibitor
420 mg once daily
Modify dose as recommended per
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AMD 11: ver. date 08.06.2022 
22
Table 4-1, Table 4-2 and Section 
4.3.2.1.1..

Voriconazole 200 mg twice daily

Posaconazole suspension 100 mg 
once daily, 100 mg twice daily, or 
200 mg twice daily
280 mg once daily
Modify dose as recommended per 
Table 4-1, Table 4-2 and Section 
4.3.2.1.1..

Posaconazole suspension 200 mg 
three times daily or 400 mg twice 
daily

Posaconazole IV injection 300 mg 
once daily

Posaconazole delayed-release 
tablets 300 mg once daily
140 mg once daily
Modify dose as recommended per 
Table 4-1, Table 4-2 and Section 
4.3.2.1.1..

Other strong CYP3A inhibitors
Avoid concomitant use.
If these inhibitors will be used short- 
term (such as anti-infectives for seven 
days or less), interrupt ibrutinib.
Coadministration of ibrutinib with strong CYP3A4/5 inducers (such 
as carbamazepine and rifampin) may decrease ibrutinib plasma 
concentrations and should be avoided. A comprehensive list of 
inhibitors, inducers, and substrates is provided in a link in 
Appendix I.
4.4.3.2 Antiplatelet Agents and Anticoagulants
There have been reports of hemorrhagic events in subjects 
treated with ibrutinib, both with and without thrombocytopenia. 
These include minor hemorrhagic events such as contusion, 
epistaxis and petechiae; and major hemorrhagic events including 
gastrointestinal bleeding, intracranial hemorrhage, and hematuria. 
Also, patients with congenital bleeding diathesis have not been 
studied.
Warfarin or vitamin K antagonists should not be administered 
concomitantly with ibrutinib. Supplements such as fish oil and 
vitamin E preparations should be avoided. Ibrutinib should be 
withheld at least 3 to 7 days pre- and post-surgery depending 
upon the type of surgery and the risk of bleeding (see Section 
prohibitions and restrictions).
Ibrutinib should be used with caution in subjects requiring other 
anticoagulants or medications that inhibit platelet function. It is 
possible that treatment with ibrutinib may increase the risk of 
bruising or bleeding, particularly in subjects receiving antiplatelet 
agents or anticoagulants. Subjects receiving antiplatelet agents in 
conjunction with ibrutinib should be observed closely for any signs 
of bleeding and ibrutinib should be held in the event of major 
bleeding events defined as adverse event of special interest 
(Section 7.2.5).
4.4.4
Precautions & Restrictions Regarding Surgical Interventions or 
Procedures
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The following guidance should be applied during the perioperative period 
for subjects who require surgical intervention or an invasive procedure 
while receiving ibrutinib:

For any planned surgery or invasive procedure requiring sutures or 
staples for closure, ibrutinib should be held at least 7 days prior to the 
intervention and at least 7 days after the procedure, and restarted at 
the discretion of the treating investigator when the surgical site is 
reasonably healed without serosanguineous drainage or the need for 
drainage tubes.

For minor planned procedures (such as a central line placement, 
needle biopsy, thoracentesis, or paracentesis), ibrutinib should be 
held for at least 3 days prior to the procedure and should not be 
restarted for at least 3 days after the procedure.

For bone marrow biopsies that are performed while the subject is on 
ibrutinib, it is not necessary to hold ibrutinib for these procedures.

For emergency procedures, ibrutinib should be held after the 
procedure until the surgical site is reasonably healed, per the 
appropriate procedural guidelines above.
4.6
Duration of Therapy
Patients may continue on ibrutinib maintenance therapy up to 4 years in the 
absence of disease progression or development of unacceptable toxicity; or 
patient preference (withdrawal of consent). Clinical suspicion of progressive 
disease (PD) or loss of response should be investigated radiographically, and will 
result in removal of active therapy if confirmed by clinical investigation.
4.7
Duration of Follow Up
Patients who complete 4 years of maintenance therapy with ibrutinib will have 
one final follow-up study visit approximately 30 days post-last dose. Patients who 
discontinue study therapy prior to this point will be followed up to a maximum of 4 
years (post-first dose of treatment) for survival endpoints (including date of 
progression). Follow-up will occur every 3 months (up to 2 years after the first 
dose of treatment) and then every 6 months thereafter (up to 4 years post-first 
dose.
4.8
Removal of Patients from Therapy and/or Study as a Whole
Patients can be removed from the study treatment (follow-up permitted) and/or 
from the study as a whole (no follow-up permitted) at any time at their own 
request, or they may be withdrawn at the discretion of the investigator for safety, 
behavioral or administrative reasons. The reason(s) for discontinuation must be 
documented on the appropriate eCRF and may include:

Patient voluntarily withdraws from treatment (follow-up continues)

Patient withdraws consent (termination of treatment and follow-up)

Patient is unable to comply with protocol requirements (termination of 
treatment, follow up continues)

Patient demonstrates disease progression (termination of treatment, follow- 
up continues). Clinical suspicion of progressive disease (PD) or loss of 
response should be investigated radiographically, and will result in removal of 
active therapy if confirmed by clinical investigation.
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AMD 11: ver. date 08.06.2022 
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
Patient experiences toxicity that makes continuation in the protocol unsafe 
(termination of treatment, follow up continues)

Treating physician determines that continuation on the study would not be in 
the patient’s best interest (termination of treatment, follow up continues)

Patient becomes pregnant, see section 7.2.6 for reporting timeframe 
(termination of treatment, but follow up continues)

Patient develops a second malignancy (except for basal cell carcinoma or 
squamous cell carcinoma of the skin) that requires treatment, which would 
interfere with this study (termination of treatment, but follow up continues). 
NOTE: Patients who stop treatment in order to receive other anti-cancer 
therapy for a second malignancy may, on a case-by-case basis and upon 
approval of PI and DMC, be considered for possible re-start of study 
medication once other anti-cancer therapy is complete. See Section 4.3.1 for 
more details.
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25
5.0
STUDY PROCEDURES
Table: Schedule of Events
Screening
On-Treatment2
Off-Treatment
Test/Assessment
Pre-Study
Baseline Tests6
Cycles 1-69
Cycles 7+10
EOT11
Follow-Up11
Documentation of induction 
chemotherapy1
X
Informed consent
X
Medical history
X
Concomitant medications
X
X
X
Physical exam12
X
X
X
X
ECOG status
X
X
X
Hematology3
X
X
X
X
Chemistries4
X
X
X
X
Pregnancy test5
X
Hep B & C serologies15
X
Tissue for research18
X
Research blood samples17
X
X
CT scan (C/A/P) or MRI7
X
X
X7
Peripheral blood for flow 
cytometry17
X
X
Bone marrow biopsy13
X
X
X13
EGD/Colonoscopy14
X
X
X14
Drug administration & 
accountability8
X
Adverse events16
X
X
X
X
X
Survival
X
X
1Must include at least 4 cycles of R-CHOP (with or without alternating R-DHAP), R-Hyper-CVAD, or bendamustine + rituximab (all with or without auto SCT). Last 
dose of cytotoxic chemotherapy must be at least 14 days prior to registration (but no more than 120 days prior). Patients who underwent auto SCT must 
show engraftment and meet all required baseline hematological parameters.
2While on treatment, one cycle will be defined as 28 days (+/- 2 days). Assessments will occur on day 1 of each cycle (± 2 days, for the first 6 months), then every 
3 cycles (± 10 days, up to 4 years). If after 2 years a patient is clinically stable and lives far from the study site, he or she may elect to be seen every 6 
cycles (±10 days), with a sufficient drug supply, as detailed in section 4.2. Labs should be resulted prior to treatment to assess the need for dose 
modifications (see section 4.3 for details). When a dose is missed or held, it will not be made up, regardless of duration. Observations and scheduled 
assessments will continue regardless of amount of drug the patient has had, and should always be based on time from C1D1. Please contact QA if you 
have any questions on timing of holds or study assessments.
3CBC with platelets/differential

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4Comprehensive chemistry panel, Mg, and LDH. Comprehensive chemistry panel includes glucose, calcium, albumin, ALT, AST, sodium, potassium, total bilirubin, 
alk phos, creatinine.
5If applicable for WOCBP (urine or serum).
6Baseline/screening tests required to be completed as follows: within 90 days prior to registration for imaging, bone marrow biopsy and EGD/Colonoscopy (if 
applicable) and within 14 days prior to registration for all other baseline assessments (except informed consent, which can be signed within 30 days prior 
to registration).
7Imaging should be performed at baseline, after cycles 3 and 6, every 6 months/cycles for the first 2 years, once at 3 years, and as clinically indicated thereafter 
(including EOT, as clinically appropriate, for patients who complete 4 years of therapy, or patients that come off study treatment early for a reason other 
than progression). In general, it is preferred that imaging be CT-based; at a minimum, the same modality should be used consistently for each patient.
8Ibrutinib will be administered at a dose of 560 mg PO daily throughout the course of treatment unless a dose reduction occurs (see section 4.3.2 for details).
Patients will be asked to keep a study calendar for the duration of treatment See section 4.2 for details on dispensing and visit frequency.
9Patients will be evaluated on Day 1 of each cycle (±2 days) for the first 6 cycles (prior to the start of each cycle). NOTE: Cycle 1 Day 1 should begin within 14 
days after registration, however Day 1 labs (hematology and chemistry tests) need only be repeated if screening labs were performed >7 days prior to 
C1D1.
10Patients will be evaluated every 3 cycles (on Day 1, ±10 days) beginning with cycle 7. After 2 years on therapy, patients will continue to be seen clinically every 3 
cycles, however collection of data for study purposes will only be required every 6 cycles (approximately every 6 months) for the remainder of study 
treatment.
11Patients who complete 4 years of maintenance therapy with ibrutinib will have one final follow-up study visit approximately 30 days post-last dose. Patients 
who discontinue study therapy prior to this point will be followed up to a maximum of 4 years (post-first dose of treatment) for survival endpoints only 
(no labs or physical exam are required), including date of progression. Follow-up will occur until progression at the following times: every 3 months (±10 
days) up to 2 years after the first dose of treatment and then every 6 months (±10 days) thereafter up to 4 years after the first dose of treatment.
12Physical exam includes height (baseline only), weight, 12-point symptom assessment and vitals (bp, heart rate, temperature)
13Bone marrow biopsy is only required (within 90 days of registration) for those with documented bone marrow involvement of MCL at time of last bone marrow 
biopsy. These patients should have repeat bone marrow biopsy after 6 cycles of therapy, in order to judge efficacy of treatment, then as clinically 
indicated during the period of follow up. If no previous bone marrow biopsy was obtained (e.g. at time of diagnosis), or if disease involvement was 
resolved as of most recent bone marrow biopsy, then none is required for trial entry, however it may be done at the discretion of the treating investigator.
14Only required (within 90 days of registration) for those with documented involvement of MCL by EGD and/or colonoscopy, at time of last EGD/colonoscopy. 
These patients should have repeat EGD/colonoscopy with biopsy after 6 cycles of therapy, in order to judge efficacy of treatment, then as clinically 
indicated during the period of follow up. If no previous EGD/colonoscopy was obtained (e.g., at time of diagnosis), or if disease involvement was resolved 
as of most recent EGD/colonoscopy with biopsy, then none is required for trial entry, however it may be done at the discretion of the treating investigator.
15 At screening, patients will have HepBcAb, HepBsAg, and HepC Antibody. Carriers of hepatitis B should be closely monitored for clinical and laboratory signs of 
active HBV infection and for signs of hepatitis during and for several months following ibrutinib treatment. Specifically, those with negative HBsAg and 
undetectable viral load should have these parameters rechecked approximately every 2-3 months while on ibrutinib and until 6 months after stopping 
ibrutinib. Any emerging HBsAg positivity, or rising viral load, should prompt interruption of drug and consultation with hepatology. Those with positive 
HBsAg and/or detectable viral load at time of enrollment should be seen by a hepatologist prior to starting study therapy, and HBV prophylaxis should be 
strongly considered.
16Adverse events will be tracked from time of signed informed consent until completion of the last study-related procedures (which may include contact for follow- 
up safety). Serious adverse events will be reported for 30 days beyond cessation of study treatment. AE’s resulting in discontinuation will be followed until 
resolution, or until patients start subsequent therapy, whichever comes first.
17Peripheral blood samples for exploratory studies (1 x 10 ml EDTA tube) will be collected cycle 1 day 1 (pre-dose), cycle 2, and cycle 7, and at approximately 18- 
24 months post-first dose of study drug. A second peripheral blood sample should be obtained at the same time as each research sample, and sent for 
flow cytometry, as standard of care, to be performed at the treating institution. Another sample (1 x 6mL EDTA tube) will be collected and stored for future 
use at each time point. Please see Section 9.0 for further details.
18Tissue (3-5 unstained FFPE slides) from a prior biopsy will be obtained at baseline from all patients (for whom such tissue is available – lack of availability will not 
disqualify patients from participating, but it is not optional for those who do have available tissue). See Section 9.0 for more details.

