Clinical trial NCT02736617
Conditions: Recurrent Mantle Cell Lymphoma Refractory Mantle Cell Lymphoma
Sponsor: OHSU Knight Cancer Institute
Start date: 2016-07-05; Completion date: 2021-06-02
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well obinutuzumab works in combination with ibrutinib in treating patients with mantle cell lymphoma that has returned (relapsed) or that does not respond to treatment (refractory). Obinutuzumab binds to a protein called cluster of differentiation (CD)20, which is found on B cells and some types of leukemia and lymphoma cells and help the immune system kill cancer cells. Ibrutinib blocks a protein called Bruton's tyrosine kinase (BTK), which may help keep cancer cells from growing. Giving obinutuzumab in combination with ibrutinib may kill more cancer cells.

Detailed description:
PRIMARY OBJECTIVE:

I. Best overall response of complete response/partial response (CR/PR).

SECONDARY OBJECTIVES:

I. Toxicity defined as any adverse event (AE) grade 3 and higher. II. Progression free survival.

EXPLORATORY/CORRELATIVE OBJECTIVES:

I. Gene expression profiling using Lymph5Cx test. II. Sequencing using the ion torrent platform (76 gene panel for known mutations in lymphoma).

III. Sequencing of BTK and phospholipase-C gamma (PLC) to evaluate for mutations.

IV. Minimal residual disease testing (MRD by flow cytometry and targeted sequencing post treatment).

OUTLINE:

Patients receive obinutuzumab intravenously (IV) over 30 minutes on days 1, 8, and 15 of cycle 1, and day 1 of cycles 2-6. Patients also receive ibrutinib orally (PO) once daily (QD) on days 1-28. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients achieving partial response (PR) continue to receive obinutuzumab IV every 2 months and ibrutinib PO QD for up to 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for up to 3 years.

Arms: arm 1: Patients receive obinutuzumab IV over 30 minutes on days 1, 8, and 15 of cycle 1, and day 1 of cycles 2-6. Patients also receive ibrutinib PO QD on days 1-28. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients who have PR continue to receive obinutuzumab IV every 2 months and ibrutinib PO QD for 2 years in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Ibrutinib intervention 2: Obinutuzumab
Intervention descriptions: intervention 1: Given PO intervention 2: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
 
TITLE: 
A Phase II study of Obinutuzumab (GA-101) in combination with 
Ibrutinib (I) for the Treatment of Relapsed Mantle Cell Lymphoma 
COORDINATING CENTER: 
OHSU Knight Cancer Institute 
PRINCIPAL INVESTIGATOR: 
Stephen E. Spurgeon MD 
Center for Hematologic Malignancies Oregon Health & Science 
University (OHSU) 3181 Sam Jackson Park Road 
Portland, OR 97239 
spurgeos@ohsu.edu  
phone: 503-494-8950, fax: 503-494-1552 
 
SUB-INVESTIGATORS: 
Craig Okada MD, PhD (OHSU) 
Andy Chen MD, PhD (OHSU)  
 
STUDY STATISTICIAN: 
 
Byung Park, PhD 
Biostatistics Shared Resource 
Knight Cancer Institute 
parkb@ohsu.edu 
phone: 503-418-1555 
 
 
SPONSOR:  
Oregon Health and Science University  
  
SUPPLIED AGENTS: 
Obinutuzumab (Gazyva, GA101); Ibrutinib (Imbruvica) 
IND #:  
129824 
NCT #: 
NCT02736617 
 
IND SPONSOR:  
Stephen Spurgeon MD 
 
ORIGINAL PROTOCOL DATE: February 1, 2016
 
PROTOCOL REVISION DATES: 
May 6, 2016 
October 10, 2016 
 
September 1, 2017 
October 25, 2017 
April 23, 2018 
August 3, 2018* 
 
April 29, 2019 
July 22, 2020 
November 4, 2020 (minor revisions) 
 
*August 3, 2018 version was uploaded in the IRB system and had to be discarded as the modification was not 
submitted in a timely manner and the annual review submission was due around the same time. Therefore the 
modification with the protocol August 8, 2018 was discarded.  
 
 


      
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STUDY SCHEMA 
 
 
 
 


      
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SUMMARY OF CHANGES 
 
As of May 11, 2018, seven patients were enrolled in the Stage I portion of the study with one patient withdrawing a 
consent prior to the initial response assessment. Of six evaluable patients, five responses (3 CR and 2 PR) were 
observed. Therefore, the study passed the Stage I futility criteria (stop if 3 or fewer responses out of 6), and it is 
currently in the Stage II portion of the study.  The trial will continue until a total of 20 patients are accrued. 
 
Version 8.1.  Summary of Changes 
Section 
Description of Change 
Section 13.3.Informed Consent  
Included language for consent/reconsent and 
modified procedures due to COVID 19 
 
 


      
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Table of Contents 
1. OBJECTIVES 
10 
1.1 
Primary Objective ..................................................................................................................... 10 
1.2 
Secondary Objectives ............................................................................................................... 10 
1.3 
Exploratory Objectives/Correlatives ........................................................................................ 10 
2. BACKGROUND .................................................................................................................................. 10 
2.1 
Mantle Cell Lymphoma ............................................................................................................ 10 
2.2 
Study Agent: Obinutuzumab (GA-101) ................................................................................... 11 
2.3 
Clinical Efficacy of Obinutuzumab in Non-Hodgkin’s Lymphoma ........................................ 12 
2.4 
Ibrutinib .................................................................................................................................... 15 
2.5 
Study and Dose Rationale ........................................................................................................ 17 
2.6 
Correlative Studies ................................................................................................................... 18 
3. STUDY POPULATION ...................................................................................................................... 21 
3.1 
Inclusion Criteria ...................................................................................................................... 21 
3.2 
Exclusion Criteria ..................................................................................................................... 22 
3.3 
Prohibitions and Restrictions .................................................................................................... 23 
4. REGISTRATION PROCEDURES .................................................................................................... 24 
4.1 
Subject Registration .................................................................................................................. 24 
4.2 
Multicenter Registration ........................................................................................................... 24 
5. TREATMENT PLAN.......................................................................................................................... 24 
5.1 
Agent Administration ............................................................................................................... 24 
5.2 
Obinutuzumab Administration and Supportive  Care .............................................................. 25 
5.3 
Ibrutinib Administration and Supportive Care ......................................................................... 27 
5.4 
Considerations for Ibrutinib plus  Obinutuzumab .................................................................... 27 
5.5 
General Concomitant Medication and Supportive Care Guidelines Use of Ibrutinib with CYP3A inhibitors or 
inducers .................................................................................................................................. 27 
5.6 
Duration of Treatment .............................................................................................................. 28 
5.7 
Duration of Follow-up .............................................................................................................. 28 
5.8 
Criteria for Removal from Study .............................................................................................. 29 
5.9 
Study Discontinuation .............................................................................................................. 29 
5.10 Definition of Dose-Limiting Toxicity ...................................................................................... 29 
6. DOSING DELAYS/DOSE MODIFICATIONS ................................................................................ 29 
6.1 
Obinutuzumab .......................................................................................................................... 29 
6.2 
Ibrutinib .................................................................................................................................... 30 


      
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7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS .......................................... 30 
7.1 
Adverse Events and Potential Risks Lists ................................................................................ 30 
7.2 
Ibrutinib .................................................................................................................................... 37 
7.3 
Adverse Event Characteristics .................................................................................................. 39 
7.4 
Attribution of the AE ................................................................................................................ 39 
7.5 
OHSU IRB Reporting of Unanticipated Problems and Adverse Events .................................. 40 
7.6 
Central Reporting of Adverse Events for Multicenter Studies: ................................................ 40 
7.7 
MedWatch Reporting ............................................................................................................... 40 
7.8 
Reporting of Adverse Events to Genentech ............................................................................. 41 
8. REPORTING OF ADVERSE EVENTS ........................................................................................... 41 
8.1 
Assessment of Safety ................................................................................................................ 41 
8.2 
Procedures for Eliciting, Recording, and Reporting Adverse Events....................................... 43 
Other reports ....................................................................................................................................... 45 
8.3 
OTHER SPECIAL SITUATION REPORTS ........................................................................... 46 
8.4 
MedWatch 3500A  Reporting Guidelines ................................................................................ 46 
REPORTING TO REGULATORY AUTHORITIES, ETHICS COMMITTEES AND INVESTIGATORS 48 
8.5 
Study Close-Out ....................................................................................................................... 48 
9. PHARMACEUTICAL AND/OR IMAGING AGENT INFORMATION ...................................... 49 
9.1 
Agent Accountability ................................................................................................................ 49 
10. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ....................................................... 49 
10.1 Collection of Specimens ........................................................................................................... 50 
10.2 Gene Expression Profiling (GEP)............................................................................................. 51 
10.3 MRD Testing ............................................................................................................................ 51 
11. STUDY PROCEDURES AND SCHEDULE OF EVENTS ............................................................. 51 
11.1 Screening/Baseline Visit .......................................................................................................... 51 
11.2 Study Visits .............................................................................................................................. 51 
11.3 End of Treatment - Obinutuzumab ........................................................................................... 51 
11.4 Follow-up Visit ......................................................................................................................... 52 
11.5 Study Assessments and Procedures .......................................................................................... 52 
11.6 Schedule of Events ................................................................................................................... 54 
12. MEASUREMENT OF EFFECT ........................................................................................................ 57 
12.1 Best Overall Response .............................................................................................................. 57 
12.2 Response Criteria ...................................................................................................................... 57 
12.3 Response Assessment ............................................................................................................... 57 
12.4 Progression Free Survival ......................................................................................................... 60 
12.5 Evaluation of Toxicity .............................................................................................................. 60 


      
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12.6 Methods for Evaluation of Measurable Disease ....................................................................... 60 
13. DATA REPORTING AND REGULATORY REQUIREMENTS .................................................. 61 
13.1 Multicenter Guidelines ............................................................................................................. 61 
13.2 Protocol Review ....................................................................................................................... 62 
13.3 Informed Consent ..................................................................................................................... 62 
13.4 Changes to Protocol .................................................................................................................. 63 
13.5 Maintenance of Records ........................................................................................................... 63 
13.6 OHSU IRB Reporting of Unanticipated Problems and Adverse Events .................................. 63 
13.7 OHSU Knight Cancer Institute Data and Safety Monitoring Plan ........................................... 63 
13.8 Inclusion of Women, Minorities and Children ......................................................................... 63 
13.9 Inclusion of Children ................................................................................................................ 64 
14. STATISTICAL CONSIDERATIONS ............................................................................................... 64 
14.1 Study Design ............................................................................................................................ 65 
14.2 Primary and Secondary Endpoints ........................................................................................... 65 
14.3 Analysis Populations ................................................................................................................ 65 
14.4 Statistical Analysis Plan ........................................................................................................... 65 
14.5 Handling of Missing Data ........................................................................................................ 66 
15. REFERENCES .................................................................................................................................... 68 
 
 
 
 


      
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LIST OF ABBREVIATIONS 
 
Abbreviation 
Meaning 
ADCC 
antibody-dependent cellular cytotoxicity 
AE 
adverse event 
anti-HBc 
antibody to hepatitis B core antigen 
aPTT 
activated partial thromboplastin time 
BM 
bone marrow 
ASCO 
American Society of Clinical Oncology 
AUC 
area under the concentration−time curve 
BSA 
body surface area 
CDC 
complement-dependent cytotoxicity 
CHOP 
cyclophosphamide, doxorubicin, vincristine, prednisone 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum   concentration observed 
CNS 
central nervous system 
CR 
complete response or complete remission 
Cru 
unconfirmed complete response 
CSR 
Clinical Study Report 
D 
Day 
DFS 
disease-free survival 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose-limiting toxicity 
EC 
Ethics Committee 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EFS 
event-free survival 
F 
Phenylalanine 
FACS 
fluorescent-activated cell sorter 
FcR 
leukocyte receptors for the Fc portion of IgG 
FDA 
Food and Drug Administration 
18F-FDG 
18F-fleurodeoxyglucose 
FFPE 
formalin-fixed paraffin-embedded 
FISH 
fluorescence in situ hybridization 
GCB 
germinal center B cell 
GCP 
Good Clinical Practice 
GCSF 
granulocyte-colony stimulating factor 
GEP 
gene expression profiling 


      
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G 
GA101 
G-FC 
GA101 in combination with fludarabine and cyclophosphamide 
HAHA 
human anti-human antibodies 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HD 
high dose 
HTLV 
human T-cell leukemia virus 
ICH 
International Conference on Harmonisation 
Ig 
Immunoglobulin 
IHC 
Immunohistochemistry 
IND 
Investigational New Drug 
IMC 
Internal Monitoring Committee 
IRR 
infusion-related reaction 
IV 
Intravenous 
IL 
Interleukin 
IPI 
International Prognostic Index 
IVRS 
interactive voice response system 
LD 
low dose 
LVEF 
left ventricular ejection fraction 
LVS. D 
left ventricular systolic dysfunction 
MCL 
mantle-cell lymphoma 
MRI 
magnetic resonance imaging 
MUGA 
multigated acquisition scan 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
NHL 
non-Hodgkin’s lymphoma 
NONMEM 
Non-Linear Mixed Effect Model 
ORR 
overall response rate 
OS 
overall survival 
 
 
PD 
progressive disease 
PICC 
peripherally inserted central catheter 
PK 
pharmacokinetic 
PET 
positron emission tomography 
PFS 
progression-free survival 
PML 
progressive multifocal leukoencephalopathy 
PR 
partial response or partial remission 


      
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R-CHOP 
rituximab in combination with cyclophosphamide, doxorubicin, 
vincristine, prednisone 
SAE 
serious adverse event 
SD 
stable disease 
SD 
stable disease 
SDI 
shorter duration of infusion 
SLL 
small lymphocytic lymphoma 
SOC 
Scientific Oversight Committee 
TLS 
tumor lysis syndrome 
ULN 
upper limit of normal 
U.S. 
United States 
V 
valine 
WHO 
World Health Organization 
 
 


      
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1. OBJECTIVES 
 
1.1 
PRIMARY OBJECTIVE 
 
Best overall response of CR/PR as defined in Section 12.3.1 
 
1.2 
SECONDARY OBJECTIVES 
a) 
Toxicity defined as any drug-related AE grade 3 and higher. 
b) 
Progression Free Survival 
 
1.3 
EXPLORATORY OBJECTIVES/CORRELATIVES 
a) Gene expression profiling using Lymph5Cx test 
b) Sequencing using the ion torrent platform (76 gene panel for known mutations in lymphoma) 
c) Sequencing of BTK and PLC to evaluate for mutations 
d) Minimal Residual Disease Testing (MRD by flow cytometry and targeted sequencing post treatment). 
 
2. BACKGROUND 
 
2.1 
MANTLE CELL LYMPHOMA 
 
Mantle cell lymphoma (MCL) accounts for 6% of all Non-Hodgkins Lymphomas (NHL).  At the molecular level, 
MCL is characterized by overexpression of the cell cycle regulator protein cyclin D1 as a result of a chromosomal 
translocation t(11;14)(q13;q32), which puts the cyclin D1 gene (bcl-1), under the control of the immunoglobulin 
(Ig) heavy chain enhancer with subsequent overexpression of cyclin D1.1,2Although there are exceptions, it is 
characterized by a unique immunophenotype with co-expression of CD5 and CD20 and lack of CD23 expression. 
 
MCL is a heterogeneous disease with some patients having a more indolent course and others having more 
aggressive disease. A number of new treatment approaches for previously untreated disease have significantly 
improved outcomes. However, despite significant improvements in therapy for mantle cell lymphoma (MCL), the 
overwhelming majority of patients will relapse after initial therapy and ultimately die from their disease. Current 
treatment options for relapsed disease include chemo-immunotherapy such as the monoclonal anti-CD20 antibody 
rituximab plus alkylating agents, anthracyclines, and nucleoside analogues. Agents with unique mechanisms of 
action such as lenalidomide, bortezemib, and mTOR inhibitors (temsirolimus, everolimus) as single agents or in 
combination with rituximab have also shown efficacy.3-5  Increasingly, the role of B-cell receptor (BCR) signaling 
and inhibition has been studied as a potential therapeutic target. Furthermore, use of Ki-67, clinical factors, gene 
expression, proliferation signatures, and minimal residual disease (MRD) negativity after treatment have emerged as 
potentially useful tools for risk stratification.7-9 
 
To date, the most effective agent for relapsed MCL is Ibrutinib, an oral Bruton’s Tyrosine Kinase (BTK) inhibitor, 
which is now FDA approved for MCL. BTK is activated upon BCR cross-linking and increased constitutive activity 
has been seen in MCL. Thus, BTK is a rationale therapeutic target.10-11  Treatment with Ibrutinib has resulted in 
high response rates, good tolerability, and durable responses in MCL patients. Importantly, however, one-third of 
patients will fail to respond to ibrutinib and the majority will ultimately progress on treatment. The etiology of 
primary resistance to single agent ibrutinib remains elusive. One mechanism that has recently been described for 
acquired resistance in responding patients on treatment is the result of BTK mutations at the ibrutinib site or 
downstream pathways. Specifically, in CLL and more recently MCL, a serine to cystine (C481S) mutation at the 
ibrutinib binding site has been appreciated as have mutations in protein lipase C gamma-2 (PLCγ2), a downstream 
target of BTK.12,13  However, the rate of ibrutinib failure in MCL cannot be explained by the relatively low 
frequency of BTK or PLC mutations seen to date. Therefore, developing more effective therapeutic regimens in 
MCL and understanding potential mechanisms of resistance remains an area of unmet medical need. 
 
The addition of anti-CD20 monoclonal antibody therapy such as rituximab is a mainstay in the treatment of all B 
cell non-Hodgkin’s lymphoma including MCL. Obinutuzumab (GA-101), a type II antibody with enhanced direct 


      
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cytotoxicity and ADCC, has shown significant activity across a broad range of NHL. It is currently FDA approved 
in combination with chlorambucil for the treatment of treatment-naïve CLL where it has shown excellent activity 
and tolerability14 and has been shown to be superior to rituximab. The use of obinutuzumab in relapsed NHL, 
including MCL, was associated with an ORR of 27% including in patients with rituximab refractory disease. In 
responding cases, there were a number of durable remissions. Importantly, this treatment was well tolerated.15 
 
Given the impressive activity and excellent tolerability of both GA-101 and ibrutinib alone and in combination, as 
well as the need for novel therapies in this population, studying this combination in MCL is warranted. 
Furthermore, in an era of increasing therapeutic options and more ready access to genomic and pathway analyses, 
further evaluation of disease biology is an essential component to a better understanding of drivers of therapeutic 
response as well as treatment resistance. In addition, in MCL, the achievement of minimal residual disease (MRD) 
after induction has been associated with improved clinical outcomes.16 However, little is known about rates of MRD 
after relapse or with novel non “geno-toxic” therapy such as GA-101 and ibrutinib or using more broadly applicable 
assays such as flow cytometry or next generation sequencing to define MRD. This warrants further investigation. 
 
2.2 
STUDY AGENT: OBINUTUZUMAB (GA-101) 
 
Refer to the Investigator Brochure (IB) for additional details. 
 
2.2.1 
INVESTIGATIONAL PRODUCT NAME AND DESCRIPTION 
 
Obinutuzumab (also known as RO5072759, GA101) is a humanized glycoengineered type II anti-CD20 monoclonal 
antibody (mAb). Obinutuzumab was derived by humanization of the parental B-Ly1 mouse antibody and 
subsequent glycoengineering leading to the following characteristics: high-affinity binding to the CD20 antigen, 
high antibody-dependent   cellular   cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP); 
low complement-dependent cytotoxicity (CDC) activity; and high direct cell death induction. 
 
2.2.2 
SUMMARY OF RELEVANT NON-CLINICAL AND CLINICAL PHARMACOLOGY DATA 
 
2.2.2.1 
Non-clinical Data 
 
Non-clinical in vitro studies show that obinutuzumab mediates superior induction of direct cell death and effector 
cell-mediated ADCC and ADCP on a panel of NHL cell lines as compared to the Type I CD20 antibodies rituximab 
and ofatumumab. Its potency to mediate CDC is significantly reduced as compared to these two antibodies. 
Obinutuzumab induced complete tumor remission and long term survival (cures) and increased the overall survival 
in disseminated NHL xenograft models. The efficacious and optimal dose range of obinutuzumab in xenograft 
models was in the range of 10-30 mg/kg, corresponding to trough levels of 300-600 μg/mL. In addition, 
obinutuzumab showed efficacy in combination with classical chemotherapeutic agents, such as chlorambucil (Clb), 
fludarabine and bendamustine. Importantly, the combination of obinutuzumab with chemotherapeutic agents was 
superior to the combination of these agents with rituximab. 
 
Treatment with obinutuzumab also resulted in potent and superior depletion of B-cells in the peripheral blood and in 
lymphoid tissues of hCD20 transgenic mice and cynomolgus monkeys. Vaccination studies in cynomolgus monkeys 
and human CD20 transgenic mice showed that the enhanced efficacy in terms of B-cell depletion of obinutuzumab 
translated into suppression of de novo antibody responses, but left the protective humoral memory responses intact. 
 
2.2.2.2 
Clinical Pharmacokinetic Data 
 
The clinical pharmacology properties of obinutuzumab have been characterized in a number of clinical studies, in 
patients with CLL or NHL. These studies include Phase I and II monotherapy studies (BO20999 and BO21003), a 
Phase Ib combination study (BO21000) and a Phase III combination study (BO21004). Population PK modeling 
was undertaken on all available serum concentration data from studies BO20999, BO21003, BO21000 and 
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compartment PK model comprising both a linear clearance pathway and a non-linear time varying clearance 
pathway adequately described serum obinutuzumab concentration data. The initial clearance of obinutuzumab was 
2.85 times higher than the steady state clearance which is consistent with a decrease in the time varying clearance 
component, which is high at the start of treatment and which declines with repeated cycles of obinutuzumab 
treatment. The time varying clearance pathway is consistent with target mediated drug disposition, such that at the 
start of treatment when there is a large quantity of CD20 positive cells, this binds obinutuzumab. 
 