IRB #: STU00098385-MOD0038 Approved by NU IRB for use on or after 5/19/2022 through 3/6/2023.
Study Numbers: NU 14H06 
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AMD 11: ver. date 08.06.2022 
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6.0
ENDPOINT ASSESSMENT
6.1
Primary Endpoint
The primary endpoint will be progression-free survival (PFS) at 3 years. PFS will 
be measured from start of treatment to time of progression or death from any 
cause. Progression-free survival will be defined as the absence of either 
progression or death from any cause. Progression will be evaluated using 
Cheson 2007 criteria (Revised Response Criteria for Malignant Lymphoma, 
modified – please see Appendix II). Evidence of clinical progression will be 
documented by imaging (CT scan or MRI) for patients who have measurable 
disease. Any patient who receives at least one dose of study treatment will be 
evaluable for this endpoint.
6.2
Secondary Endpoints
6.2.1
Toxicity
All patients who receive at least one dose of ibrutinib will be evaluable for 
toxicity (including those who are replaced for efficacy endpoints). The 
study will use the CTCAE version 4.03 (see appendices for link) for 
reporting of adverse events. The occurrence and severity of each will be 
recorded.
After the study has been opened for 18 months, patients will be evaluated 
for an interim safety analysis. The PI along with the Northwestern 
Lymphoproliferative Disorders disease team and Quality Assurance will 
assess data to ensure there are no unexpected safety signals that have 
been observed at this time. See section 10.3.4 for details on the safety 
analysis.
6.2.2
Rate of conversion from PR to CR
Progression will be evaluated using Cheson 2007 criteria (Revised 
Response Criteria for Malignant Lymphoma, modified). Patients must 
have already achieved either PR or CR during induction chemotherapy 
prior to enrolling in this study. Patients with measureable disease at time 
of enrollment will have it followed with imaging. Only patients who had a 
PR at the time of registration and who complete ≥ 1 complete cycle of 
ibrutinib maintenance therapy will be evaluable for this endpoint. Please 
refer to appendices for a summary of Cheson criteria.
6.2.3
Median overall survival at 4 years
Overall survival (OS) will be defined as the duration of time from start of 
treatment up to 4 years from the start of study treatment.
6.3
Exploratory Endpoints
We will collect archived tissue (FFPE slides) from a prior biopsy as well as 
peripheral whole blood samples from all patients. Peripheral blood samples will 
be collected at baseline, after 1 month of treatment, 6 months of treatment, and 
approximately 18-24 months post-first dose. MRD analysis will be conducted 
using PCR methods and results over time will be compared and correlated with 
PFS and OS. Please see section 9.0 for details.
IRB #: STU00098385-CR0008 Approved by NU IRB for use on or after 3/3/2023 through 3/2/2024.

IRB #: STU00098385-MOD0038 Approved by NU IRB for use on or after 5/19/2022 through 3/6/2023.
Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
28
7.0
ADVERSE EVENTS
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) 
of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University (please 
refer to the protocol page in NOTIS for additional information). The level of risk attributed 
to this study requires High Intensity Monitoring, as outlined in the DSMP. In addition, the 
study will abide by all safety reporting regulations, as set forth in the Code of Federal 
Regulations and as required by the NCI AdEERS Reporting Guidelines.
This study has been designated as an interventional study. As such, all adverse events 
and special situations, including pregnancies and product quality complaints, will be 
reported from the time a subject has signed and dated an Informed Consent Form (ICF) 
until 30 days after the last documented use of the product under the study within the 
study. Adverse events that result in treatment discontinuation will be followed until 
resolution or until the patient starts subsequent therapy, whichever comes first.
For the purposes of this study, the Janssen medicinal product is: Ibrutinib (Imbruvica)
7.1
Adverse Event Monitoring
Adverse event data collection and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of subjects enrolled in the studies as 
well as those who will enroll in future studies using similar agents.
Adverse events are reported in a routine manner at scheduled times during a 
trial. Additionally, certain adverse events must be reported in an expedited 
manner to allow for optimal monitoring of patient safety and care. All adverse 
events (regardless of severity) will be recorded in the appropriate eCRF 
throughout the study.
All patients experiencing an adverse event, regardless of its relationship to study 
drug, will be monitored until:

the adverse event resolves or the symptoms or signs that constitute the 
adverse event return to baseline;

any abnormal laboratory values have returned to baseline;

there is a satisfactory explanation other than the study drug for the changes 
observed; or

death occurs.
7.2
Definitions & Descriptions
7.2.1
Adverse event (AE)
An adverse event (AE) is any untoward medical occurrence in a patient 
receiving study treatment and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of an experimental 
intervention, whether or not related to the intervention.
Recording of AEs should be done in a concise manner using standard, 
acceptable medical terms. In general, AEs are not procedures or 
measurements, but should reflect the reason for the procedure or the 
diagnosis based on the abnormal measurement. Preexisting conditions
IRB #: STU00098385-CR0008 Approved by NU IRB for use on or after 3/3/2023 through 3/2/2024.

IRB #: STU00098385-MOD0038 Approved by NU IRB for use on or after 5/19/2022 through 3/6/2023.
Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
29
that worsen in severity or frequency during the study should also be 
recorded (a preexisting condition that does not worsen is not an AE). 
Further, a procedure or surgery is not an AE; rather, the event leading to 
the procedure or surgery is considered an AE.
If a specific medical diagnosis has been made, that diagnosis or 
syndrome should be recorded as the AE whenever possible. However, a 
complete description of the signs, symptoms and investigations which led 
to the diagnosis should be provided. For example, if clinically significant 
elevations of liver function tests are known to be secondary to hepatitis, 
“hepatitis” and not “elevated liver function tests” should be recorded. If the 
cause is not known, the abnormal test or finding should be recorded as 
an AE, using appropriate medical terminology (e/g/ thrombocytopenia, 
peripheral edema, QT prolongation).
7.2.2
Severity of AEs
All AEs will be graded according to the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.03. The CTCAE v. 4.03 is available 
at http://ctep.cancer.gov/reporting/ctc.html.
If no CTCAE grading is available, the severity of an AE is graded as follows:

Mild (grade 1): the event causes discomfort without disruption of 
normal daily activities.

Moderate (grade 2): the event causes discomfort that affects normal
daily activities.

Severe (grade 3): the event makes the patient unable to perform 
normal daily activities or significantly affects his/her clinical status.

Life-threatening (grade 4): the patient was at risk of death at the 
time of the event.

Fatal (grade 5): the event caused death.
7.2.3
Serious adverse events (SAEs)
All SAEs, regardless of attribution, occurring from time of signed informed 
consent, through 30 days after the last administration of study drug, must 
be reported upon discovery or occurrence. Additional expedited or routine 
reporting may be required, depending on the nature of the SAE (as 
outlined in 7.3 below). A “serious” adverse event or reaction is defined in 
regulatory terminology as any untoward medical occurrence that:

Results in death.
If death results from (progression of) the disease, the disease should 
be reported as the event (SAE) itself.

Is life-threatening.
The patient was at immediate risk of death at the time of the event; it 
does not refer to an event that hypothetically might have caused 
death if it were more severe.
IRB #: STU00098385-CR0008 Approved by NU IRB for use on or after 3/3/2023 through 3/2/2024.

IRB #: STU00098385-MOD0038 Approved by NU IRB for use on or after 5/19/2022 through 3/6/2023.
Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
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
Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours.
NOTE: Hospitalizations that do not meet the criteria for SAE reporting 
include:
o
Hospitalizations required for drug administration, study- 
required testing
o
Hospitalizations not intended to treat an acute illness or adverse 
event (e.g., social reasons such as pending placement in long- 
term care facility)
o
Surgery or procedure planned before entry into the study. [Note: 
Hospitalizations that were planned before the start of data 
collection and where the underlying condition for which the 
hospitalization was planned has not worsened will not be 
considered serious adverse events. Any adverse event that 
results in a prolongation of the originally planned hospitalization 
is to be reported as a new serious adverse event.]

Results in persistent or significant disability (a substantial 
disruption of the ability to conduct normal life functions) or incapacity.

Results in a congenital anomaly/birth defect.

Results in suspected transmission of infectious agents by a 
medicinal product.

Is an important medical event.
Any event that does not meet the above criteria, but that in the judgment 
of the investigator jeopardizes the patient, may be considered for 
reporting as a serious adverse event. The event may require medical or 
surgical intervention to prevent one of the outcomes listed in the definition 
of “Serious Adverse Event“.
Examples: allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; convulsions that may not result in 
hospitalization; development of drug abuse or drug dependency
7.2.4
Unanticipated Problems Involving Risks to Subject or Others
A UPIRSO is a type of SAE that includes events that meet ALL of the 
following criteria:

Is unexpected (in terms of nature, severity, or frequency) given the 
procedures described in the research protocol documents (e.g., the IRB- 
approved research protocol and informed consent document) and the 
characteristics of the human subject population being studied

Is related or possibly related to participation in the research ("possibly 
related" means there is a reasonable possibility that the incident, 
experience, or outcome may have been caused by the procedures 
involved in the research); and

Suggests that the research places human subjects or others at a greater 
risk of harm (including physical, psychological, economic, or social harm)
IRB #: STU00098385-CR0008 Approved by NU IRB for use on or after 3/3/2023 through 3/2/2024.

IRB #: STU00098385-MOD0038 Approved by NU IRB for use on or after 5/19/2022 through 3/6/2023.
Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
31
than was previously known or recognized, even if no harm has actually 
occurred.
7.2.5
Adverse Events of Special Interest
Adverse events of special interest are any events that Janssen Scientific 
Affairs (the company providing the drug) is actively monitoring as a result 
of a previously identified signal (even if non-serious). They should be 
recorded on a Serious Adverse Event Report Form and reported to 
Janssen Scientific Affairs, LLC within 24 hours of becoming aware of the 
event. The AEs of special interest for this protocol include:

Major hemorrhage – Defined as any hemorrhagic event that is Grade 
3 or greater in severity or that results in 1 of the following:
o
intraocular bleeding causing loss of vision,
o
the need for a transfusion of 2 or more units of red cells or an 
equivalent amount of whole blood
o
hospitalization, or prolongation of hospitalization

Intracranial hemorrhage – Any intracranial hemorrhage AE (of any 
grade severity) including:
o
subdural hematoma/hemorrhage
o
epidural hematoma/hemorrhage
o
intracerebral hemorrhage

Other malignancies – All new malignant tumors (including solid 
tumors, skin malignancies, and hematologic malignancies) are to be 
reported for the duration of study treatment and during any protocol- 
specified follow-up periods (including during post-progression follow- 
up for overall survival).
7.2.6
Pregnancy
Men must notify the study staff if their partner becomes pregnant while on 
study treatment or within 3 months of last dose. Women must notify the 
study staff if they become pregnant while on study treatment or within 1 
month of last dose of ibrutinib and must immediately stop taking the study 
treatment.
All initial reports of pregnancy must be reported to Scientific Affairs, LLC 
within 24 hours of knowledge of the event. Abnormal pregnancy 
outcomes (e.g., spontaneous abortion, stillbirth, and congenital anomaly) 
are considered SAEs and must be reported as SAEs. Any subject who 
becomes pregnant during the study must discontinue further study 
treatment.
Because the effect of the study drug on sperm is unknown, pregnancies 
in partners of male subjects included in the study should be reported 
within 24 hours of knowledge of the event. Follow-up information 
regarding the outcome of the pregnancy and any postnatal sequelae in 
the infant will be required on a case-by-case basis.
7.2.7
Individual Case Safety Report (ICSR)
IRB #: STU00098385-CR0008 Approved by NU IRB for use on or after 3/3/2023 through 3/2/2024.

IRB #: STU00098385-MOD0038 Approved by NU IRB for use on or after 5/19/2022 through 3/6/2023.
Study Numbers: NU 14H06 
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Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
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A valid ICSR must contain the four minimum criteria required to meet 
regulatory reporting requirements.

an identifiable subject (but not disclosing personal information such as 
the subject’s name, initials or address)

an identifiable reporter (investigational site)

a Janssen medicinal product

an adverse event, outcome, or certain special situations
The minimum information required is:

suspected Janssen medicinal product (doses, indication)

date of therapy (start and end date, if available)

batch or lot number, if available

subject details (subject ID and country)

gender

age at AE onset

reporter ID

adverse event detail (AE verbatim in English), onset date, relatedness, 
causality, action taken, outcome, (if available)

Janssen protocol ID
7.2.8
Product Quality Complaint (PQC)
A product quality compliant is defined as any suspicion of a product 
defect related to a potential quality issue during manufacturing, 
packaging, release testing, stability monitoring, dose preparation, storage 
or distribution of the product, or delivery system. Not all PQCs involve a 
subject. Lot and batch numbers are of high significance and need to be 
collected whenever available.
Examples of PQC include but not limited to:

Functional Problem: e.g., altered delivery rate in a controlled release 
product

Physical Defect: e.g. abnormal odor, broken or crushed 
tablets/capsules

Potential Dosing Device Malfunction: e.g., autoinjector button not 
working, needle detaching from syringe

Suspected Contamination

Suspected Counterfeit
7.2.9
J&J Medicinal Product:
A J&J medicinal product is defined as the specific J&J drug under study 
and any other J&J medicinal product.
7.2.10 Special Reporting Situations
Safety events of interest for a Janssen medicinal product that require 
expediting reporting and/or safety evaluation include, but are not limited 
to:
IRB #: STU00098385-CR0008 Approved by NU IRB for use on or after 3/3/2023 through 3/2/2024.

IRB #: STU00098385-MOD0038 Approved by NU IRB for use on or after 5/19/2022 through 3/6/2023.
Study Numbers: NU 14H06 
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Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
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
overdose of a J&J medicinal product

pregnancy exposure (maternal and paternal)

exposure to a medicinal product from breastfeeding

suspected abuse/misuse of a medicinal J&J product

inadvertent or accidental exposure to a medicinal J&J product

any failure of expected pharmacological action (i.e., lack of effect) of a 
J&J medicinal product

unexpected therapeutic or clinical benefit from use of a J&J medicinal 
product

medication error involving a J&J product (with or without patient 
exposure to the product, e.g., name confusion)

suspected transmission of any infectious agent via a medicinal 
product.
These safety events may not meet the definition of an adverse event; 
however, from Janssen Scientific Affairs, LLC perspective, they are 
treated in the same manner as adverse events. Special situations should 
be recorded on the Adverse Event page of the CRF.
Any special situation that meets the criteria of a serious adverse event 
should be recorded on a Serious Adverse Event Report Form and be 
reported to Janssen Scientific Affairs, LLC within 24 hours of becoming 
aware of the event.
7.3
Adverse Event Reporting
7.3.1
Routine reporting
All routine adverse events, such as those that are expected, or are unlikely 
or definitely not related to study participation, are to be reported on the 
appropriate eCRF according to the time intervals noted on the protocol 
page in NOTIS. Routine AEs will be reviewed by the Data Monitoring 
Committee (DMC) according to the study’s phase and risk level, as outlined 
in the DSMP.
7.3.2
Steps to determine if expedited reporting is required
This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of 
treatment and is attributed (possibly, probably, or definitely) to the agent(s) 
must also be reported accordingly.
1) Identify the type of adverse event using the NCI CTCAE v 4.03.
2) Grade the adverse event using the NCI CTCAE v 4.03.
3) Determine whether the adverse event is related to the protocol 
therapy. Attribution categories are as follows:

Definite: AE is clearly related to the study treatment.

Probable: AE is likely related to the study treatment.

Possible: AE may be related to the study treatment.

Unrelated: AE is clearly NOT related to the study treatment.
4) Determine the prior experience of the adverse event.
IRB #: STU00098385-CR0008 Approved by NU IRB for use on or after 3/3/2023 through 3/2/2024.

IRB #: STU00098385-MOD0038 Approved by NU IRB for use on or after 5/19/2022 through 3/6/2023.
Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
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Expected events are those that have been previously identified as 
resulting from administration of the agent. An adverse event is 
considered unexpected, for expedited reporting purposes only, 
when either the type of event or the severity of the event is not listed 
in:

the current protocol;

the drug package insert

the current Investigator’s Brochure.
For a medicinal product(s) with a marketing authorization, the 
expectedness of an adverse event will be determined by whether or not it 
is listed in the applicable product information. 
https://www.imbruvicahcp.com
7.3.3
Expedited reporting of SAEs & Other Events
7.3.3.1 Reporting to the Northwestern University QAM/DMC
All SAEs must be reported to the assigned QAM 
(croqualityassurance@northwestern.edu) within 24 hours of 
becoming aware of the event. Completion of the NU CTO SAE 
Form and Medwatch Form is required.
The completed form should assess whether or not the event 
qualifies as a UPIRSO. The report should also include:

Protocol description and number(s)

The patient’s identification number

A description of the event, severity, treatment, and outcome (if 
known)

Supportive laboratory results and diagnostics

The hospital discharge summary (if available/applicable)

Country of incidence
All SAEs will be reported to, and reviewed by, the DMC per the Data 
and Safety Monitoring Plan (DSMP).
7.3.3.2 Reporting to the Northwestern University IRB
The following information pertains to the responsibilities of the 
lead site (Northwestern University) and to participating sites whom 
have reporting responsibilities to Northwestern University.
Participating sites should follow their local IRB guidelines for 
reporting to their local IRBs.

Any death of an NU subject that is unanticipated in nature 
and at least possibly related to study participation will be 
promptly reported to the NU IRB within 24 hours of 
notification.

Any death of a non-NU subject that is unanticipated and at 
least possibly related and any other UPIRSOs will be 
reported to Northwestern University and to the NU IRB 
within 5 working days of notification.

Information pertaining to an NU subject that fits into any of 
the categories listed on the Reportable New Information
IRB #: STU00098385-CR0008 Approved by NU IRB for use on or after 3/3/2023 through 3/2/2024.

IRB #: STU00098385-MOD0038 Approved by NU IRB for use on or after 5/19/2022 through 3/6/2023.
Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
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page will be reported to the NU IRB within 5 business days 
of knowledge or notification.
For further information regarding the NU IRB policies and 
requirements for SAE reporting, please reference their website at: 
http://irb.northwestern.edu/process/when-things-go- 
wrong/reporting-requirements-timeframes.
7.3.3.3
Reporting to Janssen Scientific Affairs
In general, Janssen Scientific Affairs, LLC must be notified within 
24 hours of becoming aware of any events that qualify as SAEs, 
AEs of Special Interest, Special Reporting Situations, 
pregnancies, and PQCs (whether or not considered drug related – 
see section 7.2 for definitions and descriptions of these terms). At 
a minimum, on a quarterly basis and at the end of the study, 
Scientific Affairs, LLC will provide to the PI and QAM a listing of all 
SAEs reported to Janssen Scientific Affairs. The PI and QAM will 
review this listing and provide any discrepancies to the Janssen 
Scientific Affairs.
Study endpoints that are SAEs (e.g., all-cause mortality) will be 
reported in accordance with the protocol unless there is evidence 
suggesting a causal relationship between the drug and the event 
(e.g., death as a result of anaphylactic reaction or fatal hepatic 
necrosis). In that case, the investigator must immediately report 
the event to Janssen Scientific Affairs. Upon request, the PI (with 
assistance from the QAM) shall provide Janssen Scientific Affairs 
with a summary list of all SAEs, and AEs of Special Interest and 
Special Reporting Situation reports to date, for reconciliation 
purposes.
For each subject, AEs, SAEs, and Special Reporting Situations 
should be recorded after informed consent is obtained until the 
subject has completed participation in the study as follows:

SAEs or Special Reporting Situations must be reported from 
time of signed informed consent, through 30 days after the last 
administration of study drug (whether receiving study drug or 
not).

SAEs or Special Reporting Situations that are ongoing at the 
time a subject completes his/her participation in the study 
should be followed until any of the following occurs:
o
the event resolves or stabilizes
o
the event returns to baseline condition or value (if 
available)
o
the event can be attributed to other agents(s) or factors 
unrelated to study conduct.
o
It becomes unlikely that any additional information can 
be obtained (subject or health care practitioner refusal 
to provide additional information, lost to follow-up after 
demonstration of due diligence with follow-up efforts)
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IRB #: STU00098385-MOD0038 Approved by NU IRB for use on or after 5/19/2022 through 3/6/2023.
Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
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At a minimum, at the end of the treatment as well as the end of 
the follow-up phases of the study, Northwestern University shall 
provide a report containing all AEs, both serious and non-serious. 
However, in certain circumstances more frequent review of the 
safety data may be necessary, (e.g. to fulfill a regulatory request), 
and as such the data shall be made available within a reasonable 
timeframe at Janssen Scientific Affairs’ request. Reporting 
timeframes for non-serious AEs should be outlined in the 
Research Funding Agreement section entitled Reporting of Data.
The following methods are acceptable for transmission of safety 
information to Janssen Scientific Affairs, LLC:

Electronically via Janssen SECURE Email service (preferred; 
please contact the Janssen assigned Trial Manager for access 
at IIS-BIO-VIRO-GCO@its.jnj.com

For business continuity purposes, if SECURE Email is non- 
functional:
o
Facsimile (fax), receipt of which is evidenced in a 
successful fax transmission report: 866-451-0371
o
If fax is non-functional, contact assigned Janssen Trial 
Manager
Please use the contact information and process information 
provided by Janssen Scientific Affairs, LLC.
The FDA Medwatch Form will be used for reporting to Janssen 
Scientific Affairs; study teams will submit the NU CTO SAE and 
Medwatch form (as outlined above) to the NU QAM (note: the 
Northwestern study team should submit the Medwatch form 
directly to Janssen). Reports should include the PI’s determination 
of whether the event was caused by a J&J product. All available 
clinical information relevant to the evaluation of an SAE, AEs of 
Special Interest, and Special Reporting Situations including 
pregnancy reports (with or without an AE) including paternal 
exposure are required.

The PI is responsible for ensuring that these cases from 
clinical studies are complete and if not are promptly followed- 
up. This includes ensuring the reports are fully investigated 
and thoroughly documented, and that follow-up information is 
summarized (e.g. hospital records, coroner’s reports, autopsy 
results) and recorded on the appropriate forms.

A study case is not considered complete until all clinical details 
needed to interpret the case are received and the event has 
resolved, or otherwise explained, or the patient is lost to
follow-up. Reporting of follow-up information should follow the 
same timeline as initial reports.

Copies of any and all relevant correspondences with 
regulatory authorities and ethics committees regarding any 
and all SAEs, irrespective of association with the Study Drug
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IRB #: STU00098385-MOD0038 Approved by NU IRB for use on or after 5/19/2022 through 3/6/2023.
Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
37
in the course of the Study, by facsimile within 24 hours of such 
report or correspondence being sent to applicable health 
authorities.
All initial PQCs involving a Janssen medicinal product under study 
must be reported to Janssen Scientific Affairs, LLC by the PI 
within 24 hours after being made aware of the event. The 
Janssen contact will provide additional information/form to be 
completed.
If the defect for a Janssen medicinal product under study is 
combined with either a serious adverse event or non-serious 
adverse event, the PI must report the PQC to Janssen Scientific 
Affairs, LLC according to the serious adverse event reporting 
timelines. A sample of the suspected product should be 
maintained for further investigation if requested by Janssen 
Scientific Affairs, LLC.
Janssen Scientific Affairs will provide to the PI IND safety 
reports/SUSAR (Serious Unexpected Suspect Adverse Reaction) 
reports generated by the Janssen Scientific Affairs for the study 
drug as they become available until all subjects in the have 
completed their last Study visit according to the study parameters 
(i.e. Last Subject Last Visit has occurred).
1. Reporting Procedures for Reporting Safety Data and Product 
Quality Complaints (PQCs) for Non-Janssen Medicinal Products
For SAEs, special reporting situations and PQCs following 
exposure to a non-Janssen medicinal product under study, the PI 
should notify the appropriate regulatory/competent authority or the 
manufacturer of that medicinal product (in the absence of 
appropriate local legislation) as soon as possible
8.0
DRUG INFORMATION
8.1
Ibrutinib
8.1.1
Other names
Ibrutinib (IMBRUVICA™) or JNJ 54179060 is 1-[(3R)-3-[4-amino-3-(4- 
phenoxyphenyl)-1H-pyrazolo [3, 4 d] pyrimidin-1-yl]-1-piperidinyl]-2- 
propen-1-one and has a molecular weight of 440.50 g/mole (anhydrous 
basis).
8.1.2
Classification – type of agent
Ibrutinib is a selective BTK inhibitor.
8.1.3
Mode of action
Ibrutinib binds covalently to a cysteine residue (Cys-481) in the 
BTK active site, leading to potent and irreversible inhibition of BTK
enzymatic activity [15]. In cellular signal transduction assays with a B-cell 
lymphoma cell line, ibrutinib inhibited autophosphorylation of BTK,
IRB #: STU00098385-CR0008 Approved by NU IRB for use on or after 3/3/2023 through 3/2/2024.

IRB #: STU00098385-MOD0038 Approved by NU IRB for use on or after 5/19/2022 through 3/6/2023.
Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
38
phosphorylation of BTK’s physiological substrate, phospholipase-Cγ 
(PLCγ), and phosphorylation of a further downstream kinase, extracellular 
signal-regulated kinase (ERK). Ibrutinib also inhibited the growth of a 
subset of B-cell lymphoma derived cell lines, with 50% growth inhibition 
(GI50) values ranging from 0.1 to 5.5 μM.
8.1.4
Storage and stability
The recommended storage condition for ibrutinib capsules is controlled 
room temperature (20°C to 25°C). Excursions are permitted between 15° 
and 30°C.
8.1.5
Protocol dose specifics
Ibrutinib will be administered orally at a dose of 560 mg daily. Patients will 
be instructed to take four (4) 140mg capsules for a dose of 560 mg.
Please refer to Section 4 for dose modifications. A 30-day supply of 
Ibrutinib 140 mg capsules will be dispensed prior to the start of each cycle 
for the first 6 months of treatment. Thereafter patients will be given a 3 
month supply of ibrutinib 140mg capsules every 3 cycles.
8.1.6
Preparation
Ibrutinib is a white to off-white crystalline solid that is supplied in 140 mg 
capsules. Ibrutinib capsules are provided as a hard gelatin capsule 
containing 140 mg of ibrutinib. All formulation excipients are compendial 
and are commonly used in oral formulations. Refer to the ibrutinib USPI 
for a list of excipients.
8.1.7
Protocol administration
Ideally ibrutinib will be taken around the same time each day with 
approximately 8 ounces (240 mL) of water. All 4 capsules should be 
taken at the same time and the capsules should remain intact. Subjects 
should not attempt to open capsules or dissolve them in water. The daily 
self-administered home treatment is to be continuous (without 
interruption). Please refer to section 4 for further details and instructions.
8.1.8
Incompatibilities
Ibrutinib may be incompatible with certain agents. Please refer to Section
4.4 for complete details and instructions regarding the concomitant use of 
ibrutinib and CYP3A4/5 inhibitors and inducers and antiplatelet and 
anticoagulant agents, as well as instructions regarding surgical 
interventions and procedures while on study treatment.
Patients should also be instructed to avoid grapefruit juice, Star fruit and 
Seville oranges while on study treatment.
8.1.9
Availability and supply
Ibrutinib will be provided by Janssen Scientific Affairs and distributed as 
an investigational agent through the Investigational Pharmacy at 
Northwestern Memorial Hospital (NMH). Supply for patients at outside 
participating sites will be shipped from the NMH Investigational Pharmacy 
to each local site. To order drug, the drug order form located in NOTIS 
can be submitted following the instructions listed on the form. The 
ibrutinib capsules are packaged in opaque high-density polyethylene
IRB #: STU00098385-CR0008 Approved by NU IRB for use on or after 3/3/2023 through 3/2/2024.