With repeated dosing of Obinutuzumab this saturates the pool of CD20 positive cells, hence reducing this 
component in clearance. The linear clearance pathway is consistent with catabolism of IgG antibodies, and is 
therefore independent of CD20 positive cells.  This analysis further supports the need to minimize the time varying 
clearance component quickly, and has led to the proposed dose and regimen of 1000 mg in both induction and 
extended treatment. In the Phase II part of study BO21003, which investigated the 1000 mg obinutuzumab dose 
taken into Phase III, the PK of Obinutuzumab was assessed in patients with indolent non-Hodgkin’s lymphoma 
(iNHL) who received weekly administrations of 1000 mg of obinutuzumab during the induction phase (4 
administrations; Cycle 1 – Cycle 4) followed by an extended maintenance treatment phase of 1000 mg 
obinutuzumab every 2 months until disease progression. The mean obinutuzumab serum concentration increased 
markedly over the 4 treatment cycles. Following the final (i.e., fourth) administration of the induction treatment, 
obinutuzumab serum levels decreased. Overall, mean Ctrough serum levels of obinutuzumab observed during the 
maintenance regimen were similar across the 12 maintenance cycles. 
 
In study BO21004/CLL11, a pivotal Phase III study in CLL patients, mean serum obinutuzumab concentrations 
increased from Cycle 1 to Cycle 2 following administration of obinutuzumab on Day 1/2 (45 patients in Stage 1a 
received the first 1000 mg dose over 2 days: 100 and 900 mg on Days 1 and 2, respectively), Day 8 and Day 15 of 
Cycle 
 
From Cycle 3 until Cycle 6, pre- and post-infusion serum concentrations remained constant during the course of 
treatment. Having the first 1000 mg administered over 2 days did not impair the rapid minimization of the time 
varying clearance component indicative of depletion of CD20+ tumor cells. 
 
2.3 
CLINICAL EFFICACY OF OBINUTUZUMAB IN NON-HODGKIN’S LYMPHOMA  
 
Obinutuzumab is FDA approved for the treatment of previously untreated Chronic Lymphocytic Leukemia in 
combination with chlorambucil. This approval is based on the promising results seen in the CLL 11 trial which 
showed high overall response rates and superior PFS as compared to rituximab plus chlorambucil. Obinutuzumab 
has shown significant activity in additional studies in NHL.23 
 
2.3.1 
OBINUTUZUMAB MONOTHERAPY 
 
(Studies JO21900, BO20999, and BO21003) 
 
In the monotherapy setting, the proportion of patients who had a CR or PR at the end of treatment ranged from 28% 
to 58%. Although this was a population with treatment- refractory or relapsed disease, some patients in studies 
BO20999 and JO21900 achieved a CR by the end-of-treatment assessment. 
 
The Phase I of study BO20999 recruited 21 NHL patients; lymphoma subtypes were follicular (n=13), mantle cell 
(n=4), diffuse large B-cell (n=1), small lymphocytic (n=1), lymphoplasmacytic lymphoma (n=1) and 
Waldenström’s macroglobulinaemia (n=1). In the Phase I part of the study, 7 patients (33%) had a response at the 
end of treatment. In the Phase II part, 11 patients (28%) with aNHL and 15 patients (38%) with iNHL had a 
response at the end of treatment. In Phase II, end-of-treatment response for iNHL was 17% (3 PR) for patients 
receiving 400/400 mg (n=18) obinutuzumab and 55% (2 CR, 10 PR) in the 1600/800 mg cohort (n=22). 
 
The Phase I part of study BO21003 included 17 patients: 10 with FL, 3 with DLBCL, 2 with lymphocytic 
lymphoma, and one each with MCL and marginal zone lymphoma. At the end of the (induction) treatment period, 


      
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no patients had CR, 5 patients (29%) had PR, 2 patients had progressive disease, and 1 patient had no data. 
 
2.3.2 
OBINUTUZUMAB COMBINATION THERAPY 
 
In the Phase Ib chemotherapy combination study, BO21000, 53/56 relapsed/refractory patients (95%) had a 
response (CR+PR) at the end of treatment; one had PD, one had stable disease (SD) and one had no response 
assessment due to early withdrawal. In patients with previously untreated B-cell FL, 76/81 patients (94%) 
responded at the end of treatment; one each had SD and PD, and 3 patients had no response assessment as they 
withdrew prior to the first response assessment. 
 
The proportion of patients with a CR was higher in this chemotherapy combination study than for the monotherapy 
studies (relapsed/refractory setting: 39% [11/28 patients] in the obinutuzumab + CHOP arm and 50% [14/28 
patients] in the obinutuzumab + FC arm; first-line setting: 39% [16/41 patients] in the obinutuzumab + 
bendamustine arm and 35% [14/40 patients] in the obinutuzumab + CHOP arm). 
 
2.3.3 
OBINUTUZUMAB MAINTENANCE 
 
Obinutuzumab maintenance in responding patients after initial chemo-immunotherapy has been evaluated in NHL. 
The largest studies to date have been done in follicular lymphoma (FL) and include the GADOLIN and GALLIUM 
studies. The GALLIUM study us an ongoing randomized Phase III study evaluating 1400 treatment naïve FL 
patients randomized to Bendamustine plus Rituximab (BR) vs. Bendamustine plus obinutuzumab (B.O.) 
(www.clinicaltrials.gov; NCT01332968). The GADOLIN trial compared bendamustine vs. B.O. Interim results on 
the first 396 patients, which were recently reported at the 2015 American Society of Clinical Oncology annual 
meeting, showed significantly prolonged PFS (29 months vs 14 months) in the B.O. arm. Not surprisingly, the B.O. 
arm was associated with higher rates of neutropenia (68% vs. 62%) and infusion reactions (33% vs 26%) (Sehn L, 
et al. J Clin Oncol 33, 2015 (suppl; abstr LBA8502)). 
 
2.3.4 
SUMMARY OF OBINUTUZUMAB CLINICAL SAFETY 
 
As of the safety data cutoff date of 2 July 2014, obinutuzumab has been administered to 2863 patients with CLL or 
NHL, from doses of 50 mg to 2000 mg in monotherapy or in combination with cyclophosphamide, doxorubicin, 
vincristine, and prednisone (CHOP), fludarabine and cyclophosphamide (FC), bendamustine, or Clb. Overall, the 
safety of monotherapy Obinutuzumab, or obinutuzumab combination therapy with CHOP, FC, bendamustine, or 
Clb, was manageable. 
 
The most frequent causes of death were disease progression and adverse events (AEs) describing infectious 
diseases. This is consistent with the study population and disease being treated. The incidence of fatal events was 
similar across all ongoing trials.  Of particular interest, infusion-related reactions (IRRs) were observed consistently 
in all obinutuzumab trials; the highest incidence of IRR was at the first infusion with the incidence decreasing 
rapidly with subsequent infusions. The incidence of IRR observed with combination therapy (FC and CHOP) 
appears similar to that observed with monotherapy. Furthermore, the incidence of IRR appears to be higher in CLL 
compared to NHL patients and higher in obinutuzumab- compared to rituximab-exposed patients based on evidence 
from studies BO21003 and BO21999. There is no clear relationship between obinutuzumab dose and the incidence 
of IRR based on data from study GAO4768g. In Stage 2 of the pivotal Phase III study, BO21004/ CLL 11, 
investigating GClb vs RClb in patients with CLL, the incidence of IRR, Grade 3/4 IRR and IRR leading to 
discontinuation was higher in GClb arm compared to RClb. This study investigated several measures to minimize 
the risk of IRRs including: use of corticosteroids, withdrawal of antihypertensive treatments, slow infusion, and 
split dosing and the evidence suggests that these risk minimization measures decreased the risk of IRRs (all grades); 
however, the impact on the incidence of Grade 3-4 events and treatment discontinuations due to IRR was limited. 
 
Due to the pharmacological class of obinutuzumab, as well as the evidence from monotherapy Phase I trials and 
chemotherapy combination trials BO21004/CLL11 (Phase III), and GAO4779g (Phase I), the sponsor considers 
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thrombocytopenia is hemorrhage. In trial BO21004/CLL11, the overall incidence of hemorrhagic AEs was 
comparable between the treatment arms (8% GClb; 7% RClb) with the majority of events being of Grade 1 or 2 
severity. However, and importantly, all fatal hemorrhagic events in the GClb arm occurred in Cycle 1 in contrast to 
such events in the RClb arm which occurred later (beyond 1 year after first administration of study drug). Other 
AEs of particular interest include Tumor Lysis Syndrome (TLS), neutropenia, infections including progressive 
multifocal leukoencephalopathy (PML), and hepatitis B virus (HBV) reactivation. 
 
2.3.5 
NOTABLE RISKS OF CLINICAL RELEVANCE IDENTIFIED IN CLINICAL INVESTIGATIONS WITH 
OBINUTUZUMAB 
 
Notable risks of clinical relevance identified in clinical investigations with obinutuzumab were: IRRs, TLS, 
thrombocytopenia, neutropenia, and infection. Additional risks are presented and discussed in Section 5.5.6 
(Adverse Events of Particular Interest) and Section 6 of the IB. 
 
2.3.5.1 
Risk of Infusion Reactions 
 
The most frequently observed adverse drug reactions (ADRs) in patients receiving obinutuzumab were IRRs; these 
occurred predominantly during the first infusion. The incidence and severity of infusion related symptoms 
decreased substantially with subsequent infusions, with most patients having no IRRs during the second and 
subsequent administrations of obinutuzumab. The commonly experienced IRRs are characterized by hypotension, 
fever, chills, flushing, nausea, vomiting, hypertension, and fatigue, amongst other symptoms. In the majority of 
patients, IRRs were mild or moderate and could be managed by the slowing or temporary halting the first infusion 
but severe IRRs requiring symptomatic treatment have also been reported. IRRs may be clinically indistinguishable 
from IgE-mediated allergic reactions (e.g. anaphylaxis). Patients with a high tumor burden (i.e. high peripheral 
lymphocyte count in CLL [> 25 x 109/L]) may be at increased risk of severe IRR. 
 
2.3.5.2 
Risk of Tumor Lysis Syndrome 
 
TLS is considered an ADR of obinutuzumab and fatal TLS has been observed among patients exposed to 
obinutuzumab. Patients who are considered to be at risk of TLS (e.g. patients with a high tumor burden or a high 
circulating lymphocyte count) should receive adequate tumor lysis prophylaxis with allopurinol (or adequate 
alternative) and hydration prior to the infusion of obinutuzumab. 
 
2.3.5.3 
Risk of Thrombocytopenia and Neutropenia 
 
Neutropenia and thrombocytopenia are also considered as ADRs of obinutuzumab. Febrile neutropenia during 
treatment has been reported with obinutuzumab. The neutropenia resolved spontaneously or with use of colony-
stimulating factors. Patients who experience Grade 3/4 neutropenia should be closely monitored.  Primary 
prophylaxis with granulocyte colony stimulating factors (G-CSF) is recommended as per the ASCO, EORTC, and 
ESMO guidelines, namely in patients who are ≥ 60 years and/or with comorbidities. Additionally, the use of G-CSF 
prophylaxis is strongly recommended in Cycle 1 for all patients treated with G-CHOP. 
 
Severe and life-threatening thrombocytopenia including acute thrombocytopenia (occurring within 24 hours after 
the infusion) has been observed during treatment with obinutuzumab. In patients with CLL who were exposed to 
GClb, fatal hemorrhagic events were also reported in Cycle 1. 
 
Patients should be closely monitored for thrombocytopenia, especially during the first cycle; regular laboratory tests 
should be performed until the event resolves, and dose delays should be considered in case of severe or life-
threatening thrombocytopenia. Transfusion of blood products (i.e. platelet transfusion) according to institutional 
practice is at the discretion of the treating physician. Use of all concomitant therapies, which could possibly worsen 
thrombocytopenia related events such as platelet inhibitors and anticoagulants, should also be taken into 
consideration, especially during the first cycle. 
 


      
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2.3.5.4 
Risk of Infection including Progressive Multifocal Leukoencephalopathy 
 
With regard to the risk of infections, due to the pharmacodynamic effect of obinutuzumab, resulting in profound B-
cell depletion, obinutuzumab may be associated with an increased   risk   of   infections.   Obinutuzumab should not 
be administered   in the presence of a severe infection and caution should be exercised when considering the use of 
obinutuzumab in patients with a history of recurring or chronic infections. 
 
In particular, given that other anti-CD20 antibodies have been associated with HBV reactivation in patients with 
chronic hepatitis (HBsAg positive) with evidence of prior hepatitis B exposure, or in patients who are carriers 
(HBsAg negative and hepatitis B core antibody positive). The incidence of reactivation may be exacerbated, 
particularly when anti-CD20 antibodies are administered with immunosuppressive therapies, such as 
glucocorticoids or chemotherapy. HBV reactivation (defined as HBV DNA >100IU/mL at least once during the 
course of a trial) has been observed among patients exposed to obinutuzumab. None of these patients experienced 
any relevant, serious or non-serious, AEs (e.g. transaminitis, hepatitis, functional liver impairment, jaundice), HBV 
screening should always be performed before initiation of treatment with obinutuzumab as per institutional 
guidelines. Patients with active HBV disease should not be treated with obinutuzumab. Patients with positive 
serology should be referred to a hepatologist or gastroenterologist before start of treatment and should be monitored 
and managed following local standards to prevent hepatitis reactivation. 
 
Given the profound B-cell depletion following exposure to obinutuzumab and a possible pharmaceutical class 
effect, the risk of PML may be exacerbated among exposed patients. Patients exposed to obinutuzumab experienced 
PML. The diagnosis of PML should be considered in any patient presenting with new-onset neurologic 
manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain magnetic 
resonance imaging (MRI), and lumbar puncture (cerebrospinal fluid testing for John Cunningham [JC] viral DNA). 
Therapy with obinutuzumab should be withheld during the investigation of potential PML and permanently 
discontinued in case of confirmed PML. Discontinuation or reduction of any concomitant chemotherapy or 
immunosuppressive therapy should also be considered. The patient should be referred to a neurologist for the 
evaluation and treatment of PML. 
 
2.4 
IBRUTINIB 
 
Refer to prescribing information for details. 
 
2.4.1 
INVESTIGATIONAL PRODUCT NAME AND DESCRIPTION 
 
Ibrutinib 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). Ibrutinib is a white to off-white crystalline 
solid. It has a single chiral center and is the R-enantiomer. The investigational drug product, ibrutinib, is an oral 
formulation containing micronized ibrutinib. 
 
2.4.2 
SUMMARY OF RELEVANT NON-CLINICAL AND CLINICAL PHARMACOLOGY DATA 
 
2.4.2.1 
Non-clinical Data 
 
In vitro studies have shown that ibrutinib binds covalently to a cysteine residue (Cys-481) in the BTK active site, 
leading to potent and irreversible inhibition of BTK enzymatic activity.17 In cellular signal transduction assays with 
a B-cell lymphoma cell line, ibrutinib inhibited autophosphorylation of BTK, phosphorylation of BTK’s 
physiological substrate, phospholipase-Cγ (PLCγ), and phosphorylation of a further downstream kinase, 
extracellular signal-regulated kinase.18 
 
2.4.2.2 
Clinical Pharmacokinetic Data  
 
In vitro preclinical data show that ibrutinib is metabolized primarily by CYP3A. Guidance on concomitant use of 


      
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ibrutinib/placebo with CYP3A inhibitors or inducers is provided in Section 5.1.1. 
 
2.4.3 
CLINICAL EFFICACY OF IBRUTINIB IN MANTLE CELL LYMPHOMA 
 
2.4.3.1 
Ibrutinib Monotherapy in MCL 
 
A Phase I, multicenter, multicohort, open-label, dose-escalation study enrolled 66 subjects with a variety of B-cell 
malignancies, including chronic lymphocytic leukemia (CLL), Waldenström’s macroglobulinemia, follicular cell 
lymphoma (FL), and MCL. Nine of subject had a diagnosis of MCL and they were all evaluable for response; 7 of 
the 9 (78%) evaluable subjects achieved an objective response (3 CRs and 4 PRs). The responses have been durable, 
with a median time on ibrutinib treatment of 8 months (1.3 to 14.7 months) and median PFS of 11.6 months for the 
9 subjects.19 
 
A Phase II study of single-agent ibrutinib (560 mg daily administered orally) in subjects with relapsed or refractory 
MCL showed significant activity in MCL patients with or without prior bortezemib exposure. One hundred eleven 
subjects (63 bortezomib-naïve and 48 bortezomib-exposed) were enrolled in the study. The overall response rate for 
the 111 treated subjects was 68.0% including a CR rate of 21.0%. The rate of response was similar across all disease 
risk groups. The estimated median duration of response was 17.5 months and overall survival was not reached at the 
time of the clinical cutoff. With an estimated median follow-up of 15.3 months, the estimated median PFS was 13.9 
months. 
Median time to initial response was 1.9 months (range, 1.4 to 13.7 months). The estimated rate of overall survival 
was 58% at 18 months. Median duration of ibrutinib treatment was 8.3 months (range, 0.7 to 21.4 months).20 
 
Ibrutinib is known to effectively cross the blood brain barrier. Recent reports have demonstrated that ibrutinib 
therapy is highly active and effective in patients with a spectrum of CNS lymphomas including in 
recurrent/refractory primary CNS lymphoma patients (n=20) where a 75% response rate was seen with excellent 
tolerability29. Activity has also been seen in MCL30.For example, of 3 patients with active CNS MCL treated with 
standard dose ibrutinib (560 mg once daily), rapid responses were seen, occurring within 3-8 days. Two CR and 1 
PR were observed. CSF sampling demonstrated ibrutinib levels well above the ibrutinib IC50. No additional 
toxicity was seen31.  
 
2.4.4 
COMBINATION THERAPY 
 
Bendamustine plus rituximab (BR) in combination with ibrutinib was evaluated in 20 patients with 
relapsed/refractory NHL. In this protocol, patients received bendamustine 90 mg/m2 on Days 1 and 2 with 
rituximab 375 mg/m2 on Day 1 administered with escalating doses of ibrutinib (280 mg or 560 mg) on Days 1 to 28 
every 28 days for a total of 6 cycles. Responding patients could continue ibrutinib alone after Cycle 6 until disease 
progression or unacceptable toxicity. Nine of the 20 patients had MCL, 7 of whom had relapsed disease. The ORR 
was 100% (4 CRs and 1 PR) for the 5 evaluable MCL patients. No DLTs were seen. Grade 3/4 adverse events for 
all patients (n=20) included lymphopenia (15 subjects), neutropenia (5 subjects), rash (3 subjects), and anemia, 
thrombocytopenia, nausea and vomiting (2 subjects each event).21 
 
A phase III international trial comparing BR +/- ibrutinib is currently ongoing and has completed targeted 
enrollment (clinicaltrials.gov identifier NCT01886872). 
 
2.4.4.1 
Ibrutinib plus Rituximab in CLL and MCL 
 
Ibrutinib plus rituximab has been evaluated in CLL in a single are phase 2 study. This combination has not yet been 
reported for MCL. Patients received 28-day cycles of once-daily ibrutinib 420 mg together with rituximab (375 
mg/m(2), intravenously, every week during cycle 1, then once per cycle until cycle 6), followed by continuous daily 
single-agent ibrutinib 420 mg until disease progression or unacceptable toxicity. This study enrolled 40 patients (36 
with relapsed disease). Toxicity was mainly mild to moderate in severity (grade 1-2). Diarrhea occurred in ten 
(25%) patients (grade 1 in nine patients and grade 2 in one), bleeding events in 14 (33%) patients (eight grade 1 and 


      
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five grade 2), nausea or vomiting in 15 patients (38%) (ten grade 1 and five grade 2), and fatigue in seven (18%) 
patients (four grade 1 and three grade 2). Five patients (13%) had grade 3 infections (two lung infections, one upper 
respiratory tract infection, one sepsis, and one mucositis), and no grade 4 or 5 infections occurred. One patient had 
grade 4 neutropenia.22 
 
Ibrutinib plus Rituximab has also been evaluated in relapsed/refractory MCL. In a phase II study, 50 patients with 
R/R MCL were treated with rituximab (375mg/m2 intravenously weekly×4, then monthly for up to 2 years) and 
ibrutinib (560 mg orally daily). With a median follow up of 6.5 months (range 1–10), the ORR was 87% with 38% 
CR rate. All patients with SD or progressive disease had a Ki67 of at least 50%. Of the 33 patients with Ki67 less 
than 50%, the ORR was 100% with a 48% CR rate. These data suggest that this regimen may be more effective in 
patients without the blastoid variant, which often is associated with high Ki67. However, the clinical and biologic 
relevance of this finding should be interpreted with caution given that a Ki67 cut- off of 50% is high by MCL 
standards and likely the result of trying to stratify outcomes using a relatively small dataset. Grade 3 AEs were 
neutro- penia (1) and thrombocytopenia (1). Notably six patients developed atrial fibrillation (afib) [Wang et al. 
Blood (ASH Annual Meeting Abstracts) abstract 4453]. 
 
2.5 
STUDY AND DOSE RATIONALE 
 
This single arm Phase II study will combine obinutuzumab and ibrutinib for the treatment of patients with 
relapsed/refractory MCL.  Obinutuzumab will be administered at 1000 mg on days 1, 8, and 15, for cycle 1 and on 
day 1 of subsequent cycles. Split dosing on days 1 and 2 is performed for CLL.  NHL trials dose 1000 mg starting 
on day 1.  That said, similar to other monoclonal antibodies, the dose may be split if deemed appropriate by the 
treating MD. This is often done for patients with high tumor burden or circulating lymphoma cells. 
 
This dosing schedule results in rapid accumulation of drug, thus maximizing its effects and achieving steady state. 
The first dose of obinutuzumab may be split over two days if needed per investigator discretion (i.e. 100 mg D1, 
900 mg D2). Treatment will be administered for a total of 6 cycles or disease progression, whichever occurs first.  
This is the current FDA approved dosing strategy for obinutuzumab. 
 
Ibrutinib will be administered at 560 mg orally once daily starting on day 1.  For patients who are already receiving 
ibrutinib (for < 14 days prior to day 1), it can be continued. This is the FDA approved dose for relapsed/refractory 
MCL. Although there are pre-clinical data suggesting that ibrutinib inhibits ITK in NK/T cells thus inhibiting 
antigen dependent cellular cytotoxicity (ADCC), a key mechanism for cell killing for rituximab, this has not been 
seen in pre-clinical models with obinutuzumab or clinically with ibrutinib plus rituximab.23, 24  Patients with ≥ PR at 
the end of 6 cycles will then receive obinutuzumab maintenance (1000 mg Q 2 months) for up to two years (a total 
of 12 doses).  This obinutuzumab dose and treatment schedule were selected given the results of PK data obtained 
from Study BO21003, a Phase I study evaluating post induction obinutuzumab maintenance administered q 3 
months in NHL and CLL. Based on the PK results as shown in the figure below (page 82 of the IB), it was 
determined that the Phase II phase of this study and future studies should include maintenance at 1000 mg every 2 
months.  No dose reductions will be permitted for obinutuzumab. Dose reductions will be allowed for ibrutinib as 
described in the package insert (and outlined in section 6.2). Ibrutinib will be discontinued in subjects who are 
intolerant to ibrutinib despite dose reductions.  These subjects will be eligible to stay on study with single agent 
obinutuzumab if they have completed > 2 cycles of combination therapy and there is no evidence of disease 
progression. 
 


      
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Table 1. Summary of Planned Study Treatment  
Drug 
Dose (route) 
Duration 
Obinutuzumab  
1000 mg (IV) 
Cycle 1: Days 1*, 8, 15  
if ≥ PR, then continue Obinutuzumab 
to subsequent cycles 
Cycle 2-6: Day 1 (q2 cycles, for a total 
of 2 years) 
Ibrutinib  
 
Day 1-28 of each cycle. 
Administered on an on-
going basis until progression 
[up to 5-years] 
*the first dose of obinutuzumab may be split over two days (i.e., 100 mg on day 1 and 900 mg on day 
2) if needed per investigator discretion 
 
Staging studies will include: 
● Bone marrow biopsy prior to cycle 1 for all subjects and at the end of cycle 6 for subjects with initial bone marrow 
involvement. 
● PET prior to cycle 1, after cycle 6 
● Diagnostic CT prior to Cycle 1, after Cycle 2, and after Cycle 6, then Q 4 months. 
 
2.6 
CORRELATIVE STUDIES 
 
A number of clinical and biologic factors have been identified as having prognostic significance in MCL. For 
example, Mantle Cell International Prognostic Index or ‘MIPI’ (incorporates age, ECOG performance status, WBC, 
LDH); MCL cell proliferation (Ki67), and beta-2 microglobulin (B2M), have been shown to correlate with clinical 
outcome with initial treatment. Specifically, patients with high risk MIPI scores have inferior outcomes with median 


      
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and overall survival of 29 months after initial chemo-immunotherapy. Similarly, patients with Ki67 > 30% also 
have poor outcomes.6,7,9 Although these factors have begun to help risk-stratify MCL patients, they often do not 
provide additional insight into the biology of the disease. For example, some older patients with splenomegaly and 
leukemic MCL, who have high MIPI scores, have indolent disease5 
 
In an effort to better define disease biology, gene expression profiling has successfully been utilized to diagnose 
MCL and create a proliferation signature that can predict for inferior outcomes.8  Although this signature is 
promising, it has not yet entered standard practice and its relevance in relapsed disease remains unknown. 
Furthermore, it needs to be prospectively validated especially for relapsed disease and in the era of novel agents. 
Thus, evaluation of new platforms that can be readily applied to relapsed patients receiving novel agents is 
warranted. 
 
In addition, minimal residual disease (MRD) negativity at the end of therapy has become an important 
prognosticator across a number of lymphoid malignancies including chronic lymphocytic leukemia (CLL) and acute 
lymphoblastic leukemia (ALL).25, 26 More recently, MRD has been evaluated in MCL using patient specific PCR in 
patients receiving aggressive chemo-immunotherapy and consolidative autologous stem cell transplant. Patients 
who achieved MRD negativity after treatment had significantly improved outcomes.16 However, to date the 
techniques used to define MRD in MCL are not readily available and may not be broadly applicable outside of a 
clinical trial. Similar to other prognostic scores, little is known about rates of MRD after relapse or with novel non- 
“geno-toxic” therapy such as GA-101 and ibrutinib. 
 
Data are also emerging that ibrutinib resistance in some patients with CLL and MCL while on treatment is the result 
of a mutation in BTK at the ibrutinib binding site or in key downstream targets. For example, of 7 relapsing CLL 
patients, a serine to cystine (C481S) mutation in BTK at the binding site of ibrutinib was seen in five patients and 
three distinct mutations in PLCγ2 in two patients. Functional analysis showed that the C481S mutations in PLCγ2 
are both potentially gain-of-function mutations that lead to autonomous B-cell-receptor activity.12 Acquired 
mutations in the BTK binding site, also resulting in C481S have also been detected in MCL patients after prolonged 
ibrutinib treatment but not in patients with primary resistance or short duration of drug exposure, suggesting a 
unique, as of yet, undefined mechanism for patients with primary resistance.13 
 
To summarize, clinical factors, Ki67, gene expression profiling/proliferation (GEP) signatures, molecular 
remission/MRD negativity, and BTK mutations have all shown significant promise in better defining disease 
biology and prognostic groups; however, it remains clear that additional, more widely available studies are needed 
that can better define disease biology and further risk stratify patients. Using these approaches may allow for an 
improved understanding of treatment resistance and outcome especially in the era of targeted agents and ready 
access to gene expression and genomics data. To this end, we will be conducting a number of correlative studies. 
Every attempt will be made to biopsy (bone marrow and/or lymph node and/or soft tissue) patients as part of the 
screening process after enrollment on study and prior to initiation of on-study therapy. In the event tissue is 
unobtainable, studies will be performed on archival tissue. Patients will also be biopsied at the time of disease 
progression. 
 
2.6.1 
GENE EXPRESSION PROFILING USING NANOSTRING 
 
Formalin fixed, paraffin embedded MCL tissue biopsies or lysates from 10^4 lymphoma cells, qualified by an 
expert hematopathologist, with matching snap frozen case materials will be collected. 100-200 ng of RNA will be 
isolated using the Qiagen AllPrep kit. This approach is based on the successful work done by the Lymphoma & 
Leukemia Molecular Profiling Project (LLMPP) using Nanostring technology (Seattle, WA) for the characterization 
of cell of origin in diffuse large b-cell lymphoma.27 NanoString technology (Seattle, WA) will be used to evaluate 
key MCL genes. To date, the LLMPP has successfully validated probes designed (Lymph5Cx) specifically to 
evaluate key MCL genes using the nCounter Analysis System (Nanostring, Seattle, WA). In addition to diagnostic 
verification, with this approach, the LLMPP was able to define key biologic information (proliferation signature) in 
MCL (Scott et al., Abstract 3016, ASH annual meeting). Dr. Braziel is currently leading this effort at OHSU. 
Specifically, nucleic acid extraction/RNA preparation will be performed at OHSU using a nano-string prep station. 


      
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Samples will then be analyzed using the nCounter system. Proliferation signatures will be defined and correlated 
with clinical prognostic features including MIPI5, Ki67, as well as clinical outcomes. 
 
2.6.2 
SEQUENCING USING THE ION TORRENT PLATFORM (FOR KNOWN MUTATIONS IN LYMPHOMA) 
 
In conjunction with the OHSU Hematopathology group, the Knight Diagnostic Lab (KDL) has developed a 
GeneTrails® assay for myeloid and lymphoid hematologic malignancies. The GeneTrails® Lymphoid Genotyping 
Panel delivers information on 76 predictive and prognostic mutations commonly involved in NHL as well as 
detecting some mutations that may directly inform targeted or non-targeted treatment options.  The panel has a 
sensitivity of ~5 % mutant allele with strict next generation sequencing quality control parameters. The Genotyping 
Panel is performed on DNA extracted from blood, bone marrow aspirate or biopsy, lymph nodes, soft tissue, or 
formalin-fixed, paraffin-embedded (FFPE) tissue. The assay uses next-generation, semiconductor- based massively 
parallel sequencing (Ion Torrent PGM platform). Input DNA is amplified using the AmpliSeq technology (Ion 
Torrent), after which the amplicons are modified with adaptors and subjected to emulsion PCR. The final products 
are sequenced on a 316 or 318 chip. Test parameters are as follows: Input DNA: 20 ng, number of multiplexed 
amplicons: 701, average read depth per amplicon: 1750. Specimen Requirements include: Peripheral blood: 5 mL 
EDTA (lavender top tube) or 5 mL Citrate tube or Bone marrow aspirate: 5 mL in EDTA (lavender top tube) or a 
paraffin block or 10 unstained sections of a bone marrow or lymph node biopsy (4-5 microns).Additional details 
regarding these specific genes as well as procedures can be found at the KDL website 
(http://www.knightdxlabs.com). Potential gene targets are frequently evaluated to determine if additional genes 
need to be added to panel. 
 
2.6.3 
SEQUENCING OF BTK TO EVALUATE FOR BTK OR PLC MUTATIONS 
 
To augment the gene trails assay, next generation sequencing may also be utilized to evaluate for mutations in 
specific genes that may not be included in the gene trails panel, such as BTK and PLCγ2. Patients not responding to 
initial therapy at 6 months or who progress on therapy, will have BTK and PLCγ evaluated. The same sample 
acquisition/isolation techniques as described above will be utilized for this approach. 
 
2.6.4 
MRD BY FLOW CYTOMETRY AND SEQUENCING POST TREATMENT 
 
Evaluation of MRD by flow cytometry at the end of treatment is routinely performed at OHSU for patients with 
hematologic malignancies including ALL, CLL, and MCL. For patients with bone marrow involvement prior to the 
initiation of therapy who achieve a radiographic CR after the completion of treatment, bone marrow samples will be 
obtained 2 months after completion of therapy and prior to initiation of maintenance obinutuzumab. For those 
subjects not in CR after induction and who had marrow involvement prior to initiation of therapy, MRD testing 
should be evaluated if/once nodal CR achieved. This assay uses 8 color flow cytometry for lymphoid specific 
antigens with a sensitivity of 1:10,000 and will be performed as part of routine clinical care. For select cases that are 
MRD negative by flow cytometry, Next Generation Sequencing using the aforementioned ion torrent platform for 
MCL specific genes found on pre-treatment specimens will be performed and correlated with flow cytometry 
results. 
 
 
 
 
 
 
 
 
 
 
 
 


      
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3. STUDY POPULATION 
 
3.1 
INCLUSION CRITERIA 
 
 
3.1.1 
 
Subjects must have a diagnosis of Relapsed or Refractory Mantle Cell Lymphoma as follows: 
 
a) Diagnosis of MCL must include morphology and expression of either cyclin D1 in association 
with other relevant markers (eg, CD19, CD20, CD5) or evidence of t(11;14) as assessed by 
cytogenetics, fluorescent in situ hybridization (FISH), or polymerase chain reaction (PCR). 
 
b) Relapsed or refractory disease, which is defined as no response or progressive disease to prior 
treatment if the prior treatment comprised any of the following: 
 
i. 1 regimen containing an anti-CD20 antibody administered for ≥ 2 doses, and/or 
ii. ≥ 1 regimen containing 1 cytotoxic agent (e.g., bendamustine, chlorambucil, 
cyclophosphamide, cytarabine, doxorubicin) administered for 2 cycles. 
 
3.1.2 
 
At least 1 measurable site of disease according to Revised Response Criteria for: 
● Malignant Lymphoma (Cheson Criteria). The site of disease must be greater than 
1.5 cm in the long axis regardless of short axis measurement or greater than  1.0 
cm  in  the  short  axis  regardless  of  long  axis  measurement,  and  clearly 
measurable in 2 perpendicular dimensions. 
3.1.3 
 
Age ≥ 18 years.  Both men and women and members of all races and ethnic groups will 
be included. 
3.1.4 
 
ECOG performance status ≤ 2 (Karnofsky ≥ 60%, see Appendix A). 
3.1.5 
 
Subjects must have normal organ and marrow function as defined below: 
● absolute neutrophil count (ANC) ≥ 1.0 K/cu mm* 
 
● Platelets (plt) ≥ 50 K/cu mm* 
 
● total bilirubin ≤ 2.5 X institutional limits 
 
● AST(SGOT)/ALT(SGPT) ≤ 2.5 X institutional upper limit of normal 
 
● Creatinine ≤ 2  
*for subjects with plt < 50 K/cu mm or ANC < 1.0 K/cu mm due to significant marrow 
involvement by MCL, ANC must be > .5 K/cu mm and plt > 25 K/cu mm 


      
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3.1.6 
 
Women of childbearing  potential  and  men  who  are  sexually  active  must be   
practicing a highly effective method of birth control during and after the study   
consistent with local regulations regarding the use of birth control methods for   
subjects participating in  clinical  trials.  Men must agree to not donate sperm during 
and after the study. For females, these restrictions apply for 18 months after last dose 
of obinutuzumab, or 1 month after the last dose of ibrutinib, whichever is later. For 
males, these restrictions apply for 180 days after the last dose of obinutuzumab or 3 
months after the last dose of ibrutinib, whichever is later. 
3.1.7 
 
Women of childbearing potential must have a negative serum (beta-human chorionic 
gonadotropin [β-hCG]) or urine pregnancy test at Screening. Women who are pregnant 
or breastfeeding are ineligible for this study. 
3.1.8 
 
Ability to understand and the willingness to sign a written informed consent document. 
 
 
 
3.2 
EXCLUSION CRITERIA 
 
3.2.1 
 
Major surgery within 4 weeks of drug administration 
3.2.2 
 
Diagnosed or treated for malignancy other than MCL, except: 
a) Malignancy treated with curative intent and with no known active disease present for ≥ 2 
years before randomization (the exception is prostate cancer) 
b) Adequately treated non-melanoma skin cancer or melanoma in situ without evidence of 
disease. 
c) Adequately treated cervical carcinoma in situ without evidence of disease. 
d) Asymptomatic prostate cancer managed with “active surveillance.” 
e) Localized prostate cancer treated with definitive treatment including radiation or surgery. 
Patients on adjuvant hormone deprivation treatment such as Lupron are eligible. Patients 
with known metastatic disease are ineligible.  


      
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3.2.3 
 
History of stroke or intracranial hemorrhage within 6 months prior to randomization. 
 
3.2.4 
 
Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon). 
3.2.5 
 
Vaccinated with live, attenuated vaccines within 4 weeks of randomization. 
3.2.6 
 
Requires treatment with strong CYP3A inhibitors (see section 5.5.1). 
3.2.7 
 
Subjects who have had standard cytotoxic chemotherapy within 3 weeks prior to entering the study 
or those whose adverse events due to agents administered more than 3 weeks earlier have not 
recovered to ≤ Grade 1. This excludes alopecia and hematologic adverse events. 
3.2.8 
 
Subjects who have had radiotherapy within 2 weeks prior to entering the study or those whose 
adverse events due to radiotherapy more than 2 weeks earlier have not recovered to ≤ Grade 1. 
3.2.9 
 
Subjects who have received investigational or approved oral or “targeted” agents (such as SYK, 
PI3K, bcl-2, BTK inhibitors) or lenalidomide within 1 week prior to entering the study or those 
whose adverse events due to agents administered more than 1 week earlier have not recovered to ≤ 
Grade 1. This excludes hematologic adverse events. The exception is subjects who are currently 
receiving ibrutinib (for < 14 days). In this case, ibrutinib can be continued.  
3.2.10  
Subjects who have received monoclonal antibodies (such as Rituxan) within 1 week prior to 
entering the study or those whose adverse events due to agents administered more than 1 week 
earlier have not recovered to ≤ Grade 1. This excludes hematologic adverse events. 
3.2.11  
Subjects who are actively receiving any other investigational agents. 
3.2.12  
History of severe allergic reactions attributed to compounds of similar chemical or biologic 
composition as obinutuzumab or ibrutinib or other agents used in the study 
3.2.13  
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance with study requirements. 
3.2.14  
Pregnant or lactating women are excluded from this study. 
3.2.15  
Known history of human immunodeficiency virus (HIV) or active Hepatitis C. 
3.2.16  
Virus or active Hepatitis B Virus infection. Patients who are HBcAb positive may be eligible as 
long as there is no evidence of active infection with negative Hep B by PCR. In this case, Hep B 
PCR must be monitored monthly. 
3.2.17  
Any uncontrolled active systemic infection requiring intravenous (IV) antibiotics. 
3.2.18  
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 undue risk. 
3.2.19  
Patients previously treated with ibrutinib > 14 days are ineligible. No drug intervention or 
cessation is required for patients already receiving ibrutinib prior to initiation of on-study therapy. 
3.2.20  
Active graft vs. host disease (GVHD). 
3.2.21  
Ongoing glucocorticoids (prednisone > 10 mg daily, or equivalent). Higher doses (> 10 mg daily) 
are permitted for up to 5 days to help control disease related symptoms 
 
3.3 
PROHIBITIONS AND RESTRICTIONS 
 
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 surgery or invasive procedure requiring 
sutures or staples for closure, ibrutinib and/or obinutuzumab should be held at least 7 days prior to the intervention 
and should be held at least 7 days after the procedure, and restarted at the discretion of the investigator when the 
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For minor procedures (such as a central line placement, needle biopsy, thoracentesis, or paracentesis) ibrutinib and 
obinutuzumab 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 and/or 
obinutuzumab, it is not necessary to hold ibrutinib and/or obinutuzumab for these procedures. 
 
For emergency procedures, ibrutinib and/or obinutuzumab should be held after the procedure until the surgical site 
is reasonably healed, for at least 7 days after the urgent surgical procedure. 
 
4. REGISTRATION PROCEDURES 
 
4.1 
SUBJECT REGISTRATION 
 
Detailed Instructions for subject registration can be found in the separate study operations manual. 
 
This is a phase II trial with an intention to treat all patients who are enrolled in this clinical trial.  There is no 
randomization for treatment.  Potential subjects will be seen by study investigators study as new patient, consult, or 
follow-up visits.  Referral of potential subjects to co-investigators of this study is made as part of standard of care, 
with the referring physician seeking advice on the diagnosis, evaluation, and/or treatment of relapsed or refractory 
MCL. 
 
Registrations from all consented subjects must be entered into the Knight Clinical Research Management System 
(CRMS).  Registration of OHSU patients will include the minimum of the following: 
● A completed Subject Enrollment Form 
● A completed Eligibility Checklist signed by the investigator 
● Signed copies of the most recently IRB-approved, informed consent form and HIPPA authorization 
 
4.2 
MULTICENTER REGISTRATION  
 
The OHSU coordinating center study team will manage subject registration.  Investigators at participating sites will 
identify eligible subjects and send screening materials with source documents that support eligibility to OHSU in 
real time and in accordance with study protocol.  Designated Knight clinical staff must review and verify eligibility 
before the participating site may enroll and treat its subject. The OHSU coordinating center team will verify 
completeness of documents, enter registration information into eCRIS, and assign a study number/identifier.  The 
coordinating center will send an email to the participating site indicating whether or not the subject is eligible, 
verify registration, and assign a participant number/identifier.   
 
 
Registration will include a minimum of the following: 
● A completed Subject Enrollment Form 
● A completed Eligibility Checklist signed by the investigator 
● Signed copies of the most recently IRB-approved, informed consent form and HIPAA authorization 
 
Each participating research site is expected to maintain a screening log of all participants who are approached for 
the study.  The log documents an explanation for exclusion due to screen failure.  This log should be submitted to 
the OHSU coordinating center on a regular basis. Participating sites are required to retain, in a confidential manner, 
sufficient information on each participant so that the participant may be contacted should the need arise. 
 
5. TREATMENT PLAN 
 
5.1 
AGENT ADMINISTRATION 
 
The treatment described herein is an outpatient regimen. Therefore, treatment will primarily be administered on an 
outpatient basis. 


      
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Obinutuzumab: Treatment induction will consist of obinutuzumab 1000 mg (IV) administered on days 1, 8, 15 for 
cycle 1 and on day 1 for subsequent cycles (cycles 2-6). Each cycle is 28 days.  The first dose of obinutuzumab may 
be split over two days if needed per investigator discretion (i.e. 100 mg D1, 900 mg D2). Responding patients (i.e., 
≥ PR) after initial induction will proceed with obinutuzumab maintenance 1000 mg Q2 cycles. 
 
Ibrutinib: Will be self-administered (4 x 140 mg tabs, total dose 560mg daily) starting on day 1 of treatment.  
 
Infrequently patients with high tumor burden receiving monoclonal antibodies such as rituximab or obinutuzumab 
may be admitted for initial tumor lysis monitoring as per standard of care. Thus, inpatient admission for initial 
obinutuzumab administration may be done per the discretion of the treating physician. Reported adverse events and 
potential risks associated with obinutuzumab and ibrutinib are described in Section 7. 
 
Planned admission for obinutuzumab administration will not be considered an adverse event (AE). 
 
Appropriate dose modifications for ibrutinib are described in Section 6.2.  No dose reductions will be allowed for 
obinutuzumab. No investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the subject's malignancy. 
 
5.2 
OBINUTUZUMAB ADMINISTRATION AND SUPPORTIVE  CARE 
 
Obinutuzumab has been associated with infusion reactions. To help prevent infusion reactions, pre-medications with 
dexamethasone, Tylenol, and an anti-histamine (Benadryl or loratadine) will be administered per standard of care 
and institutional guidelines. Additional supportive measures will include interruption of obinutuzumab infusion, IV 
hydration, meperidine (for rigors), anti- emetics, and corticosteroids (dexamethasone, hydrocortisone, or 
methylprednisolone). Epinephrine will also be available in the event of anaphylaxis. All order sets will include these 
supportive measures as per current standard of care. 
 
5.2.1 
INFUSION RATE 
 
Obinutuzumab must be administered in a clinical setting (inpatient or outpatient). Full emergency resuscitation 
facilities should be immediately available, and patients should be under close supervision by the investigator at all 
times. Obinutuzumab should be given as a slow IV infusion through a dedicated line. IV infusion pumps should be 
used to control the infusion rate of obinutuzumab. Do not administer as an IV push or bolus. Obinutuzumab will be 
provided by the Sponsor to up to four investigational centers. 
 
5.2.1.1 
Infusion rate (per SOC guidelines): 
 
Cycle 1 (day 1 [C1D1]): Initiate infusion at 50 mg/hour for 30 minutes; if tolerated, may escalate rate in increments 
of 50 mg/hour every 30 minutes to a maximum rate of 400 mg/hour. 
 