IRB #: STU00098385-MOD0038 Approved by NU IRB for use on or after 5/19/2022 through 3/6/2023.
Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
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(HDPE) plastic bottles containing 120 capsules with labels bearing the 
appropriate label text as required by governing regulatory agencies. All 
bottles will utilize child resistant packaging (caps will be child resistant). 
Unused ibrutinib, dispensed during previous visits, must be returned and 
drug accountability records updated per institutional standards. Returned 
capsules must be discarded and cannot be re-used in this study or 
outside the study. Please refer to the Drug Management Plan for further 
details about drug supply and accountability.
8.1.10 Side effects
Refer to the current investigator’s brochure for toxicity information.
9.0
EXPLORATORY STUDIES
MRD analysis will be conducted using PCR methods and results will be compared over 
time (four time-points total). In addition, we will correlate results with PFS and OS. At 
Northwestern University, the Pathology Core Facility (PCF) Clinical Trials staff will be 
responsible for procuring, processing, and shipping all samples (tissue and peripheral 
blood) for exploratory studies. Participating sites should use whatever local services they 
have available to handle this aspect.
9.1
Sample Collection & Processing Guidelines
9.1.1
Tissue
Archived tissue from a previous biopsy will be obtained from all patients 
who have it available at baseline (lack of available tissue for exploratory 
studies will not preclude patients from participating in this study – 
however it is not optional for those who do have tissue available).
Approximately 3-5 unstained FFPE slides (from diagnosis or time of high 
disease load) will be procured. Each slide should be 5-10 microns (or 
equivalent) in thickness; slides may be stored at ambient temperature 
until shipment.
9.1.2
Peripheral Blood
Three peripheral blood samples for exploratory studies will be collected at 
baseline (prior to treatment on Cycle 1 Day 1), after 1 month of treatment, 
6 months of treatment, and approximately18-24 months post-first dose of 
treatment. All study blood samples will be collected at the same time as 
blood is being drawn for routine care/tests. Two samples will be collected 
using lavender-top EDTA Vacutainer® sample collection tube. Label the 
tube with the date of the draw, patient ID number, and patient initials.
Using the labeled, lavender-top EDTA Vacutainer® sample collection 
tube, approximately 10cc of blood will be drawn. Tubes should be gently 
inverted 8 times to ensure adequate mixing of the anticoagulant. Blood 
samples may be stored at ambient temperature for up to 24 hours.
Within 24 hours of sample collection, perform cell preparation using Ficoll 
protocol on one of the EDTA tubes. Isolate peripheral blood mononuclear
IRB #: STU00098385-CR0008 Approved by NU IRB for use on or after 3/3/2023 through 3/2/2024.

IRB #: STU00098385-MOD0038 Approved by NU IRB for use on or after 5/19/2022 through 3/6/2023.
Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
40
cells (PBMCs). Store PBMCs at -80C until shipment (see lab manual for 
details).
For the second sample of peripheral blood, flow cytometry will be 
performed, as standard of care at the treating institution. The results of 
the flow cytometry will be interpreted as positive or negative per the 
treating investigator and recorded for comparison with simultaneous 
results of MRD testing by PCR.
A third optional sample will be collected in a 6mL EDTA tube for future 
research that involves evaluating the treatment response by analyzing 
changes in the proportion of tumorigenic clones within the patient’s blood 
as compared to the initial biopsy. These samples will be stored in PCF 
Clinical Trials Unit (CTU). Such future research must be reviewed and 
approved by Janssen prior to use of the samples.
9.2
Shipping Instructions
See separate lab manual for instructions on shipping both tissue and peripheral 
blood samples.
9.3
Assay Methodology
Baseline tissue slides will be used to identify clones. All peripheral blood samples 
will undergo MRD analysis testing using PCR methods. Analysis will be 
performed by an outside laboratory that is contracted for these services (see 
separate lab manual for details).
10.0
STATISTICAL CONSIDERATIONS
10.1
Study Design/Study Endpoints
10.1.1 Primary Endpoint
Progression-free survival (PFS) will be defined as the absence of disease 
progression or death from any cause. The rate of PFS will be calculated 
after 3 years.
10.1.2 Secondary Endpoints
Adverse events will be defined according to the National Cancer 
Institute’s Common Terminology Criteria for Adverse Events (NCI 
CTCAE) version 4.03. The occurrence and severity of each will be 
recorded. The rate of conversion from PR to CR will be calculated. 
Overall survival (OS) will be assessed after 4 years.
10.1.3 Exploratory Endpoints
Minimum residual disease (MRD) will be quantified as being either 
categorical or continuous.
10.2
Sample Size and Power Calculations
The primary endpoint is three-year PFS. Our null hypothesis is that ibrutinib 
maintenance will yield no improvement upon the 60% three-year PFS observed in
IRB #: STU00098385-CR0008 Approved by NU IRB for use on or after 3/3/2023 through 3/2/2024.

IRB #: STU00098385-MOD0038 Approved by NU IRB for use on or after 5/19/2022 through 3/6/2023.
Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
41
studies described above. We consider an observed three-year PFS of 80% both 
feasible and of significant clinical improvement. The study will have 10% Type I 
error and 90% power to detect an effective treatment using a one-stage design 
based on the true proportion of patients achieving 3-year PFS is at least 80% 
versus the null hypothesis that the true complete response rate is at most 60%.
Based upon these parameters, our sample size will be 36 evaluable patients. For 
the final analysis, if 25 or fewer patients are alive and without progression from 
among all 36 evaluable patients accrued, we will consider this regimen ineffective 
for this patient population. If, on the other hand, 26 or more patients are alive and 
without progression, this will be considered sufficient evidence that this treatment 
may be recommended for further testing in subsequent studies, particularly in a 
randomized setting.
10.3
Planned Analyses
10.3.1 Primary Objective
The primary objective will be to determine the progression-free survival 
(PFS) rate after 2 and 3 years. This will be done in two ways. First, the 
proportion of patients alive and progression-free at 2 and 3 years will be 
calculated, along with an exact 90% confidence interval, both two-sided 
as well as a lower 90% confidence limit. The number of patients alive 
and progression-free at 2 and 3 years will be used to address the primary 
hypothesis as indicated in section 10.2 above. In addition, a Kaplan- 
Meier curve will be calculated to obtain the actuarial estimate of two-year 
progression-free survival.
10.3.2 Secondary Objectives
To assess toxicity, all adverse events will be summarized as to type, 
severity, frequency, timing and attribution. Descriptive frequencies and 
proportions will be used for this analysis.
To determine rates of conversion from PR to CR, only patients who had a 
PR at the time of registration and who complete ≥ 1 complete cycle of 
ibrutinib maintenance therapy will be evaluable for this endpoint. These 
rates will be calculated as a proportion together with exact 90% 
confidence limits.
To determine median overall survival (OS) after 4 years, Kaplan-Meier 
curves will be determined for overall survival and the five-year point on 
this curve, along with 90% confidence limits, will be determined. Patients 
will be evaluated monthly for the first 6 months on treatment, then every 3 
months thereafter. Patients who go off treatment will continue to be 
followed for survival up to a maximum of 4 years post-first dose. Follow- 
up will occur every 3 months (up to 2 years after the first dose of 
treatment) and then every 6 months thereafter (up to 4 years post-first 
dose).
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IRB #: STU00098385-MOD0038 Approved by NU IRB for use on or after 5/19/2022 through 3/6/2023.
Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
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10.3.3 Exploratory Objectives
To compare MRD results over time by PCR , correlational analyses such 
as McNemar’s test, Pearson and Spearman correlations and Lin’s 
concordance statistics will be used, depending on the metric for MRD (as 
detected by either flow cytometry or by PCR) used in the analysis. To 
correlate MRD with either PFS or OS, proportional hazards regression 
with a time dependent covariate (MRD) will be used.
10.3.4 Interim Analysis
Patients will be formally evaluated for an interim safety analysis as 
described below after 15, 20 and 25 patients have been observed. The PI 
along with the Northwestern Lymphoproliferative Disorders disease team 
and Quality Assurance will assess data to ensure there are no 
unexpected safety signals that have been observed at this time.
Serious adverse event (SAE, Section 7.2.3) assessment will be done 
using a Pocock-type boundary [16]. With 36 patients, if the drug- 
related SAE rate is 25%, and there is a 5% probability of detecting an 
excess of SAEs when the SAE rate at most 25%, then the number of 
SAEs that need to be observed as the trial progresses in order to detect 
an excess of SAEs are 9 SAES/15 patients, 10/20 or 12/25. The 
boundary can be calculated for any interim sample size.
With 36 patients, if the drug-related Grade 5 SAE rate is 1%, and there is 
a 5% probability of detecting an excess of Grade 5 SAEs when the SAE 
rate is at most 1%, then using the Pocock-type boundary, the number of 
Grade 5 SAEs that need to be observed as the trials progresses in order 
to detect an excess of Grade 5 SAEs are at least 2 if the current sample 
size is 26 or less, and at least 3 if the current sample size is between 27 
and 36.
11.0
STUDY MANAGEMENT
11.1
Institutional Review Board (IRB) Approval and Consent
It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations. The IRB should approve the 
consent form and protocol.
In obtaining and documenting informed consent, the investigator should comply 
with the applicable regulatory requirement(s), and should adhere to Good Clinical 
Practice (GCP) and to ethical principles that have their origin in the Declaration of 
Helsinki.
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent 
form. Each consent form must include all the relevant elements currently required 
by the FDA Regulations and local or state regulations. Once this essential 
information has been provided to the patient and the investigator is assured that 
the patient understands the implications of participating in the study, the patient
IRB #: STU00098385-CR0008 Approved by NU IRB for use on or after 3/3/2023 through 3/2/2024.

IRB #: STU00098385-MOD0038 Approved by NU IRB for use on or after 5/19/2022 through 3/6/2023.
Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
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will be asked to give consent to participate in the study by signing an 
IRB-approved consent form.
Prior to a patient’s participation in the trial, the written informed consent form 
should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion.
11.2
Amendments
Amendments to the protocol will be initiated and maintained by the assigned 
Medical Writer. Requests for revisions may come from multiple sources, 
including but not limited to the Principal Investigator, study team, drug company, 
or FDA. All amendments will be subject to the review and approval of the 
appropriate local, institutional, and governmental regulatory bodies, as well as by 
Janssen Scientific Affairs. Amendments will be distributed by the lead institution 
(Northwestern) to all participating sites upon approval by the Northwestern 
University IRB.
11.3
Subject Registration Procedures
Patients may not begin protocol treatment prior to registration. All patient 
registrations will be registered centrally through the Clinical Trials Office at 
Northwestern University before enrollment to study. Please contact the assigned 
Quality Assurance Monitor (QAM) or email the QA Department 
(croqualityassurance@northwestern.edu) for questions regarding patient 
registration.
Prior to registration, eligibility criteria must be confirmed by the assigned QAM. 
The study coordinator will screen all subjects for potential registration via the 
web-based application NOTIS (Northwestern Oncology Trial Information 
System), which is available at: https://notis.nubic.northwestern.edu. Please note 
that a username and password is required to use this program, and will be 
provided during site activation prior to training on the NOTIS system.
BEFORE a patient can be treated on study, please complete and submit the 
following items to confirm eligibility and receive an identification number:

Patient’s signed and dated informed consent form (upload to NOTIS and 
keep original hard copy in a secure location/study chart)

Eligibility checklist (signed and dated by the treating physician – upload to 
NOTIS)

Eligibility eCRF (complete in NOTIS)

Copy of the pathology report (upload to NOTIS)
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IRB #: STU00098385-MOD0038 Approved by NU IRB for use on or after 5/19/2022 through 3/6/2023.
Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
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Training on eCRF completion will be provided at the time of site activation. 
Please refer to the eCRF demonstration videos on the CTO website for additional 
instructions on registering a patient.
The QAM will review the registration, register the patient, assign a subject 
identification number, and send a confirmation of registration to study personnel. 
Registration will then be complete and the patient may begin study treatment.
11.4
Instructions for Participating Sites
Before the study can be initiated at any site, the following documentation must be 
provided to the Clinical Trials Office at Northwestern University:

Signed and completed Letter of Invitation to participate in the study.

Signed copy of Northwestern University’s Data Monitoring Committee policy 
pertaining to data submission.

A copy of the official IRB approval letter for the protocol and informed 
consent.
NOTE: Informed consent form should be submitted to the Clinical Trials 
Office for review/approval prior to submission to the local IRB.

CVs and medical licensure for the local PI and any sub-investigators who will 
be involved in the study at the site.