All subsequent infusions: If no reaction or grade 1 reaction to previous infusion and the final infusion rate was 100 
mg/hour or faster, initiate infusion at 100 mg/hour for 30 minutes; if tolerated, may escalate rate in increments of 
100 mg/hour every 30 minutes to a maximum rate of 400 mg/hour. If a grade 2 or higher infusion reaction occurred 
during the previous infusion, initiate infusion at 50 mg/hour for 30 minutes; if tolerated, may escalate rate in 
increments of 50 mg/hour every 30 minutes to a maximum rate of 400 mg/hour. Rate may be adjusted if clinically 
indicated, at the discretion of the RN or investigator. Refer to FDA approved prescribing information and 
www.gazyva.com. 
 
Vital Signs (all infusions):  Vital signs should be taken every 15 minutes for the first hour of infusion until stable, 
then every 30 minutes with rate escalation, until completion of infusion. Pulse oximetry on room air should be 
performed at baseline and as needed if dyspnea occurs. Epinephrine 1 mg/ml, diphenhydramine 50 mg IV and 
hydrocortisone 100 mg IV should be readily available during obinutuzumab infusion 


      
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5.2.1.2 
Premedication Guidelines to prevent infusion reactions: 
 
C1D1: All patients should receive acetaminophen (650 to 1,000 mg) and an antihistamine (e.g., diphenhydramine 
25-50 mg) at least 30 minutes prior to infusion. In addition, an IV glucocorticoid (dexamethasone 20 mg or 
methylprednisolone 80 mg) should be administered at least 1 hour prior to infusion.  
 
All subsequent infusions: All patients should receive acetaminophen 650 to 1,000 mg at least 30 minutes prior to 
infusion. 
If patients experienced grade 1 or 2 infusion-related reaction with previous infusion: Administer an antihistamine 
(e.g., diphenhydramine 25-50 mg or loratadine 10 mg) in addition to acetaminophen at least 30 minutes prior to 
infusion. 
 
If patients experienced a grade 3 infusion-related reaction with previous infusion or have a lymphocyte count 
>25,000 cells/mm3 prior to next treatment: Administer an IV glucocorticoid (dexamethasone 20 mg or 
methylprednisolone 80 mg) at least 1 hour prior to infusion, in addition to acetaminophen and an antihistamine at 
least 30 minutes prior to infusion. 
 
5.2.2 
INFECTIONS 
 
Like other monoclonal anti-CD20 antibodies (rituximab, ofatumumab), treatment with obinutuzumab can 
potentially lead to infectious complications. Viral reactivation including hepatitis, which can potentially lead to 
fulminant hepatic failure, can occur. Therefore, patients with active Hepatitis B infection are excluded from study 
participation. 
 
Also, given the potential for HSV/VZV reactivation, all subjects will receive antiviral prophylaxis such as: 
● acyclovir 800 mg po once daily or 400 mg po twice daily BID, OR 
● valacyclovir 500 mg daily 
 
HSV/VZV prophylaxis will continue throughout the induction phase of obinutuzumab plus ibrutinib (for the first 6 
cycles). Subjects who are allergic/intolerant to or refuse these agents may discontinue antiviral prophylaxis and stay 
on study if a) he/she does not have a known history of HSV/VZV and b) after discussion with the PI and 
coordinating center. Additional prophylactic antifungals or anti-bacterials are not required but may be administered 
per the discretion of the treating physician per institutional standards. 
 
5.2.3 
TUMOR LYSIS SYNDROME 
 
Patients with high tumor burden and/or high circulating lymphocyte count (> 25 x 109/L) are at greater risk for TLS 
and should receive appropriate tumor lysis prophylaxis with antihyperuricemics (e.g., allopurinol) and hydration 
beginning 12–24 hours prior to the infusion of obinutuzumab. For treatment of TLS, correct electrolyte 
abnormalities, monitor renal function, and fluid balance, and administer supportive care, including dialysis or 
rasburicase as indicated. 
 
5.2.4 
WORSENING OF PRE-EXISTING CARDIAC CONDITIONS 
 
Infusions should be administered in an environment where full resuscitation facilities are immediately available, and 
under the close supervision of a physician. Hypotension may occur during intravenous infusions. Therefore, 
withholding of antihypertensive treatments should be considered for 12 hours prior to and throughout each infusion 
and for the first hour after administration. Patients at acute risk of hypertensive crisis should be evaluated for the 
benefits and risks of withholding their anti-hypertensive medication. Patients who have pre-existing cardiac or 
pulmonary conditions should be monitored carefully throughout the infusion and the post-infusion period. 
 
 


      
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5.3 
IBRUTINIB ADMINISTRATION AND SUPPORTIVE CARE 
 
With formulary change, subjects are instructed to take 1 tablet for a dose of 560 mg (which used to be 4 capsules of 
Ibrutinib for a dose of 560 mg) by mouth once daily, starting on Day 1 of Cycle 1. Ibrutinib is to be taken around 
the same time each day with approximately 240 mL of water (i.e., 8 ounces). Ibrutinib should be swallowed whole 
and should not be opened, broken, or chewed. Ibrutinib should be taken at least 30 minutes before eating or at least 
2 hours after a meal. 
 
If Ibrutinib is missed, it can be taken as soon as possible on the same day with a return to the normal schedule the 
following day. The subject should not take extra capsules to make up the missed dose. 
 
5.4 
CONSIDERATIONS FOR IBRUTINIB PLUS  OBINUTUZUMAB 
 
5.4.1 
TUMOR LYSIS SYNDROME 
 
Obinutuzumab has been associated with tumor lysis syndrome (TLS). Therefore, it is recommended that patients 
with high tumor burdens receive allopurinol therapy starting 48 hours prior to the initiation of treatment and have 
frequent TLS lab monitoring per the treating investigator’s discretion. 
 
5.4.2 
BONE MARROW SUPPRESSION 
 
Obinutuzumab and ibrutinib treatment can lead to anemia and thrombocytopenia requiring transfusions as well as 
significant neutropenia. Granulocyte Colony stimulating factors (filgrastim, pegfilgrastim) are not required but may 
be administered per the discretion of the treating physician.  Ibrutinib dose reductions as described in section 6.2. 
 
5.4.3 
NEUTROPENIC FEVER 
 
Will be treated per institutional standards. 
 
5.5 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES USE OF 
IBRUTINIB WITH CYP3A INHIBITORS OR INDUCERS 
 
Ibrutinib is metabolized primarily by CYP3A.  Avoid co-administration with strong or moderate CYP3A inhibitors. 
Strong inhibitors of CYP3A (e.g., ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, 
telithromycin, itraconazole, and nefazadone) should be avoided. If a strong CYP3A inhibitor must be used, consider 
reducing the ibrutinib dose to 140 mg or withhold treatment temporarily. Subjects should be monitored for signs of 
ibrutinib toxicity.  If the benefit outweighs the risk and a moderate CYP3A inhibitor must be used, monitor subject 
for toxicity and follow dose modification guidance as needed. Avoid grapefruit and Seville oranges during ibrutinib 
treatment, as these contain moderate inhibitors of CYP3A. Avoid concomitant use of strong CYP3A inducers (e.g., 
carbamazepine, rifampin, phenytoin, and St. John’s Wort). Consider alternative agents with less CYP3A induction. 
 
Subjects must discontinue all herbal and nutritional supplements. If the investigator determines the supplement to be 
benefitting the patient, the subject may stay on the supplement ONLY AFTER it has been reviewed by an oncology 
certified pharmacist and deemed NOT to have significant interactions with ibrutinib. If the interaction or risk is 
unknown, subjects will be required to discontinue all herbals and/or supplements. 
 
Examples of inhibitors, inducers, and substrates are included below: 
 
5.5.1 
INHIBITORS OF CYP3A 
 
Examples of inhibitors and inducers of CYP3A can be found at the following website: 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx 
 


      
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AND 
http://www.pharmacologyweekly.com/content/pages/ online-drug-therapy- tables.17, 34  The list below reflects 
information obtained from the Indiana University, Division of Clinical Pharmacology, Indianapolis, IN website on 
July 2013. 
 
Strong inhibitors: Indinavir, Nelfinavir, Ritonavir, Clarithromycin, Itraconazole, Ketoconazole, Nefazodone, 
Saquinavir, Telithromycin 
 
Moderate inhibitors: Aprepitant, erythromycin, diltiazem, fluconazole, grapefruit juice, Seville orange juice, 
verapamil 
 
Weak inhibitors: cimetidine 
 
All other inhibitors: amiodarone chloramphenicol, boceprevir, ciprofloxacin, delaviridine, diethyl-dithiocarbamate, 
fluoxetine-metabolite, norfluoxetine, fluvoxamine, gestodene, imatinib, mibefradil 
 
5.5.2 
INDUCERS OF CYP3A 
 
Efavirenz, nevirapine, barbiturates, carbamazepine, glucocorticoids, modafinil, oxcarbazepine, phenobarbital, 
phenytoin, pioglitazone, rifabutin, rifampin, St. John's wort, troglitazone.  
 
Because there is a potential for interaction of study agent(s) with other concomitantly administered drugs through 
the cytochrome P450 system, the case report form must capture the concurrent use of all other drugs, over-the-
counter medications, or alternative therapies. The principal investigator should be alerted if the subject is taking any 
agent known to affect or with the potential to affect selected CYP450 isoenzymes. 
 
5.6 
DURATION OF TREATMENT 
In the absence of treatment delays due to adverse events, treatment may continue up to 2 years or until one of the 
following criteria applies: 
● Disease progression, 
● Intercurrent illness that prevents further administration of treatment, 
● Unacceptable adverse events(s) including: 
o Grade 4 infusion reactions 
o Grade 4 bleeding 
● Subject decides to withdraw from the study, 
● General or specific changes in the subject's condition render the subject unacceptable for further treatment 
in the judgment of the investigator, or 
● For any reason, at the Sponsor’s (OHSU) discretion. 
 
Additionally; 
● Need to hold Obinutuzumab for > 14 days due to the toxicities listed in section 6.1, 
● Need to hold ibrutinib for > 14 days or for those who require more than 3 dose reductions due to the 
toxicities listed in Section 6.2 if occurring prior to Day 56 of therapy.  
 
Subjects who need to discontinue ibrutinib due to the toxicities in Section 6.2 after day 56 (after completion of 2 
cycles of combination therapy) are eligible to stay on study for ongoing treatment with Obinutuzumab as outlined in 
Section 6.2. 
 
5.7 
DURATION OF FOLLOW-UP 
 
Subjects will be followed up to 3 years or until disease progression. Subjects removed from study for unacceptable 
adverse event(s) will be followed until resolution or stabilization of the adverse event. 
 


      
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If a subject withdraws consent for further treatment, it is important to clarify and document the subject’s 
willingness to continue in the follow-up phase of the study. 
 
5.8 
CRITERIA FOR REMOVAL FROM STUDY 
 
Subjects will be removed from study when any of the criteria listed in Section 5.6 apply.  The reason for study 
removal and the date the subject was removed must be documented in the Case Report Form. 
 
5.9 
STUDY DISCONTINUATION 
 
There are pre-planned stopping rules for this study for toxicity for the entire cohort based on the incidence of > 
Grade 2 treatment related toxicity. The study may be discontinued if: 
● The incidence or severity of adverse events indicates a potential health hazard to subjects. 
● Subject enrollment is not proceeding at a pace that is compatible with trial completion within a reasonable 
amount of time so that the data are informative and the field moves forward. 
 
5.10 
DEFINITION OF DOSE-LIMITING TOXICITY 
 
The following events are dose-limiting toxicities. Note that these events are only considered DLTs if assessed as 
related to the study drug: 
 
● Grade 3 neutropenia or thrombocytopenia lasting > 14 days 
● Grade 3 thrombocytopenia with significant bleeding 
● Grade 3 diarrhea lasting > 7 days despite holding treatment or therapeutic intervention 
● Grade 4 neutropenia or thrombocytopenia lasting > 7 days 
● Grade 4 infusion reaction 
● Grade 4 bleeding 
● Grade 4 diarrhea > 48 hours despite holding treatment or therapeutic intervention 
● Grade 4 infection 
● Death 
 
Management and dose modifications associated with the above treatment related adverse events are outlined in 
Section 6. 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
All subjects will be evaluated for potential drug related toxicities at each visit.  Dose interruptions or reductions will 
be permitted. In some cases, non-hematologic toxicities may be attributable to one drug but not the other.  In this 
case a subject may have one drug withheld while the other is continued. 
 
If a Grade 3 hematologic DLT occurs, repeat CBC 2x/month (Day 1 and Day 15) will be performed. If a Grade 4 
hematologic DLT occurs, repeat CBC weekly until toxicity resolves to < Grade 2. 
 
6.1 
OBINUTUZUMAB 
 
No dose reductions for obinutuzumab will be permitted.  Dose interruptions/delays will be allowed.  For infusion 
reactions, appropriate changes in infusion rate and pre- medications/supportive care will be utilized as described in 
Section 5.2.  Subjects experiencing a Grade 4 infusion reaction will be removed from the study. Obinutuzumab may 
be delayed for up to 14 days for toxicity irrespective of causality. If the toxicity is present on D8 of Cycle 1, 
Obinutuzumab should be omitted. Obinutuzumab may also be delayed per the discretion of the treating physician.  
 
Dose interruptions/delays must be performed for the following toxicities, when related to obinutuzumab: 


      
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● Grade 3 or greater neutropenia with infection or fever. 
● Grade 4 neutropenia (ANC < 0.5 x 109/L [< 500/mm3]) >14 days 
● Grade 3 thrombocytopenia (platelets < 50 x 109/L [< 50,000/mm3]) in the presence of significant bleeding. 
● Grade 4 thrombocytopenia (platelets < 25 x 109 /L [< 25,000/mm3]) 
● Grade 3 or greater non-hematological toxicity 
 
6.2 
IBRUTINIB 
 
Dose reductions will be allowed for ibrutinib drug-related toxicities as defined in Table 2.  Ibrutinib will be 
discontinued in subjects who are intolerant to ibrutinib despite dose reductions. Treatment with ibrutinib may be 
held for up to 14 days. If treatment is held for > 14 days, ibrutinib must be discontinued for the remainder of the 
study. These subjects will be eligible to stay on study with single agent obinutuzumab if they have completed > 2 
(up to day 56, which can include dose interruptions and/or reductions) cycles of combination therapy and there is no 
evidence of disease progression.  Specifically, dose reductions will be performed for the following ibrutinib drug 
related toxicities: 
● Grade 3 or greater neutropenia with infection or fever 
● Grade 4 neutropenia (ANC < 0.5 x 109/L [< 500/mm3]) > 14 days. 
● Grade 3 thrombocytopenia (platelets < 50 x 109/L [< 50,000/mm3]) in the presence of significant bleeding. 
● Grade 4 thrombocytopenia (platelets < 25 x 109 /L [< 25,000/mm3]). 
● Grade 3 or greater non-hematological toxicity 
 
Table 2. Recommended Management for Ibrutinib-related toxicities 
Occurrence 
Action 
First 
Hold ibrutinib until recovery to Grade ≤ 1 or baseline; 
may restart at original dose level 
Second 
Hold ibrutinib until recovery to Grade ≤ 1 or baseline; 
restart at 1 dose level lower (3 capsules [i.e., 420 mg 
daily]) 
Third 
Hold ibrutinib until recovery to Grade ≤ 1 or baseline; restart 
at 1 dose level lower (2 capsules [i.e., 280 mg daily]) 
Fourth 
Discontinue study drug 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. To inform the potential trial 
stopping rules (DLTs as defined in section 5.10) and the secondary endpoint of grade 3 or higher toxicities, we will 
report Gr. 3 or higher toxicities irrespective of attribution and denote if these satisfy criteria for a DLT. Any other 
(i.e. < Gr. 3) AE (unless otherwise specified i.e. tumor lysis), will not be reported. In addition, we will follow the 
list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) to determine whether the event 
requires expedited reporting. 
 
7.1 
ADVERSE EVENTS AND POTENTIAL RISKS LISTS 
 
7.1.1 
OBINUTUZUMAB 
 
In monotherapy studies (BO20999 and BO21003) which included 243 patients (205 NHL, 38 CLL) thirty (79%) 
CLL and 84 (41%) NHL patients experienced Grade 3 or 4 AEs. Among CLL patients, the most frequent Grade 3 or 
4 AEs were infusion reactions (IRRs) (n=11; 29%) and neutropenia (n=13; 34%). Among NHL patients, the most 
frequent Grade 3 or 4 AEs were IRRs (n=18; 9%) followed by neutropenia (n=14; 7%) and lymphopenia (n=12; 
6%). Four (11%) CLL and 11(5%) NHL patients experienced AEs leading to withdrawal of obinutuzumab. The 
most frequent AE leading to obinutuzumab withdrawal among NHL patients was IRRs (n=3; 1%). Other events 
occurred in one patient each. Among the 4 CLL patients who experienced AEs leading to obinutuzumab 


      
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withdrawal, 3 discontinued due to IRR and 1discontinued due to interstitial lung disease. The table below (also 
Table 15 from page 98 of IB) represents the incidence of fatal AEs, Grade 3 or 4 AEs, treatment withdrawals due to 
AEs, and AEs of particular interest in monotherapy NHL/CLL studies. Another Japanese monotherapy study 
(JO21900) of 12 NHL patients had a similar toxicity profile (Table 20, IB page 93). 
 
 
Figure 2. Summary of deaths an AEs in patients with iNHL by treatment arm 
 (obinutuzumab or rituximab) Study BO1003 Phase II 
 
Percentages based on N 
a one patient in the rituximab arm died due to graft versus host disease post-transplant and is not included in this table 
b Defined based on grouped preferred terms 
c Percentages based on the number of patients with at least one AE 
 
In combination studies, obinutuzumab has been combined with CHOP, FC, and bendamustine. Deaths due to causes 
other than disease progression occurred in 5 patients in the obinutuzumab + FC arm and in 1 patient in the 
obinutuzumab + CHOP arm. Among the 5 deaths, one case (fatal PML) was considered as related to obinutuzumab. 
The other causes of death were all considered to be unrelated to obinutuzumab: Parkinson’s disease, chronic 
obstructive pulmonary disease, ascites (the patient died from the event of ascites more than 6 months after 
interruption of obinutuzumab), and cardiac arrest. The table below (IB page 106) is a summary of significant AEs in 
patients treated with combination chemo-immunotherapy. 
 


      
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7.1.1.1 
Infusion Related Reactions (IRR) 
 
The most frequently observed ADRs in patients receiving obinutuzumab were IRRs which occurred predominantly 
during infusion of the first 1000 mg. In patients who received the combined measures for prevention of IRRs 
(adequate glucocorticoid, oral analgesic/anti-histamine, omission of antihypertensive medication in the morning of 
the first infusion, and the Cycle 1 Day 1 dose administered over 2 days), a decreased incidence of all grade IRRs 
was observed. The rates of Grade 3-4 IRRs (which were based on a relatively small number of patients) were 
similar before and after mitigation measures were implemented.  
 
The incidence and severity of infusion-related symptoms decreased substantially after the first 1000 mg was 
infused, with most patients having no IRRs during subsequent administrations of obinutuzumab.  In the majority of 
patients, IRRs were mild to moderate and could be managed by the slowing or temporary halting of the first 
infusion, but severe and life-threatening IRRs requiring symptomatic treatment have also been reported. IRRs may 
be clinically indistinguishable from IgE-mediated allergic reactions (e.g. anaphylaxis). Patients with a high tumor 
burden (i.e. high peripheral lymphocyte count in CLL [> 25 x 109/L]) may be at increased risk of severe IRR. 
 
If the patient experiences an IRR, the infusion should be managed according to the grade of the reaction. For Grade 
4 IRR, the infusion must be stopped and permanently discontinued. For Grade 3 IRR, the infusion should be 
temporarily interrupted and appropriate medication administered to treat the symptoms. For Grade 1–2 IRR, the 
infusion should be slowed down and symptoms treated as appropriate. Upon resolution of symptoms, infusion can 
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experience the same adverse event with the same severity, infusion rate escalation may resume at the increments 
and intervals as appropriate for the treatment dose. If the previous infusion rate was not well tolerated, subsequent 
infusions should be adjusted per standard of care and institutional guidelines.  
 
Patients should not receive further obinutuzumab infusions if they experience: 
● acute life-threatening respiratory symptoms, 
● a Grade 4 (i.e. life threatening) IRR or, 
● a second occurrence of a Grade 3 (prolonged/recurrent) IRR (after resuming the first infusion or during a 
subsequent infusion). 
 
Patients who have pre-existing cardiac or pulmonary conditions should be monitored carefully throughout the 
infusion and the post-infusion period. Hypotension may occur during obinutuzumab intravenous infusions. 
Therefore, withholding of antihypertensive treatments should be considered for 12 hours prior to, and throughout, 
each obinutuzumab infusion and for the first hour after administration. Patients at acute risk of hypertensive crisis 
should be evaluated for the benefits and risks of withholding their anti-hypertensive medication. 
 
7.1.1.2 
Hypersensitivity Reactions including Anaphylaxis 
 
Hypersensitivity may be difficult to distinguish from infusion related reactions; however, anaphylaxis has been 
reported in patients treated with obinutuzumab. If a hypersensitivity reaction is suspected during infusion (e.g. 
symptoms typically occurring after previous exposure and very rarely with the first infusion), the infusion should be 
stopped and treatment permanently discontinued. Patients with known IgE mediated hypersensitivity to 
obinutuzumab must not be treated (refer to IB Section 6.2 Contraindications). 
 
7.1.1.3 
Tumor Lysis Syndrome (TLS) 
 
Tumor lysis syndrome (TLS), including fatal TLS, has been reported with obinutuzumab. Patients who are 
considered to be at risk of TLS [e.g. patients with a high tumor burden or a high circulating lymphocyte count (> 25 
x 109/L)] should receive adequate tumor lysis prophylaxis with uricostatics (e.g. allopurinol or adequate alternative) 
and hydration starting 12-24 hours prior to the infusion of obinutuzumab. For treatment of TLS, correct electrolyte 
abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as 
indicated. 
 
7.1.1.4 
Neutropenia 
 
Severe and life threatening neutropenia including febrile neutropenia has been reported during treatment with 
obinutuzumab. Patients who experience neutropenia should be closely monitored with regular laboratory tests until 
resolution. If treatment is necessary, it should be administered in accordance with local guidelines and 
administration of granulocyte colony-stimulating factors should be considered. Any signs of concomitant infection 
should be treated as appropriate. Cases of late onset neutropenia (occurring 28 days after the end of treatment) or 
prolonged neutropenia (lasting more than 28 days after treatment has been completed/stopped) have also been 
reported. 
 
7.1.1.5 
Thrombocytopenia 
 
Severe and life threatening thrombocytopenia including acute thrombocytopenia (occurring within 24 hours after 
the infusion) has been observed during treatment with obinutuzumab. Fatal hemorrhagic events have also been 
reported in Cycle 1 in patients treated with obinutuzumab. 
 
Patients should be closely monitored for thrombocytopenia, especially during the first cycle; regular laboratory tests 
should be performed until the event resolves, and dose delays should be considered in case of severe or life-
threatening thrombocytopenia. Transfusion of blood products (i.e., platelet transfusion) according to institutional 
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thrombocytopenia related events such as platelet inhibitors and anticoagulants, should also be taken into 
consideration, especially during the first cycle. 
 
7.1.1.6 
Worsening of Pre-existing Cardiac Conditions 
 
In patients with underlying cardiac disease, arrhythmias (such as atrial fibrillation and tachyarrhythmia), angina 
pectoris, acute coronary syndrome, myocardial infarction and heart failure have occurred when treated with 
obinutuzumab. These events may occur as part of an IRR and can be fatal. Therefore, patients with a history of 
cardiac disease should be monitored closely. In addition, these patients should be hydrated with caution in order to 
prevent a potential fluid overload. 
 
7.1.1.7 
Infections 
 
Obinutuzumab should not be administered in the presence of an active infection and caution should be exercised 
when considering the use of obinutuzumab in patients with a history of recurring or chronic infections. Serious, 
bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of 
obinutuzumab therapy. Fatal infections have been reported. 
 
7.1.1.8 
Hepatitis B reactivation 
 
Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can 
occur in patients treated with anti-CD20 antibodies including obinutuzumab (refer to IB). 
 
Hepatitis B virus (HBV) screening should be performed in all patients before initiation of treatment with 
obinutuzumab. At minimum this should include HBsAg-status and HBcAb- status. These can be complemented 
with other appropriate markers as per local guidelines. Patients with active Hepatitis B disease should not be treated 
with obinutuzumab. Patients with positive hepatitis B serology should consult liver disease experts before start of 
treatment and should be monitored and managed following local medical standards to prevent hepatitis reactivation. 
Please refer to respective protocols for detailed guidance on this subject. 
 
7.1.1.9 
Progressive multifocal leukoencephalopathy (PML) 
 
PML has been reported in patients treated with obinutuzumab. The diagnosis of PML should be considered in any 
patient presenting with new-onset or changes to pre- existing neurologic manifestations. The symptoms of PML are 
unspecific and can vary depending on the affected region of the brain. Motor symptoms with corticospinal tract 
findings (e.g. muscular weakness, paralysis, and sensory disturbances), sensory abnormalities, cerebellar symptoms, 
and visual field defects are common. Some signs/symptoms regarded as “cortical” (e.g. aphasia or visual-spatial 
disorientation) may occur. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain 
MRI, and lumbar puncture (cerebrospinal fluid testing for JCV DNA). Therapy with obinutuzumab should be 
withheld during the investigation of potential PML and permanently discontinued in case of confirmed PML. 
Discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy should also be 
considered. The patient should be referred to a neurologist for the evaluation and treatment of PML. 
 
7.1.1.10 
Immunization 
 
The safety of immunization with live or attenuated viral vaccines, following obinutuzumab therapy has not been 
studied and vaccination with live virus vaccines is not recommended during treatment and until B-cell recovery. 
 
7.1.1.11 
The Obinutuzumab Adverse Events of Special Interest (AESIS) 
 
AESIs are a subset of Events to Monitor (EtMs) of scientific and medical concern specific to the product, for which 
ongoing monitoring and rapid communication by the Investigator to the Sponsor is required. Such an event might 
require further investigation in order to characterize and understand it. Depending on the nature of the event, rapid 


      
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communication by the trial Sponsor to other parties (e.g., Regulatory Authorities) may also be warranted. 
 
 
 
The Obinutuzumab Events of Special Interest are: 
o All TLS (irrespective of seriousness, causality or severity): 
o Secondary Malignancies    
 
 
Adverse events of special interest for this study include the following: 
o Cases of potential drug-induced liver injury that include an elevated ALT or AST in combination 
with either an elevated bilirubin or clinical jaundice, as defined by Hy’s law: 
 Treatment-emergent ALT or AST  3  ULN in combination with total bilirubin  2  ULN 
 Treatment-emergent ALT or AST  3  ULN in combination with clinical jaundice 
o Data related to a suspected transmission of an infectious agent by the study drug (STIAMP), as 
defined below: 
 Any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible 
spongiform encephalopathy), pathogenic or non-pathogenic, is considered an infectious agent.  
A transmission of an infectious agent may be suspected from clinical symptoms or laboratory 
findings that indicate an infection in a patient exposed to a medicinal product.  This term 
applies only when a contamination of the study drug is suspected 


      
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Figure 4. Summary of Deaths and AEs (Pooled Studies BO20999 and BO21003 Phase I/II) 
Excerpted from Table 31 of IB 


      
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7.2 
IBRUTINIB 
 
Refer to Ibrutinib Package Insert/prescribing information for additional details. 
 
To date, the most common adverse events seen with ibrutinib as a single agent include diarrhea, fatigue, nausea, 
cough, and peripheral edema. Grade 3 or higher adverse events were experienced by include neutropenia, 
thrombocytopenia, and anemia. Pneumonia was the most frequent nonhematologic Grade 3 or higher adverse event. 
The only serious events occurring in more than 2% of subjects were pneumonia, atrial fibrillation, and febrile 
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Combination studies with chemotherapy including bendamustine plus rituximab, fludarabine with rituximab, R-
CHOP plus ibrutinib, as well as ofatumumab plus ibrutinib have also been reported. For these combination studies, 
the ibrutinib related toxicity profile was similar to that seen with single agent ibrutinib with diarrhea and nausea 
being the most frequent events followed by myelosuppression including neutropenia, anemia, and 
thrombocytopenia. The most common Grade 3 or higher adverse events in these combination studies were 
neutropenia, anemia, and thrombocytopenia, febrile neutropenia, and pneumonia. 
 
Additional toxicities attributable to ibrutinib include atrial fibrillation as well as hemorrhagic AEs. The majority of 
the hemorrhagic adverse events were of Grade 1 or 2 in severity and include epistaxis and petechiae. Grade 3 or 
higher hemorrhagic AEs occurred at a low frequency (< 5%). Accordingly, although it is not entirely clear if this 
risk is due to ibrutinib, treatment with anticoagulants and anti-platelets must be evaluated closely. 
 
Significant potential toxicities as defined by the package insert as captured by Lexicomp© are shown below. 
 
Incidences combined for mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) unless otherwise 
specified. 
 
7.2.1 
IBRUTINIB AE OCCURRING >10%: 
 
Cardiovascular: Peripheral edema (MCL: 35%, CLL: 23%), hypertension (CLL: 17%) 
Central nervous system:  Fatigue (MCL:  41%, CLL:  31%), dizziness (14% to 21%), headache (13% to 19%), chills 
(CLL: 13%) 
Dermatologic: Skin rash (25% to 27%), skin infection (14% to 17%) 
Endocrine & metabolic: Increased uric acid (38% to 40%; hyperuricemia >10 mg/dL:  MCL 13%, CLL 4%), 
dehydration (MCL: 12%) 
Gastrointestinal: Diarrhea (CLL:  63%, MCL:  51%), nausea (MCL:  31%, CLL: 21%), constipation (23% to 25%), 
abdominal pain (MCL: 24%, CLL: 15%), vomiting (19% to 23%), decreased appetite (17% to 21%), stomatitis 
(17% to 21%), dyspepsia (11% to 13%) 
Genitourinary: Urinary tract infection (10% to 14%) 
Hematologic & oncologic: Decreased platelet count (CLL: 71%, MCL: 57%; grades 3/4: 10% to 17%), bruise 
(CLL: 54% to 63%, MCL: 30% to 48%), neutropenia (47% to   54%; grades 3/4: 27% to 29%), decreased 
hemoglobin (41% to 44%; grades 3/4 MCL: 9%), petechia (11% to 17%) 
Infection: Infection (grades 3/4: CLL 35%, MCL ≥25%) 
Neuromuscular & skeletal: Musculoskeletal pain (MCL: 37%, CLL: 27%), arthralgia (CLL: 23%, MCL: 11%), 
muscle spasm (14% to 19%), weakness (13% to 14%) 
Renal: Increased serum creatinine (≤1.5 x ULN: MCL 67%, CLL 23%; 1.5 to 3 x ULN: 4% to 9%) 
Respiratory: Upper respiratory tract infection (CLL: 48%, MCL: 34%), dyspnea (MCL: 27%, CLL: 10%), sinusitis 
(13% to 21%), cough (19%), oropharyngeal pain (CLL:  15%), pneumonia (10% to 14%), epistaxis (MCL: 11%) 
Miscellaneous: Fever (18% to 25%) 
 
7.2.2 
IBRUTINIB AE OCCURRING 1% TO 10%: 
 
Cardiovascular: Atrial fibrillation (≥5%) 
Central nervous system: Anxiety (CLL: 10%), insomnia (CLL: 10%), peripheral neuropathy (CLL: 10%) 
Hematologic & oncologic: Malignant neoplasm (secondary; 5% to 10%; includes one death due to histiocytic 
sarcoma), anemia (MCL; grades 3/4: 9%), malignant neoplasm of skin (4% to 8%), hemorrhage (5% to 6%; grade 3 
or higher bleeding events including subdural hematoma, ecchymosis, gastrointestinal bleeding, and hematuria), 
other carcinomas (1% to 2%) 
Miscellaneous: Laceration (CLL: 10%) 
 
 
 


      
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7.3 
ADVERSE EVENT CHARACTERISTICS 
 
CTCAE term (AE description) and grade: The descriptions and grading scales found in the current NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. All 
appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 
5.0 can be downloaded from the CTEP web site. 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
Below Table should be used for assessing severity for adverse events that are not specifically listed in the NCI 
CTCAE 
 
Adverse Event Severity Grading Scale for Events Not Specifically Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or 
limiting age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
or limiting self-care activities of daily living b,c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse 
Events. 
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a. Instrumental activities of daily living refer to preparing meals, shopping for 
groceries or clothes, using the telephone, managing money, etc. 
b. Examples of self-care activities of daily living include bathing, dressing and 
undressing, feeding oneself, using the toilet, and taking medications, as 
performed by patients who are not bedridden. 
c. If an event is assessed as a "significant medical event," it must be reported as a 
serious adverse event  
d. Grade 4 and 5 events must be reported as serious adverse events  
 
 
Expectedness: Adverse Events can be ‘Unexpected’ or ‘Expected.’ Please see section 8.2.5 for definitions of 
Expectedness.  
 
7.4 
ATTRIBUTION OF THE AE 
● Definite – the AE is clearly related to the study treatment. 
● Probable – the AE is likely related to the study treatment. 
● Possible – the AE may be related to the study treatment. 
● Unlikely – the AE is unlikely related to the study treatment, but a causal relation cannot be completely 
excluded. 
● Unrelated – the AE is clearly NOT related to the study treatment. 
 
 
 


      
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7.5 
OHSU IRB REPORTING OF UNANTICIPATED PROBLEMS AND ADVERSE EVENTS  
 
Unanticipated Problems (UP) and Adverse Events (AE) will be reported to OHSU IRB according to the policies, 
procedures and guidelines posted on the OHSU IRB web site  
 
All UP reports, including fatal and life-threatening events, must be reported to OHSU IRB within 5 business days 
after the PI learns of the event. If any of these require a change (as determined by the PI or the IRB) to the protocol 
or consent form, the PI will make those changes promptly and submit the revised documents to the OHSU IRB. 
 
UP and AE reports are submitted through OHSU e- IRB and will be reviewed by OHSU IRB. 
 
7.6 
CENTRAL REPORTING OF ADVERSE EVENTS FOR MULTICENTER STUDIES:  
 
The SAE/Unanticipated Problem reporting for multicenter investigator initiated clinical trials will follow the 
guidelines outlined in the OHSU Knight Cancer Institute Multi-Center Investigator Initiated Trials Coordinating 
Center Operations Manual.  
 
 
A participating site must report an SAE to the to the institution’s local IRB for action as required, as well as to the 
OHSU coordinating center study team by phone, fax, or email within 24 hours of learning of the event. The 
participating center will send the coordinating center materials regarding the SAE by completing and submitting 
FDA Form 3500, Voluntary reporting form as referenced in Section 7.5. The participating site should submit the 
following to OHSU to report an SAE: 
 
● Redacted .pdf of submitted FDA Form 3500 
● Investigator’s judgment of attribution to study drug, obinutuzumab and/or study-driven procedures (should 
be included in form 3500A at time of report) 
● CTCAE grade and name of the event (should be included in Form 3500A at time of report), 
● Whether the investigator believes the event to be expected or unexpected based on the known risks of study 
drug and obinutuzumab 
● Indication of whether the event will require follow up/ongoing 
● All relevant source documentation related to the event, redacted 
 
The OHSU coordinating center study team will review and submit SAEs to the FDA, OHSU IRB, and any other 
required contacts as required by the Knight Cancer Institute’s Data Safety and Monitoring Plan. The principal 
investigator at the Coordinating Center is responsible for distributing IND and/or IDE Action Letters or Safety 
Reports, as applicable, to participating institutions for review and submission to their institution’s local IRB. 
 
And Oregon Health and Science University will be responsible for the distribution of safety information to Site 
IRB: 
 
 
OHSU Institutional Review Board 
3181 SW Sam Jackson Park Rd. 
L106-RI 
Portland, OR 97239 
Phone# 503-494-7887 
 
 
7.7 
MEDWATCH REPORTING 
 
For this investigator-initiated study, the investigator is the study sponsor. The investigator/sponsor is required to 
report adverse experiences to the FDA through the MedWatch reporting program, even if the trial involves a 
commercially available agent. Adverse experiences to be reported include any unexpected (not listed in the package 


      
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label), serious adverse experiences with a suspected association to the study drug. 
 
Adverse events that occur during clinical studies are to be reported to FDA as specified in the investigational new 
drug/biologic regulations using the Form FDA 3500A MedWatch for Mandatory reporting. Please refer to section 
8.5 for MedWatch reporting guidelines  
 
When the serious adverse event is reported to the FDA, copies of the Form FDA 3500A MedWatch and supporting 
materials will be submitted to the OHSU Knight Cancer Institute and the IRB. A copy of the Form FDA 3500A 
MedWatch and supporting materials will be kept on file in the study regulatory binder. 
 
7.8 
REPORTING OF ADVERSE EVENTS TO GENENTECH 
 
Obinutuzumab, as well as funding/support for this study is provided by Genentech.  As such, additional reporting 
requirements are required as described in Section 8. Adverse events attributed as probable, possible and unlikely 
may generate queries to confirm causality and/or requests for additional information from the site. 
 
8. REPORTING OF ADVERSE EVENTS 
 
8.1 
ASSESSMENT OF SAFETY 
 
8.1.1 
SPECIFICATION OF SAFETY VARIABLES 
 
Safety assessments will consist of monitoring and reporting adverse events (AEs) and serious adverse events 
(SAEs) that are considered related to obinutuzumab per protocol, all events of death, and any study specific issue of 
concern. 
 
8.1.2 
ADVERSE EVENTS 
 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an 
investigational medicinal product (IMP) or other protocol- imposed intervention, regardless of attribution. 
 
This includes the following: 
 
AEs not previously observed in the patient that emerge during the protocol-specified AE reporting period, 
including signs or symptoms associated with Mantle Cell Lymphoma that were not present prior to the AE 
reporting period. 
 
Complications that occur as a result of protocol-mandated interventions (e.g., invasive procedures such as 
cardiac catheterizations). 
 
If applicable, AEs that occur prior to assignment of study treatment associated with medication washout, no 
treatment run-in, or other protocol-mandated intervention. 
 
Preexisting medical conditions (other than the condition being studied) judged by the investigator to have 
worsened in severity or frequency or changed in character during the protocol-specified AE reporting 
period. 
 
8.1.3 
SERIOUS ADVERSE EVENTS 
 
An AE should be classified as an SAE if the following criteria are met: 
 
It results in death (i.e., the AE actually causes or leads to death). 
 
It is life threatening (i.e., the AE, in the view of the investigator, places the patient at immediate risk of 
death. It does not include an AE that, had it occurred in a more severe form, might have caused death.). 
 
It requires or prolongs inpatient hospitalization. 
 
It results in persistent or significant disability/incapacity (i.e., the AE results in substantial disruption of the 
patient’s ability to conduct normal life functions). 
 
It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. 


      
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 
It is considered a significant medical event by the investigator based on medical judgment (e.g., may 
jeopardize the patient or may require medical/surgical intervention to prevent one of the outcomes listed 
above). 
 
8.1.4 
METHODS AND TIMING FOR ASSESSING AND RECORDING SAFETY VARIABLES 
 
The investigator is responsible for ensuring that all AEs and SAEs, that are observed or reported during the study, 
are collected and reported to the U.S. Food and Drug Administration (FDA), appropriate IRB(s), and Genentech, 
Inc. in accordance with CFR 312.32 (IND Safety Reports). 
 
8.1.5 
ADVERSE EVENT REPORTING PERIOD 
 
The study period during which AEs and SAEs must be reported begins after informed consent is obtained and 
initiation of study treatment and ends 30 days following the last administration of study treatment or study 
discontinuation/termination, whichever is earlier. After this period, investigators should only report SAEs that are 
attributed to prior study treatment. 
 
 
8.1.6 
ASSESSMENT OF ADVERSE EVENTS 
 
All AEs and SAEs whether volunteered by the patient, discovered by study personnel during questioning, or 
detected through physical examination, laboratory test, or other means will be reported appropriately. Each reported 
AE or SAE will be described by its duration (i.e., start and end dates), regulatory seriousness criteria if applicable, 
suspected relationship to the obinutuzumab and/or ibrutinib (see following guidance), and actions taken. 
 
To ensure consistency of AE and SAE causality assessments, investigators should apply the general guidelines in 
sections 8.1.7 and 8.1.8. 
 
8.1.7 
AES ATTRIBUTED TO OBINUTUZUMAB OR IBRUTINIB 
 
There is a plausible temporal relationship between the onset of the AE and administration of obinutuzumab or 
ibrutinib, and the AE cannot be readily explained by the patient’s clinical state, intercurrent illness, or concomitant 
therapies; and/or the AE follows a known pattern of response to the obinutuzumab or ibrutinib: and/or the AE 
abates or resolves upon discontinuation of the obinutuzumab or ibrutinib or dose reduction and, if applicable, 
reappears upon re-challenge. 
 
8.1.8 
AES NOT ATTRIBUTED TO OBINUTUZUMAB OR IBRUTINIB 
 
Evidence exists that the AE has an etiology other than the obinutuzumab or ibrutinib (e.g., preexisting medical 
condition, underlying disease, intercurrent illness, or concomitant medication); and/or the AE has no plausible 
temporal relationship to obinutuzumab or ibrutinib (e.g., cancer diagnosed 2 days after first dose of study drug). 
 
8.1.9 
EXPECTED AND UNEXPECTED AES 
 
Expected AEs are those AEs that are listed or characterized in the package insert or current IB. 
 
Unexpected AEs are those not listed in the package insert or current Investigator’s Brochure or not identified. This 
includes AEs for which the specificity or severity is not consistent with the description in the package insert or IB. 
For example, under this definition, hepatic necrosis would be unexpected if the package insert or IB only referred to 
elevated hepatic enzymes or hepatitis. 
 
For patients receiving combination therapy, causality will be assessed individually for each protocol-mandated 
therapy. 


      
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8.2 
PROCEDURES FOR ELICITING, RECORDING, AND REPORTING ADVERSE EVENTS 
 
8.2.1 
ELICITING ADVERSE EVENTS 
A consistent methodology for eliciting AEs at all evaluation time points should be adopted. Examples of non-
directive questions include: 
● “How have you felt since your last clinical visit?” 
● “Have you had any new or changed health problems since you were last here?” 
 
8.2.2 
SPECIFIC INSTRUCTIONS FOR RECORDING ADVERSE EVENTS 
 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs.  Avoid colloquialisms 
and abbreviations. 
 
8.2.2.1 
Diagnosis versus Signs and Symptoms 
 
If known at the time of reporting, a diagnosis should be reported rather than individual signs and symptoms (e.g., 
record only liver failure or hepatitis rather than jaundice, asterixis, and elevated transaminases). However, if a 
constellation of signs and/or symptoms cannot be medically characterized as a single diagnosis or syndrome at the 
time of reporting, it is acceptable to report the information that is currently available. If a diagnosis is subsequently 
established, it should be reported as follow-up information. 
 
8.2.2.2 
Deaths 
 
All deaths that occur during the protocol-specified AE reporting period, regardless of attribution, will be reported to 
the appropriate parties.  When recording a death, the event or condition that caused or contributed to the fatal 
outcome should be reported as the single medical concept. If the cause of death is unknown and cannot be 
ascertained at the time of reporting, report “Unexplained Death”. 
 
8.2.2.3 
Preexisting Medical Conditions 
 
A preexisting medical condition is one that is present at the start of the study. Such conditions should be reported as 
medical and surgical history. A preexisting medical condition should be re-assessed throughout the trial and 
reported as an AE or SAE only if the frequency, severity, or character of the condition worsens during the study. 
When reporting such events, it is important to convey the concept that the preexisting condition has changed by 
including applicable descriptors (e.g., “more frequent headaches”). 
 
8.2.2.4 
Hospitalizations for Medical or Surgical Procedures 
 
Any AE that results in hospitalization or prolonged hospitalization should be documented and reported as an SAE. 
If a patient is hospitalized to undergo a medical or surgical procedure as a result of an AE, the event responsible for 
the procedure, not the procedure itself, should be reported as the SAE. For example, if a patient is hospitalized to 
undergo coronary bypass surgery, record the heart condition that necessitated the bypass as the SAE. 
 
Hospitalizations for the following reasons do not require reporting: 
● Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for preexisting 
conditions, 
● Hospitalization or prolonged hospitalization required to allow efficacy measurement for the study, or 
● Hospitalization or prolonged hospitalization for scheduled therapy of the target disease of the study. 
 