Form FDA 1572 appropriately filled out and signed with appropriate 
documentation.
Additional activities may be required prior to site activation (i.e. contract 
execution, study-specific training). Full requirements will be outlined in a memo 
upon receipt of the signed Letter of Invitation.
11.5
Data Management and Monitoring/Auditing
This study will be conducted in compliance with the Data Safety Monitoring Plan 
(DSMP) of the Robert H. Lurie Comprehensive Cancer Center of Northwestern 
University (please refer to the protocol page of NOTIS for additional information). 
The level of risk attributed to this study requires High Intensity Monitoring, as 
outlined in the DSMP. The assigned Quality Assurance Monitor, with oversight 
from the Data Monitoring Committee, will monitor this study in accordance with 
the study phase and risk level. Please refer to NOTIS for additional data 
submission instructions.
11.6
Adherence to the Protocol
Except for an emergency situation in which proper care for the protection, safety, 
and well-being of the study patient requires alternative treatment, the study shall 
be conducted exactly as described in the approved protocol.
11.6.1 Emergency Modifications
Investigators may implement a deviation from, or a change of, the 
protocol to eliminate an immediate hazard(s) to trial subjects without prior 
IRB approval.
For any such emergency modification implemented, an IRB modification 
form must be completed within five (5) business days of making the
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IRB #: STU00098385-MOD0038 Approved by NU IRB for use on or after 5/19/2022 through 3/6/2023.
Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
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change, and Janssen Scientific Affairs must be notified in parallel. The 
QAM must be notified within 24 hours of such a change.
11.6.2 Other Protocol Deviations
All other deviations from the protocol must be reported to the assigned 
QAM using the appropriate form.
A protocol deviation is any change, divergence, or departure from the 
study design or procedures of a research protocol that is under the 
investigator's control and that has not been approved by the Institutional 
Review Board (IRB). Protocol deviations must be reported according to 
the policies and procedures of the IRB of record.
A protocol deviation may be considered an instance of Promptly 
Reportable Non-Compliance (PRNC) if it:

Has harmed or increased the risk of harm to one or more research 
participants.

Has compromised the rights and welfare of the research subject.

Has damaged the scientific integrity of the data collected for the study.

Results from willful or knowing misconduct on the part of the 
investigator(s).

Demonstrates serious or continuing noncompliance with federal 
regulations, State laws, or University policies.
All protocol deviations will be documented by the study team on eCRFs in 
NOTIS, as they occur. At NU, deviations will be reviewed during research 
meetings by the PI, with PI review and responses being documented and 
entered into the appropriate eCRF. Other participating sites will follow local 
procedures or SOPs for PI review of deviations. For all sites deviations 
should be entered into the eCRF in real time with regular PI review, and 
immediate routing to QA after PI review. Deviation reports (with appropriate 
documentation of PI review) will be made available to the assigned QAM on 
request, during monitoring visits and at time of audit.
11.7
Obligations of Investigators
The Principal Investigator is responsible for the conduct of the clinical trial at the 
site in accordance with Title 21 of the Code of Federal Regulations and/or the 
Declaration of Helsinki. The PI is responsible for personally overseeing the 
treatment of all study patients. The PI must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study 
protocol and all FDA/GCP/NCI regulations and guidelines regarding clinical trials 
both during and after study completion.
The Principal Investigator at each institution or site will be responsible for 
assuring that all the required data will be collected, entered onto the appropriate 
eCRFs, and submitted within the study-specific timeframes. Periodically, 
monitoring visits may be conducted and the Principal Investigator will provide 
access to his/her original records to permit verification of proper entry of data.
The study may also be subject to routine audits by the Audit Committee, as 
outlined in the DSMP.
11.8
Publication Policy
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IRB #: STU00098385-MOD0038 Approved by NU IRB for use on or after 5/19/2022 through 3/6/2023.
Study Numbers: NU 14H06 
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Initial version: September 24, 2014
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46
All potential publications and/or data for potential publications (e.g. manuscripts, 
abstracts, posters, clinicaltrials.gov releases) must be approved in accordance 
with the DSMC Data Release Policies and Processes. The assigned QAM will 
prepare a preliminary data set for DSMC approval no later than 3 months after 
the study reaches its primary completion date, as defined by ClinicalTrials.gov. 
This is the date that the final patient was examined or received an intervention for 
the purposes of final collection of data for the primary outcome, whether the 
clinical trial concluded according to the pre-specified protocol or was terminated.
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If the investigator would like data release to be approved by the DSMC prior to 
when study design specifies, and/or prior to three months after a study’s primary 
completion date, the PI must send a written request for data approval to the QAM 
which includes justification. Requests must be made a minimum of six to eight 
weeks in advance of the expected deadline. The request will be presented to the 
DSMC at their next available meeting. Any DSMC decisions regarding data 
release will be provided to the PI. If the request is approved, the QAM will 
present the data set to the DSMC for approval. A final, DSMC-approved dataset, 
as applicable, will then be released 6-8 weeks after the request was made. The 
investigators are expected to use only DSMC-approved data and statistical 
analyses any time they are disseminating trial data. The investigators must send 
a copy of the draft abstract/poster/manuscript to the study’s biostatistician and 
assigned QAM to confirm that the DSMC-approved data and statistical analyses 
are used appropriately. Once the biostatistician, Janssen Scientific Affairs and 
QAM gives final approval, the publication may be submitted to external publisher.
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Study Numbers: NU 14H06 
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AMD 11: ver. date 08.06.2022 
48
REFERENCES
1.
Geisler, C.H., et al., Long-term progression-free survival of mantle cell lymphoma after 
intensive front-line immunochemotherapy with in vivo-purged stem cell rescue: a 
nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group. Blood, 2008. 
112(7): p. 2687-93.
2.
Hermine O, e.a., Alternating Courses of 3x CHOP and 3x DHAP Plus Rituximab Followed 
by a High Dose ARA-C Containing Myeloablative Regimen and Autologous Stem Cell 
Transplantation (ASCT) Increases Overall Survival When Compared to 6 Courses of 
CHOP Plus Rituximab Followed by Myeloablative Radiochemotherapy and ASCT in 
Mantle Cell Lymphoma: Final Analysis of the MCL Younger Trial of the European Mantle 
Cell Lymphoma Network. ASH Annual Meeting, 2012. Abstract 153.
3.
Geisler, C.H., et al., The Mantle Cell Lymphoma International Prognostic Index (MIPI) is 
superior to the International Prognostic Index (IPI) in predicting survival following intensive 
first-line immunochemotherapy and autologous stem cell transplantation (ASCT). Blood, 
2010. 115(8): p. 1530-3.
4.
Arranz, R., et al., First-line treatment with rituximab-hyperCVAD alternating with rituximab- 
methotrexate-cytarabine and followed by consolidation with 90Y-ibritumomab-tiuxetan in 
patients with mantle cell lymphoma. Results of a multicenter, phase 2 pilot trial from the 
GELTAMO group. Haematologica, 2013. 98(10): p. 1563-70.
5.
Harris, N.L., et al., A revised European-American classification of lymphoid neoplasms: a 
proposal from the International Lymphoma Study Group. Blood, 1994. 84(5): p. 1361-92.
6.
Van Den Berghe, H.P., C; David, G; Michaux, JL; Sokal, G, A new characteristic karyotypic 
anomaly in lymphoproliferative disorders. Cancer, 1979. 44(1): p. 188-195.
7.
Williams, M.E., et al., Characterization of chromosome 11 translocation breakpoints at the 
bcl-1 and PRAD1 loci in centrocytic lymphoma. Cancer Res, 1992. 52(19 Suppl): p. 5541s- 
5544s.
8.
Romaguera, J.E., et al., High rate of durable remissions after treatment of newly 
diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating 
with rituximab plus high-dose methotrexate and cytarabine. J Clin Oncol, 2005. 23(28): p. 
7013-23.
9.
Dreyling, M. and W. Hiddemann, Current treatment standards and emerging strategies in 
mantle cell lymphoma. Hematology Am Soc Hematol Educ Program, 2009: p. 542-51.
10.
Lymphoma, L.R.F.G.t.F.M.C. National comprehensive clinical network clinical practice 
guidelines in oncology (NCCN guidelines). Non-Hodgkin's Lymphomas v 4 2011 [cited 
2012.
11.
LaCasce, A.S., et al., Comparative outcome of initial therapy for younger patients with 
mantle cell lymphoma: an analysis from the NCCN NHL Database. Blood, 2012. 119(9):
p. 2093-9.
12.
Kluin-Nelemans, H.C., et al., Treatment of older patients with mantle-cell lymphoma. N 
Engl J Med, 2012. 367(6): p. 520-31.
13.
Wang, M.L., et al., Targeting BTK with ibrutinib in relapsed or refractory mantle-cell 
lymphoma. N Engl J Med, 2013. 369(6): p. 507-16.
14.
Cheson, B.D., et al., Revised response criteria for malignant lymphoma. J Clin Oncol, 
2007. 25(5): p. 579-86.
15.
Pan, Z., et al., Discovery of selective irreversible inhibitors for Bruton's tyrosine kinase.
ChemMedChem, 2007. 2(1): p. 58-61.
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IRB #: STU00098385-MOD0038 Approved by NU IRB for use on or after 5/19/2022 through 3/6/2023.
Study Numbers: NU 14H06 
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49
APPENDIX I – Lists of Concomitant Medications/Treatments Requiring Special 
Precautions
A list of drugs that may affect the CYP3A system (and other CYP variants) can be found at:
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionsl 
abeling/ucm093664.htm
IRB #: STU00098385-CR0008 Approved by NU IRB for use on or after 3/3/2023 through 3/2/2024.

Study Numbers: NU 14H06
Initial version: September 24, 2014
PCI-32765MCL2003
AMD 11: ver. date 08.06.2022 
Appendix II – Cheson 2007 Criteria
48