      
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8.2.2.5 
Pregnancy 
 
If a female patient becomes pregnant while receiving obinutuzumab or within 18 months after the last dose of 
obinutuzumab, or the partner of a male patient becomes pregnant while receiving therapy or within three months of 
completing therapy, a report should be completed and expeditiously submitted to the Genentech, Inc. Follow-up to 
obtain the outcome of the pregnancy should also occur. Abortion, whether accidental, therapeutic, or spontaneous, 
should always be classified as serious, and expeditiously reported as an SAE. Similarly, any congenital 
anomaly/birth defect in a child born to a female patient exposed to obinutuzumab should be reported as an SAE. 
 
8.2.2.6 
Post-Study Adverse Events 
 
For studies involving extended follow up period, the investigator should report all deaths, (regardless of cause), and 
any serious adverse event including development of cancer or a congenital anomaly in a subsequently conceived 
offspring of a female subject [including pregnancy occurring in the partner of a male study subject] who 
participated in the study that is believed to be related to prior exposure to obinutuzumab, after the end of the adverse 
event reporting period (defined as 30 days after the last dose of obinutuzumab). 
 
Case Transmission Verification will be performed by both parties during this period to ensure successful 
transmission of Single case reports  
 
 
8.2.2.7 
Case Transmission Verification of Single Case Reports   
 
The Sponsor agrees to conduct the Case Transmission verification to ensure that all single case reports have been 
adequately received by Genentech via Oregon Health and Science University emailing Genentech a Quarterly line-
listing documenting single case reports sent by Oregon Health and Science University to Genentech in the preceding 
time period.  
 
The periodic line-listing will be exchanged within seven (7) calendar days of the end of the agreed time period. 
Confirmation of receipt should be received within the time period mutually agreed upon. 
                    
If discrepancies are identified, the Sponsor and Genentech will cooperate in resolving the discrepancies. The 
responsible individuals for each party shall handle the matter on a case-by-case basis until satisfactory resolution.  
The sponsor shall receive reconciliation guidance documents within the ‘Activation Package’. 
 
Following Case Transmission Verification, single case reports which have not been received by Genentech shall be 
forwarded by Oregon Health and Science University to Genentech within five (5) calendar days from request by 
Genentech. 
 
At the end of the study, a final cumulative Case Transmission Verification report will be sent to Genentech. 
 
 
8.2.2.8 
EXGHANGE OF SINGLE CASE REPORTS   
 
Oregon Health and Science University will be responsible for collecting all protocol-defined Adverse Events (AEs), 
Special Situation Reports (including pregnancy reports) and Product Complaints originating from the Study for the 
Product.  
 
The completed MedWatch form or Genentech approved reporting forms should be faxed/emailed immediately upon 
completion to Genentech at the following contacts: 
 
All protocol-defined AEs, SAEs, AESIs, Special Situation Reports (including pregnancy reports) and Product 
Complaints with an AE should be sent to: 
 


      
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Fax: 650-238-6067 
Email: usds_aereporting-d@gene.com 
 
 
All Product Complaints without an AE should be sent to: 
 
Email: kaiseraugst.global_impcomplaint_management@roche.com 
 
It is understood and agreed that the Sponsor will be responsible for the evaluation of AEs/SAEs, AESIs, Special 
Situation Reports (including pregnancy reports) and Product Complaints (with or without an AE) originating from 
the study.  
 
These single case reports will be exchanged between the parties as outlined below so that regulatory obligations are 
met. 
 
Serious adverse events (SAEs), AEs of Special Interest (AESIs), pregnancy reports (including pregnancy occurring 
in the partner of a male study subject), other Special Situation Reports and Product Complaints (with or without an 
AE), where the patient has been exposed to the Genentech Product, will be sent on a MedWatch form or CIOMS I 
form or on Genentech approved reporting forms to Genentech Drug Safety  
 
Transmission of these reports (initial and follow-up) will be either electronically or by fax and within the timelines 
specified below: 
 
 
SADR: 
Serious AE reports that are related to obinutuzumab shall be transmitted to Genentech within 15 calendar days of 
the awareness Date. 
 
Other SAEs 
Serious AE reports that are unrelated to the Product shall be transmitted to Genentech within thirty (30) calendar 
days of the awareness date. 
 
AESIs 
AESIs shall be forwarded to Genentech within fifteen (15) calendar days of the awareness date. 
 
Special Situation Reports 
 
Pregnancy reports 
While such reports are not serious AEs or Adverse Drug Reactions (ADRs) per se, as defined herein, any reports 
of pregnancy (including pregnancy occurring in the partner of a male study subject), where the fetus may have 
been exposed to the Product, shall be transmitted to Genentech within thirty (30) calendar days of the awareness date. 
Pregnancies will be followed up until the outcome of the pregnancy is known, whenever possible, based upon due 
diligence taken to obtain the follow-up information. 
 
Pregnancies in Female Partners of Male Patients  
Male patients will be instructed through the Informed Consent Form to immediately inform the investigator if their 
partner becomes pregnant during the study or within 180 days after the last dose of study drug.  A Clinical Trial 
Pregnancy Reporting Form should be completed and submitted to Genentech within thirty (30) calendar days of the 
awareness date. 
 
 
OTHER REPORTS 
 
OHSU will forward a copy of the Final Study Report to Genentech upon completion of the Study. 
      


      
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8.3 
OTHER SPECIAL SITUATION REPORTS  
 
 
In addition to all SAEs, pregnancy reports and AESIs, the following other Special Situations Reports should be 
collected even in the absence of an Adverse Event and transmitted to Genentech within thirty (30) calendar days: 
 
Data related to the product usage during breastfeeding 
 
Data related to overdose, abuse, misuse or medication error (including potentially exposed or intercepted 
medication errors) 
 In addition, reasonable attempts should be made to obtain and submit the age or age group of the patient, 
in order to be able to identify potential safety signals specific to a particular population 
 
 
Product Complaints  
All Product Complaints (with or without an AE) shall be forwarded to Genentech within fifteen (15) 
calendar days of the awareness date. 
 
A Product Complaint is defined as any written or oral information received from a complainant that alleges 
deficiencies related to identity, quality, safety, strength, purity, reliability, durability, effectiveness, or 
performance of a product after it has been released and distributed to the commercial market or clinical 
trial. 
 
 
 
8.4 
MEDWATCH 3500A  REPORTING GUIDELINES 
 
In addition to completing appropriate patient demographic (Section A) and suspect medication information (Section 
C & D), the report should include the following information within the Event Description (Section B.5) of the 
MedWatch 3500A form: 
 
 
Protocol number and title description  
 
Description of event, severity, treatment, and outcome if known 
 
Supportive laboratory results and diagnostics (Section B.6) 
Investigator’s assessment of the relationship of the adverse event to each investigational product and suspect 
medication 
 
 
8.4.1 
FOLLOW-UP INFORMATION 
 
Additional information may be added to a previously submitted report by any of the following methods: 
● Adding to the original MedWatch 3500A report and submitting it as follow-up 
● Adding supplemental summary information and submitting it as follow-up with the original MedWatch 
3500A form 
● Summarizing new information and faxing it with a cover letter including patient identifiers (i.e. D.O.B. 
initial, patient number), protocol description and number, if assigned, brief adverse event description, and 
notation that additional or follow-up information is being submitted (The patient identifiers are important 
so that the new information is added to the correct initial report) 
 
 
MedWatch 3500A (Mandatory Reporting) form is available at https://www.fda.gov/media/69876/download 
 
 
 
 


      
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8.5.2     Additional Reporting Requirements for IND Holders:  
 
For Investigator-Initiated IND Studies, some additional reporting requirements for the FDA apply in accordance 
with the guidance set forth in 21 CFR §600.80. 
 
Events meeting the following criteria need to be submitted to the Food and Drug Administration (FDA) as expedited 
IND Safety Reports according to the following guidance and timelines: 
  
7 Calendar Day Telephone or Fax Report: 
 
The Investigator is required to notify the FDA of any fatal or life-threatening adverse event that is unexpected and 
assessed by the Investigator to be possibly related to the use of obinutuzumab. An unexpected adverse event is one 
that is not already described in the obinutuzumab Investigator Brochure. Such reports are to be telephoned or faxed to 
the FDA and Genentech within 7 calendar days of first learning of the event. 
 
 
15 Calendar Day Written Report 
 
The Investigator is also required to notify the FDA and all participating investigators, in a written IND Safety 
Report, of any serious, unexpected AE that is considered reasonably or possibly related to the use of obinutuzumab. 
An unexpected adverse event is one that is not already described in the obinutuzumab investigator brochure. 
 
Written IND Safety reports should include an Analysis of Similar Events in accordance with regulation 21 CFR 
§ 312.32. All safety reports previously filed by the investigator with the IND concerning similar events should be 
analyzed and the significance of the new report in light of the previous, similar reports commented on. 
 
Written IND safety reports with Analysis of Similar Events are to be submitted to the FDA, Genentech, and all 
participating investigators within 15 calendar days of first learning of the event. The FDA prefers these reports on a 
MedWatch 3500 form, but alternative formats are acceptable (e.g., summary letter). 
 
 
FDA fax number for IND Safety Reports: 
 
Fax: 1 (800) FDA 0178 
 
 
All written IND Safety Reports submitted to the FDA by the Investigator must also be faxed to Genentech 
Drug Safety: 
 
Fax: (650) 225-4682 or (650) 225-4630 
 
 
For questions related to safety reporting, please contact Genentech Drug Safety: 
 
Tel: (888) 835-2555 
Fax: (650) 225-4682 or (650) 225-4630 
 
AGGREGATE REPORTS 
 
All IND annual reports submitted to the FDA by the Sponsor-Investigator should be copied to Genentech.  
 
Copies of such reports should be emailed to Genentech at:   
 
Genentech Drug Safety CTV mail box: ctvist_drugsafety@gene.com 
 


      
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REPORTING TO REGULATORY AUTHORITIES, ETHICS COMMITTEES AND INVESTIGATORS  
 
Oregon Health and Science University, as the Sponsor of the Study, will be responsible for the expedited reporting 
of safety reports originating from the Study to the Regulatory Authorities (FDA) where it has filed a clinical trial 
approval, in compliance with local regulations. 
 
 
Oregon Health and Science University, as the Sponsor of the Study, will be responsible for the expedited reporting 
of safety reports originating from the study to the EMA through Eudravigilance Clinical Trial Module (EVCTM), 
where applicable.  
 
Oregon Health and Science University will be responsible for the expedited reporting of safety reports originating 
from the Study to the Ethics Committees and Institutional Review Boards (IRB), where applicable. 
 
Oregon Health and Science University will be responsible for the distribution of safety information to its own 
investigators, where relevant, in accordance with local regulations. 
 
 
8.5 
STUDY CLOSE-OUT 
 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to Genentech. This includes 
all IND annual reports and the Clinical Study Report (final study report). Additionally, any literature articles that are 
a result of the study should be sent to Genentech. Copies of such reports should be mailed to the assigned Clinical 
Operations contact for the study: 
 
Obinutuzumab (GA101) Protocols Email: ga101-gsur@gene.com Fax: 866-706-3927 
 
And to Genentech Drug Safety CTV oversight mail box at: ctvist_drugsafety@gene.com 
 
 
8.7        QUERIES 
 
Queries related to the Study will be answered by Oregon Health and Science University. However, responses to all 
safety queries from regulatory authorities or for publications will be discussed and coordinated between the Parties. 
The Parties agree that Genentech shall have the final say and control over safety queries relating to the Product. 
Oregon Health and Science University agrees that it shall not answer such queries from regulatory authorities and 
other sources relating to the Product independently but shall redirect such queries to Genentech. 
 
Both Parties will use all reasonable effort to ensure that deadlines for responses to urgent requests for information or 
review of data are met. The Parties will clearly indicate on the request the reason for urgency and the date by which a 
response is required. 
 
8.8         SAFETY CRISIS MANAGEMENT 
 
In case of a safety crisis, e.g., where safety issues have a potential impact on the indication(s), on the conduct of the 
Study, may lead to labeling changes or regulatory actions that limit or restrict the way in which the Product is used, 
or where there is media involvement, the Party where the crisis originates will contact the other Party as soon as 
possible. 
 
The Parties agree that Genentech shall have the final say and control over safety crisis management issues relating 
to the Product. Oregon Health and Science University agrees that it shall not answer such queries from media and 
other sources relating to the Product but shall redirect such queries to Genentech. 


      
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9. PHARMACEUTICAL AND/OR IMAGING AGENT INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or commercial agents 
administered in this study can be found in Section 7.1. 
 
9.1 
AGENT ACCOUNTABILITY 
 
The Investigator, or a responsible party designated by the Investigator, must maintain a careful record of the 
inventory and disposition of the study agent.  In the case of this study which uses an FDA approved standard of care 
oral agent that is sent to the patient, we will aim to follow the guidelines as outlined in section 15.3 of the NCI 
investigator handbook. “Verification of Compliance” 
(https://ctep.cancer.gov/investigatorResources/docs/InvestigatorHandbook.pdf). Of note, in this setting it is 
recognized that for a SOC medication may be difficult and/or impractical to do an actual study drug inventory. 
Thus, we will document patient reporting of compliance with taking ibrutinib with the patient’s drug diary. 
 
 
9.1.1 
OBINUTUZUMAB 
 
9.1.1.1 
Availability 
 
Obinutuzumab is supplied to investigators by Genentech (South San Francisco, CA) 
 
9.1.1.2 
Product description 
 
Obinutuzumab is provided as a single 1000 mg dose liquid concentrate with a strength of 25 mg/mL. It is supplied 
in 50 mL glass vials containing 40 mL of the 25 mg/mL liquid concentrate. In addition to the antibody, the liquid 
also contains histidine/histidine-HCl, trehalose, poloxamer 188 and highly purified water (HPW). 
 
9.1.1.3 
Storage requirements 
 
The recommended storage conditions for obinutuzumab drug product are between 2°C and 8°C, protected from 
light. For clinical formulation-specific and batch-specific instructions, and information on in-use stability, see the 
packaging label. 
 
9.1.1.4 
Stability 
 
Stable in Normal Saline 
 
9.1.1.5 
Route of administration 
 
Infusion as noted in Section 5.1.1 
 
9.1.2 
IBRUTINIB 
 
Ibrutinib will be provided per standard of care (as a commercial agent). Details of its administration are listed in 
Section 5.1. 
 
10. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
Details and background regarding correlative studies are described in Section 2.4. Correlative studies include Gene 
Expression Profiling using the nanostring platform, sequencing of specific lymphoid genes using the ion torrent 
platform, BTK and PLCγ mutations, and MRD testing using flow cytometry and next generation sequencing. 


      
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In order to participate in this study, all subjects must agree to assessment of tumor tissues for correlatives. Every 
attempt should be made to obtain tissue immediately prior to on study treatment. However, in the event fresh tissue 
is not available, archival tissue may be used. Additional biopsies to assess for mechanisms of resistance should be 
obtained at the time of disease progression. Tissue sources can include lymph nodes, extranodal sites, or bone 
marrow. 
 
Specimens collected for correlative studies will be stored at OHSUBatch testing of the specimens will be conducted 
either periodically throughout the study or at the end. The specimens will be used for this research study only and 
not made available for future unspecified research. Specimens will be assigned a code number and only the sponsor- 
investigator and designated investigators and study staff involved in the conduct of the study will be authorized to 
link the code number to a subject. 
 
10.1 
COLLECTION OF SPECIMENS 
 
Additional details of testing performed is available in Section 2.6 and further outlined below. 
 
In addition to standard pathology testing, samples for correlative studies will be obtained as follows: 
1) Screening:   
a. Nodal Tissue: Fresh or archival tumor tissue will be collected for gene expression profiling and 
targeted sequencing including BTK mutations.  
b. Bone Marrow: 5 mL of fresh bone marrow aspirate in EDTA tube or heparinized syringe. 
c. Peripheral Blood: 5 mL EDTA or citrate tube.  
2) Post Induction/on Treatment:  
a. If patient is in CR: Bone Marrow: 5-7 mL or Bone Marrow aspirate in a EDTA tube for MRD 
testing by flow cytometry. 1-2 mL of this sample is to be placed in a separate EDTA tube for 
evaluation by next gen sequencing.  
3) Disease Progression: 
a. Nodal Tissue: Fresh tumor tissue will be collected for gene expression profiling and targeted 
sequencing including BTK mutations.  
b. Bone Marrow: 5 mL of fresh bone marrow aspirate in EDTA tube or heparinized syringe. 
 
Blood samples and bone marrow aspirates collected at OHSU will be transported to Dr. Spurgeon’s laboratory 
within 2 hours after collection. Samples will be transported at room temperature. Blood samples collected at 
participating sites will be shipped ambient to Dr. Spurgeon’s laboratory the day of collection.  Sample shipments 
from participating sites can only be accepted at Dr. Spurgeon’s lab Monday-Friday. Prior to shipping, timing of the 
shipment should be coordinated with the OHSU study team. 
 
Shipping Address: 
 
Spurgeon Lab 
Oregon Health & Science University, Knight Cancer Institute 
Knight Cancer Research Building 
Dock 61, Room 2141 
2720 SW Moody Ave 
Portland, OR 97201 
 
Samples for standard MRD testing via flow cytometry will be performed at the treating institution.  OHSU MRD 
testing will be performed at OHSU pathology.  For non-OHSU participants, this can be performed per standard of 
care at the treating institution.  
 
 


      
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10.2 
GENE EXPRESSION PROFILING (GEP) 
 
Formalin fixed, paraffin embedded MCL tissue biopsies or lysates from 104 lymphoma cells. Reports will be 
generated by hematopathology through the OHSU system. 
 
10.2.1 SEQUENCING USING ION TORRENT PLATFORM AND EVALUATING BTK MUTATIONS 
 
Specimen Requirements include: Peripheral blood: 5 mL EDTA (lavender top tube) or 5 mL Citrate tube or Bone 
marrow aspirate: 5 mL in EDTA (lavender top tube) or a paraffin block or 10 unstained sections of a bone marrow 
or lymph node biopsy (4-5 microns). DNA will be isolated using QIAamp isolation kit (QIAGEN). Sequencing will 
be performed by the Knight Diagnostic Lab (KDL). 
 
10.3 
MRD TESTING 
 
MRD testing should be performed according to institutional standards. Samples may be assessed at each 
investigative subsite or shipped to lead site (OHSU) for processing. For all samples processed at OHSU, 5-7 ml of 
bone marrow aspirate in a heparinized syringe should be sent refrigerated for MRD flow cytometry analysis. 1 ml 
will be frozen for possible MRD testing by next gen sequencing. Samples should be shipped to: 
 
Hematopathology Division, Mailcode L471 
Surgical Pathology Office 
Department of Pathology 
Oregon Health & Sciences University 
3181 SW Sam Jackson Park Road 
Portland, OR 97239 
 
Surgical Pathology Office # is (503) 494-6776 
 
11. STUDY PROCEDURES AND SCHEDULE OF EVENTS 
 
11.1 
SCREENING/BASELINE VISIT 
 
Baseline screening evaluations are to be conducted within 4 weeks prior to start of protocol treatment. Refer to 
Section 11.6 and Table 3 for more detailed description of study procedures. 
 
11.2 
STUDY VISITS 
 
Subjects will be followed until disease progression. Subjects removed from study for unacceptable adverse event(s) 
will be followed until resolution or stabilization of the adverse event. The schedule of events, Tables 3-4, lists the 
mandatory data collected at each time point for the clinical trial but it is expected that additional tests/procedures or 
visits may occur as standard of care, which is entirely at the discretion of the investigator. Most patients will have 
additional laboratory studies and clinical evaluations outside of this schedule as part of their standard of care. Every 
effort will be made to adhere to the schedule as close as possible. This is the minimum schedule of laboratory 
studies and follow-up visits required for the study. 
 
11.3 
END OF TREATMENT - OBINUTUZUMAB 
 
Subjects will be evaluated 1 month (28 days) ±7 days after completion of obinutuzumab maintenance for End of 
Treatment procedures. Every attempt will be made to devise a treatment plan weeks before the patient stops 
Obinutuzumab. In the case where the patient withdraws from the study abruptly for any reason, a standard of care 
treatment plan will be formulated as soon as possible. Subjects will be encouraged to return for the follow- up visit. 
 


      
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11.4 
FOLLOW-UP VISIT 
 
After completion of maintenance obinutuzumab (up to 2 years of maintenance) patients will be continued on 
ibrutinib per standard of care. Follow up will be performed per standard of care and patients will be followed until 
disease progression or death. No planned study follow up is mandated. However, every 6 months, patients and/or 
patient records may be queried for progression and survival status for up to 3 years. The PI may terminate the study 
prior to 5 years; however, after 5 years, the study must be terminated. 
 
11.5 
STUDY ASSESSMENTS AND PROCEDURES 
 
Dose adjustments or the occurrence of hematologic or non-hematologic grade 3 or 4 adverse events may require 
additional clinical evaluations and/or laboratory studies but should not be any less frequent than the schedule 
outlined. 
 
● Demographics and Medical History: Demographics and a complete medical history will be collected at 
visits prior to starting study treatment. 
 
● Concomitant Medications: All concomitant medications and treatments must be recorded in the case 
report form (CRF). Any prior medication received up to 30 days prior to the Screening visit will be 
recorded in the CRF. Concomitant treatments that are required to manage a subject’s medical condition 
during the study will also be recorded in the CRF. Prior and/or ongoing medications will be reviewed 
during screening to determine subject eligibility. The medication record will be maintained following 
enrollment including any changes to the dose or regimen. Prior and concomitant mediation including any 
prescription, over the counter or natural/herbal/multivitamin preparations taken will be recorded. 
 
● Physical Exam: The physical exam at Screening should include weight, vital signs (heart rate, blood 
pressure, respiratory rate, oxygen saturation), and a detailed exam of lymph nodes as well as liver and 
spleen. 
 
● Targeted Physical Exam: Physical exam to include heart, lungs, abdomen, lymph nodes and lower 
extremities. 
 
● Performance Status: ECOG will be determined and performed at the visits indicated in the schedule of 
events. 
 
● Nursing Assessment: Standard nursing assessment performed by chemotherapy certified infusion nurses 
prior to drug administration. Assessment should include study drug diary review of ibrutinib self-
administration. 
 
● Pregnancy Test: A urine pregnancy test is required for all female subjects during screening for women of 
childbearing potential. If the urine pregnancy test is positive, serum pregnancy tests must be performed per 
institutional standards. 
 
● Weight: Must be collected at each study visit. 
 
● Height: Must be collected prior to day of study treatment and at additional visits as defined on Study Visit 
table. 
 
● Vital Signs: Vital sign measurements should be taken per institutional standards at each study visit. 
 
● Laboratories: The following labs will be collected as outlined in Table 3: 
o Complete Blood Count (CBC): Should include a 5 point differential (CBC w/ diff.), including, at a 
minimum: white cell count, hematocrit, hemoglobin, absolute neutrophil count, absolute lymphocyte 


      
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count, and platelet count. 
o Complete Metabolic Panel (CMP): Should include, at a minimum, creatinine, K, Na, total bilirubin, 
albumin, AST, ALT, Ca, ALP, phosphorous, glucose, uric acid, LDH (point of care labs acceptable), 
and BUN. 
o beta-2 microglobulin (B2M) 
o Hepatitis B surface antigen (sAg) 
o Hepatitis B core antibody (cAb) 
o Immunoglobulin G (IgG) 
o Uric acid 
 
● FDG-PET: Should be performed at baseline and at the end of cycle 6. Additional scans will be done per 
standard of care if, as assessed by the investigator, the subject may have had CR. 
 
● Imaging: Subjects should undergo staging (and restaging) CT scans with IV contrast including neck (if 
involved at baseline), chest, abdomen, and pelvis. MRI of these areas may be substituted for CT scan if the 
subject a) refuses CT or b) has contraindications to IV contrast i.e. allergy. Imaging will be performed at 
baseline, prior to cycle 3 initiation, end of cycle 6 and Q 4 months (± 7 days) while on obinutuzumab 
maintenance. Index lesions will be followed from baseline.  
 
● Bone Marrow Aspirate and Biopsy: Will be performed at baseline and at the end of cycle 6 if involved at 
baseline. Additional marrow is required after attaining a CR by imaging studies.  IHC including cyclin D1 
staining, flow cytometry for MRD, and FISH including t (11, 14). If found to be MRD negative, next gene 
sequencing will be performed to confirm. 
 
● Optional Lymph Node Fine Needle Aspiration: For Correlative Studies for gene expression profiling and 
sequencing. Subjects must provide explicit consent to participate in this optional specimen collection. A 
second lymph node fine needle aspiration will be collected at baseline and upon disease progression, if 
applicable. 
 
● Peripheral Blood:  Collected at baseline and disease progression. For Correlative Studies for gene 
expression profiling and sequencing. 
 
● Adverse Event assessments: Toxicities and adverse experiences will be assessed at each visit using the 
NCI Common Toxicity Criteria for Adverse Events 4.0. 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
 
 


      
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11.6 
SCHEDULE OF EVENTS 
 
Table 3. INDUCTION SCHEDULE: Screening/Baseline, Cycles 1 through 6, and End of Induction 
Visit 
Screening/ Baseline Cycle 1 Cycle 1 
Cycle 1 
Cycles 2-6 End of 
Induction 
End of 
Induction1 
Day 
Day 1 
Day 8 
Day 15 
Day 1 
Day 28 
Day 56 
Window 
- 28 days of C1D1 
±7 days 
±7 days 
Performance Status 
X 
X 
X 
X 
Complete Physical 
X 
X 
X 
Targeted physical exam 
X 
RN assessment 
X 
X 
X 
X 
Height 
X 
X 
Vital signs (heart rate, BP, RR, O2) 
X 
X 
X 
X 
X 
X 
CBC w/differential2 
X 
X 
X 
X 
X 
X 
X 
Chemistry panel (CMP) 
X 
X 
X 
X 
X4 
X4 
LDH 
X 
X 
X 
X 
X 
X 
Uric Acid 
X 
X 
X 
X 
X 
Urine or β-hCG pregnancy test3 
X 
Beta-2 microglobulin 
X 
Hepatitis B surface antigen (sAg) 
X 
Hepatitis B core antibody (cAb) 
X 
Immunoglobulin G (IgG) 
X 
CT and PET with contrast (neck, 
chest, abdomen and pelvis)5 
X 
X6 
X 
Bone Marrow Aspirate with Biopsy 
(IHC including cyclin D1 staining, flow 
cytometry, and FISH including t (11,14) 
X 
X7 
OPTIONAL: Lymph node fine needle 
aspiration or biopsy 
X8 
5 mL peripheral blood 
X 
X 
Obinutuzumab IV administration 
X 
X 
X 
X 
Ibrutinib PO administration 
Daily starting at Cycle 1 Day 1 
Ibrutinib drug diary 
Daily starting at Cycle 1 Day 1 
Ibrutinib drug diary review 
X 
X 
X 
AE Assessment 
X 
X 
X 
X 
X 
X 


      
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KEY: 
1Visit may be combined with the first maintenance infusion visit but bone marrow biopsy must be performed prior to the first 
dose of obinutuzumab maintenance. 
2 If a Grade 3 hematologic DLT occurs, repeat CBC 2x/month (Day 1 and Day 15) will be performed. If Grade 4 hematologic DLT 
occurs, repeat CBC weekly until toxicity resolves to < Grade 2. 
3For women of childbearing potential only 
4May be performed as Basic Metabolic Panel plus (BMP +) or as point of care chemistry panel 
5MRI of these areas may be substituted for CT scan if the subject a) refuses CT or b) has contraindications to IV contrast i.e. allergy. 
6 Prior to Cycle 3 drug initiation (a window of 7 days prior to C3D1) 
7 End of Cycle 6 bone marrow biopsy will be done only in participants with initial bone marrow involvement. If found to be MRD negative, 
gene sequencing will then be performed to confirm. 
8Additional fine needle aspiration will be collected upon disease progression, for subjects for whom this applies. 
 
 
 
Table 4. MAINTENANCE SCHEDULE: Visits 1 through 12 and End of Study Visit 
Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
End of 
Study 
Day 
Day 
56 
Day 
112 
Day 
168 
Day 
224 
Day 
280 
Day 
336 
Day 
392 
Day 
448 
Day 504 Day 560
Day 
616 
Day 
672 
Day 700 
Window 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 days 
Performance 
Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete 
Physical 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height and 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs (heart 
rate, BP, RR, 
O2) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC w/diff1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CMP 2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


      
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LDH 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Uric Acid 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CT and PET 
with contrast 
(neck, chest, 
abdomen and 
pelvis)3 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Obinutuzumab IV 
administration 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ibrutinib PO 
administration 
Daily 
Ibrutinib drug 
diary 
Daily 
Ibrutinib drug 
diary review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
KEY: 
1 If a Grade 3 hematologic DLT occurs, repeat CBC 2x/month (Day 1 and Day 15) will be performed. If Grade 4 hematologic DLT occurs, 
repeat CBC weekly until toxicity resolves to < Grade 2. 
2 May be performed as Basic Metabolic Panel plus (BMP +) or as point of care chemistry panel 
3Imaging to be performed every 4 months (+ or – 7 days) while on obinutuzumab maintenance. MRI of these areas may be substituted for 
CT scan if the subject a) refuses CT or b) has contraindications to IV contrast i.e. allergy. A PET scan should be performed per standard of 
care if in the eyes of the investigator, the subject may have had a CR. 
 
Table 5. FOLLOW UP SCHEDULE: Every 6 months for 3 years 
Month 
Month 6 
Month 12 
Month 18 
Month 24 
Month 30 
Month 36 
Disease 
Status 
X 
X 
X 
X 
X 
X 
Survival 
Status 
X 
X 
X 
X 
X 
X 
 
 


      
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12. MEASUREMENT OF EFFECT 
 
The primary objective of this study is best overall response of CR/PR and secondary objectives will include 
progression free survival (PFS) and toxicity. 
 
12.1 
BEST OVERALL RESPONSE 
 
Subjects who received both study medications and have had one response assessment (first radiologic response 
assessment takes place after cycle 2) will be evaluable for Best Overall Response. Patients who progress prior to 
the initial planned radiologic evaluation will be defined as having progressive disease and go off study. Diagnostic 
CT and PET will be used to measure response. Progression must be confirmed by imaging. 
 
12.1.1 TARGET LESIONS/MEASURABLE DISEASE 
 
Subjects must have at least 1 measurable site of disease according to Revised Response Criteria for Malignant 
Lymphoma. Up to six of the largest dominant nodes or tumor masses should be selected. If possible, these should 
be from different body regions and whenever possible, should include mediastinal and retroperitoneal disease sites. 
The site of disease must be greater than 1.5 cm in the long axis regardless of short axis measurement or greater 
than 1.0 cm in the short axis regardless of long axis measurement, and clearly measurable in 2 perpendicular 
dimensions. Extranodal sites can be included and for extranodal sites in the liver or spleen, these must measure at 
least 1.0 cm in the two greatest dimensions. 
 
12.1.2 EVALUABLE NON-TARGETED DISEASE RESPONSE 
 
Subjects who have lesions present at baseline that do not meet the size criteria to be considered measurable 
disease, have received at least two cycles of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease response. The response assessment is based on the presence, absence, or 
unequivocal progression of the lesions. 
 
12.2 
RESPONSE CRITERIA 
 
Response to therapy will be assessed per the Lugano criteria28. Pre-treatment evaluations include FDG-PET and 
diagnostic CT as outlined. Best overall response (PR or CR) as per Section 12.3.1 will be evaluated throughout the 
study and used to inform the primary endpoint. Only patients achieving a PR or greater after induction (the first 6 
cycles of treatment) are eligible for ongoing therapy. Therefore, prior to proceeding with maintenance therapy (ie 
after cycle 6), best overall response (PR or CR) will be documented by PI. Subjects with a PR or greater are 
eligible to continue with ibrutinib plus obinutuzumab maintenance. 
 
For FDG-PET response Deauville criteria will also be used in conjunction with CT as described below to assign 
PR or CR. 
 
The Deauville scale ranges from 1 to 5, where 1 is best and 5 is the worst. Each FDG- avid (or previously FDG-
avid) lesion is rated independently. 
 
1) no uptake or no residual uptake (when used interim)  
2) slight uptake, but below blood pool (mediastinum)  
3) uptake above mediastinal, but below or equal to uptake in the liver  
4) uptake slightly to moderately higher than liver  
5) markedly increased uptake or any new lesion (on response evaluation) 
 
12.3 
RESPONSE ASSESSMENT 
 
Imaging Response Assessment using Deauville Criteria 


      
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Complete response (CR): scores 1, 2 or 3 together with absence of FDG-avid bone marrow lesion(s) are interpreted 
as complete metabolic response (CR), irrespective of a persistent mass on CT 
 
Partial response (PR): a Deauville score of 4 or 5, provided: 
● uptake is decreased compared with baseline and 
● absence of structural progression development on CT 
 
Stable disease (SD): also called  no  metabolic  response: a  Deauville  score  of  4  or 5 without significant change 
in FDG uptake from baseline. 
 
Progressive disease (PD): a Deauville score of 4 to 5 with increasing intensity compared to baseline or any interim 
scan and/or any new FDG-avid focus consistent with malignant lymphoma. 
 
12.3.1 BEST OVERALL RESPONSE  
 
Determined by evaluation of measurable and non-measurable disease as well as marrow evaluation as outlined 
below 
 
12.3.1.1 
Complete Response (CR) 
 
Complete disappearance of all detectable clinical evidence of disease and disease- related symptoms if present prior 
to therapy. Typically FDG-avid lymphoma: in patients with no pre-treatment PET scan or when  
1) the PET scan was positive before therapy, a post-treatment residual mass of any size is permitted as long as 
it is PET negative. Variably FDG-avid lymphomas/FDG avidity unknown: in patients without a 
pretreatment PET scan, or if a pretreatment PET scan was negative, the designation of CR requires all nodal 
indicator lesions to regress to the size of normal lymph nodes. Lymph nodes that were > 15 mm in GTD 
regardless of the short axis diameter at the screening tumor assessment must regress to ≤ 15 mm in GTD 
regardless of the short axis diameter. Lymph nodes that were 11 to 15 mm in GTD and > 10 mm in the short 
axis diameter at the screening tumor assessment must regress to ≤ 10 mm in the short axis diameter.  
2) The spleen and/or liver, if considered enlarged prior to therapy on the basis of a physical examination or CT 
scan, should not be palpable on physical examination and should be considered normal size by imaging 
studies, and nodules related to lymphoma should disappear. However, determination of splenic involvement 
is not always reliable because a spleen considered normal in size may still contain lymphoma, whereas an 
enlarged spleen may reflect variations in anatomy, blood volume, the use of hematopoietic growth factors, 
or causes other than lymphoma.  
3) If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have cleared on repeat 
bone marrow biopsy. The biopsy sample on which this determination is made must be adequate (> 20 mm 
unilateral core). If the sample is indeterminate by morphology, it should be negative by 
immunohistochemistry. A sample that is negative by immunohistochemistry but demonstrating a small 
population of clonal lymphocytes by flow cytometry will be considered a CR until data become available 
demonstrating a clear difference in patient outcome. 
 
12.3.1.2 
Partial Remission (PR) 
 
1) ≥ 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or 
nodal masses. These nodes or masses should be selected according to the following: (a) they should be 
clearly measurable in at least 2 perpendicular dimensions; (b) if possible they should be from disparate 
regions of the body; (c) they should include mediastinal and retroperitoneal areas of disease whenever these 
sites are involved.  
2) No increase in the size of the other nodes, liver, or spleen. 


      
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3) Splenic and hepatic nodules must regress by ≥ 50% in their SPD or, for single nodules, in the greatest 
transverse diameter.  
4) With the exception of splenic and hepatic nodules, involvement of other organs is usually assessable and no 
measurable disease should be present.  
5) Bone marrow assessment is irrelevant for determination of a PR if the sample was positive prior to 
treatment. However, if positive, the cell type should be specified (e.g., large-cell lymphoma or small 
neoplastic B cells). Patients who achieve a complete remission by the above criteria, but who have 
persistent morphologic bone marrow involvement will be considered partial responders.  
6) No new sites of disease should be observed (e.g., nodes > 1.5 cm in any axis).  
7) Typically, FDG-avid lymphoma: for patients with no pretreatment PET scan or if the PET scan was positive 
before therapy, the post-treatment PET should be positive in at least one previously involved site.  
8) Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a pretreatment PET scan, or if 
a pretreatment PET scan was negative, CT criteria should be used. 
 
In patients with follicular lymphoma, a PET scan is only indicated with one or at most two residual masses that have 
regressed by more than 50% on CT; those with more than two residual lesions are unlikely to be PET negative and 
should be considered partial responders. 
 
12.3.1.3 
Stable Disease (SD) 
 
Failing to attain the criteria needed for a CR or PR, but not fulfilling those for progressive disease (see below). 
 
Typically, FDG-avid lymphomas: the PET should be positive at prior sites of disease with no new areas of 
involvement on the post- treatment CT or PET. 
 
Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a pretreatment PET scan or if the 
pretreatment PET was negative, there must be no change in the size of the previous lesions on the post-treatment CT 
scan. 
 
Relapsed Disease (RD; after CR) or Progressive Disease (PD; for Patients with PR or SD) 
 
12.3.1.4 
Progressive/Relapsed Disease 
 
Lymph nodes should be considered abnormal if the long axis is > 1.5 cm, regardless of the short axis. If a lymph 
node has a long axis of 1.1−1.5 cm, it should only be considered abnormal if its short axis is > 1.0. Lymph nodes ≤ 
1.0 cm by ≤ 1.0 cm will not be considered as abnormal for relapse or progressive disease. 
 
Appearance of any new lesion more than 1.5 cm in any axis during or at the end of therapy, even if other lesions are 
decreasing in size. Increased FDG uptake in a previously unaffected site should only be considered relapsed or 
progressive disease after confirmation with other modalities 
 
1) At least a 50% increase from nadir in the SPD of any previously involved nodes, or in a single involved 
node, or the size of other lesions (e.g., splenic or hepatic nodules). To be considered progressive disease, a 
lymph node with a diameter of the short axis of less than 1.0 cm must increase by ≥ 50% and to a size of 1.5 
× 1.5 cm or more than 1.5 cm in the long axis.  
2) At least a 50% increase in the longest diameter of any single previously identified node more than 1 cm in 
its short axis.  
3) Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the lesion was PET positive 
before therapy unless the lesion is too small to be detected with current PET systems (< 15 mm in its long 
axis by CT).  


      
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4) Measurable extranodal disease should be assessed in a manner similar to that for nodal disease. For these 
recommendations, the spleen is considered nodal disease. 
 
Notes:  Bone marrow status is evaluated as follows: 
Positive: Unequivocal cytological or architectural evidence of malignancy. Negative: No aggregates or only a few 
well-circumscribed lymphoid aggregates. 
 
12.3.2 EVALUATION OF BEST OVERALL RESPONSE 
 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the 
treatment started). The subject's best response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
12.4 
PROGRESSION FREE SURVIVAL 
 
Progression Free Survival (PFS) is defined as the time from the first day of combined study treatment 
(obinutuzumab plus ibrutinib -Day 1 of Cycle 1) to disease progression or death, whichever occurs first. If a patient 
has not experienced progressive disease or death, PFS will be censored at the day of the last tumor assessment or 
Cycle 1, Day 1 if no post-baseline tumor assessment. 
 
12.5 
EVALUATION OF TOXICITY 
 
All subjects will be evaluable for toxicity from the time of their first treatment with obinutuzumab (Day 1 of Cycle 
1) and through 30 days after completion of on-study therapy (either combination or single agent ibrutinib). Toxicity 
event will be classified according to the NCI Common Terminology Criteria for Adverse Events (CTCAE v4.0)  
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).  
 
Adverse events collection will begin at first administration of one or both study drugs. 
 
12.6 
METHODS FOR EVALUATION OF MEASURABLE DISEASE 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All baseline evaluations 
should be performed as closely as possible to the beginning of treatment and never more than 4 weeks before the 
beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each identified and reported 
lesion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by clinical examination 
unless the lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules 
and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers (e.g., skin nodules). In the case of skin 
lesions, documentation by color photography, including a ruler to estimate the size of the lesion, is recommended. 
 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is not advised. 
However, such techniques may be useful to confirm complete pathological response when biopsies are obtained or 
to determine relapse in trials where recurrence following complete response (CR) or surgical resection is an 
endpoint. 
 
PET: A positive scan is defined as focal or diffuse FDG uptake above background in a location incompatible with 
normal anatomy or physiology. In order to make this assessment, potential PET avid areas must be compared to 
mediastinal and liver blood pools. For splenic lesions, uptake must be greater than surrounding liver and spleen. 
PET will NOT be used to measure marrow disease. 


      
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13. DATA REPORTING AND REGULATORY REQUIREMENTS 
 
Study outcome data will be captured in electronic case report forms (eCRFs) using an electronic data capture (EDC) 
system stored on REDCap CLOUD secure servers, which facilitates information being stored in a unified format 
and location. REDCap Cloud is a web-hosted application hosted by nPhase (located in Encinitas, California), and is 
an approved system that has been reviewed by OHSU Security. To further preserve confidentiality, PHI in the EDC 
system will be limited to just birth date and dates associated with patient’s medical care and life events. The web-
accessible EDC system is password protected and encrypted with role-based security, and administered by 
designated informatics staff within OHSU or Knight Cancer Institute. All users of the database are assigned a 
unique ID, username, and password and must complete training appropriate to their role before they are authorized 
to enter, access, and store data in the database. 
 
Basic accrual tracking information (demographic, consent, visit information) will be captured in OHSU’s electronic 
clinical information research system (eCRIS), hosted on OHSU secure servers and managed by OHSU’s 
information technology group at their data center in downtown Portland, Oregon. Any additional printed documents 
containing participant identifiers, such as those from the medical record to confirm eligibility, will be filed in 
binders and kept in a locked, secure location. 
 
Data from correlative studies will be entered into the EDC system by study personnel at OHSU. All other electronic 
data extracts will be stored only on OHSU computers and restricted drives, limited only to study investigators and 
staff with authorization to access the data. 
 
Quality assurance will be conducted as outlined in section 13.7 under data safety and monitoring. 
 
13.1 
MULTICENTER GUIDELINES  
 
Collaborating research subsites may be invited to participate in this study.  In such cases, OHSU will serve as the 
coordinating center and will manage trial data in the following ways: 
 
a. Confirm that all sites have received and are using the most recent version of the protocol. The protocol must not 
be rewritten or modified by anyone other than the OHSU Investigator. Documentation of the version that was 
sent to the site must be kept in the regulatory binders.  
b. Confirm that the protocol and informed consent form have local IRB approval at each site prior to registration 
of the first participant. Documentation of IRB approval from other sites for continuing review must be 
submitted and kept in the binder.  
c. Provide centralized participant registration in the clinical research management system. 
d. Ensure collection and review of applicable source documents and case reports by the OHSU Investigator to 
ensure protocol compliance. 
e. Maintain documentation for all SAE reports and submit regular summaries of all AEs, SAEs and UPs from all 
sites to the Knight DSMC per DSMC requirements. 
f. Ensure that relevant IRB correspondence and study status changes are communicated to all participating sites 
within 5 business days. Any changes that affect participant safety of study enrollments will be communicated 
immediately. 
g. Submit documentation to the FDA such as protocol amendments, annual reports, and safety reports for 
unexpected, fatal or life-threatening events that are associated with the use of the investigational product. 
h. Participating sites must submit regulatory documents including, but not limited to the following:  
● Current CV (signed and dated) for each Investigator. 
● Current medical license number for physician investigators. 
● Current signed FDA Form 1572.  
● Certificate of completion of institution-required human participant training course, the NIH online training 
in the protection of human research participants or other appropriate training. 
● Documentation of institutional Conflict of Interest. 


      
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i. 
IRB-approved site-specific ICF (must be reviewed and approved by OHSU Investigator and study team prior to 
submission to the local IRB. 
j. 
All IRB-approved documents and approval memos. 
k. Site delegation of authority and signature log. 
l. 
Site DSMP. 
m. Completed CRFs (data entry) within 10 business days of study visit. 
 