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Study Numbers: NU 14H06 
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AMD 11: ver. date 08.06.2022 
49
Appendix III
The following equations should be used to calculate creatinine clearance.
For males:
Creatinine Clearance =
(140 - age [years] x weight [kg])
72 x (serum creatinine [mg/dL])
OR
(140–age [years] x weight [kg])
0.81 x (serum creatinine [µmol/L])
For females:
Creatinine Clearance =
0.85 (140-age [years] x weight [kg])
72 x (serum creatinine [mg/dL])
OR
0.85 (140-age [years] x weight [kg])
0.81 x (serum creatinine [µmol/L])
Source: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16(1):31-41.
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IRB #: STU00098385-MOD0038 Approved by NU IRB for use on or after 5/19/2022 through 3/6/2023.
Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
50
Appendix IV- Protocol History of Changes
Amendment 1 –May 06, 2015
Approved by Scientific Review Committee- May 06, 2015
Sections(s) Affected
Prior Version
Amendment 1 Changes
Rationale
Title page, Study 
Summary Table, & 3.0
Tufts and Cleveland 
Clinic listed as 
participating sites
Cleveland Clinic removed, 
Duke University, University 
of Michigan, Dana Farber 
added as sites
Administrative
Study Summary table &
3.1.2 (Inclusion 
Criteria)
“Patients must have 
received 4 or more 
cycles of one of the 
following prior systemic 
induction 
chemotherapy 
regimens: R-CHOP 
(with or without 
alternating R-DHAP)
with or without auto 
SCT.”
Revised to “Patients must 
have received 4 or more 
cycles of one of the 
following prior systemic 
induction chemotherapy 
regimens:
R-CHOP (with or without 
cytarabine-containing 
cycles, including “Nordic” 
and MCL-NET protocols) 
with or without auto SCT.”
Revised for 
clarification
Study Summary table, 
1.1, 2.1, 6.1, 10.1.1,
10.2, 10.3.1
“The primary objective 
will be to determine 
the progression-free 
survival (PFS) rate after
2 years.”
“The primary objective will 
be to determine the 
progression-free survival 
(PFS) rate after 3 years.”
Correction of clerical 
error
5.0 “Study Procedures”
“Induction 
Chemotherapy”
Revised to 
“Documentation of 
Induction Chemotherapy”
Revised for 
clarification
5.0 (Study Procedures)
Footnote 17: 
“Peripheral blood 
samples for exploratory 
studies (1 10 ml EDTA 
tube) will be collected 
at baseline...”
“X” removed from 
screening baseline column 
and footnote 17 revised to 
“Peripheral blood samples 
for exploratory studies (1 
10 ml EDTA tube) will be 
collected cycle 1 day 1…”
rather than at baseline.
Revised for 
clarification
5.0 “Study Procedures”,
9.1.2
n/a
Added line in table for 
“Peripheral blood for flow 
cytometry” and added to 
footnote 17 “A second 
tube of peripheral blood 
should be obtained at the 
same time as each 
research sample, and sent 
for flow cytometry, as 
standard of care, to be 
performed at the treating
Revised for 
clarification
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IRB #: STU00098385-MOD0038 Approved by NU IRB for use on or after 5/19/2022 through 3/6/2023.
Study Numbers: NU 14H06 
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51
institution.”
10.3.3 (Exploratory 
Objectives)
“To compare MRD 
results over time by 
PCR , correlational 
analyses such as 
McNemar’s test, 
Pearson and Spearman 
correlations and Lin’s 
concordance statistics 
will be used, depending 
on the metric for MRD 
used in the analysis.”
Revised to “To compare 
MRD results over time by 
PCR , correlational analyses 
such as McNemar’s test, 
Pearson and Spearman 
correlations and Lin’s 
concordance statistics will 
be used, depending on the 
metric for MRD (as 
detected by either flow 
cytometry or by PCR) used 
in the analysis.
Revised for clarity
Amendment 2 – July 21, 2015
Approved by Scientific Review Committee – July 21, 2015
Sections(s) Affected
Prior Version
Amendment 2 Changes
Rationale
Title page, Version Date
May 6, 2015
July 21, 2015
Updated version date
Study Schema
Study Summary
1.1 Disease background 
& Current Therapies
1.3 Rationale for
Current Study
3.1.2 Inclusion Criteria
4.1 Overview
5.0 Study Procedures:
Footnote 1
Hyper-CVAD
R-Hyper-CVAD
To update hyper- 
CVAD to R-Hyper- 
CVAD (R=Rituximab)
Amendment 2 – November 18, 2015
Section(s) Affected
Prior Version
Amendment 1 Changes
Rationale
Cover-page, 3.0 
(Selection of Subjects),
4.3.1 (Dose Delays)
Adam Petrich listed as 
Principal Investigator
Adam Petrich has been 
removed as PI and Jason 
Kaplan has been added; 
contact information and 
IND Holder Name have 
been updated appropriately
Administrative – Dr. 
Petrich has left the 
institution and will no 
longer serve as the 
study PI; Dr. Kaplan 
will take over role of 
PI
Cover-page
n/a
Adds Barbara Pro as a 
Sub-Investigator
Administrative – Dr. 
Pro is a new faculty 
member who will be 
involved with this 
study
Cover-page
Lists Tufts University 
and Duke University as 
participating sites
Removes Tufts University 
and Duke University as 
participating sites and adds 
University of Utah
Administrative – Tufts 
and Duke will no 
longer participate, and 
University of Utah has 
been added to the 
contract
Signature Page
Includes Signature
Removes Signature Page
Administrative – NU
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Pages
protocol template no 
longer includes a 
signature page
4.1 (Treatment Plan 
Overview),
n/a
Adds language to specify 
that patients will start 
treatment with ibrutinib 
within 14 days of study 
registration
Clarification
4.2 (Administration)
States that ibrutinib 
should be taken at least 
30 minutes before 
eating or 2 hours after a 
meal
Removes fasting language
Update to match 
Investigator’s 
Brochure
4.2 (Administration)
n/a
“In general, vomited doses 
should not be made up.
Patients should contact 
their physician to discuss 
options in the event of a 
vomited dose.”
Clarification on dosing 
instructions
4.4.3 (Concomitant 
Medications/Treatments 
requiring Special 
Precautions)
“If ibrutinib must be 
administered with a 
strong or moderate 
CYP3A4/5 inhibitor, the 
medical monitor at 
Jansen should be 
consulted before use, 
and a dose reduction of 
ibrutinib to 140 mg daily 
or a temporary hold of 
ibrutinib should be 
considered.”
“If ibrutinib must be 
administered with a strong 
or moderate CYP3A4/5 
inhibitor, a dose reduction 
of ibrutinib to 140 mg daily 
or a temporary hold of 
ibrutinib should be 
considered. The PI, 
Janssen Medical Monitor, 
and the NU Quality 
Assurance Monitor (QAM) 
must be notified as well.”
Clarification – allows 
investigator autonomy
5.0 (Study Procedures 
– Peripheral blood for 
flow cytometry), 9.1.2 
(Peripheral blood)
Flow cytometry marked 
as required during 
screening
“X” removed from 
procedure table for flow 
cytometry at Screening; it is 
only required at C1D1.
Clarification added to 
footnote 17 and section 
9.1.2.
Clarification - 
streamlines sample 
collection at C1D1
7.0 (Adverse Events),
7.2.3 (Serious Adverse 
Events),
7.2.7 (Individual Case 
Safety Report),
7.2.8 (Product Quality 
Complaint),
7.2.10 (Special 
Reporting Situations),
7.3.3.3 (Reporting to 
Janssen Scientific 
Affairs)
n/a
Adds language from 
Janssen defining AE’s, 
SAE’s, and reporting 
timelines
Updated to align with 
Janssen’s new 
reporting template
8.1.10 (Ibrutinib Side 
Effects)
n/a
Includes additional side 
effects of ibrutinib
Updated to align with 
risk language in new 
investigator’s 
brochure
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IRB #: STU00098385-MOD0038 Approved by NU IRB for use on or after 5/19/2022 through 3/6/2023.
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Amendment 3 – March 15, 2016
Approved by Scientific Review Committee –
Section(s) Affected
Prior Version
Amendment 3 Changes
Rationale
Abbreviations
n/a
Adds the following 
abbreviations:
PCF = Pathcore Facility 
CTU = Clinical Trials Unit
Administrative
3.0 (Selection of 
Subjects)
Trial is conducted at 
Northwestern Medicine 
Developmental 
Therapeutic Instituted 
(NMDTI) of
Northwestern University
Removes NMDTI.
States that the trial will be 
conducted at 
Northwestern University
Not all patients are 
seen in NMDTI
3.1.2 (Inclusion Criteria)
Referring to induction 
chemotherapy options: 
“Patients who received 
combinations of the 
above regimens are not 
eligible”
“Patients are allowed to 
receive combinations of 
the above regimens”
PI feels that a 
combination of the 
listed regimens is 
appropriate and 
should not preclude a 
patient from entering 
the study
3.1.10 (Inclusion criteria),
4.2 (Administration),
4.4.3.1 (CYP3A4/5
Inhibitors/Inducers),
8.1.8 Incompatibilities
Patients should avoid 
consuming Grapefruit 
and Seville orange 
products for the 
duration of the study
Adds that patients should 
also avoid consuming Star 
fruit for the duration of the 
study
Updated safety 
information
3.2.9 (Exclusion Criteria);
4.4.3.1 (CYP3A4/5
Inhibitors/Inducers)
n/a
Refers to Appendix I for a 
list of CYP3A4/5 inhibitors
Clarification
3.2.15 (Exclusion 
Criteria)
Patients with clinically 
active hepatitis A, B, or 
C infections are not 
eligible.
Adds the following note: 
“Patients with a history of 
hepatitis may be eligible if 
they have a normal titer. 
Such cases should be 
approved by the study PI.”
PI feels that a normal 
titer would make the 
patient an appropriate 
study candidate
4.2 (Administration)
Instructed patients not 
to make up missed 
doses, and also to 
contact their physician 
to discuss other options
Clarifies that while 
vomited doses should 
generally not be made up, 
patients should still 
contact their physician to 
discuss such cases.
Clarification – since 
vomited doses are a 
rare occurrence, it is 
appropriate for 
patients to contact 
their physician
4.2 (Administration), 5.0
(Study Table, #8)
Study calendars were 
not required after 6 
months of treatment
Patients must continue 
maintaining a study 
calendar for the duration 
of treatment
QA requirement for 
appropriate drug 
accountability
4.3.1 (Dose Delays)
PI should be 
contacted regarding 
unmanageable 
toxicity
Study drug could be 
restarted after 28 
days on a case-by-
PI and QAM should be 
contacted regarding 
unmanageable toxicity
Removes language 
about restarting drug. 
Any patient who is held 
for 28 days must come
QAM needs to be 
involved in toxicity 
and dose 
management
QA request – allows 
for more 
streamlined
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IRB #: STU00098385-MOD0038 Approved by NU IRB for use on or after 5/19/2022 through 3/6/2023.
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AMD 11: ver. date 08.06.2022 
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case basis
off study
management of 
patient dosing
4.3.2 (Dose 
Modifications)
n/a
The PI should be 
contacted for dose 
modifications due to a 
Grade 4 or unmanageable 
Grade 3 drug-related 
toxicity
Provides guidance 
since such toxicities 
are open-ended
4.4.2 (Prohibited 
Concomitant Meds/ 
Treatment)
Chronic use of systemic 
corticosteroids was 
prohibited unless 
reviewed and approved 
by the PI
Chronic use of systemic 
corticosteroids above 
prednisone 10mg po daily 
(or equivalent) is 
prohibited
Provides more 
concrete instruction
4.4.4 (Precautions & 
Restrictions Regarding 
Surgical Interventions or 
Procedures)
Ibrutinib should be held 
until the surgical site is 
healed or at the 
discretion of the 
investigator
Removes the option for 
investigator’s discretion 
and instead refers to 
procedural guidelines for 
specific surgical 
procedures
Clarification
4.6 (Duration of
Therapy), 4.8 (Removal 
of Patients)
n/a
Adds language: 
“Clinical suspicion of
progressive disease (PD) 
or loss of response should 
be investigated 
radiographically, and will 
result in removal of active 
therapy if confirmed by 
clinical investigation.”
PI wants to ensure 
investigator discretion 
and clinical 
investigation is 
permitted before 
taking a patient off 
treatment; stopping 
Ibrutinib may result in
5.0 (Study Table)
#1: Prior chemo can be 
no more than 90 days 
from study treatment 
#2: n/a
#4: Chemistry panel 
includes 
comprehensive 
chemistry, Mg, LDH 
#6, 13, 14: Window for 
screening procedures 
was 14 days and 90 
days for imaging
#1: Prior chemo can be no 
more than 120 days from 
study treatment
#2: Adds that labs should 
be resulted prior to 
treatment to assess the 
need for dose 
modifications in 4.3
#4: Lists specific labs 
within a comprehensive 
chem panel
#6, 13, 14: Window for 
screening window 
includes 90 days for bone 
marrow biopsy and 
EGD/colonoscopy
#1: To clarify 
discrepancy from 
3.1.2
#2: Treatment 
clarification
#4: Clarification – 
affiliates may have a 
different 
comprehensive panel 
#6, 13, 14:
Clarification – BMBX 
and EGD were 
previously falling 
under “imaging”
5.0 (Study table,
Footnote 17),
9.1.2 (Peripheral blood)
n/a
Adds a third correlative 
sample (6mL EDTA) to be 
collected for future 
research
Dr. Kaplan has a 
grant pending that will 
allow analysis of extra 
blood samples. In the 
meantime, blood will 
be collected for future 
use.
6.1 (Primary Endpoint)
“Progression will be 
documented by imaging 
(CT scan)”
“Progression will be 
documented by imaging 
(CT scan or MRI)”
Clarification of 
discrepancy
7.0 (Adverse Events)
Adverse events were to
Adverse events will now
Clarification per
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IRB #: STU00098385-MOD0038 Approved by NU IRB for use on or after 5/19/2022 through 3/6/2023.
Study Numbers: NU 14H06 
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AMD 11: ver. date 08.06.2022 
55
be reported from the 
time of consent until 30 
days from the last dose 
of study drug
be reported from the time 
of consent until 
completion of the subject’s 
last study related 
procedures (which may 
include contact for follow 
up safety). Note clarifies 
that follow-up will only 
apply to patients who 
discontinue for reasons 
other than PD.
Janssen request.
7.2.5 (Adverse Events of 
Special Interest)
n/a
Adds the following 
sentence re AE’s of 
special interest:
“They should be recorded 
on a SAE Report Form 
and reported to Janssen 
Scientific Affairs, LLC 
within 24 hours of 
becoming aware of the 
event”
Clarification per 
Janssen request.
7.2.6 (Pregnancy)
Pregnancy outcomes 
must be followed
Pregnancy outcomes 
must be followed “on a 
case-by-case basis”
Janssen does not 
have a specific 
timeline for reporting 
pregnancy outcomes, 
but we agreed to 
report on a case-by- 
case basis
7.3.3 (Expedited 
reporting of SAE’s & 
Other Events)
Study coordinators 
were to complete the 
NU CRO SAE form
Study coordinators must 
complete the Medwatch 
and NU CRO SAE form
Administrative - 
Janssen needs the 
Medwatch form
7.3.1 (Routine 
Reporting),
11.5 (Data Management 
and Monitoring/Auditing), 
Appendices
Included Data 
Collection & 
Submission Guidelines 
as Appendix I
Removes Appendix I and 
replaces any submission 
guideline appendix 
references with NOTIS 
references;
Renumbers remaining 
Appendices and 
corresponding references 
in protocol
Administrative - aligns 
with current 
departmental SOP’s
7.3.3.3 (Reporting to 
Janssen Scientific 
Affairs)
n/a
Includes contact 
information for gaining 
access to Janssen’s 
Secure email service and 
faxing SAE reports
Administrative
8.1.9 (Availability and 
Supply)
n/a
Adds the number of 
capsules (120) included in 
each bottle of ibrutinib
Clarification
Updated Amendment 3 Prior to IRB Submission – April 5, 2016
Study Summary, 3.0 
(Selection of Subjects)
Listed affiliate sites as: 
Tufts, Duke, University 
of Michigan, and Dana 
Farber
Removes Tufts and Duke 
as affiliate sites and adds 
University of Utah
Administrative change 
to update affiliates
4.4.2 (Prohibited
Prohibited “Chronic use
Prohibits “Chronic use of
Clarification to provide
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IRB #: STU00098385-MOD0038 Approved by NU IRB for use on or after 5/19/2022 through 3/6/2023.
Study Numbers: NU 14H06 
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AMD 11: ver. date 08.06.2022 
56
Concomitant 
Medications)
of systemic 
corticosteroids, unless 
reviewed and approved 
by the PI”
systemic corticosteroids 
above prednisone 10mg 
po daily (or equivalent 
dose of other 
corticosteroid)
more specific 
medication guidelines
8.1.7 (Protocol 
administration)
Ibrutinib was to be 
taken “preferably 30 
minutes before eating 
or at least 2 hours after 
a meal”
Removes language
Janssen request – 
these prandial 
conditions are not 
required
8.1.10 (Side Effects)
n/a
Adds language for the 
following side effects:
Effects on the heart
Infections
Decreased blood 
counts
Allergic reactions
Tumor Lysis Syndrome 
(TLS)
Liver Failure
Interstitial Lung Disease
Janssen added 
language to align with 
updated ibrutinib 
safety information
Amendment 4 – November 3, 2016
Approved by Scientific Review Committee – November 17, 2016
Section(s) Affected
Prior Version
Amendment 4 Changes
Rationale
Cover Page
n/a
Adds Valerie Nelson as 
sub-Investigator at Lake 
Forest
Lake Forest would 
like to participate in 
the study
Cover Page;
3.0 (Selection of 
Subjects)
Listed University of 
Michigan is a 
participating site
Removes University of 
Michigan as site
University of Michigan 
will no longer 
participate
Study Summary
Included short title of 
protocol
Removes short title
To align with new NU 
protocol template – no 
longer required
1.1 (Disease Background 
and Current Therapies)
n/a
Updates FDA-approval 
status for ibrutinib – “It has 
since been approved for 
CLL/SLL, SLL with 17p 
deletion, and 
Waldenstrӧm’s 
macroglobulinemia.”
To align with current 
regulatory status of 
ibrutinib
2.2.1 (Secondary 
Objectives);
6.2.1 (Toxicity);
7.2.2 (Severity of AE’s);
7.3.2 (Steps to determine 
if expedited reporting is 
required); 10.1.2 
(Secondary Endpoints)
CTCAE version 4.0
CTCAE version 4.03
Administrative
3.1.2 (Inclusion Criteria)
n/a
Adds note: “Patients who 
progress during induction 
therapy are not eligible to 
enroll in this study.”
Clarification
3.1.9 (Inclusion Criteria)
Required pregnancy
Requires pregnancy test
Clarification to
IRB #: STU00098385-CR0008 Approved by NU IRB for use on or after 3/3/2023 through 3/2/2024.

IRB #: STU00098385-MOD0038 Approved by NU IRB for use on or after 5/19/2022 through 3/6/2023.
Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
57
test within 28 days of 
registration
within 14 days of 
registration
address discrepancy 
in 5.0 footnote 6
3.2.6 (Exclusion Criteria)
n/a
Adds exclusion of prior 
allogeneic stem cell 
transplant, and an 
engraftment stipulation for 
prior auto SCT
Patients with prior 
transplant may be 
more susceptible to 
side effects from 
ibrutinib
3.2.7 (Exclusion Criteria)
Patients with a 
malignancy other than 
MCL are not eligible 
unless they meet one of 
the criteria listed.
Adds exception: 
“Malignancy is not 
considered life-threatening 
in the opinion of the 
investigator and does not 
require treatment (for 
example, low risk prostate 
cancer undergoing active 
surveillance or low-risk 
myelodysplastic syndrome 
not requiring therapy).”
A non-life-threatening 
malignancy is not felt 
to be an interfering 
factor in study 
treatment
3.2.10 (Exclusion
Criteria); 4.4.3.1 
(CYP3A4/5
Inhibitors/Inducers)
n/a
Adds that CYP3A4/5 
inhibitors are not allowed
≤14 days prior to 
registration
Clarification
4.3 (Toxicity 
Management & Dosing 
Holds/ Dose 
Modifications)
Referred to dose 
“delays”
Changes “delay” to “hold”
To clarify that doses 
will be skipped rather 
than delayed
4.3.1 (Dose Holds);
4.3.2 (Dose 
Modifications);
5.0 (Study Procedures
#2)
n/a
“When a dose is missed 
or held, it will not be made 
up, regardless of duration. 
Observations and 
scheduled assessments 
will continue regardless of 
amount of drug the patient 
has had, and should 
always be based on time 
from C1D1. (For example, 
if a patient is held on 
C2D14 for a week, the 
day they re-start will be 
C2D21, and the patient 
will still have scheduled 
assessments as planned 
on C3D1) Please contact 
QA if you have any 
questions on timing of 
holds or study 
assessments.”
Clarification – 
previously it was not 
clear whether doses 
would be skipped or 
just delayed
4.8 (Removal of Patients 
from Therapy)
Patients who stop 
treatment to receive 
anti-cancer therapy for 
a second malignancy 
may be considered for 
re-start of study therapy
Adds that approval must 
be sought from PI and 
DMC
Clarification – a 
discussion should 
take place for such a 
significant decision
#2: n/a
#8: Ibrutinib is to be
#2: Adds a window of ±2 
days for study
#2: Clarification
#8: Clarification
IRB #: STU00098385-CR0008 Approved by NU IRB for use on or after 3/3/2023 through 3/2/2024.

IRB #: STU00098385-MOD0038 Approved by NU IRB for use on or after 5/19/2022 through 3/6/2023.
Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
58
given at 560mg 
throughout the study 
#9: “Patients will be 
evaluated monthly” 
#10: “Patients will be 
evaluated every 3 
cycles”
#11: Follow-up to occur 
every 3 months
#12: Vitals to include 
respirations
#15: n/a
assessments and ±7 days 
for scans
#8: Adds clarification 
“unless a dose reduction 
occurs”
#9: “Patients will be 
evaluated on Day 1 of 
each cycle (±2 days)” 
#10: “…every 3 cycles (on
Day 1, ±7 days)
#11: Adds window of ±7 
days
#12: Removes 
respirations from vitals 
and adds “12-point 
symptom assessment” to 
physical exam
#15: Adds specific 
hepatitis tests to be 
performed at screening 
(HepBcAb, HepBsAg, 
HepC Antibody)
#9: Clarification
#10: Clarification#11:
Clarification
#12: Clarification
#15: Clarification
5.0 (Study Procedures
#16);
7.0 (Adverse Events)
AE’s were to be 
followed for 30 days 
after treatment 
discontinuation
“Adverse events will be 
tracked from time of 
signed informed consent 
until completion of the last 
study-related procedures 
(which may include 
contact for follow-up 
safety). Serious adverse 
events will be reported for 
30 days beyond cessation 
of study treatment. AE’s 
resulting in 
discontinuation will be 
followed until resolution, 
or until patients start 
subsequent therapy, 
whichever comes first.”
Clarification
6.1 (Primary Endpoint)
“Only patients who 
complete > 1 complete 
cycle (28 days) of 
ibrutinib maintenance 
therapy” were 
evaluable for PFS
Changes evaluable 
patients to “any patient 
who receives at least one 
dose of study treatment”
This is to be an 
intention to treat 
design, therefore any 
patient who receives 
treatment will be 
included in the 
analysis
6.2.1 (Toxicity)
n/a
Adds language about an 
interim safety analysis: 
“After the study has been 
opened for 18 months, 
patients will be evaluated 
for an interim safety 
analysis. The PI along with 
the Northwestern 
Lymphoproliferative 
Disorders disease team
Upon request from 
Janssen
IRB #: STU00098385-CR0008 Approved by NU IRB for use on or after 3/3/2023 through 3/2/2024.

IRB #: STU00098385-MOD0038 Approved by NU IRB for use on or after 5/19/2022 through 3/6/2023.
Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
59
and Quality Assurance will 
assess data to ensure 
there are no unexpected 
safety signals that have 
been observed at this 
time”
7.3.2 (Steps to determine 
if expedited reporting is 
required)
n/a
Updates product 
information website for 
Imbruvica
Administrative; new 
information provided 
by Janssen
8.1.9 (Availability and 
Supply)
n/a
Drug accountability 
records are to be 
recorded with unused 
ibrutinib
Adds: “To order drug, 
the drug order form 
located in NOTIS can be 
submitted following the 
instructions listed on the 
form”
Adds that records 
should be updated “per 
institutional standards”
Clarification for sub- 
sites
Affiliate request 
since sites have 
varying 
accountability 
methods
8.1.10 (Side Effects)
FOCBP and men 
were to use a high 
effective method of 
birth control
n/a
Adds the requirement of 
a barrier method for 
both FOCBP and 
sexually active men
Updates side effects of 
ibrutinib to align with 
latest IB
Additional safety 
language provided 
by Janssen
10.2 (Samples Size and 
Power Calculations)
References two-year 
PFS observed in prior 
studies
Changes to three-year 
PFS observed in prior 
studies
Typographical error
Updated Amendment 4 Prior to IRB Submission – November 28, 2016
Approved by Scientific Review Committee – December 15, 2016
6.2.1 (Toxicity); 5.0
(Study Procedures #8)
n/a
References section 10.3.4 
for details on the interim 
safety analysis
Clarification 
requested by Janssen
10.3.4 (Interim Analysis)
n/a
Expands on exactly how 
the interim safety analysis 
will take place. Toxicity 
will be monitored by the PI 
and disease team after 
the study has been 
opened for 18 months.
Specifically, SAE’s will be 
monitored for unexpected 
safety signals.
Clarification 
requested by 
Janssen.
Amendment 5 – May 9, 2017
Approved by Scientific Review Committee – June 12, 2017
Section(s) Affected
Prior Version
Amendment 5 Changes
Rationale
Study Schema;
4.2 (Administration); 5.0
(Study Procedures, #2,8)
n/a
Patients should normally 
have visits every 3 
months, however patients 
can have 6-month study 
visits (with local clinic 
visits in between) if after 2 
years they are clinically 
stable and live far from the
To allow flexibility for 
patients who are 
inconvenienced by 
study visits. In 
patients who are 
clinically stable a local 
clinic visit is 
appropriate.
IRB #: STU00098385-CR0008 Approved by NU IRB for use on or after 3/3/2023 through 3/2/2024.

IRB #: STU00098385-MOD0038 Approved by NU IRB for use on or after 5/19/2022 through 3/6/2023.
Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
60
study site. Drug may be 
provided every 6 months 
in these cases.
3.1.7 (Inclusion Criteria)
Labs were required 
within 28 days prior to 
registration
Labs are required within 
14 days prior to 
registration
To fix discrepancy
Dose modifications 
were to take place for 
any Grade 4 or 
unmanageable Grade 3 
drug-related toxicities
Dose modifications may 
now take place for Grade 
4 or unmanageable Grade 
2 or 3 drug-related 
toxicities.
To allow for more 
investigator discretion 
of unmanageable 
toxicities.
At the first occurrence 
of an AE requiring dose 
modification, the 
original dose level was 
to be resumed.
Adds that drug can be 
restarted either at the 
original dose level or one 
dose level lower per 
investigator discretion.
To allow for more 
investigator discretion 
of appropriate 
ibrutinib dosing
4.3.2 (Dose 
Modifications)
The table for dose 
modification actions 
dictated the exact dose 
level to adjust to 
(420mg at the second 
occurrence, and 280mg 
at the third occurrence).
Adds dose levels in Table 
4-2 (560mg, 420mg,
280mg), and refers to 
dose levels in Table 4-1, 
rather than specific doses.
Fixes discrepancy if a 
patient’s dose has 
already been reduced 
for a prior toxicity.
#6: All screening 
procedures were to 
take place within 14 
days of registration
#6: Adds exception for 
informed consent, which 
can be signed within 30 
days of registration.
Clarification
#7: Scans were to take 
place after cycles 3 and 
6 and every6 months 
thereafter
#7: Scans should take 
place after cycles 3 and 6, 
every 6 months for the 
first 2 years, once at 3 
years, and as clinically 
indicated thereafter.
To align more closely 
with standard practice 
and allow more 
flexibility.
#7: Scans did not 
specify an end of 
treatment time point
#7: “…as clinically 
indicated thereafter 
(including EOT, as 
clinically appropriate, for 
patients who complete 4 
years of therapy, or 
patients that come off 
study treatment early for a 
reason other than 
progression)”
An EOT scan was felt 
to be clinically 
appropriate for 
patients who fall into 
these categories; this 
scan will be highly 
encouraged but not 
mandatory.
#11: Patients who 
discontinue treatment 
early will be followed for 
up to 4 years for 
survival endpoints”
Adds “…for survival 
endpoints only (no labs 
or physical exam are 
required)”
Clarification that no 
labs will be required in 
follow-up
5.0 (Study Procedures)
#17: “Another sample 
will be collected and 
stored for future use”
#17: “Another sample will 
be collected and stored for 
future use at each time 
point.”
#17: Clarification
7.3.3.3 (Reporting to 
Janssen Scientific 
Affairs)
Patricia Corbin was 
Janssen contact
Removes Patricia Corbin 
and adds Brooke 
Ackerman
Administrative staff 
change
IRB #: STU00098385-CR0008 Approved by NU IRB for use on or after 3/3/2023 through 3/2/2024.

IRB #: STU00098385-MOD0038 Approved by NU IRB for use on or after 5/19/2022 through 3/6/2023.
Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
61
10.3.4 (Interim Analysis)
Section referenced both 
a one-time interim 
safety analysis at 18 
months, and continuous 
SAE monitoring using a 
Pocock-type boundary.
Clarifies that the interim 
safety analysis will be 
continuous, with 
monitoring after 15, 20 
and 25 patients have been 
observed. Updates the 
numbers of SAEs to be 
observed for an excess of 
SAEs.
Clarifications for 
consistency; the 
interim analysis needs 
to be either one-time 
or continuous, and the 
PI and statistician 
have decided that 
continuous is most 
appropriate.
Amendment 6 – November 30, 2017
Approved by Scientific Review Committee – December 12, 2017
Section(s) Affected
Prior Version
Amendment 6 Changes
Rationale
Cover Page;
3.0 (Eligibility);
4.3.1 (Dose Holds)
Study PI was Dr. Jason 
Kaplan
Updates study PI to Dr. 
Barbara Pro
Administrative faculty 
change due to Dr.
Kaplan leaving the 
institution
Amendment 7 – March 19, 2019
Approved by Scientific Review Committee – April 5, 2019
Section(s) Affected
Prior Version
Amendment 7 Changes
Rationale
Cover Page
n/a
Adds Reem Karmali as 
sub-investigator
Administrative update 
to account for new 
faculty
Cover Page
Alfred Rademaker was 
listed as the 
biostatistician
Replaces Alfred 
Rademaker with Denise 
Scholtens
Administrative update 
to account for new 
biostatistician
Cover Page; 7.3.3 
(Expedited reporting of 
SAEs & Other Events);
Referenced 
Northwestern 
University’s Clinical 
Research Office (CRO)
References Northwestern 
University’s Clinical Trials 
Office (CTO)
Administrative update
4.4.3.1 (CYP3A4/5
Inhibitors/Inducers)
n/a
Adds Table 4-3 to provide 
additional instructions for 
ibrutinib dose 
modifications for patients 
who must take 
moderate/strong CYP3A 
inhibitors
Updated to align with 
revised 
IMBRUVICATM
(ibrutinib) prescribing 
information
5.0 (Study Procedures;
Footnote 11)
Follow up was stated 
as every 3 months 
which conflicted with 
other sections
Follow up is stated as 
every 3 months up to 2 
years and every 6 months 
thereafter to match other 
sections
Corrected 
discrepancy
5.0 (Study Procedures)
The window for visits 
every 3 cycles and 
during follow-up was ±7 
days, and there was no 
window for visits every 
6 cycles
Updates window to ±10 
days for visits both every 
3 and 6 cycles; also 
updates window to for 
follow-up to ± 10 days
Updated for 
consistency and to 
provide more flexibility 
to patients in a 
maintenance phase of 
treatment and follow- 
up; drug provision has 
been accounted for
7.0 (Adverse Events)
The timeline for AE 
reporting referenced 
the follow-up schedule
Clarifies that AE reporting 
is to occur for 30 days 
after the last dose of drug,
Administrative update
IRB #: STU00098385-CR0008 Approved by NU IRB for use on or after 3/3/2023 through 3/2/2024.

IRB #: STU00098385-MOD0038 Approved by NU IRB for use on or after 5/19/2022 through 3/6/2023.
Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
62
in line with the follow-up 
schedule
7.3.2 (Steps to determine 
if expedited reporting is 
required)
Referenced link within 
website 
www.imbruvicahcp.com 
to obtain product 
information
Updates website to 
www.imbruvicahcp.com
Administrative update
8.1.10 (Ibrutinib Side 
Effects)
n/a
Includes additional 
risk/side effects of ibrutinib
Updated to align with 
revised/new risk 
language provided by 
Janssen
9.1.2 (Peripheral Blood);
9.2 (Shipping
Instructions); 9.3 (Assay 
Methodology)
Referenced Sequenta 
Laboratories for 
analysis of correlative 
peripheral blood
Removes Sequenta and 
instead refers to lab 
manual.
Sequenta is no longer 
providing services for 
correlative analysis. 
Referencing the lab 
manual allows for 
flexibility as a new lab 
is identified and 
avoids unnecessary 
future protocol 
amendments
Throughout
n/a
Updates minor formatting 
and grammatical changes
Administrative update
Amendment 8 – January 15, 2020
Section(s) Affected
Prior Version
Amendment 8 Changes
Rationale
Title Page and 
Throughout
Protocol version dated 
March 19, 2019
(Amendment 7)
Updates to a new protocol 
version dated January 15, 
2020 (Amendment 8)
Administrative update.
Title Page
The Biostatistician was 
Denise Scholtens, 
PhD.
The Biostatistician has 
been changed to Masha 
Kocherginsky, PhD.
Administrative update 
due to staffing 
change.
Table of Contents
N/A
Updates page numbers
Administrative update.
1.2.3 (Toxicity Data)
N/A
Adds the below text:
Refer to the investigator’s 
brochure for additional 
toxicity information.
Administrative update. 
Adds text for clarity.
4.3.2 (Dose 
Modifications)
Stated:
The actions described 
below should be taken 
for the following drug- 
related toxicities:…
Any other Grade 4 or 
unmanageable 
Grade 2 or 3 drug- 
related toxicities. The 
PI should be 
contacted in these
Now states:
The actions described 
below should be taken for 
the following drug-related 
toxicities:…
• Any Grade 4 drug- 
related toxicity
• Any unmanageable 
Grade 2 or 3 drug- 
related toxicities. The PI
Revises language for 
clarity; separates 
Grade 4 events and 
Grade 2/3 events into 
two bullet points.
IRB #: STU00098385-CR0008 Approved by NU IRB for use on or after 3/3/2023 through 3/2/2024.

IRB #: STU00098385-MOD0038 Approved by NU IRB for use on or after 5/19/2022 through 3/6/2023.
Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
63
cases.
should be contacted in 
these cases.
7.2.4 (UPIRSO);
7.3.3 (Expedited 
Reporting of SAEs & 
Other Events);
7.3.3.2 (Reporting to the 
NU IRB;
11.2 (Amendmentsl);
11.6.2 (Other Protocol 
Deviations);
11.8 (Publication Policy)
N/A
Updates standard 
language to align with new 
Northwestern University 
protocol template and 
updates contact 
information for the 
Janssen assigned Trial 
Manager
Administrative update
8.1.10 (Side Effects of 
Ibrutinib)
N/A
Updates risk language for 
ibrutinib
Updates risk 
language to align with 
the release of a new 
ibrutinib investigator 
brochure, Edition 13.
Throughout
N/A
Minor corrections to 
typographical errors, style, 
and formatting.
Administrative update.
Amendment 9 – November 18, 2021
Section(s) Affected
Revision
Rationale
Cover page & throughout
Updates the principal investigator from Dr. Barbara 
Pro to Dr. Reem Karmali and provides contact 
information
Administrative 
revision
Throughout
Editorial revisions: Updates the protocol version/date 
and Appendix IV (Protocol History of Changes)
Administrative 
revision
Amendment 10 – February 22, 2022
Section(s) Affected
Revision
Rationale
Section 8.1.10 (Side 
Effects)
Deletes informed consent template risk 
language from the trial protocol. Instructs end
Deletes informed consent 
template risk language from
IRB #: STU00098385-CR0008 Approved by NU IRB for use on or after 3/3/2023 through 3/2/2024.

IRB #: STU00098385-MOD0038 Approved by NU IRB for use on or after 5/19/2022 through 3/6/2023.
Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
64
users to refer to the current investigator’s 
brochure for toxicity information.
the trial protocol. This 
information is located in the 
patient-facing informed 
consent document.
Additional toxicity 
information is located in the 
current investigator’s 
brochure.
Section 8.1.10 (Side 
Effects)
&
Exclusion criterion 
3.2.17
The following breastfeeding language is moved 
from Section 8.1.10 to Section 3.2.17:
“It is not known whether ibrutinib or its 
metabolites are excreted in human milk. 
Because many drugs are excreted in human 
milk and because of the potential for serious 
adverse reactions in nursing infants from 
ibrutinib, breastfeeding should be discontinued 
during ibrutinib treatment.”
Administrative revision for 
ease of use by end users
Section 8.1.10 (Side 
Effects),
Inclusion criterion 3.1.8, 
&
Section 7.2.6 
(Pregnancy)
The following contraception language is moved 
from Section 8.1.10 to Section 3.1.8:
Adequate contraception “is defined as a method 
that has a low failure rate (i.e. less than 1% per 
year) when used consistently and correctly and 
includes implants, injectables, birth control pills 
with two hormones, some intrauterine devices 
(IUDs), sexual abstinence (which is defined as 
refraining from all aspects of sexual activity) or a 
sterilized partner. If using hormonal 
contraceptives such as birth control pills or 
devices, a second barrier method of 
contraception (e.g., condoms) must be used.
The following pregnancy language is moved 
from Section 8.1.10 to Sections 3.1.8 and 7.2.6:
“Men must notify the study staff if their partner 
becomes pregnant while on study treatment or 
within 3 months of last dose. Women must 
notify the study staff if they become pregnant 
while on study treatment or within 1 month of 
last dose of ibrutinib, and must immediately stop 
taking the study treatment.”
Administrative revision for 
ease of use by end users
Throughout
Editorial revisions: Updates formatting, the 
protocol version/date, the Table of Contents, 
and Appendix IV (Protocol History of Changes)
Administrative revision
Amendment 11 –  August 08, 2022
Section(s) Affected
Revision
Rationale
Section 4.3.2 Dose 
Modifications, Table 4-1 
Dose Modification 
The actions described below should be 
followed for the indicated drug- related 
toxicities per Table 4-1:
Updated Section 4.3.2 and 
Table 4-1 due to release of 
updated prescribing 
IRB #: STU00098385-CR0008 Approved by NU IRB for use on or after 3/3/2023 through 3/2/2024.

IRB #: STU00098385-MOD0038 Approved by NU IRB for use on or after 5/19/2022 through 3/6/2023.
Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
65
Actions

Grade 3 (ANC <1000/mm3) or Grade 4 
neutropenia (ANC <500/mm3)

Grade 3 thrombocytopenia (platelets 
<50,000/mm3) in the presence of 
significant bleeding

Grade 4 thrombocytopenia (platelets 
<25,000/mm3)

Grade 3 or 4 neutropenia with infection or 
fever

All other Grade 4 hematological toxicities

Grade 3 or Grade 4 non-
hematological toxicities including 
nausea, vomiting or diarrhea (if 
persistent despite optimal antiemetic 
or antidiarrheal therapy), exceptions 
noted below for cardiac related 
toxicities (see Sections 4.3.2.1 & 
Section 4.3.2.1.1)

Grade 2 cardiac failure

Any unmanageable Grade 2 or Grade 
3 drug-related toxicities. The PI 
should be contacted in these cases.
Table 4-1 revised.
information for ibrutinib 
dated 05/2022  and dear 
investigator letter from 
Janssen Scientific Affairs, 
LLC dated June 21, 2022.
4.3.2.1 Dose 
Modifications for Grade 
3 Cardiac Arrhythmias &  
4.3.2.1.1 Dose 
Modifications for Grade 
3 and higher Cardiac 
Failure & Grade 4 
Cardiac Arrhythmias, 
Table 4-2 Dose 
Modification Actions for 
Grade 3 Cardiac 
Arrhythmias
4.3.2.1 Dose modifications for Grade 3 
Cardiac Arrhythmias
The actions described below should be 
followed for the indicated following drug- 
related toxicities:
•
Grade 3 cardiac arrhythmias
See new Table 4-2
4.3.2.1.1 Dose Modifications for Grade 3 and 
higher Cardiac Failure & Grade 4 Cardiac 
Arrhythmias
Ibrutinib is to be discontinued if the following 
drug related toxicities occur:
•
Grade 3 or 4 cardiac failure
•
Grade 4 cardiac arrhythmias
Table 4-2 revised, see Table 4-2.
New sections and new Table 
(Table 4-2) added due to 
updated prescribing 
information for ibrutinib 
dated 05/2022  and dear 
investigator letter from 
Janssen Scientific Affairs 
dated June 21, 2022.
Table 4-3: Dose 
Modifications for Use 
with CYP3A Inhibitors
Table revised, see Table 4-3. 
Table updated to appropriate 
sections in the protocol per 
revised prescribing 
information for ibrutinib 
dated 05/2022  and dear 
investigator letter from 
Janssen Scientific Affairs 
dated June 21, 2022.
Cover page and 
throughout document 
Editorial , updated document to clarify 
Amendment 11 and version date with this 
revision to the protocol; update to statistician 
on Cover page,  Xinlei Mi, PhD, replacing 
former statistician.
Administrative changes
IRB #: STU00098385-CR0008 Approved by NU IRB for use on or after 3/3/2023 through 3/2/2024.

IRB #: STU00098385-MOD0038 Approved by NU IRB for use on or after 5/19/2022 through 3/6/2023.
Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
66
Throughout document
Editorial changes for typos/spacing.
Administrative changes
Section 11.6.2 
All protocol deviations will be documented by 
the study team on eCRFs in NOTIS, as they 
occur. At NU, deviations will be reviewed 
during research meetings by the PI, with PI 
review and responses being documented and 
entered into the appropriate eCRF. Other 
participating sites will follow local procedures 
or SOPs for PI review of deviations. For all 
sites deviations should be entered into the 
eCRF in real time with regular PI review, and 
immediate routing to QA after PI review. 
Deviation reports (with appropriate 
documentation of PI review) will be made 
available to the assigned QAM on request, 
during monitoring visits and at time of audit.
Revised protocol deviation 
language per RHLCCC 
updated template language 
for protocol deviation 
reporting.
IRB #: STU00098385-CR0008 Approved by NU IRB for use on or after 3/3/2023 through 3/2/2024.

IRB #: STU00098385-MOD0038 Approved by NU IRB for use on or after 5/19/2022 through 3/6/2023.
Study Numbers: NU 14H06 
PCI-32765MCL2003
Initial version: September 24, 2014
AMD 11: ver. date 08.06.2022 
67
IRB #: STU00098385-CR0008 Approved by NU IRB for use on or after 3/3/2023 through 3/2/2024.