13.2 
PROTOCOL REVIEW 
 
The protocol and informed consent form for this study must be reviewed and approved in writing by the OHSU 
Knight Cancer Institute (CI) Clinical Research Review Committee (CRRC) and the OHSU Institutional Review 
Board (IRB) prior to any subject being consented on this study. 
 
13.3 
INFORMED CONSENT 
 
Written informed consent will be obtained from all subjects, or the legally authorized representative of the subject, 
participating in this trial, as stated in the Informed Consent section of the case of Federal Regulations, Title 21, Part 
50. If a subject’s signature cannot be obtained, and for all subjects under the age of 18, the investigator must ensure 
that the informed consent is signed by the subject’s legally authorized representative. 
 
Documentation of the consent process and a copy of the signed consent shall be maintained in the subject’s medical 
record. 
   COVID-19 Modified Procedures  
 In the event of an initial consent or a re-consent (due to a protocol amendment or an updated investigator’s 
brochure, or any other change to the Informed Consent Form where the participants must be informed) where 
COVID-19 restrictions prevent the participant from consenting in person at the clinic, the participant will be 
emailed, faxed, or mailed the new consent or the revised consent and a phone call will take place between the 
consenting staff member, the participant and an impartial witness. An impartial witness is involved when the 
participant is not able to return the signed page for documentation of consent.  The witness will be able to hear both 
sides of the conversation and attest to the subject’s decision to participate.  If an impartial witness is not available, a 
recording of the conference call can be used in place of the witness. The recording will be used as documentation 
and will be kept in the trial records. 
The consent form or any changes to the consent form for a re-consent will be explained in detail and the participant 
will be given time to ask any questions. The staff member will ask questions to gauge understanding. Once all 
questions have been addressed, the participant will be instructed to sign and date the consent. The consent form will 
then be mailed, faxed, or scanned and emailed, in its entirety to the study site. The conversation and signing of the 
consent is then documented in the participant’s records. Upon receipt of the signed consent, the consenting staff 
member who performed the phone consent will sign and date the consent and document in the participant’s records. 
Copies of fully-executed consent forms (i.e. signed by participant and site personnel) will be provided to 
participants. MyChart may be used to collect study consents remotely.  
Research participant visits will be conducted remotely whenever possible during the COVID-19 outbreak. On-site 
visits will be limited to visits that are “essential to the health and/or well-being” of our subjects. Participants may 
have procedures done locally, assessments conducted over the phone, or procedures may be skipped or performed 
outside of window depending on the PI assessment of what is essential to the health and well-being of the 
participant. Every participant will be considered on a case by case basis by the PI and the study team. Decisions will 
be documented by the study team.  
Participants will be informed of the modified procedures by phone or at a visit and their verbal agreement 
noted.  All deviations from the protocol will be logged and its relation to the COVID-19 restrictions will be noted. 
Additionally, site-monitoring visits may be conducted remotely or postponed during this time.   
Consenting, re-consenting and participant visits will be followed per work instructions developed at OHSU.   
 


      
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13.4 
CHANGES TO PROTOCOL 
 
Any modification of this protocol must be documented in the form of a protocol revision or amendment signed by 
the principal investigator and approved by the CRRC and IRB, before the revision or amendment may be 
implemented. The only circumstance in which the amendment may be initiated without regulatory approval is for a 
change necessary to eliminate an apparent and immediate hazard to the subject. In that event, the investigator must 
notify the CRRC and IRB in writing within 10 working days after the implementation. Investigators holding the 
IND must notify FDA of substantive changes to the protocol. 
 
13.5 
MAINTENANCE OF RECORDS 
 
If the investigator relocates or for any reason withdraws from the study, the study records must be transferred to an 
agreed upon designee, such as another institution, another investigator, or to OHSU Knight Cancer Institute Clinical 
Trials Office. Records must be maintained according to sponsor or FDA requirements. 
 
13.6 
OHSU IRB REPORTING OF UNANTICIPATED PROBLEMS AND ADVERSE EVENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 
7.0 (Adverse Events: List and Reporting Requirements). 
 
13.7 
OHSU KNIGHT CANCER INSTITUTE DATA AND SAFETY MONITORING PLAN 
 
In addition to complete study and pharmacy files, complete records must be maintained on each subject treated on 
this protocol. OHSU Knight Cancer Institute, through the auditing function of the Knight Clinical Trials Office, is 
responsible for ensuring that all member investigators and affiliate investigators conduct clinical research studies in 
compliance with local IRB standards, FDA regulations and NIH policies and in accordance with the Data and 
Safety Monitoring Plan policies and procedures here. 
 
Locally initiated studies will be audited by OHSU Knight CI Auditor. Newly approved studies may be audited any 
time after enrollment has been initiated. Each OHSU Knight approved treatment protocol will be audited on an 
annual basis in accordance with the Knight Data and Safety Monitoring Plan. 
 
13.8 
INCLUSION OF WOMEN, MINORITIES AND CHILDREN 
 
No OHSU Knight Cancer Institute study will focus on any particular gender, racial or ethnic subset. No subject will 
be excluded from the study on the basis of gender, racial or ethnic origin. Male, female and minority volunteers will 
be recruited for this study from the general population and approximately 50% men and 50% women will be 
studied.  The projected gender, racial, and ethnic composition of the study will represent that of the state of Oregon 
(Table 6 and Table 7). 
 
Table 6. Population Demographics - Oregon (%) 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
5.9 
5.8 
11.7 
Not Hispanic or Latino 
44.5 
43.8 
88.3 
Ethnic Category: Total of all 
subjects* 
50.4 
49.3 
100* 
Racial Category 
American Indian or Alaskan Native 
0.7 
0.7 
1.4 


      
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Asian 
1.9 
1.8 
3.7 
Black or African American 
0.9 
0.9 
1.8 
Native Hawaiian or other Pacific 
Islander 
0.2 
0.1 
0.3 
White 
42.1 
41.5 
83.6 
More than one race 
1.9 
1.9 
3.8 
Unknown/Other 
2.7 
2.6 
5.3 
Racial Category: Total of all 
subjects* 
50.4 
49.5 
100* 
TOTALS 
50.4 
49.6 
100* 
Source:   U.S. Census Bureau, 2010 
*Totals may not equal 100 due to rounding. 
 
Table 7. Projected Accrual for the Present Study 
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
1 
1 
0-1 
2 
Not Hispanic or Latino 
9 
9 
0-1 
18 
Unknown 
0-1 
0-1 
0-1 
0-1 
Ethnic Category: Total of all 
subjects* 
10 
10 
0-1 
20 
Racial Category 
American Indian or Alaskan Native 
0-1 
0-1 
0-1 
0-1 
Asian 
0-1 
0-1 
0-1 
1 
Black or African American 
0-1 
0-1 
0-1 
0-1 
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Native Hawaiian or other Pacific 
Islander 
0-1 
0-1 
0-1 
0-1 
White 
8 
8 
0-1 
20 
More than one race 
0-1 
0-1 
0-1 
1 
Unknown 
1 
1 
0-1 
1 
Racial Category: Total of all 
subjects* 
10 
10 
0-1 
20 
Source:   Adapted from U.S. Census Bureau, 2010 
*Totals may not equal 100 due to rounding. 
 
13.9 
INCLUSION OF CHILDREN 
This protocol does not include children for the following reasons: 
1) The number of children with this type of cancer is limited.  
2) No dosing or adverse event data are currently available on the use of this study agent in this way in subjects <18 
years of age, therefore, children are excluded from this study. 
 
14. STATISTICAL CONSIDERATIONS 
 


      
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14.1 
STUDY DESIGN 
 
This is a single-arm two-stage phase II trial combining obinutuzumab and ibrutinib for the treatment of 
relapsed/refractory mantle cell lymphoma. It is designed according to Simon’s optimum two-stage design, and a 
total of 20 patients will be enrolled at OHSU. In Stage I, 6 patients are enrolled, and if there are 3 or fewer 
responses (CR/PR), the trial will be closed. Otherwise the trial will continue until 20 patients are enrolled. The 
treatment is considered unworthy of further investigation if 14 or fewer respond. Of note, this study will use two 
already FDA approved agents-obinutuzumab is FDA approved for chronic lymphocytic leukemia, not MCL, and 
ibrutinib is FDA approved for relapsed/refractory MCL as a single agent. 
 
14.2 
PRIMARY AND SECONDARY ENDPOINTS 
 
14.2.1 PRIMARY ENDPOINT 
 
Best overall response of CR/PR as defined in Section 12.1. 
 
14.2.2 SECONDARY ENDPOINTS 
 
Toxicity is defined as any adverse event grade 3 or higher, defined in Sections 5 and 6.  Progression free survival is 
defined in Section 12.1.3. 
 
14.2.3 EXPLORATORY AND CORRELATIVE ENDPOINTS 
1. Gene expression profiling using Lymph5Cx test 
2. Sequencing using the ion torrent platform (for MRD and known mutations in lymphoma) 
3. Sequencing of BTK and PLC2 to evaluate for BTK and PLC2  mutations 
4. MRD by flow cytometry and next generation sequencing post treatment 
 
14.3 
ANALYSIS POPULATIONS 
 
An evaluable patient set consists of those who receive at least one dose of both drugs (obinutuzumab and ibrutinib). 
A per protocol patient set consists of those who receive at least 2-cycles of combined therapy. Primary and 
secondary endpoints will be assessed using the evaluable patient set as well as the per-protocol patient set. 
Progression must be confirmed radiologically. Patients progressing (PD) prior to the first scheduled response 
assessment of measurable disease will be counted as non-responding patients. Evaluable patients who do not have 
response assessments (e.g. are removed for toxicity) will also be counted as non-responding patients. Safety 
analysis will include all subjects receiving at least one dose of obinutuzumab and ibrutinib. Ibrutinib treatment may 
be interrupted for 14 days. If ibrutinib is held > 14 days, patients are allowed to stay on study and are evaluable for 
response if they have completed at least 2 cycles (56 days) of combination therapy. 
 
14.4 
STATISTICAL ANALYSIS PLAN 
 
A treatment is considered not worthy of further investigation if 14 or fewer responses are observed among 20 
patients. Phase II data will be used to provide evidence of anti- tumor activities. We will provide a point and 
interval estimate (95% confidence interval) of the overall response (CR/PR). Kaplan-Meier method will be used to 
estimate progression-free survival (PFS). For exploratory analyses, a logrank test will be used to compare PFS 
between patients with and without MRD negativity after induction (obinutuzumab plus ibrutinib) treatment. A 
Fisher’s exact test will be used to compare the best overall response between patients with and without BTK or 
PLCγ2 mutations. 
 
14.4.1 INTERIM ANALYSES AND STOPPING RULES 
 
This trial is designed according to Simon’s two-stage optimal design. The primary endpoint of the best overall 
response is the best response recorded from the start of the treatment until disease progression (section 12.1). For 


      
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the purpose of the interim analysis, we will use the best response achieved during the first six months. *After Stage 
I enrollment of 6 patients, an interim analysis of the response (CR/PR) within the first six months of treatment will 
be conducted. If there are 3 or fewer responses (CR/PR) among 6 patients, the trial will be closed due to futility. 
Stage II will enroll additional 14 patients. After completion of Stage II a final analysis will be conducted to 
determine the best overall response rate defined in 12.1.  If 14 or fewer responses, this combination will not be 
deemed worthy of additional investigation. 
 
There are two safety stopping rules in this trial. Sequential boundaries are constructed based on the method by 
Ivanova et al32.  Specifically the accrual will be suspended if excessive numbers of DLT events (as defined in 
Section 5.10) are observed, that is, if the number of DLT is equal to or exceeds bn out of n patients with full follow-
up (see Table 8 for Grade 4+ DLTs and Table 9 for Grade 3+ DLTs). The boundary is equivalent to testing the null 
hypothesis that, after each patient, that the event rate is significantly higher than 20% (Table 8: Grade 4+ DLTs) and 
33% (Table 9: Grade 3+ DLTs) using one-sided 10% significance level. 
 
Table 8. Sequential boundary and stopping rule for Grade 4 or higher DLTs: suspend the accrual 
if there are bn or higher events out of n patients. 
Number of 
Patients, n 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
Boundary, bn - 
2 
3 
3 
3 
3 
4 
4 
4 
5 
5 
5 
6 
6 
6 
6 
7 
7 
7 
7 
 
Table 9. Sequential boundary and stopping rule for Grade 3 or higher DLTs: suspend the accrual 
if there are bn or higher events out of n patients. 
Number of 
Patients, n 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
Boundary, bn - 
- 
3 
4 
4 
4 
5 
5 
6 
6 
7 
7 
8 
8 
8 
9 
9 
10 
10 
10 
 
*Please note: As of May 11, 2018, seven patients were enrolled in the Stage I portion of the study with one patient 
withdrawing a consent prior to the initial response assessment. Of six evaluable patients, five responses (3 CR and 
2 PR) were observed. Therefore, the trial passed the Stage I futility criteria (stop if 3 or fewer responses out of 6), 
and it is currently in the Stage II portion of the study. Further, there were 2 patients with Grade 3 or higher DLT 
events and 1 patient with Grade 4 or higher DLT events among seven patients exposed to the study drugs. 
Therefore, the toxicity boundaries were not crossed, and the treatment is considered safe to continue.  
 
14.4.2 SAMPLE SIZE AND POWER 
 
Patients treated on the Pivotal ibrutinib trial with relapsed/refractory mantle cell lymphoma had achieved the best 
overall response rate (CR/PR) of 68%. Treatment of relapsed MCL with obinutuzumab resulted in a CR/PR 
response rate of 27%. Therefore, based on one- sided 5% significance and 90% power using a control response rate 
of 55% vs. an experimental response rate (obinutuzumab plus ibrutinib) of 85% and Simon’s two-stage optimum 
design, 20 subjects will need to be enrolled. Stage I will enroll 6 subjects, and if there are 3 or fewer responses 
(CR/PR), the trial will be closed due to futility. Otherwise, Stage II will enroll additional 14 patients with the total 
sample size of 20 patients. 
 
14.5 
HANDLING OF MISSING DATA 
 
Every attempt will be made to obtain data at the defined time points as described in the primary and secondary 
endpoints. The labs or studies outlined in the schedule of events may be completed within 7 days of the target 
calendar date (7 days before or 7 days after, inclusive). However, every effort will be made to adhere to this 
schedule. If critical data (that which would have contributed to primary or secondary endpoints) for a given subject 
is missed at a timepoint, we will evaluate whether or not data from other time points will be sufficient to conduct 
the study analyses adequately. If the data is not sufficient to analyze specified endpoints, the subject’s data may be 
excluded entirely or partially, depending on the specific endpoints in question, and in consultation with the 
biostatistician. 


      
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15. REFERENCES 
 
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disorders. Cancer. 1979; 44 (1):188-195). 
 
2. Williams ME, Swerdlow SH, Rosenberg CL, et al. Characterization of chromosome 11 translocation breakpoints at 
the bcl-1 and PRAD1 loci in centrocytic lymphoma. Cancer Res. 1992; 52 (19Suppl): 41s-5544s. 
 
3. Furtado M, Johnson R, Kruger A, et al. Addition of bortezomib to standard dose chop chemotherapy improves 
response and survival in relapsed mantle cell lymphoma. Br J Haematol. 2014 Aug 22. doi: 
10.1111/bjh.13101. 
 
4. Morrison VA, Jung SH, Johnson J, et al. Therapy with bortezomib plus lenalidomide for relapsed/refractory 
mantle cell lymphoma: final results of a phase II trial (CALGB 50501). Leuk Lymphoma. 2014 Aug 13:1-7. 
[Epub ahead of print] 
 
5. Hoster et. al. A new prognostic index (MIPI) for patients with advanced mantle cell lymphoma. Blood 
111:558-565. (2008) 
 
6. Coiffier B. Clinical efficacy and management of temsirolimus in patients with relapsed or refractory mantle cell 
lymphoma.  Clin Lymphoma Myeloma Leuk. 2013 Aug;13(4):351-9. 
 
7. Katzenberger T, Petzoldt C, Höller S, et al. The Ki67 proliferation index is a quantitative indicator of clinical 
risk in mantle cell lymphoma. Blood. 2006 Apr 15;107(8):3407. 
 
8. Rosenwald A1, Wright G, Wiestner A, et al. The proliferation gene expression signature is a quantitative integrator 
of oncogenic events that predicts survival in mantle cell lymphoma. Cancer Cell. 2003 Feb;3(2):185-97. 
 
9. Salek D, Vesela P, Boudova L, et al. Retrospective analysis of 235 unselected patients with mantle cell lymphoma 
confirms prognostic relevance of Mantle Cell Lymphoma International Prognostic Index and Ki-67 in the era of 
rituximab; long-term data from the Czech Lymphoma Project Database. Leuk Lymphoma 2014 Apr; 55(4):802-10. 
 
10. Hartmann EM, Campo E, Wright G, et al. Pathway discovery in mantle cell lymphoma by integrated analysis of 
high-resolution gene expression and copy number profiling. Blood 2010 Aug 12;116(6): 953-61. 
 
11. Cinar M, Hamedani F, Mo Z, et al. Bruton tyrosin kinase is commonly overexpressed in mantle cell lymphoma and 
its attenuation by ibrutinib induces apoptosis. Leuk Res 2013 Oct; 37(10):1271-7. 
 
12. Woyach JA, Furman RR, Liu TM, et al. Ibrutinib Resistance in Chronic Lymphocytic Leukemia. N Engl J Med 
2014; 370:2547, June 26, 2014. 
 
13. Chiron D, Di Liberto M, Martin P. Cell-Cycle Reprogramming for PI3K Inhibition Overrides a Relapse-Specific 
C481S BTK Mutation Revealed by Longitudinal Functional Genomics in Mantle Cell Lymphoma. Cancer Discov. 
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14. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting 
conditions. N Engl J Med. 2014 Mar 20;370(12) 
 
15. Morschhauser FA1, Cartron G, Thieblemont C, et al. Obinutuzumab (GA101) monotherapy in relapsed/refractory 
diffuse large b-cell lymphoma or mantle-cell lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 
2013 Aug 10;31(23):2912-9. doi: 10.1200/JCO.2012.46.9585. Epub 2013 Jul 8. 
 
16. Pott C, Hoster E, Delfau-Larue MH, et al. Molecular remission is an independent predictor of clinical outcome in 
patients with mantle cell lymphoma after combined immunochemotherapy: a European MCL intergroup study. 
(2010) Blood 115(16):3215–3223. 
 
17. Pan Z, Scheerens H, Li SJ, et al. Discovery of selective irreversible inhibitors for Bruton's tyrosine kinase. 
ChemMedChem. 2007;2(1):58-61. 
 
18. Honigberg LA, Smith AM, Sirisawad M, et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell 
activation and is efficacious in models of autoimmune disease and B-cell malignancy. 
Proc Natl Acad Sci U S 
A. 2010 Jul 20;107(29):13075-80. 
 
19. Advani RH, Buggy JJ, Sharman JP, Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity 
in patients with relapsed/refractory B-cell malignancies. J Clin Oncol. 2013 Jan 1;31(1):88-94. 
 
20. Wang ML, Rule S, Martin P, et al. Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell 
Lymphoma. N Engl J Med. 2013 Jun 19. 
 
21. Blum KA, Christian B, Flynn JM, et al. A Phase I Trial of the Bruton’s Tyrosine Kinase (BTK) Inhibitor, Ibrutinib 
(PCI-32765), in Combination with Rituximab (R) and Bendamustine in Patients with Relapsed/Refractory Non-
Hodgkin’s Lymphoma (NHL) [abstract]. ASH. December 8-11, 2012. Abstract 1643. 
 
22. Burger JA1, Keating MJ2, Wierda WG Safety and activity of ibrutinib plus rituximab for patients with high-risk 
chronic lymphocytic leukaemia: a single-arm, phase 2 study. Lancet Oncol. 2014 Sep 15(10):1090-9. doi: 
10.1016/S1470-2045(14)70335-3. Epub 2014 Aug 20. 
 
23. Kohrt HE, Sagiv-Barfi I, Rafiq S. Ibrutinib antagonizes rituximab-dependent NK cell- mediated 
cytotoxicity. Blood. 2014 Mar 20;123(12):1957-60. 
 
24. Dubovsky JA1, Beckwith KA, Natarajan G, et al. Ibrutinib is an irreversible molecular inhibitor of ITK 
driving a Th1-selective pressure in T lymphocytes. Blood. 2013 Oct 10;122(15):2539-49. doi: 
10.1182/blood-2013-06-507947. Epub 2013 Jul 25. 
 
25. Eckert C, von Stackelberg A, Seeger K, et al. Minimal residual disease after induction is the strongest 
predictor of prognosis in intermediate risk relapsed acute lymphoblastic leukaemia-long-term results 
of trial ALL-REZ BFM P95/96. Eur J Cancer. 2013 Apr;49(6):1346-55. 
 
26. Böttcher S, Hallek M, Ritgen M, et al. The role of minimal residual disease measurements in the therapy for CLL: is 
it ready for prime time? Hematol Oncol Clin 
North Am. 2013 Apr;27(2):267-88. 
 
27. Scott et al, Blood 2014. Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene 


      
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expression in formalin-fixed paraffin-embedded tissue. Scott DW, Wright GW, Williams PM. Blood. 2014 Feb 
20;123(8):1214-7 
 
28. Cheson et al, Recommendations for Initial Evaluation, Staging and Response Assessment of Hodgkin and Non-
Hodgkin Lymphoma:  The Lugano Classification.  J Clin Onc. 2014: 32(27): 3059-3067.  
 
29. Grommes C, Pastore A, Gavrilovic I.  Single-agent Ibrutinib in Recurrent/Refractory Central Nervous System 
Lymphoma.  ASH Abstracts, Blood.  2016  128:783. 
 
30. Mannina D, Loteta B.  Ibrutinib treatment of mantle cell lymphoma relapsing at central nervous system:  A case 
report and literature review.  Case Rep Hematol.  2017. 
 
31. Bernard S, Goldwirt L, Amorim S, et al.  Activity of ibrutinib in mantle cell lymphoma patients with central 
nervous system relapse.  Blood.  2015 Oct 1; 126(14):1695-8. 
 
32. Ivanova A, Qaqish BF, Schell MJ. Continuous toxicity monitoring in phase II trials in oncology. Biometrics 2005: 
61; 540-545 
 
 
 


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


      
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APPENDIX B. CURRENT NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (CTCAE) 
 
Please use the following link to the NCI CTCAE website: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm