Clinical trial NCT02869633
Conditions: Blastoid Variant Mantle Cell Lymphoma Recurrent Chronic Lymphocytic Leukemia Recurrent Follicular Lymphoma Recurrent Hodgkin Lymphoma Recurrent Mantle Cell Lymphoma Refractory Chronic Lymphocytic Leukemia Refractory Follicular Lymphoma Refractory Hodgkin Lymphoma Refractory Mantle Cell Lymphoma
Sponsor: Vanderbilt-Ingram Cancer Center
Start date: 2016-11-01; Completion date: 2023-10-01
Enrollment: 23 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well ibrutinib works in treating patients after a donor stem cell transplant for lymphoma that is not responding to treatment or has come back. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To study the use of ibrutinib starting between day 60 and day 90 after allogeneic hematopoietic cell transplant (HCT) until 12 months post hematopoietic cell transplant to improve the progression-free survival (PFS) at 12 months post hematopoietic cell transplant by 25% compared to historical controls.

SECONDARY OBJECTIVES:

I. To increase the incidence of successful outcome (defined as lack of requirement of second line therapy for acute graft-versus-host disease, lack of National Institutes of Health \[NIH\] severe chronic graft-versus-host disease, lack of progression or relapse of chronic lymphocytic leukemia/mantle cell lymphoma \[MCL\], lack of death from disease or non-relapse causes) to at least 60% at 1 year post hematopoietic cell transplant. (Cohort A) II. To study the safety and tolerability of ibrutinib post hematopoietic cell transplant in patients with non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma. (Cohort A and B combined) III. To study the incidence of grade 3-4 acute graft-versus-host disease in the first 6 months post hematopoietic cell transplant in patients with non-Hodgkin lymphoma and Hodgkin lymphoma. (Cohort A and B combined) IV. To study the incidence of second line therapy (systemic only) for acute graft-versus-host disease in the first 6 months post hematopoietic cell transplant in patients with non-Hodgkin lymphoma and Hodgkin lymphoma. (Cohort A and B combined) V. To study the incidence of recurrent acute graft-versus-host disease in the first 6 months post hematopoietic cell transplant in patients with non-Hodgkin lymphoma and Hodgkin lymphoma. (Cohort A and B combined) VI. To study the incidence and severity of chronic graft-versus-host disease in the first 12 months post hematopoietic cell transplant in patients with not-Hodgkin lymphoma and Hodgkin lymphoma. (Cohort A and B combined) VII. To study the incidence of lung involvement with graft-versus-host disease in the first 12 months post hematopoietic cell transplant in patients with non-Hodgkin lymphoma and Hodgkin lymphoma. (Cohort A and B combined) VIII. To study the incidence of sclerotic skin chronic graft-versus-host disease in the first 12 months post hematopoietic cell transplant in patients with non-Hodgkin lymphoma and Hodgkin lymphoma. (Cohort A and B combined) IX. To study the incidence of infectious deaths not related to graft-versus-host disease in patients with non-Hodgkin and Hodgkin lymphoma. (Cohort A and B combined)

TERTIARY OBJECTIVES:

I. To study the association of minimal residual disease (MRD) as detected by immunoglobulin heavy chain (IgH) sequencing prior to starting ibrutinib and compare to post ibrutinib at month 6, 9 and 12 after HCT. (Cohort A)

II. To study the impact of onset of new acute or chronic graft-versus-host disease on minimal residual disease. (Cohort A)

III. To study the association of T-cell clonality by T cell receptor (TCR) Vb sequencing prior to starting ibrutinib and compare to post ibrutinib at month 6, 9 and 12 after hematopoietic cell transplant. (Cohort A)

IV. To study the impact of onset of new acute or chronic graft-versus-host disease on T cell receptor sequencing. (Cohort A)

V. To study the association of B cell receptor signaling pathways and immune function with response by single cell mass cytometry prior to starting ibrutinib and compare to post ibrutinib at month 6, 9 and 12 after hematopoietic cell transplant. (Cohort A)

VI. To study the association of single cell mass cytometry that investigates B cell receptor signaling and its association with new acute or chronic graft-versus-host disease on B-cell receptor (BCR) signaling. (Cohort A)

OUTLINE:

Beginning between 60-90 days post donor stem cell transplant, patients receive ibrutinib orally (PO) once daily (QD) until 1 year post donor stem cell transplant in the absence of disease progression or unacceptable toxicity.

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

Arms: arm 1: Beginning between 60-90 days post donor stem cell transplant, patients receive ibrutinib PO QD until 1 year post donor stem cell transplant in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Ibrutinib intervention 2: Laboratory Biomarker Analysis
Intervention descriptions: intervention 1: Given by mouth intervention 2: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
VICC BMT1651 Protocol v7: 2020DEC09 
Page 1 of 107 
Study Title:  Optimizing post-allogeneic hematopoietic cell transplant outcomes for lymphoma using ibrutinib 
IND Number: 130292 
Vanderbilt Protocol Number:  VICCCTT1651 
Sponsor-Investigator:  Bhagirathbhai R. Dholaria, MD 
Co-Investigators: 
•
Vanderbilt: Nishitha Reddy, MD; Olalekan Oluwole, MD; Jonathan Irish, PhD
•
Stanford: David Miklos, MD
•
Dana Farber Cancer Center: Edwin Pascal Alyea, III, MD and Joseph H. Antin, MD
•
MD Anderson Cancer Center: Sairah Ahmed, MD and Chitra Hosing, MD
•
University of Alabama, Birmingham: Luciano Costa, MD, PhD
•
University of Kansas: Joseph McGuirk, DO
Statistician: Heidi Chen, PhD; Center of Quantitative Sciences, Vanderbilt-Ingram Cancer Center 
Providing drug and funding for the study:  Janssen Scientific Affairs, LLC 
Protocol Version:  v7 December 9, 2020 
NCT02869633


VICC BMT1651 Protocol v7: 2020DEC09 
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Table of Contents:  
 
 
 
 
 
 
 
Page Number 
 
1. Synopsis 
 
 
 
 
 
 
 
 
 
3 
2. Introduction 
 
 
 
 
 
 
 
 
 
6 
 
3. Primary Objective 
 
 
 
 
 
 
 
 
7 
4. Secondary and Exploratory Objectives 
 
 
 
 
 
7 
5. Scientific Rationale 
 
 
 
 
 
 
 
 
8 
6. Ibrutinib 
 
 
 
 
 
 
 
 
 
11 
7. Correlative Studies 
 
 
 
 
 
 
 
 
15 
8. Correlative Study Description  
 
 
 
 
 
 
16 
9. Eligibility Criteria: Inclusion 
 
 
 
 
 
 
 
19 
10. Eligibility Criteria: Exclusion  
 
 
 
 
 
 
21 
11. Dose Modification for Adverse Reaction 
 
 
 
 
 
22 
12. Prohibition and Restrictions  
 
 
 
 
 
 
25 
13. Concomitant Medications 
 
 
 
 
 
 
 
26 
14. Management of Immunosuppression  
 
 
 
 
 
27 
15. Management of Corticosteroids 
 
 
 
 
 
 
28 
16. Prophylaxis for Infection 
 
 
 
 
 
 
 
28 
17. Use of Donor Lymphocyte Infusion (DLI) 
 
 
 
 
 
28 
18. Efficacy Measurement 
 
 
 
 
 
 
 
28 
19. Registration of Patient 
 
 
 
 
 
 
 
34 
20. Study Schedule 
 
 
 
 
 
 
 
 
36 
21. Subject Withdrawal 
 
 
 
 
 
 
 
 
44 
22. Study Table 
 
 
 
 
 
 
 
 
 
47 
23. Drug Shipment 
 
 
 
 
 
 
 
 
53 
24. Statistical Analyses Plan 
 
 
 
 
 
 
 
53 
25. Safety Data Collection and Reporting 
 
 
 
 
 
57 
26. Study Administration and Investigator Obligations  
 
 
 
67 
 
Appendices 
Appendix 1 
 
 
 
 
 
 
 
 
 
74 
Appendix 2 
 
 
 
 
 
 
 
 
 
78 
Appendix 3 
 
 
 
 
 
 
 
 
 
87 
References 
 
 
 
 
 
 
 
 
 
106 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1. SYNOPSIS 
 
Title 
Optimizing post-allogeneic hematopoietic cell transplant outcomes for lymphoma using 
ibrutinib 
Background 
Given the emergence of non-hematopoietic cell transplant (HCT) options for this patient 
population, and the relatively high risk of non-relapse mortality (NRM) associated with 
HCT, only patients with advanced disease (and thus at a high risk for post HCT relapse) 
are typically referred for transplant. HCT has become increasingly safe, but relapse post 
HCT and immune mediated disorders after HCT (viz. graft-versus-host disease, GVHD) 
remain the main obstacles to successful outcome. Maintaining control of the neoplasm in 
the early post HCT period until GVT is established should lead to improved outcomes. 
Primary Objective 
 
To study the use of ibrutinib starting between days 60 and day 90 after allogeneic HCT 
until 12 months post HCT to improve the PFS at 12 months post HCT by 25% compared 
to historical controls in patients with MCL and CLL.  
Secondary 
Objective: 
 
• 
CLL/MCL cohort (Cohort A) 
o To increase the incidence of successful outcome (defined as lack of 
requirement of second line therapy for acute GVHD, lack of NIH severe 
chronic GVHD, lack of progression or relapse of CLL/MCL, lack of death from 
disease or non-relapse causes) to at least 60% at 1 y post HCT.  
• 
To study the safety and tolerability of ibrutinib post HCT in patients enrolled on cohort 
A (CLL and MCL) and cohort B (follicular center cell lymphoma [FL] and Hodgkin 
lymphoma [HL]). 
• 
  Acute GVHD 
o To study the incidence of grade 3-4 acute GVHD in the first 6 months post 
HCT in patients with non-Hodgkin and Hodgkin lymphoma (cohort A and B 
combined). 
o To study the incidence of second line therapy (systemic only) for acute GVHD 
in the first 6 months post HCT in patients with non-Hodgkin and Hodgkin 
lymphoma (cohort A and B combined). 
o To study the incidence of recurrent acute GVHD in the first 6 months post 
HCT in patients with non-Hodgkin and Hodgkin lymphoma (cohort A and B 
combined). 
• 
Chronic GVHD 
o To study the incidence and severity of chronic GVHD in the first 12 months 
post HCT in patients with non-Hodgkin and Hodgkin lymphoma (cohort A and 
B combined). 
o To study the incidence of lung involvement with GVHD in the first 12 months 
post HCT in patients with non-Hodgkin and Hodgkin lymphoma (cohort A and 
B combined). 
o To study the incidence of sclerotic skin chronic GVHD in the first 12 months 
post HCT in patients with non-Hodgkin and Hodgkin lymphoma (cohort A and 
B combined) 
• 
To study the incidence of infectious deaths not related to GVHD in patients with non-
Hodgkin and Hodgkin lymphoma (cohort A and B combined). 
• 
Correlative studies 
o Cohort A: To study the association of MRD as detected by IgH sequencing 
prior to starting ibrutinib and compare to post ibrutinib at month 6, 9 and 12 


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after HCT. In addition to study the impact of onset of new acute or chronic 
GVHD on MRD. 
o Cohort A: To study the association of T-cell clonality by T cell receptor (TCR) 
Vb sequencing prior to starting ibrutinib and compare to post ibrutinib at month 
6, 9 and 12 after HCT. In addition to study the impact of onset of new acute or 
chronic GVHD on TCR sequencing. 
o Cohort A: To study the association of B cell receptor signaling  pathways and 
immune function with response by single cell mass cytometry prior to starting 
ibrutinib and compare to post ibrutinib at month 6, 9 and 12 after HCT.  
o Cohort A: To study the association of single cell mass cytometry that 
investigates B cell receptor signaling and its association with new acute or 
chronic GVHD on BCR signaling. 
Inclusion criteria 
• 
Pre-SCT 
o Adult (≥ 18 y) patients undergoing their first T cell replete allo-HCT chronic 
lymphocytic leukemia (CLL), Hodgkin Lymphoma (HL), or the following 
subtypes of Non-Hodgkin lymphoma: Mantle cell lymphoma (MCL) and 
follicular center cell lymphoma (FL) 
o Meeting institutional criteria for allo-HCT. Ejection fraction by echocardiogram 
or MUGA >40%, pulmonary function test with adjusted DLCO ≥ 60% 
o Matched (8/8) or mismatched (7/8) related, unrelated HCT 
o Stem cell source: bone marrow, peripheral blood stem cell  
o Disease criteria:  
Cohort A: 
CLL  
-Disease burden: lymph node size <5cm and/or extra-nodal involvement <5 
cm 
AND 
-17 p deletion (detected by any assay) (≥20% of cells involved if assay is 
conventional cytogenetics or FISH) or NOTCH mutation at any time point 
during disease course. Patient should have received at least 1 line of 
therapy. Prior ibrutinib therapy is permitted.  
OR 
-Relapsed/refractory CLL ≥ 2 lines of therapy. Prior ibrutinib therapy is 
permitted 
 
MCL 
-Disease burden: lymph node size <5 cm and/or extra-nodal involvement < 5 
cm 
AND 
--Relapsed/refractory MCL ≥ 1 line of therapy. Prior ibrutinib therapy is 
permitted. Prior autologous HCT is permitted 
OR 
-MCL blastoid variant in CR1 or MCL being considered for allo HCT in CR1 
 
 
 
 


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Cohort B: 
FL 
- Disease burden: lymph node size <5cm and/or extra-nodal involvement <5 
cm 
AND 
-Relapsed/refractory FL ≥ 2 lines of therapy. Prior ibrutinib therapy is 
permitted 
 
HD 
- Disease burden: lymph node size <5cm and/or extra-nodal involvement <5 
cm 
AND 
-Relapsed/refractory HD ≥ 2 lines of therapy  
 
 
• 
Prior to administration of ibrutinib (day 60 to day 90 post HCT) 
o KPS ≥ 60% 
o Engraftment of neutrophils (ANC ≥ 1.0 X10^9/L) for 3 days without g-csf 
support 
o Platelets ≥100,000/mm3 or ≥50,000/mm3 if bone marrow involvement 
independent of transfusion support in either situation 
o GFR ≥ 30 ml/min 
o LFTs (ALT and AST) ≤ 3 X ULN; total bilirubin ≤ 1.5 mg/dL XULN unless 
bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin 
o Predominant donor chimerisms of ≥ 51% as measured by CD3 and CD33 (or 
other myeloid marker) 
Exclusion criteria 
• 
Pre-SCT 
o Progression of CLL or MCL or FL or HD at time of transplant 
o Use of Coumadin (warfarin) or other vitamin-K antagonists for 
anticoagulation. Non-coumadin anticoagulation is permitted. 
o Active uncontrolled CNS involvement  
o Active uncontrolled bacterial or invasive fungal infections  
o History of malignancy other than the underlying disease unless treated with a 
curative intent and/or no evidence of disease for at least 3 y OR expected to 
be cured with SCT 
o Planned use of post-HCT cyclophosphamide for GVHD prophylaxis 
o Anticipated planned donor lymphocyte infusion in the first 3 months post-SCT 
o T cell depleted HCT 
o Umbilical cord HCT 
o History of stroke or intracranial hemorrhage within 6 months prior to 
enrollment. 
o Clinically significant cardiovascular disease such as uncontrolled or 
symptomatic arrhythmias, congestive heart failure, or myocardial infarction 
within 6 months of Screening, or any Class 3 (moderate) or Class 4 (severe) 
cardiac disease as defined by the New York Heart Association Functional 
Classification. 
 


VICC BMT1651 Protocol v7: 2020DEC09 
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• 
Prior to administration of ibrutinib (day 60 to day 90 post SCT) 
o In the critical care unit, or use of mechanical ventilation or use of renal 
replacement therapy at any time post SCT and prior to administration of 
ibrutinib 
o Active uncontrolled stage 3-4 acute GI GVHD prior to administration of 
ibrutinib 
o Active uncontrolled stage 4 acute liver GVHD prior to administration of 
ibrutinib 
o Evidence of progressive disease as compared to pre-SCT (persistence of 
disease is permitted) 
o Anticipated planned donor lymphocyte infusion in the first 3 months post-SCT 
o Active uncontrolled bacterial or invasive fungal infections  
o Prednisone equivalent of >2mg/kg for treatment of GVHD prior to 
administration of ibrutinib 
o Use of second line systemic therapy for treatment of acute GVHD prior to 
administration of ibrutinib 
o 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 including the presence of chronic/active HBV 
and HBC infections and Child-Pugh Class C. 
o Major surgery or a wound that has not fully healed within 4 weeks of starting 
ibrutinib 
o Requires anticoagulation with warfarin or equivalent vitamin K antagonists 
(e.g., phenprocoumon). 
o Requires chronic treatment with strong CYP3A inhibitors 
o Vaccinated with live, attenuated vaccines within 4 weeks of starting ibrutinib 
Study schedule 
Patients will start ibrutinib at a dose of 420 mg by mouth once a day between day 60-90 
post HCT and continue until 1 y post HCT.  
 
Patients on azoles will start  ibrutinib at a dose of 140 mg by mouth once a day between 
day 60-90 post HCT and continue until 1 year post HCT. 
Patients using Posaconazole as outlined in section 11.2 will start ibrutinib at a dose of 70 
mg by mouth once a day between day 60-90 post HCT and continue until 1 year post 
HCT. 
 
 
2. INTRODUCTION  
 
Chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) represent the heterogeneity of 
B-cell Non-Hodgkin lymphoma, with varying natural histories and pathobiology. Interestingly, targeting 
the B-cell receptor signaling pathway using ibrutinib, a Bruton tyrosine kinase inhibitor, favorably 
impacts both of these diseases1-6. Despite advances in both cytotoxic and immunotherapeutic 
approaches, an allogeneic hematopoietic cell transplant (HCT) is the only curative option7-11. This is 
primarily mediated by graft-versus-tumor (GVT) effect12-14. Given the emergence of non-HCT options for 
this patient population, and the relatively high risk of non-relapse mortality (NRM) associated with HCT, 


VICC BMT1651 Protocol v7: 2020DEC09 
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only patients with advanced disease (and thus at a high risk for post HCT relapse) are typically referred 
for transplant. HCT has become increasingly safe, but relapse post HCT and immune mediated 
disorders after HCT (viz. graft-versus-host disease, GVHD) remain the main obstacles to successful 
outcome. Maintaining control of the neoplasm in the early post HCT period until GVT is established 
should lead to improved outcomes. Use of conventional cytotoxic agents is not practical in the early 
post HCT period.  
 
We propose the following primary objective: to study the use of ibrutinib starting between day 60 and 
day 90 after HCT until 12 months post HCT to improve the progression-free survival (PFS) at 12 
months post HCT by 25% compared to historical controls in patients with of CLL and MCL (cohort A). 
 
GVHD is a complex immune phenomenon that is 
classically defined as acute and chronic and 
affects a variety of organ systems. The initial 
phase of GVHD is primarily T cell mediated. 
Figure 1 shows the various roles of the normal B 
cell. Adequate pre-clinical and clinical data shows 
that B-cell dysfunction contributes to chronic 
GVHD15-20 .  Pre-clinical data shows that part of 
this dysfunction is due to hyper-responsiveness of 
the B-cell receptor (BCR), which can be 
abrogated by disrupting the signaling downstream 
of the BCR21. Thus, it is conceivable that using 
ibrutinib post HCT may not only lead to effective 
tumor control but down modulate GVHD.  Based 
on these data, ibrutinib was studied as a single 
agent for established chronic GVHD 
(NCT02195869) and approved for chronic GVHD after failure of one or more lines of systemic therapy. 
It is likely that the effect on GVHD may be prevalent in patients with other lymphomas as well.  
 
Thus, in the secondary objective:  we propose to study the safety, tolerability and impact on acute and 
chronic GVHD. This aim will encompass diagnoses other than CLL and MCL and will include follicular 
center cell lymphoma (FL) and Hodgkin lymphoma (HL) (Cohort B).  
 
3. 
PRIMARY OBJECTIVE 
 
To study the use of ibrutinib starting between day 60 and day 90 after allogeneic HCT until 12 months 
post HCT to improve the PFS at 12 months post HCT by 25% compared to historical controls. The 
sample size is designed to address this primary endpoint.                      
           
4. 
SECONDARY AND EXPLORATORY OBJECTIVES 
• 
CLL/MCL cohort (Cohort A) 
o To increase the incidence of successful outcome (defined as lack of requirement of second 
line therapy for acute GVHD, lack of NIH severe chronic GVHD, lack of progression or 
relapse of CLL/MCL, lack of death from disease or non-relapse causes) to at least 60% at 1 
year post HCT.  
Figure 1: The various functions of the normal B cell 
in the setting of HCT 


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• 
To study the safety and tolerability of ibrutinib post HCT in patients with non-Hodgkin lymphoma 
(NHL) and HL (cohort A and B combined) 
• 
Acute GVHD 
o To study the incidence of grade 3-4 acute GVHD in the first 6 months post HCT in patients 
with NHL and HL (cohort A and B combined) 
o To study the incidence of second line therapy (systemic only) for acute GVHD in the first 6 
months post HCT in patients with NHL and HL (cohort A and B combined) 
o To study the incidence of recurrent acute GVHD in the first 6 months post HCT in patients 
with NHL and HL (cohort A and B combined) 
• 
Chronic GVHD 
o To study the incidence and severity of chronic GVHD in the first 12 months post HCT in 
patients with NHL and HL (cohort A and B combined) 
o To study the incidence of lung involvement with GVHD in the first 12 months post HCT in 
patients with NHL and HL (cohort A and B combined) 
o To study the incidence of sclerotic skin chronic GVHVD in the first 12 months post HCT in 
patients with NHL and HL (cohort A and B combined) 
• 
To study the incidence of infectious deaths not related to GVHD in patients with non-Hodgkin and 
Hodgkin lymphoma (cohort A and B combined) 
• 
Correlative studies 
o Cohort A: To study the association of MRD as detected by IgH sequencing prior to starting 
ibrutinib and compare to post ibrutinib at month 6, 9 and 12 after HCT. In addition to study 
the impact of onset of new acute or chronic GVHD on MRD. 
o Cohort A: To study the association of T-cell clonality by T cell receptor (TCR) Vb sequencing 
prior to starting ibrutinib and compare to post ibrutinib at month 6, 9 and 12 after HCT. In 
addition to study the impact of onset of new acute or chronic GVHD on TCR sequencing. 
o Cohort A: To study the association of B cell receptor signaling pathways and immune 
function with response by single cell mass cytometry prior to starting ibrutinib and compare 
to post ibrutinib at month 6, 9 and 12 after HCT.  
o Cohort A: To study the association of single cell mass cytometry that investigates B cell 
receptor signaling and its association with new acute or chronic GVHD on BCR signaling. 
 
5. 
SCIENTIFIC RATIONALE 
 
5.1 
Rationale for Use of Ibrutinib Post HCT-Control of Neoplasm 
 
Ibrutinib is a first-in-class, potent, orally administered covalently-binding inhibitor of Bruton’s 
tyrosine kinase (BTK). Inhibition of BTK blocks downstream BCR signaling pathways and thus 


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prevents B-cell proliferation. In vitro, ibrutinib inhibits purified BTK and selected members of the 
kinase family with 10-fold specificity compared with non-
BTK kinases. The phosphorylation and activation of BTK by 
Src family protein kinases (e.g.: LYN, SYK) leads to PLCγ2 
phosphorylation, calcium mobilization and activation of 
downstream pathways (AKT, MAP kinase, NFkB) that leads 
to changes that promote cell differentiation, proliferation and 
survival22;23. Ibrutinib covalently binds to a cysteine residue 
in the BTK active site and irreversibly inhibits BCR signaling 
downstream of BTK. In vivo, ibrutinib reduces the 
phosphorylation of BTK, PLC γ2, AKT, and ERK 
pathways24.  Similar effects were observed in vitro in MCL 
cells. NFkB downregulation was not 
limited to peripheral blood but was also 
noted in bone marrow and lymph nodes. 
BTK is a member of the Tec kinase 
family that transmits signals from 
various cell surface receptors most 
prominently from the BCR. BTK plays a role in the intermediate stages of BCR signaling cascade and is 
commonly overexpressed in MCL and CLL25.  Ibrutinib (IMBRUVICA™) is approved by the U.S. Food 
and Drug Administration (FDA) for the treatment of patients with chronic lymphocytic leukemia (CLL) or 
mantle cell lymphoma (MCL) who have received at least one prior therapy and in CLL patients with del 
17. In January 2015, it was approved for Waldenstrom’s macroglobulinemia. In August 2017, it was 
approved for chronic GVHD after failure of one or more lines of systemic therapy.  Patients undergoing 
HCT remain at a high risk of relapse post-HCT. Continued post-HCT treatment may be of benefit until 
GVT has had a chance to eliminate the neoplasm. Thus, patients on the proposed study will start 
ibrutinib post-HCT, to see if post-HCT use can decrease the risk of relapse or progression.  For the 
most comprehensive nonclinical and clinical information regarding ibrutinib background, safety, 
efficacy, and in vitro and in vivo preclinical activity and toxicology of ibrutinib, refer to the latest version 
of the ibrutinib USPI. 
 
 
5.2 
Rationale for Use of Ibrutinib Post HCT-Impact on GVHD Biology 
 
Ibrutinib is a first-in-class, potent, orally administered covalently-binding inhibitor of Bruton’s tyrosine 
kinase (BTK) and may be a more potent B cell malignancy drug than rituximab4;26. BTK is a critical 
intermediate in BCR signaling 27. It is a non-receptor tyrosine kinase belonging to the Tec family of 
kinases (TFKs), and critical for B cell processes effected by the BCR27. Individuals who lack functioning 
BTK lack circulating B cells and are unable to produce immunoglobulins or mount humoral immune 
responses28. BCR ligation leads to BTK activation which subsequently phosphorylates phospholipase 
Cγ2 (PLCγ2) triggering a series of downstream events including transcriptional regulation involving NF-
κB and NFAT27.BTK appears to regulate B cell survival by triggering the classical pathway in response 
to BAFF under both BCR and BAFF-R signaling29. Ibrutinib is also an irreversible inhibitor of interleukin-
2 inducible kinase (ITK). ITK is involved in proximal T-cell receptor (TCR) signaling which activates the 
signaling cascade that includes NFAT, NFkB, and MAPK pathways resulting in T cell activation. ITK 
has a dominant role in the activation of Th2 cells, but not in Th1 cells. 
 
GVHD is a complex immune phenomenon that is classically defined as acute and chronic and affects a 
Figure 2: Outcome of 46 patients with CLL/MCL after first HCT at 
Vanderbilt University Medical Center. Cumulative incidence of failure by 
1 y post HCT (defined as requirement of second line therapy of acute 
GVHD, development of NIH moderate to severe chronic GVHD, death 
due to relapse/progression, death due to non-relapse causes) was 50%. 


VICC BMT1651 Protocol v7: 2020DEC09 
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variety of organ systems. The initial phase of GVHD is primarily T cell mediated. Figure 1 shows the 
various roles of the normal B cell. Adequate pre-clinical and clinical data shows that B-cell dysfunction 
contributes to chronic GVHD15;17;19;30;31.  Pre-clinical data shows that part of this dysfunction is due to 
hyper-responsiveness of the B-cell receptor (BCR), which can be abrogated by disrupting the signaling 
downstream of the BCR21.  
Thus, it is conceivable that using ibrutinib post HCT, may not only lead to effective tumor control but 
may down modulate GVHD as well.  Ibrutinib was studied as a single agent for established chronic 
GVHD (NCT02195869) and has been approved by the FDA for treatment of chronic GVHD after failure 
of 1 or more systemic therapies. However, the relationship between early ibrutinib use post-
transplantation and the incidence (and severity of) GVHD development has not been examined and 
may impact NRM. The RP2D in patients with established chronic GVHD is 420 mg.  
 
5.3 
Rationale for Duration of Ibrutinib Post HCT 
Although the incidence of complete response (CR) in MCL and CLL in the non-transplant population is 
low1;4-6 , the incidence of CR post HCT is higher. Also, it is expected that GVT will be the final pathway 
to effect cure. The role of ibrutinib post HCT is to maintain effective tumor control until GVT is 
established. In the absence of clinical GVHD, immunosuppressive therapy (IST) is tapered starting at 
day 100, with a goal of IST cessation by 6 months post HCT. Thus, stopping ibrutinib at 12 months post 
HCT in patients who have achieved a CR reflects a time point at which one would expect GVT to be 
established. Also, it is expected that ibrutinib may down modulate chronic GVHD. It is not clear if 
ibrutinib can facilitate transplantation tolerance. We hypothesize that using ibrutinib starting at day 60-
90 post HCT until 12 months post HCT, will increase the incidence of a successful outcome by 25% 
compared to historical controls. The correlative studies will address molecular monitoring of disease (in 
cohort A), mechanisms of relapse of disease and development (or lack of) GVHD.  
 
5.4 
Rationale for Composite Secondary Endpoint  
Typically, IST is continued until day 100 post HCT followed by a planned taper and attempts at IST 
cessation by day 180-day 270. Recurrent acute GVHD, grade 3-4 acute GVHD and severe chronic 
GVHD (as defined by NIH criteria)32 represents the cohort of patients most likely to experience high risk 
of NRM33-35.Patients at high risk of early post HCT relapse or persistence of disease at day 30 post 
HCT are often managed by forced IST tapers to elicit GVT. This often increases the risk of early GVHD 
and sets the stage for chronic GVHD. Although the primary objective of the proposed study is 
improvement in PFS in patients with MCL and CLL, this endpoint is intertwined with risk of NRM from 
GVHD. The sample size is designed to address this primary objective and stopping rules have been 
developed to ensure safety.  In addition, we propose a composite secondary endpoint. A successful 
outcome post HCT is defined as lack of recurrence of the underlying disease with achievement of 
transplantation immunological tolerance, typically documented as cessation of all immunosuppression 
without active GVHD and functional immune reconstitution. As these endpoints can be distant, we 
propose a composite secondary endpoint to be measured at 12 months post HCT with success being 
defined as lack of progression or recurrence of disease, lack of second line therapy for acute GVHD, 
lack of NIH severe chronic GVHD and lack of death. In review of our single center data (2002-2013) of 
46 patients with CLL (N=31) and MCL (N=15) undergoing their first HCT, the cumulative incidence of 
success at 1 y post HCT (lack of relapse or progression, lack of second line therapy for acute GVHD, 
lack of NIH moderate to severe chronic GVHD) was only 50% (Figure 2) (unpublished institutional 
data). 


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6. 
IBRUTINIB 
   
Ibrutinib is a first-in-class, potent, orally administered covalently-binding inhibitor of Bruton’s tyrosine 
kinase (BTK) and interleukin-2-inducible kinase (ITK). Inhibition of BTK blocks downstream BCR 
signaling pathways and thus prevents B-cell proliferation. In vitro, ibrutinib inhibits purified BTK and 
selected members of the kinase family with 10-fold specificity compared with non-BTK kinases. Ibrutinib 
(IMBRUVICA™) is approved by the U.S. Food and Drug Administration (FDA) for the treatment of 
patients with the following conditions: 
• 
Mantle cell lymphoma (MCL) who have received at least one prior therapy.  Accelerated approval 
was granted for this indication based on overall response rate. Continued approval for this 
indication may be contingent upon verification and description of clinical benefit in a confirmatory 
trial.  
• 
Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL)  
• 
Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) with 17p deletion  
• 
Waldenström’s macroglobulinemia (WM) 
• 
Marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior 
anti-CD20-based therapy Accelerated approval was granted for this indication based on overall 
response rate. Continued approval for this indication may be contingent upon verification and 
description of clinical benefit in a confirmatory trial.  
• 
Chronic graft versus host disease (cGVHD) after failure of one or more lines of systemic therapy 
 
6.1 
Summary of Non-Clinical Data   
For the most comprehensive nonclinical and clinical information regarding ibrutinib background, safety, 
efficacy, and in vitro and in vivo preclinical activity and toxicology of ibrutinib, refer to the latest version 
of the ibrutinib USPI. 
 
6.2 
Data on Use of Ibrutinib Post-HCT  
 
NCT02195869 investigated the role of single agent ibrutinib in patients post HCT for established 
steroid–refractory or dependent chronic GVHD, and a dose of 420 mg orally once a day was 
established as the recommended dose for chronic GVHD.  
 
Ibrutinib has been used post HCT for CLL and MCL for management of recurrent disease. Coutre et al 
reported on 16 patients who had received an HCT prior to ibrutinib in studies 1102, 1109, 1112 and 
1117 were pooled to consolidate the experience of treating patients with Ibrutinib after HCT failure. 
Median time since the most recent HCT was 27 months (range, 8-115). Best overall response rate 
(ORR) was 87.5% and was consistent with results observed in the overall /broader population. The 
authors concluded that Ibrutinib was well tolerated in patients who had prior HCT, with a safety profile 
similar to that observed in the overall R/R CLL population. They also presented a case showing a 
patient who achieved donor chimerism (i.e. full acceptance of the donor B Cells) following ibrutinib 
treatment, achieved MRD-ve disease and then interrupted for 10 months without relapse to date36. 
 
Ryan et al reported on 5 patients with CLL relapsing after HCT who were treated with Ibrutinib. All 
patients responded and 2 patients (11q and 17p) have returned to MRD negative status. Three patients 


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have achieved donor chimerism. In addition, there was symptomatic improvement in oral and skin 
chronic GVHD37. 
 
To date, ibrutinib shows clinically meaningful efficacy with a tolerable safety profile. For additional 
information, please see the text below, as well as the USPI and Investigator’s Brochure. 
 
 
6.3 
Drug Information 
 
6.3.1 Pharmacology 
 
Ibrutinib is a small-molecule inhibitor of BTK and ITK. Ibrutinib is a white to off-white solid, and its 
molecular formula is C25H24N6O2 and molecular weight is 440.50 g/mole Both tablet and capsule 
forms are available, and the results of bioequivalence studies may be found in the Investigator’s 
Brochure. Ibrutinib forms a covalent bond with a cysteine residue (Cys-481) in the BTK active site, 
leading to inhibition of BTK enzymatic activity; ibrutinib also binds irreversibly to the equivalent cysteine 
in the ITK pocket BTK is a signaling molecule of the B-cell antigen receptor (BCR) and cytokine 
receptor pathways. BTK’s role in signaling through the B-cell surface receptors results in activation of 
pathways necessary for B-cell trafficking, chemotaxis, and adhesion. Nonclinical studies show that 
ibrutinib inhibits malignant B-cell proliferation and survival in vivo as well as cell migration and substrate 
adhesion in vitro (refer to the current USPI and Investigator’s Brochure).  
 
Ibrutinib was designed as a selective and covalent inhibitor of BTK (Pan 2007). In vitro, ibrutinib is a 
potent inhibitor of BTK activity (IC50 = 0.39 nM). The irreversible binding of ibrutinib to cysteine-481 in 
the active site of BTK results in sustained inhibition of BTK catalytic activity and enhanced selectivity 
over other kinases that do not contain a cysteine at this position. When added directly to human whole 
blood, ibrutinib inhibits signal transduction from the B-cell receptor and blocks primary B-cell activation 
(IC50 = 80 nM) as assayed by anti-IgM stimulation followed by CD69 expression (Herman 2011). 
 
For comprehensive information regarding the nonclinical pharmacology and toxicology of ibrutinib, 
please refer to the current USPI and Investigator’s Brochure. 
 
 
6.3.2 Clinical Pharmacology of Ibrutinib 
 
For the most comprehensive clinical pharmacology information regarding ibrutinib, please refer to the 
current version of the USPI and the Investigator’s Brochure.  
 
 
 
 
6.3.3 Summary of Clinical Safety Data 
 
As of 12 November 2019, ibrutinib has been studied as both a monotherapy and combination therapy in 
53 completed (primary or final analyses) and 17 ongoing company-sponsored studies, 9 early access 
programs (ongoing or completed), and 175 investigator-initiated studies (ongoing or completed). Safety 
data for completed studies is available for 4,439 subjects, of which, 2,132 were treated with ibrutinib 
monotherapy (1,600 subjects with hematologic malignancies, 42 subjects with cGVHD, 460 healthy 


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volunteers, and 30 subjects in a hepatic impairment study). Ibrutinib has been approved in 
approximately 100 countries for 1 or more indications.  
 
Treatment-emergent AEs and adverse events leading to treatment discontinuation were assessed by 
performing an integrated analysis of 1600 subjects with hematologic malignancies treated with ibrutinib 
monotherapy.  
 
Treatment-emergent AEs were observed in 98.8% of subjects taking ibrutinib monotherapy; 86.4% of 
subjects experienced AEs that were considered to be related to ibrutinib treatment by the assessing 
investigator. Grade 3 or 4 and serious AEs were experienced by 70.8%, and 52.9% of subjects, 
respectively, and fatal AEs were reported in 9.9% of subjects.  
Treatment-emergent adverse events (observed in >20% of patients) that were considered by the 
investigator to be related to ibrutinib use were:  
− 
Diarrhea 
− 
Fatigue 
The most commonly reported Grade 3 or 4 treatment-emergent AEs (observed in >5% of patients) 
were:  
− 
Neutropenia 
− 
Pneumonia 
− 
Thrombocytopenia 
− 
Anemia 
− 
Hypertension 
The most common serious treatment-emergency AEs (observed in >2% of patients) were:  
− 
Pneumonia 
− 
Atrial fibrillation 
− 
Pyrexia 
− 
Febrile neutropenia 
− 
Sepsis 
− 
Cellulitis 
Treatment-emergent AEs that most commonly resulted in death (excluding disease progression) were:  
− 
Pneumonia 
− 
Sepsis 
− 
Richter’s syndrome 
− 
Respiratory failure 
− 
Cardiac arrest 
− 
Death (unspecified) 
 
16.8% of patients discontinued ibrutinib due to a treatment-emergent AE. Treatment-emergent AEs that 
most often lead to discontinuation were:  
− 
Pneumonia (1.7%) 
− 
Sepsis (0.8%) 
− 
Thrombocytopenia (0.7%) 
− 
Subdural hematoma (0.6%) 


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Treatment-emergent AEs in patients with cGVHD, steroid-dependent or refractory, were similar to those 
observed in patients with hematologic malignancies. The median and mean duration of ibrutinib 
treatment was 4.4 months and 9.1 months, respectively. Data from 47 patients was included in the 
analysis, and all patients were taking ibrutinib in combination with prednisone.  
Treatment-emergent adverse events (observed in >20% of patients) that were considered by the 
investigator to be related to ibrutinib use were:  
− 
Diarrhea 
− 
Fatigue 
The most commonly reported Grade 3 or 4 treatment-emergent AEs (observed in >5% of patients) 
were: 
− 
Pneumonia 
− 
Fatigue 
− 
Diarrhea 
− 
Cellulitis 
− 
Hyperglycemia 
− 
Hypokalemia 
 
 
The most common serious treatment-emergency AEs (observed in >2% of patients) were: 
− 
Pneumonia 
− 
Cellulitis 
− 
Dyspnea 
− 
Headache 
− 
Septic Shock 
Fatal treatment-emergent AEs were observed in 2 subjects (4.8%): bronchopulmonary aspergillosis 
(considered related) and pneumonia (considered unrelated). 
42.9% of patients (18 subjects) discontinued ibrutinib due to at least 1 treatment-emergent AE. The 
most common treatment-emergent AEs that led to discontinuation were: 
− 
Fatigue (4.8%) 
− 
Pneumonia (4.8%) 
For additional information on the clinical safety of ibrutinib, refer to the ibrutinib Investigator’s Brochure. 
 
6.4 
Formulation/Packaging/Storage 
The white opaque 140 mg and 70 mg capsules marked with “ibr 140 mg” or “ibr 70 mg” respectively in 
black ink are available in white HDPE bottles with a child-resistant closure: 
Store bottles at room temperature 20°C to 25°C (68°F to 77°F). Excursions are permitted between 
15°C and 30°C (59°F to 86°F). Retain in original package until dispensing. 
6.5 
Dose and Administration 
 
Ibrutinib will be administered at a dose of 420 mg by mouth once a day starting between day 60-90 post 
HCT and continue until 1y post HCT. Ibrutinib is dispensed as 140 mg capsules and patients will be 


VICC BMT1651 Protocol v7: 2020DEC09 
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instructed to take 3 capsules by mouth once a day. Patients will be instructed to take the drug at 
approximately the same time every day. Patients will be instructed to swallow the capsules whole with 
water and not to open, break or chew the capsules. 
 
If a dose of ibrutinib is not taken at the scheduled time, it can be taken as soon as possible on the same 
day with a return to the normal schedule the following day. Extra capsules of ibrutinib should not be 
taken to make up for the missed dose.  
 
For patients on azoles, the starting dose will be 140 mg by mouth once a day starting between day 60-
90 post HCT and continue until 1y post HCT.   
 
Patients using Posaconazole as outlined in section 11.2 will start ibrutinib at a dose of 70 mg by mouth 
once a day between day 60-90 post HCT and continue until 1 year post HCT. 
 
6.6 
Overdose 
 
Any dose of study drug in excess of that specified in this protocol is considered to be an overdose. 
Signs and symptoms of an overdose that meet any Serious Adverse Event criterion must be reported 
as a Serious Adverse Event in the appropriate time frame and documented as clinical sequelae to an 
overdose. There is no specific antidote for ibrutinib. In the event of an overdose, subjects should be 
closely monitored and given appropriate supportive treatment. 
 
7. 
CORRELATIVE STUDIES (COHORT A ONLY)  
 
7.1 
Molecular Monitoring for Minimal Residual Disease 
 
Molecular monitoring using immunoseqMRD testing (refer to Study Schedule) will be done at pre-
specified endpoints for CLL and MCL patients (cohort A) and will be considered as standard of care.  
 
7.2 
Molecular Monitoring in Presence of Relapse/Progression for CLL and MCL Patients (Cohort A) 
 
Patients suspected of relapse or progression of disease typically undergo histological confirmation. If 
there is histological presence of disease, these samples from lymph node, BM or other areas will be 
sent for immunoseqMRD testing to try and identify any clonal shift at time of relapse. This may allow us 
to gain insight into mechanisms of ibrutinib and escape from GVT effect. 
 
7.3 
Molecular Studies for T-cell Repertoire Analyses Using IMMUNOSEQ 
 
Molecular studies for T-cell repertoire analyses using IMMUNOSEQ will be considered a research test 
and will be done at pre-specified endpoints (refer to Study Schedule). This will be done in all patients in 
cohort A. 
 
CyTOF Analyses 
 
• 
For patients in CR (Cohort A): We will employ single-cell mass cytometry to gain a more 
complete understanding of the impact of ibrutinib on B cell subsets and signalling post SCT 
 


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• 
For patients in CR (Cohort A): We will employ single-cell mass cytometry to gain a more 
complete understanding of the impact of ibrutinib and GVHD on T cell subsets and signalling 
post SCT 
 
• 
For patients with relapse/progression post HCT (cohort A): We will employ single-cell mass 
cytometry to gain a more complete understanding of the impact of ibrutinib on B cell subsets 
and identification of signalling pathways that escape BTK inhibition 
CyTOF studies will be coordinated by Irish Lab at Vanderbilt University 
 
7.4 
Correlative Sample Collection and Handling 
The actual dates and time and appropriate laboratory parameters must be recorded in the electronic 
clinical trial database. See the Laboratory Manual for appropriate processing and shipping 
instructions. 
 
8. 
CORRELATIVE STUDY DESCRIPTION  
 
8.1 
immunoseqMRD 
 
 immunoseqMRD analysis involves amplification of immunoglobulin heavy chain (IGH) loci using 
consensus V and J segment primers 
followed by high-throughput 
sequencing (HTS) 38, enabling 
quantification with a detection limit of 
one cell per million mononuclear cells. 
Both peripheral blood and marrow 
aspirate can be used for this assay. 
This next-generation sequencing 
method has been used with success 
for monitoring MRD in multiple 
lymphoid malignancies39;40.  
immunoseqMRD sequencing-based 
MRD assessment provides greater 
sensitivity compared to traditional 
MRD detection methods, such as flow 
cytometry and allele-specific oligonucleotide PCR approaches38.  Moreover, the prognostic value of 
MRD assessment by sequencing in patients with chronic lymphocytic leukemia41, multiple myeloma39, 
acute lymphocytic leukemia42 and diffuse large B-cell lymphoma43 has been demonstrated.  
Dr. Miklos and Stanford investigators pioneered immunoglobulin heavy chain high throughput 
sequencing (IGH-HTS) technologies to provide ultrasensitive CLL MRD detection44;45. Minimal Residual 
Disease (MRD) was quantified by the commercially available CLONOSIGHT method (Sequenta) with a 
sensitivity of 1 CLL clone in a million blood WBC. Beginning at 9 months post-transplant, MRD detected 
at 10-6 or higher (at least one CLL clone per million PBMC genomes) indicates a significant risk of 
relapse46. As shown in Figure 3, the 
one-year post allo-HCT detection of 
CLL by CLONOSIGHT is highly 
predictive of CLL relapse (p=0.0002). 
Figure 3: Disease free survival is predicted by MRD (as detected by 
ClonoSIGHT) at 1 y post HCT 


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In patients with chronic GVHD, there is often production of alloreactive antibodies. This has been 
demonstrated by the Miklos lab, using gender mismatch HCT as a model30;47;48.  
 
We propose to correlate the presence of HY antibodies with clonal diversity as measured by the 
Immunoseq assay.  
 
8.2 
Immunoseq 
 
ImmunoSeq Assays illuminate the adaptive immune system with controlled Multiplex PCR amplification 
and high throughput sequencing of T-cell receptors combined with sophisticated bioinformatics. 
 
8.3 
CyTOF 
 
Although B cell dysfunction has been implicated in the pathogenesis of chronic GVHD, the role of B-cell 
dysfunction in acute GVHD remains less well defined. Acute GVHD is typically thought of as a T cell 
mediated process, with complex interactions through antigen presenting cell (APC) populations, 
regulatory T cells (T regs), B cell immune response and cytokine secretion.  Very recently, a new 
technology has been developed for the analysis of complex cell subsets, termed single-cell mass 
cytometry using the DVS CyTOF mass cytometer. Figure 4 shows a schematic of the CyTOF 
technology. This allows a systems level description of immune response through the simultaneous 
measurement of more than thirty cell surface marker proteins. The Irish lab has expertise in this 
technology and has used this assay in single cell interrogation in lymphoma and more specifically in 
BCR signalling49-51. 
 
 
 
 
 
Appendix 1: Figures 5 to 8 outline the utility of CyTOF in not only dissecting the BCR signaling network 
but also to generate 2 dimensional heat-maps of 34+ dimensional data. The Irish lab has proven 
expertise in B cell biology using CyTOF. 
• 
We will employ single-cell mass cytometry to gain a more complete understanding of the impact 
of ibrutinib on B cell subsets and signalling post SCT 
Figure 4: Workflow of CyTOF technology. Cells in single cell suspension are labelled with 
antibody conjugates tagged to chelated elemental isotope. Each cell can be tagged with 34 
probes and thus the output reflects 34+ dimensional single cell analyses. Both surface and 
intracellular targets can be interrogated. 


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• 
We will employ single-cell mass cytometry to gain a more complete understanding of the impact 
of ibrutinib and GVHD on T cell subsets and signalling post SCT 
 
It is anticipated that this may provide novel insights into the changes induced by ibrutinib on the 
immune system in the early post SCT period.   
 
Samples will be analysed through a collaborative effort with Drs. Dholaria and Irish (both at Vanderbilt 
University). Single-cell mass cytometry will be used to analyse blood taken from patients prior to 
administration of ibrutinib, day 100 post SCT, and at month 6 post HCT. If patients develop new onset 
acute or chronic GVHD while on ibrutinib, an additional sample will be collected. We will objectively 
assess cellular heterogeneity from single-cell measurement data using an established computational 
approach, spanning-tree progression analysis of density-normalized events (SPADE) and ViSNE. In 
this work, we will ensure that all cell surface markers previously implicated in GVHD are included in the 
analysis. Single-cell mass cytometry will be carried out using the DVS CyTOF mass cytometer in the 
Flow Cytometry Core facility at Vanderbilt University. Dr. Irish’s laboratory has validated a B-cell panel 
to interrogate B cell dysfunction in the context of lymphoma (see Figures 6-8, Appendix 1). We expect 
that the same panel of B cell markers to give us adequate insight into the effect of ibrutinib on BCR 
signaling in the post-HCT period. In addition, we will interrogate cell subsets to include Th1, Th2, Treg, 
Th17, T effector cells, CD4+ T cell subsets (naïve, effector, memory, and central memory), antigen 
presenting cells, dendritic cells, and macrophages. Following core hematopoietic surface markers (12) 
have been validated by the (CD3, CD4, CD8, CD11b, CD19, CD20, CD38, CD45, CD45RA, CD90, 
CD123, HLADR). In addition, the following 15 markers are available (CD16, CD25, CD27, CD28, CD36, 
CD39, CD56, CD95, CD103, CTLA4, CD161, CD62L, CD14). Eight intracellular epitopes from mitogen 
pre-activated cells can be interrogated (IFN-gamma, TNF-alpha, IL-10, IL-17, FoxP3, IL-6, IL-4, and IL-
13). This will allow us to get a complete picture of the interaction of ibrutinib on the T cell subsets in the 
post HCT setting. 
 
9. 
ELIGIBILITY CRITERIA: INCLUSION 
 
Pre-SCT 
 
1. Adult (≥18 y) patients undergoing their first T cell replete allo-HCT for chronic lymphocytic 
leukemia (CLL), Hodgkin Lymphoma (HL), or the following subtypes of Non-Hodgkin lymphoma: 
Mantle cell lymphoma (MCL) and follicular center cell lymphoma (FL) 
 
2. Meeting institutional criteria for allo-HCT. Ejection fraction by echocardiogram or MUGA >40%, 
pulmonary function test with adjusted DLCO ≥ 60% 
 
3. Matched (8/8) or mismatched (7/8) related, unrelated HCT 
 
4. Stem cell source: bone marrow, peripheral blood stem cell  
 
5. Disease criteria:  
 
Cohort A: 
 
CLL  


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• 
Disease burden: lymph node size <5cm and/or extra-nodal involvement <5 cm 
 
AND 
 
• 
17 p deletion (detected by any assay) (≥20% of cells involved if assay is 
conventional cytogenetics or FISH) or NOTCH mutation at any time point during 
disease course. Patient should have received at least 1 line of therapy. Prior 
ibrutinib therapy is permitted.  
 
OR 
 
• 
Relapsed/refractory CLL ≥ 2 lines of therapy. Prior ibrutinib therapy is permitted 
 
MCL 
• 
Disease burden: lymph node size <5 cm and/or extra-nodal involvement < 5 cm 
 
• 
Relapsed/refractory MCL ≥ 1 line of therapy. Prior ibrutinib therapy is permitted. 
Prior autologous HCT is permitted. 
 
• 
MCL blastoid variant in CR1 or high risk MCL being considered for allo HCT in 
CR1 
 
 
 
Cohort B: 
 
FL 
• 
Disease burden: lymph node size <5cm and/or extra-nodal involvement <5 cm 
 
AND 
 
• 
Relapsed/refractory FL ≥ 2 lines of therapy. Prior ibrutinib therapy is permitted. 
 
HD 
• 
Disease burden: lymph node size <5cm and/or extra-nodal involvement <5 cm 
 
AND 
 
• 
Relapsed/refractory HD ≥ 2 lines of therapy  
 
6. Preparative regimen: both reduced intensity and ablative regimens are permitted. Each center 
will pre-specify the regimen they intend to use during the conduct of the study 
 
7. Donor criteria: HLA ≥ 7/8 related or unrelated donors.  
 
8. 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 


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agree to not donate sperm during and after the study. For females, these restrictions apply for 1 
month after the last dose of study drug. For males, these restrictions apply for 3 months after 
the last dose of study drug. 
 
9. 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. 
 
10. Sign (or their legally-acceptable representatives must sign) an informed consent document 
indicating that they understand the purpose of and procedures required for the study, including 
biomarkers, and are willing to participate in the study. 
 
11. Prior to administration of ibrutinib (day 60 today 90 post HCT) 
• 
KPS ≥ 60% 
• 
Engraftment of neutrophils (ANC ≥ 1.0 X10^9/L) for 3 days without g-csf support 
• 
Platelets ≥100,000/mm3 or ≥50,000/mm3 if bone marrow involvement independent of 
transfusion support in either situation 
• 
GFR ≥ 30 ml/min 
• 
LFTs (ALT and AST) ≤3 X ULN; total bilirubin ≤ 1.5 mg/dL X ULN unless bilirubin rise is 
due to Gilbert’s syndrome or of non-hepatic origin 
• 
Predominant donor chimerisms of ≥ 51% as measured by CD3 and CD33 (or other myeloid 
marker) 
 
10. 
ELIGIBILITY CRITERIA: EXCLUSION  
 
Pre-SCT 
 
1. Progression of CLL or MCL or FL or HD at time of transplant 
 
2. Use of Coumadin (warfarin) or other vitamin-K antagonists for anticoagulation. Non-coumadin 
anticoagulation is permitted. 
 
3. Known CNS involvement  
 
4. Active uncontrolled bacterial or invasive fungal infections  
 
5. History of malignancy other than the underlying disease unless treated with a curative intent 
and/or no evidence of disease for at least 3 y OR expected to be cured with SCT 
 
6. Planned use of post-HCT cyclophosphamide for GVHD prophylaxis 
 
7. Anticipated planned donor lymphocyte infusion in the first 3 months post-SCT 
 
8. T deplete HCT 
 
9. Umbilical cord HCT 
 
10. History of stroke or intracranial hemorrhage within 6 months of enrollment. 


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11. Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, 
congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 
(moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association 
Functional Classification. 
 
12. Known HIV 
 
13. Active Hepatitis B or C virus 
 
14. Child-Pugh Class C 
 
Prior to Administration of Ibrutinib (Day 60-Day 90 Post SCT) 
 
1. In the critical care unit, or use of mechanical ventilation or use of renal replacement therapy at 
any time post HCT and prior to administration of ibrutinib 
 
2. Active uncontrolled stage 3-4 acute GI GVHD prior to administration of ibrutinib 
 
3. Active uncontrolled stage 4 acute liver GVHD prior to administration of ibrutinib 
 
4. Evidence of progressive disease as compared to pre-HCT (persistence of disease is permitted) 
 
5. Anticipated planned donor lymphocyte infusion in the first 3 months post-SCT 
 
6. Active uncontrolled bacterial or invasive fungal infections  
 
7. Prednisone equivalent of >2m/kg for treatment of GVHD prior to administration of ibrutinib 
 
8. Use of second line systemic therapy for treatment of acute GVHD prior to administration of 
ibrutinib 
 
9. 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 including the 
presence of chronic/active HBV and HBC infections and Child-Pugh Class C. 
 
10. Major surgery or a wound that has not fully healed within 4 weeks of starting ibrutinib 
 
11. Requires anticoagulation with warfarin or equivalent vitamin K antagonists 
(e.g., phenprocoumon). 
 
12. Requires chronic treatment with strong CYP3A inhibitors 
 
13. Vaccinated with live, attenuated vaccines within 4 weeks of starting ibrutinib 
 
 


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11. 
DOSE MODIFICATIONS  
 
11.1  Dose Modifications for Adverse Reactions 
 
Interrupt IMBRUVICA therapy for any Grade 3 or greater non-hematological, Grade 3 or greater 
neutropenia with infection or fever, or Grade 4 hematological toxicities. Once the symptoms of the 
toxicity have resolved to Grade 1 or baseline (recovery), IMBRUVICA therapy may be reinitiated at the 
starting dose. If the toxicity reoccurs, reduce dose by one capsule (140 mg per day). A second 
reduction of dose by 140 mg may be considered as needed. If these toxicities persist or recur following 
two dose reductions, discontinue IMBRUVICA. 
The dose of ibrutinib will be modified according to the dose modification guidelines in the table below if 
any of the following toxicities occur: 
 
Parameter for 
which dose is 
being modified 
Dose 
modification 
duration 
Dose restarting 
parameters 
Dose to be 
restarted 
Comments 
Grade 3 ANC 
(<1,000/ μL) with 
an associated 
temperature of 
≥38.5°C 
Hold ibrutinib 
Restart after 7 
days provided 
ANC ≥ 1,000/ μL 
and patient is 
afebrile for at least 
72 hrs. 
Level -1 
If toxicity is felt to be 
due to ibrutinib 
Grade 4 ANC 
(<500/μL) for more 
than 7 days 
Hold ibrutinib 
Restart after 14 
days provided 
ANC ≥ 500/ μL for 
at least 7 days 
Level -2 
 
If toxicity is felt to be 
due to ibrutinib 
Grade 3 
thrombocytopenia 
(<50,000/μL) in the 
presence of Grade 
≥2 bleeding events 
Hold ibrutinib 
Restart after 14 
days provided 
platelet count 
≥50,000/μL and no 
bleeding for at 
least 7 days 
Level -2 
If patient is on 
concomitant 
anticoagulation 
therapy, stabilize the 
anticoagulation 
therapy (if it was 
restarted) before 
ibrutinib is restarted 
Grade 4 
thrombocytopenia 
(<25,000/μL) 
Hold ibrutinib 
Restart after 14 
days provided 
platelet count ≥ 
50,000/ μL for at 
least 7 days 
Level -2 
 
Grade 3 or 4 
nausea, vomiting, 
or diarrhea if 
persistent, despite 
optimal anti-emetic 
and/ or anti-
diarrheal therapy 
 
Hold ibrutinib 
Restart after 14 
days provided 
toxicity is at grade 
2 or lower for at 
least 7 days 
Level-2 
Acute or chronic 
GVHD may cause 
nausea, vomiting, 
diarrhea and needs to 
be ruled out. If toxicity 
is attributed to GVHD 
and resolves drug can 
be restarted at dose 
level -1. Similarly, 
diarrhea can be due 
to Clostridium difficile 
colitis-if yes, no dose 


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Parameter for 
which dose is 
being modified 
Dose 
modification 
duration 
Dose restarting 
parameters 
Dose to be 
restarted 
Comments 
reduction may be 
necessary 
Any other Grade 4 
or unmanageable 
Grade 3 toxicity 
attributed to 
ibrutinib 
Hold ibrutinib 
Discontinue drug 
(level -3) 
Not applicable 
None 
Dose Levels: 
• 
Dose level 0 = 420 mg po qd 
• 
Dose level -1 = 280 mg po qd 
• 
Dose level -2 = 140 mg po qd 
• 
Dose level -3 =discontinue drug 
 
For patients starting with 140 mg qd (due to concomitant moderate CYP3A inhibitor or azole use as 
outlined in section 11.2) 
 
• 
Dose level 0 = 140 mg po qd 
• 
Dose level -1 = 70mg po qd 
• 
Dose level -2 = 70 mg po qod 
• 
Dose level -3 = discontinue 
 
If a patient was on 140 mg po qd (due to concomitant azole use) and then stopped azole, the dose will 
be increased to 420 mg po qd. This will not be considered a dose escalation. 
 
For patients starting with 70 mg qd (due to concomitant Posaconazole use as out lined in section 11.2) 
• 
Dose level 0 = 70 mg po qd 
• 
Dose level -1 = 70 mg po qod 
• 
Dose level -2 = discontinue 
 
11.2 
Dose Modifications for Use with CYP3A Inhibitors 
 
Avoid co-administration with strong or moderate CYP3A inhibitors and consider alternative agents with 
less CYP3A inhibition.  
 
Concomitant use of strong CYP3A inhibitors which would be taken chronically (e.g., ritonavir, indinavir, 
nelfinavir, saquinavir, boceprevir, telaprevir, nefazodone) is not recommended. For short-term use 
(treatment for 7 days or less) of strong CYP3A inhibitors (e.g., antifungals and antibiotics) consider 
interrupting IMBRUVICA therapy until the CYP3A inhibitor is no longer needed.  
 
Reduce IMBRUVICA dose to 140 mg if a moderate CYP3A inhibitor must be used (e.g., fluconazole, 
darunavir, erythromycin, diltiazem, atazanavir, aprepitant, amprenavir, fosamprevir, crizotinib, imatinib, 
verapamil, and ciprofloxacin).  
 


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Patients taking concomitant strong or moderate CYP3A inhibitors should be monitored more closely for 
signs of IMBRUVICA toxicity. 
As most post-HCT patients are expected to be on azoles (fluconazole, voriconazole or lower 
doses of posazconazole as outlined in the table below) until day 100 after HCT, the dose of 
IMBRUVICA will be 140 mg per day. For patients receiving higher doses of posaconazole as 
outlined below, the dose of IMBRUVICA will be 70 mg per day. Once these agents are stopped, 
the dose will be escalated to 420 mg per day.  
 
11.3 
Dose Modifications for Hepatic Impairment 
. For patients with mild liver impairment (Child-Pugh class A), the recommended dose is 140 mg daily 
(one capsule). Avoid the use of IMBRUVICA in patients with moderate or severe hepatic impairment 
(Child-Pugh classes B and C). 
 
12. 
PROHIBITION 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 planned surgery or invasive procedure requiring sutures or staples for closure, ibrutinib 
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 surgical site is reasonably 
healed without serosanguineous drainage or the need for drainage tubes.   
 


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• 
For planned minor procedures (such as a central line placement, needle biopsy, thoracentesis, or 
paracentesis) ibrutinib should be held for at least 3 days prior to the procedure and should not be 
restarted for at least 3 days after the procedure. For bone marrow biopsies that are performed while 
the subject is on ibrutinib, it is not necessary to hold ibrutinib for these procedures. 
 
• 
For emergency procedures, ibrutinib should be held after the procedure until the surgical site is 
reasonably healed, for at least 7 days after the urgent surgical procedure, or at the discretion of the 
investigator. 
 
13. 
CONCOMITANT MEDICATIONS 
 
13.1 
Permitted Concomitant Medications 
 
Supportive medications in accordance with standard practice (such as for emesis, diarrhea, etc.) are 
permitted. Use of neutrophil growth factors (filgrastim and pegfilgrastim or other biosimilar GCSF) or 
red blood cell growth factors (erythropoietin) is permitted per institutional policy and in accordance with 
the ASCO guidelines. Transfusions may be given in accordance with institutional policy.  
 
13.2 
Medications to be Used with Caution 
 
CYP3A Inhibitors/Inducers 
Concomitant use of ibrutinib and drugs that strongly or moderately inhibit CYP3A can increase 
ibrutinib exposure, and strong CYP3A inhibitors should be avoided. In healthy volunteers, co-
administration of ketoconazole, a strong CYP3A inhibitor, increased Cmax and AUC of ibrutinib by 29- 
and 24-fold, respectively.  
 
Voriconazole and posaconazole can be used concomitantly with ibrutinib, with dose modifications as 
described above in Section 11.2. 
 
Strong inhibitors of CYP3A (eg, ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, 
telithromycin, itraconazole, nefazodone, and cobicistat) should be avoided, and an alternative with less 
CYP3A inhibitory potential should be considered.  
 
For strong CYP3A inhibitors used short-term (e.g., antifungals and antibiotics for 7 days or less, e.g., 
ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin) consider 
interrupting IMBRUVICA therapy during the duration of inhibitor use.  
 
Concomitant use of strong CYP3A inhibitors which would be taken chronically (e.g., ritonavir, indinavir, 
nelfinavir, saquinavir, boceprevir, telaprevir, nefazodone) is not recommended.  
 
Patients taking concomitant strong or moderate CYP3A4 inhibitors should be monitored more closely 
for signs of IMBRUVICA toxicity.Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as 
these contain moderate inhibitors of CYP3A.  
 
Administration of ibrutinib with strong inducers of CYP3A decreases ibrutinib plasma 
concentrations by up to 90%. Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, 
rifampin, phenytoin and St. John’s Wort). Consider alternative agents with less CYP3A induction. 
 


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A comprehensive list of inhibitors, inducers, and substrates may be found at 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx. This website is continually revised and should be 
checked frequently for updates. 
 
13.3 
Drugs That May Have Their Plasma Levels Altered by Ibrutinib 
 
In vitro studies indicated that ibrutinib is a weak reversible inhibitor toward CYP2B6, CYP2C8, 
CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 and does not display time-dependent CYP inhibition. 
The dihydrodiol metabolite of ibrutinib is a weak inhibitor toward CYP2B6, CYP2C8, CYP2C9, and 
CYP2D6. Both ibrutinib and the dihydrodiol metabolite are at most weak inducers of CYP450 
isoenzymes in vitro. Therefore, it is unlikely that ibrutinib has any clinically relevant drug-drug 
interactions with drugs that may be metabolized by the CYP450 enzymes. 
 
In vitro studies indicated that ibrutinib is not a substrate of P-glycoprotein (P-gp), but is a mild inhibitor 
(with an IC50 of 2.15 μg/mL). Ibrutinib is not expected to have systemic drug-drug interactions with P-
gp substrates. However, it cannot be excluded that ibrutinib could inhibit intestinal P-gp after a 
therapeutic dose. There is no clinical data available. Therefore, to avoid a potential interaction in the GI 
tract, narrow therapeutic range P-gp substrates such as digoxin, should be taken at least 6 hours 
before or after ibrutinib. 
 
13.4 
Antiplatelets and Anticoagulants 
Fatal bleeding events have occurred in patients treated with IMBRUVICA includinggrade 3 or higher 
bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria and post procedural 
hemorrhage).IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or 
anticoagulant therapies. 
 
Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery 
depending upon the type of surgery and the risk of bleeding. 
 
Warfarin or vitamin K antagonists should not be administered concomitantly with ibrutinib. Supplements 
such as fish oil and vitamin E preparations should be avoided. Use ibrutinib with caution in subjects 
requiring other anticoagulants or medications that inhibit platelet function. Subjects with congenital 
bleeding diathesis have not been studied. Ibrutinib should be held at least 3 to 7 days pre- and post-
surgery depending upon the type of surgery and the risk of bleeding (refer to the Concomitant 
Medications section). 
 
Subjects requiring the initiation of therapeutic anticoagulation therapy (other than warfarin or a vitamin 
K antagonist) during the course of the study should have treatment with ibrutinib held, and ibrutinib 
should not be restarted until the subject is clinically stable. Subjects should be observed closely for 
signs and symptoms of bleeding. No dose reduction is required when study drug is restarted. 
 
13.5 
Prohibited Concomitant Medications 
Any chemotherapy, anticancer immunotherapy, experimental therapy, or radiotherapy is 
prohibited while the subject is receiving ibrutinib treatment. Localized, hormonal, or bone 
sparing treatment for non-B-cell malignancies may be considered with approval of the PI. 
 
Warfarin or vitamin K antagonists should not be administered concomitantly with ibrutinib. 


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14. 
MANAGEMENT OF IMMUNOSUPPRESSION 
Participants may be receiving other immunosuppressive therapies (including extra-corporeal 
photopheresis [ECP]) in addition to glucocorticoids. In addition, due to potential drug-drug interactions 
with ibrutinib, drug levels for immunosuppressant agents such as cyclosporine, tacrolimus, and/or 
sirolimus are highly recommended during the clinical trial. The doses for these immune-suppressants 
should be adjusted per institutional practices based on the measured drug level.  
 
Other strategies of GVHD therapy including PUVA, UVB light therapy, topical use of calcineurin 
inhibitors (e.g. for ocular GVHD) is permitted. 
15. 
MANAGEMENT OF CORTICOSTEROIDS 
 
Systemic steroids may be decreased at the treating physician’s discretion. Non-absorbable oral 
steroids will be allowed and recorded. 
 
16. 
PROPHYLAXIS FOR INFECTION 
 
Prophylaxis for infections, including routine monitoring for CMV, EBV will be done per institutional 
practice. Pre-emptive therapy for CMV will be per institutional practice.  
 
Given the interaction of ibrutinib with azoles, please refer to dose modification section for 
appropriate dosing guidelines of ibrutinib. 
 
17. 
USE OF DONOR LYMPHOCYTE INFUSION (DLI) 
 
Use of DLI for mixed chimerism will be at the discretion of the treating physician. Ibrutinib will be held 
for at least 7 days prior to DLI and resumed at least after 14 days post DLI. Anticipated planned donor 
lymphocyte infusion in the first 3 months post-HCT is an exclusion criterion. 
 
18. 
EFFICACY MEASUREMENT 
 
18.1 
A review committee led by Nishitha Reddy, MD, MS (Vanderbilt University) will review all response 
assessments. Cases requiring review of imaging studies will be done in coordination by Dr. Reddy and 
a radiologist from the individual centers. 
 
18.2 
The primary endpoint is to study the use of ibrutinib starting between days 60 to day 90 after allogeneic  
HCT until 12 months post HCT to improve the PFS at 12 months post HCT by 25% compared to 
historical controls in patients with MCL and CLL.    
 
18.3 
The following established definitions of relapse, recurrence and responses will be used for CLL.52  
 
18.3.1 Progressive Disease is Defined if One of the Criteria is Documented€: 
 
• 
The appearance of a new enlarged node >1.5 cm, splenomegaly or hepatomegaly * 
 
• 
An increase of 50% or more in size if a previously involved site (lymph node, spleen or liver)^ 
 


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• 
Richter’s transformation documented by lymph node biopsy 
 
• 
Development of neutropenia, anemia or thrombocytopenia attributable to CLL§  
€  The iwCLL definition of PD defined as an increase of 50% or more in the total circulating 
lymphocyte count with absolute lymphocyte count of >5000/µl or greater has been deleted as 
patients are to receive the B-cell receptor kinase inhibitor  
*  Post allogeneic stem cell transplantation, patients may develop adenopathy that can be 
attributable to other causes (infections, inflammatory state). Adenopathy should be 
attributable to CLL by the investigator.^  
^  A lymph node that was 1 to 1.5 cm previously must increase by 50% or more to a size greater 
than 1.5 to 2.0 cm in the longest axis  
§   Cytopenias cannot be used to determine disease progression in the presence of other 
immunosuppressive therapies. The cytopenias are defined as a decrease in hemoglobin level 
by more than 2 g/dl (20g/L) or to less than 10 g/dl (100g/L) or a decrease in platelet count to 
less than 100,000µl (100x109/L) in the presence of clonal CLL infiltrates on the bone marrow 
biopsy. 
 
18.3.2 Complete Remission Requires All of the Following Criteria:  
 
• 
Absolute lymphocyte count <4000/microL (4 x 109/L).  
 
• 
No lymph nodes >1.5 cm in diameter.  
 
• 
No hepatomegaly or splenomegaly.  
 
• 
No constitutional symptoms attributable to CLL.* 
 
• 
Bone marrow recovery as demonstrated by ANC >1500/microL (1.5 x 109/L), platelet count 
>100,000/microL (100 x 109/L), and hemoglobin concentration >11 g/dL (110 g/L) in the 
absence of transfusion or growth factor support.  
 
• 
Bone marrow free of clonal CLL cells by conventional flow cytometry and/or 
immunohistochemistry and without nodular lymphoid aggregates. 
 
*  Constitutional symptoms include ≥10% unintentional weight loss within the previous six months, 
fatigue that interferes with work or usual activities, fevers greater than 100.5°F (>38°C) for ≥2 weeks, 
or night sweats for >1 month. Note that in our trial, patients are post allogeneic stem cell 
transplantation and may have these symptoms that are not a result of CLL but attributable as a 
primary or secondary cause related to allogeneic stem cell transplant. The cause of these symptoms 
should be documented by the investigator.  
 
 


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18.3.3. Partial Remission: At Least One of These Criteria Must be Documented:  
• 
A decrease in the peripheral absolute lymphocyte count by at least 50% from the level prior to 
therapy.  
 
• 
A reduction in previously enlarged nodes by at least 50% with no increase in the size of any 
single lymph node and no new enlarged lymph nodes. An increase of <25% in a lymph node <2 
cm is not considered significant.  
 
• 
If enlarged prior to therapy, the liver and spleen should be reduced in size by at least 50%.  
 
One of the following hematologic parameters must be met in addition to one of the above criteria in 
order to qualify for a PR:  
 
 
 
• 
ANC ≥1500/microL (1.5 x 109/L) or greater than 50% improvement over baseline (if this value 
was abnormally low at baseline) without granulocyte colony-stimulating factor support.  
 
• 
Platelet count ≥100,000/microL (100 x 109/L) or at least 50% improvement over baseline (if this 
value was abnormally low at baseline).  
 
• 
Hemoglobin concentration ≥11 g/dL (110 g/L) or 50% improvement over baseline (if this value 
was abnormally low at baseline) without red blood cell transfusions or erythropoietin support.  
 
Note: Partial remission with Lymphocytosis: PR criteria with the exception of ALC are met is 
consistent with a PR with lymphocytosis. 
 
 
18.3.4 Nodular Partial Remission:  
 
Persistent bone marrow nodules on bone marrow biopsy in patients achieving a CR or PR. Lymphoid 
aggregates should be evaluated with immunohistochemistry to determine whether they are comprised 
of CLL cells, lymphocytes other than CLL cells, or T cells. 
 
18.3.5 Stable Disease:  
 
Patients, who do not meet the criteria for a complete remission, partial remission, or progressive 
disease, have stable disease. Stable disease is therapeutically equivalent to a nonresponse (i.e., 
refractory disease). 
 
18.4 
The Following Established Definitions of Relapse, Recurrence and Responses Will Be Used for  
MCL and FL 
 
18.4.1 Progressive disease or relapse is defined if one of the criteria is documented (either 
PET/CT or CT can be used).  
 
 
 


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PET-Based Response:  
 
• 
Progressive metabolic disease 
 
• 
Score of 4 or 5 (on a 5-point scale) with an increase in intensity of uptake from baseline and /or  
 
• 
New FDG-avid foci consistent with lymphoma rather than another etiology (infection, 
inflammation). If uncertain regarding etiology of new lesions, biopsy or interval scan may be 
considered. 
CT-Based Response:  
• 
An individual node/lesion must be abnormal with an LDi > 1.5 cm and Increase by > 50% from 
PPD nadir and an increase in LDi or SDi from nadir (0.5 cm for lesions < 2 cm, 1.0 cm for 
lesions > 2 cm) 
 
• 
In the setting of splenomegaly, the splenic length must increase by > 50% of the extent of its 
prior increase beyond baseline (for e.g., a 16-cm spleen must increase to > 17.5 cm). If no prior 
splenomegaly, must increase by at least 2 cm from baseline¥ 
 
• 
New or recurrent splenomegaly 
 
• 
New or clear progression of preexisting non-measured lesions 
 
• 
A new node >1.5 cm in any axis 
 
• 
A new extranodal site >1.0 cm in any axis; if <1.0 cm in any axis its presence must be 
unequivocal and must be attributed to lymphoma.  
 
• 
Assessable disease of any size unequivocally attributable to lymphoma  
 
• 
New or recurrent Bone marrow involvement 
¥ Spleen size baseline 13 cm in vertical length 
LDi: longest transverse diameter of a lesion; SDi: Shortest axis perpendicular to LDi; PPD: cross 
product of LDi and SDi.  
 
18.4.2 Complete remission is defined by the following criteria (should meet all criteria) 
PET-Based Response: 
 
• 
Complete metabolic response with a score of 1, 2 or 3 with or without residual mass on a 5-
point scale  
 
 
CT-Based Response:  
 


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• 
Target nodes/nodal masses must regress to <1.5 cm in LDi 
 
• 
No extralymphatic sites of disease 
 
• 
Absence of non-measured lesions 
 
• 
No new lesions 
 
• 
Bone marrow normal by morphology and if indeterminate, IHC negative 
 
 
18.4.3 Partial Remission is defined by the following criteria:  
 
 
PET-Based Response 
 
• 
Score 4 or 5 with reduced uptake compared with baseline and residual mass(es) of any size 
 
 
CT-Based Response 
 
• 
50% decrease in SPD of up to six target measurable nodes and extranodal sites £ 
 
 
£ 
When a lesion is too small to measure on scan, 0.5x0.5 cm is the default value, if  
no longer visible 0x0 cm, for a node greater than 0.5 x0.5 cm but smaller than normal 
use the actual measurement for calculation. 
 
• 
Spleen must have regressed by >50% in length beyond normal 
 
 
 
Stable disease:  
 
 
PET-based response 
 
• 
No metabolic response with a score of 4 or 5 on the five point scale  
 
 
CT-based response 
 
• 
>50% decrease from baseline in SPD of up to 6 dominant, measurable nodes and extranodal 
sites; no criteria for progressive disease are met 
 
 
18.5 
The following established definitions of relapse, recurrence and responses will be used for HD 
 
Progressive disease or relapse is defined if one of the criteria is documented (either PET/CT or CT can 
be used)  
 
PET-Based response:  
• 
Progressive metabolic disease 
 


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• 
Score of 4 or 5 (on a 5-point scale) with an increase in intensity of uptake from baseline  
 
and /or  
 
• 
New FDG-avid foci consistent with lymphoma rather than another etiology (infection, 
inflammation). If uncertain regarding etiology of new lesions, biopsy or interval scan may be 
considered. 
CT based response:  
• 
An individual node/lesion must be abnormal with an LDi > 1.5 cm and Increase by> 50% from 
PPD nadir and an increase in LDi or SDi from nadir (0.5 cm for lesions < 2 cm, 1.0 cm for 
lesions > 2 cm) 
 
• 
In the setting of splenomegaly, the splenic length must increase by > 50% of the extent of its 
prior increase beyond baseline (for e.g., a 16-cm spleen must increase to > 17.5 cm). If no prior 
splenomegaly, must increase by at least 2 cm from baseline¥ 
 
• 
New or recurrent splenomegaly 
 
• 
New or clear progression of preexisting non-measured lesions 
 
• 
A new node >1.5 cm in any axis 
 
• 
A new extranodal site >1.0 cm in any axis; if <1.0 cm in any axis its presence must be 
unequivocal and must be attributed to lymphoma  
 
• 
Assessable disease of any size unequivocally attributable to lymphoma  
 
• 
New or recurrent Bone marrow involvement 
¥ Spleen size baseline 13 cm in vertical length 
LDi: longest transverse diameter of a lesion; SDi: Shortest axis perpendicular to LDi; PPD: cross 
product of LDi and SDi.  
 
Complete remission is defined by the following criteria (should meet all criteria) 
 
PET-based response: 
 
• 
Complete metabolic response with a score of 1, 2, or 3 with or without residual mass on a 5-
point scale  
 
CT- based response:  
 
• 
Target nodes/nodal masses must regress to < 1.5 cm in LDi 
 
• 
No extralymphatic sites of disease 


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• 
Absence of non-measured lesions 
 
• 
No new lesions 
 
• 
Bone marrow normal by morphology and if indeterminate, IHC negative 
  
  
Partial Remission is defined by the following criteria:  
 
  
PET-based response 
 
• 
Score 4 or 5 with reduced uptake compared with baseline and residual mass(es) of any size 
 
  
CT-based response 
 
• 
>50% decrease in SPD of up to six target measurable nodes and extranodal sites £ 
 
£ 
When a lesion is too small to measure on scan, 0.5x0.5 cm is the default value, if no longer visible 
0x0 cm, for a node greater than 0.5 x0.5 cm but smaller than normal use the actual measurement 
for calculation. 
  
 
• 
Spleen must have regressed by >50% in length beyond normal 
  
 
  
Stable disease is defined by the following criteria:  
 
  
PET-based response 
 
• 
No metabolic response with a score of 4 or 5 on the five-point scale  
 
  
CT-based response 
 
• 
>50% decrease from baseline in SPD of up to 6 dominant, measurable nodes and extranodal 
sites; no criteria for progressive disease are met 
 
Footnote: A score of 3 in many patients indicates a good prognosis with standard treatment, especially 
if at the time of an interim scan. However, in trials involving PET where de-escalation is investigated, it 
may be preferable to consider a score of 3 as inadequate response to avoid under treatment 
 
19. 
REGISTRATION OF PATIENT 
 
Each center will decide at time of study activation their preferred preparative regimens for HCT and 
complete the preparative regimen selection worksheet. Centers will not be allowed to deviate from their 
standard during the conduct of the study. Regimens will be stratified as reduced intensity (RIC), 
myeloablative (MAC) for related (matched and mismatched) and unrelated (matched and mismatched). 
 
Prior to registration, a copy of the IRB approval at the site will be requested and kept on file at the 


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Vanderbilt-Ingram Cancer Center (VICC) Coordinating Center. Eligible participants will be entered on 
study centrally at the VICC Coordinating Center. All sites should email the Coordinating Center at 
Coordinating.Center@Vanderbilt.edu to verify slot availability prior to enrollment.  
 
All patients MUST be registered with the VICC prior to the start of the preparative regimen and 
again prior to start of protocol treatment. Registration can only be conducted during the 
business hours of 8AM – 5PM Central Standard Time Monday through Friday. 
 
1) All sites must email the VICC CTSR Coordinating Center at 
Coordinating.Center@Vanderbilt.edu to notify of upcoming registration and ensure slot 
availability. The following information should be included in your email: 
• 
Study number 
• 
Patient initials 
• 
Disease type  
• 
Anticipated consent date 
Anticipated start date 
2) If a subject ID number is required prior to patient enrollment (i.e. at screening due to sample 
collection requirement), the site must submit the following documents with their email 
notification to the Coordinating Center: 
• 
Copy of the patient’s signed and dated Informed Consent including documentation of the 
consent process. 
• 
HIPAA authorization form (if separate from the main consent form) 
• 
VICC Patient Enrollment Form 
The Coordinating Center will then provide a subject ID number via email. 
 
3) Email the following documents to the Coordinating Center for eligibility review and patient 
enrollment (coordinating.center@vanderbilt.edu): 
• 
Copy of the patient’s signed and dated Informed Consent, including documentation of the 
consent process. 
• 
HIPAA authorization form (if separate from the main consent form) 
• 
VICC Patient Enrollment Form 
• 
Eligibility supporting documents such as pathology reports, laboratory tests, etc. or EMR 
access. Note: all source documents should be de-identified and screening/subject ID 
number added prior to sending. 
• 
Tissue Block Registration Form (see the Lab Manual) 
• 
Signed and completed Eligibility Checklist. To be eligible for registration to the study, the 
participant must meet each inclusion and exclusion criterion listed in the eligibility 
checklist.  
Note: All study documents should be received 24-48 hours prior to the patient’s anticipated start date. 
Same day treatment registrations will only be accepted with prior notice and discussion with the 
Coordinating Center. Please email the Coordinating Center if enrollment is needed sooner. 
 
Upon satisfactory review of eligibility documents submitted, the Coordinating Center will approve 
enrollment and issue a subject ID number if one was not issued at screening. Once 
registration/enrollment confirmation from Coordinating Center is received, proceed with protocol 
procedures. 
 


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Please contact the assigned Study Contact with any questions regarding this process. You can also 
reach out to your assigned CRA once the study is activated. 
 
The VICC Coordinating Center will assign Subject ID numbers to all patients whose eligibility has been 
confirmed.  Only patients deemed eligible will be registered to investigational treatment.  
 
Sequence/study ID numbers will not be re-used if a patient screen fails. Following registration, eligible 
participants should begin study treatment consistent with the protocol no later than [XXX days/weeks] 
after registration/enrollment by the VICC Coordinating Center. If a participant does not receive protocol 
therapy following registration within the allowed time period, the participant’s registration on the study 
will be canceled. The Study Contact should be notified of cancellations as soon as possible. Patients 
being re-screened will need to consent to repeated procedures. As such, the Coordinating Center will 
require a new, signed Informed Consent document.  
 
Issues that would cause treatment delays should be discussed with the Protocol Chair. Any requests 
for eligibility exceptions and/or deviations must be approved in writing by the Protocol Chair and the 
VICC DSMC.  
 
As is generally accepted, standard of care procedures performed prior to consent, but within the 
protocol defined screening window for each assessment, can be used for study purposes. All research-
only procedures must be performed after patient consent.  
 
 
20. STUDY SCHEDULE 
 
Informed Consent 
 
• 
The subject must read, understand, and sign the Institutional Review Board/Research Ethics 
Board/Independent Ethics Committee (IRB/IEC) approved informed consent form (ICF) confirming 
his or her willingness to participate in this study before any study-specific screening procedures 
are performed. Performance of procedures considered standard of care within window of 
screening but prior to consent will be permitted. Subjects must also grant permission to use 
protected health information per the Health Insurance Portability and Accountability Act (HIPAA). 
 
• 
In addition, subjects must sign all approved ICF amendments per the site IRB/IEC guidelines 
during the course of the study. 
 
 
 
Confirm Eligibility 
 
• 
Eligibility will be confirmed pre-HCT and then second confirmation will be prior to administration of 
ibrutinib between day 60-90 post-HCT. 
 
• 
Complete enrollment checklist and submit to coordinating center for review prior to enrollment. 
Preparative regimen for HCT should not be started until enrollment checklist has been reviewed 
and approved by coordinating center. A minimum of 48 hour notice will be mandated. 
 


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• 
Second confirmation: Complete enrollment checklist and submit to coordinating center for review 
and approval prior to start of ibrutinib between day 60-90 post-HCT. Ibrutinib will not be started 
until enrollment checklist has been reviewed and approved by coordinating center. A minimum of 
48 hour notice will be mandated. 
 
Pre-SCT: Screening visit:  
 
All research studies to be completed within 4 weeks of starting preparative regimen unless specified 
otherwise.  Timing of all pre-SCT standard of care assessments may be completed per the institutional 
practice. 
 
• 
Standard of care: History and physical including Karnofsky performance status (KPS) (See the 
Clinical Assessment Manual) 
 
• 
Standard of care: Transplant evaluation: follow institutional protocol on timing of evaluation prior to 
HCT and at a minimum will include: 
 
o Hematology 
 
Hematology parameters performed at local laboratory will include a complete blood 
count: white blood cells, red blood cells, hemoglobin, hematocrit, platelets, and 
absolute neutrophil count. 
 
o Chemistry 
 
Serum chemistry parameters performed at local laboratory will include: creatinine, 
AST, ALT, alkaline phosphatase, and total bilirubin.  
 
o Coagulation studies 
 
Measurement of prothrombin time (PT)/INR, and activated partial thromboplastin 
time (aPTT) will be performed at local laboratory at Screening. 
 
o Hepatitis serologies 
 
Hepatitis serologies include Hepatitis C antibody, Hepatitis B surface antigen, 
Hepatitis B surface antibody, and Hepatitis B core antibody will be evaluated by local 
laboratory. If Hepatitis B core antibody or Hepatitis B surface antigen is positive, then 
Hepatitis B PCR to quantitate Hepatitis B DNA must be performed. DNA PCR needs 
to be confirmed negative prior to enrollment in subjects who are Hepatitis B core 
antibody positive or Hepatitis B surface antigen positive. 
 
 
o Pregnancy test for women of child bearing potential 
 
Serum pregnancy tests are required at Screening by local laboratory and only for 
women of childbearing potential. If positive, pregnancy must be ruled out by 
ultrasound to be eligible.  
 
o EKG and Echo  
 
At baseline, per inclusion criterion patients must have an ejection fraction by 
echocardiogram or MUGA of ≥ 40%. EKGs should be performed at the investigator’s 


VICC BMT1651 Protocol v7: 2020DEC09 
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discretion, particularly in subjects with arrhythmic symptoms (eg, palpitations, 
lightheadedness) or new onset of dyspnea.  
 
o Pulmonary function tests 
 
PFT should be done as part of transplant evaluation per institutional criteria and at a 
minimum report FeV1%, FeV1/FVC ratio and DLCO %. Patients should have a 
DLCO of ≥ 60% per inclusion criterion. 
 
o Quantitate immunoglobulins including IgG, IgM and IgA 
 
o Peripheral blood T-cell, B-cell and NK cell subsets (CD3+, CD4+, CD8+, CD19+, CD16/56+) 
 
• 
Standard of care: Disease assessment: Data forms for CIBMTR (CLL Form 2013 R2.0, 10 pages 
or other lymphomas: Form 2018 Revision 3, 17 pages) will be made available to the coordinating 
center (see appendix 2 and 3 respectively). Alternatively, detailed disease assessment data will be 
entered directly into the electronic database.  
 
• 
Standard of care: DNA sample from recipient and donor to establish allele markers for post HCT 
chimersim analyses. 
 
• 
Research: a peripheral blood sample on all patients should be sent for immunoseqMRD analysis 
(see the Laboratory Manual). This specimen will serve as a baseline to track neoplastic clones 
post HCT.  Diagnostic sample from disease onset (paraffin block of lymph node only is applicable), 
if available must be sent for immunoseqMRD analyses (See the Laboratory Manual).  
 
• 
Research: Toxicity assessment will be done to establish baseline severities. 
 
• 
Research: Peripheral blood sample will be sent to coordinating center for CYTOF analyses. See 
the Laboratory Manual for detailed instruction on collection, processing and shipping. 
 
• 
Research: BM aspirate in patients with active marrow disease will be sent to coordinating center 
for CYTOF analyses. See the Laboratory Manual for detailed instruction on collection, processing 
and shipping. 
 
• 
Research: Complete enrollment checklist and submit to coordinating center for review prior to 
enrollment. Preparative regimen for HCT should not be started until enrollment checklist has been 
reviewed by coordinating center 
 
• 
Research: Toxicity assessment will be done at screening to establish baseline 
 
• 
Research: concomitant medication data will be obtained to establish baseline 
 
Start of preparative regimen to day +60 post-HCT: 
 
• 
Standard of care: History and physical and KPS (See the Clinical Assessment Manual.) 
 
• 
Standard of care: weekly assessment of acute GVHD (and chronic GVHD if applicable) KPS (see 
the Clinical Assessment Manual). KPS will be recorded every 2 weeks. 


VICC BMT1651 Protocol v7: 2020DEC09 
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• 
Standard of care: Disease reassessment between day 30 and day 60 will include: appropriate 
imaging (CT scan and/or PET scan or other imaging) and bone marrow biopsy.  
 
• 
Standard of care: PB should be sent for chimerism analyses. Ablative transplants will require only 
% recipient vs. donor. RIC HCT will require sorted chimerism (CD 3: % recipient vs. donor and 
CD33 [or other suitable myeloid lineage markers]: % recipient vs. donor) 
 
• 
Research: BM aspirate from patients with active marrow disease will be sent to coordinating center 
for CyTOF analyses. See the Laboratory Manual for detailed instruction on collection, processing 
and shipping. The BM biopsy and aspiration itself is considered standard of care. 
 
• 
Research: Toxicity assessment will be done every 2 weeks 
 
• 
Research: concomitant medication data will be obtained every 2 weeks 
 
Prior to administration of ibrutinib (day 60-90): (All studies to be done within 2 weeks of starting 
ibrutinib) 
 
• 
Standard of care: Following should be done within 2 weeks prior to starting ibrutinib 
 
o History and physical and KPS (see the Clinical Assessment Manual). KPS will be recorded 
every 2 weeks during this time period. 
 
o Hematology 
 
Hematology parameters performed at local laboratory will include at a minimum a 
complete blood count: white blood cells, red blood cells, hemoglobin, hematocrit, 
platelets, and absolute neutrophil count. 
 
o Chemistry 
 
Serum chemistry parameters performed at local laboratory will include at a minimum: 
creatinine, AST, ALT, alkaline phosphatase, and total bilirubin  
 
o Coagulation studies 
 
Measurement of prothrombin time (PT)/INR, and activated partial thromboplastin time 
(aPTT) will be performed at local laboratory at Screening 
 
 
o Pregnancy test for women of child bearing potential 
 
Serum pregnancy tests are required at Screening by local laboratory and only for women 
of childbearing potential. If positive, pregnancy must be ruled out by ultrasound to be 
eligible.  
 
o EKG  
 
EKGs should be performed at the investigator’s discretion, particularly in subjects with 
arrhythmic symptoms (e.g., palpitations, lightheadedness) or new onset of dyspnea. 
 
o Quantitative immunoglobulins including IgG, IgM and IgA 


VICC BMT1651 Protocol v7: 2020DEC09 
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o Peripheral blood T-cell, B-cell and NK cell subsets (CD3+, CD4+, CD8+, CD19+, CD16/56+) 
 
o Continue weekly assessment of acute GVHD (see the Clinical Assessment Manual) 
 
o Chronic GVHD assessment (see the Clinical Assessment Manual) using NIH 2015 forms for 
diagnosis and scoring of chronic GVHD 
 
 
Please note: For patients who come off study prior to start of Ibrutinib, an End of Study visit should be 
completed as outlined under “12 Months post HCT or earlier if withdrawing from the study” 
 
Research: Following should be done within 2 weeks prior to starting ibrutinib 
 
• 
 Peripheral blood samples on all patients should be sent for Immunoseq for T-cell receptor and for 
immunoseqMRD analysis. See the Laboratory Manual for sample acquisition, processing and 
shipping logistics. 
 
• 
Research: A peripheral blood sample will be collected for CyTOF analyses. See the Laboratory 
Manual for detailed instruction on collection, processing and shipping. 
 
• 
Research: Complete enrollment checklist and submit to coordinating center for review prior to 
enrollment. Ibrutinib should not be started until enrollment checklist has been reviewed by 
coordinating center. 
 
• 
Research: Toxicity assessment will be done and continued every 2 weeks during this time period 
weeks 
 
• 
Research: Concomitant medication data will be obtained and continued every 2 weeks during this 
time period 
 
Post-ibrutinib (start of ibrutinib until 1 y post HCT). All studies to be done within +/- 1 week of the 
planned time-points 
 
• 
Standard of care: History and physical including Karnofsky performance status (KPS) (see the 
Clinical Assessment Manual) will be done monthly until month 6 and then at month 9 
 
• 
Standard of care: Following should be done weekly for 4 weeks and then monthly until 6 
months post HCT and then at month 9 after starting ibrutinib 
 
o Hematology 
 
Hematology parameters performed at local laboratory will include at a minimum a 
complete blood count: white blood cells, red blood cells, hemoglobin, hematocrit, 
platelets, and absolute neutrophil count. 
 
o Chemistry 
 
Serum chemistry parameters performed at local laboratory will include at a minimum: 
creatinine, AST, ALT, alkaline phosphatase, and total bilirubin. 


VICC BMT1651 Protocol v7: 2020DEC09 
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• 
Standard of care: To be done at month 6 and 9 post-HCT Peripheral blood T-cell, B-cell and NK 
cell subsets (CD3+, CD4+, CD8+, CD19+, CD16/56+) 
 
• 
Research: Following should be done at month 6 and 9 after starting ibrutinib 
 
o A peripheral blood sample on all patients should be sent for Immunoseq for T-cell receptor. 
See the Laboratory Manual for sample acquisition, processing and shipping logistics. 
 
o Research: a peripheral blood sample will be collected for CyTOF analyses. See the 
Laboratory Manual for detailed instruction on collection, processing and shipping. 
 
• 
Toxicity assessment:  
 
o Research: Toxicity assessment will be done on first day of administration of ibrutinib to 
establish post-HCT baseline.  
 
o Research: Toxicity assessment will be done weekly after the start of ibrutinib until day 100 
post HCT or at least 4 weeks post-ibrutinib (whichever is longer) 
 
o Research: Toxicity assessment will be done monthly until 12 months post HCT. Month 7,8, 
10, and 11 toxicity assessment can be done telephonically if a patient is unable to travel 
back to the transplant center. A final toxicity assessment will be conducted 12 months post 
HCT. 
 
o Concomitant  medication use will be recorded at month 6 and month 9 
 
• 
Acute GVHD assessment 
o Standard of care: weekly assessment of acute GVHD until day 100 (+/- 1     week) post HCT 
or at least 4 weeks post-ibrutinib (whichever is longer). See the Clinical Assessment Manual 
for acute GVHD assessment forms 
 
• 
Chronic GVHD assessment 
 
o Standard of care: Assessment at month 6 and 9 post HCT. NIH 2015 diagnosis and scoring 
forms will be used. See the Clinical Assessment Manual for chronic GVHD assessment 
forms 
 
o Research: a peripheral blood sample on all patients (in cohort A only) should be sent for 
IMMUNOSEQ for T-cell receptor and immunoseqMRD for MRD analyses if a new diagnosis 
of chronic GVHD is made and ideally before starting new therapy. This may happen in 
between the planned assessment time points. See the Laboratory Manual for collection, 
processing and shipping details. 
 
o Research: a peripheral blood sample on all patients (in cohort A only) should be sent for 
CyTOF analyses if a new diagnosis of chronic GVHD is made and ideally before starting 
new therapy. This may happen in between the planned assessment time points. See the 
Laboratory Manual for collection, processing and shipping details 


VICC BMT1651 Protocol v7: 2020DEC09 
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• 
Disease reassessment 
 
o Standard of care: disease reassessment at month 6 and 9 post HCT per institutional criteria 
and may include imaging (CT scan and/or PET scan or other imaging) as indicated 
 
o Chimerism analyses 
 
Standard of care: Assessment at months 6 and 9. Peripheral blood should be sent 
for chimerism analyses. Ablative transplants will require only % recipient vs. donor. 
RIC HCT will require sorted chimersims (CD 3: % recipient vs. donor and CD33 [or 
other suitable myeloid lineage markers]: % recipient vs. donor) 
 
o MRD analyses 
 
Research: Assessment at months 6 and 9 post HCT. A peripheral blood sample on 
all patients should be sent for immunoseqMRD analysis. See the Laboratory Manual. 
 
• 
Suspected relapse 
 
o Research: BM aspirate (5 ml in EDTA) in patients with active marrow disease will be sent to 
the coordinating center. See the Clinical Assessment Manual for detailed instruction on 
collection, processing and shipping. 
 
o Research: Tumor biopsy performed for suspected relapse should be collected and sent to 
coordinating center for CyTOF and IMMUNOSEQ.  See the Laboratory Manual for detailed 
instruction on collection, processing and shipping. 
 
o Research: Peripheral blood samples on Cohort A patients should be sent for IMMUNOSEQ 
for T-cell receptor and immunoseqMRD analyses at end of study, only if it has been more 
than 4 weeks from previous research sample for this assay. See the Laboratory Manual for 
collection, processing and shipping details. 
 
o Research: A peripheral blood sample on all patients should be sent for CyTOF analyses 
only if it has been more than 4 weeks from previous research sample for this assay. See the 
Laboratory Manual for collection, processing and shipping details. 
 
 
 
 
At the time of new diagnosis of acute or chronic GVHD (from start of ibrutinib until 1 y post-HCT) 
 
• 
Standard of care: Assessment of acute GVHD (See the Clinical Assessment Manual if applicable.) 
 
• 
Standard of care: Assessment of chronic GVHD (See the Clinical Assessment Manual if 
applicable.) 
 
• 
Research: Peripheral blood samples on all patients (cohort A only) should be sent for 
IMMUNOSEQ for T-cell receptor and for immunoseqMRD analysis if a new diagnosis of acute or 
chronic GVHD is made and ideally before starting new therapy. This may happen in between the 


VICC BMT1651 Protocol v7: 2020DEC09 
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planned assessment time points. See the Laboratory Manual for collection, processing and 
shipping details. 
 
• 
Research: peripheral blood sample on all patients (cohort A only) should be sent for CyTOF 
analyses if a new diagnosis of acute or chronic GVHD is made and ideally before starting new 
therapy. This may happen in between the planned assessment time points. See the Laboratory 
Manual for collection, processing and shipping details. 
 
12 Months post HCT or earlier if withdrawing from the study (including withdrawal prior to initiation of 
Ibrutinib) 
 
• 
Standard of care:  
 
o History and physical, KPS (see the Clinical Assessment Manual) 
 
o Hematology 
 
Hematology parameters performed at local laboratory will include at a minimum a 
complete blood count: white blood cells, red blood cells, hemoglobin, hematocrit, 
platelets, and absolute neutrophil count. 
 
o Chemistry 
 
Serum chemistry parameters performed at local laboratory will include at a minimum: 
creatinine, AST, ALT, alkaline phosphatase, and total bilirubin  
 
o Quantitative immunoglobulins including IgG, IgM and IgA 
 
o Peripheral blood T-cell, B-cell and NK cell subsets (CD3+, CD4+, CD8+, CD19+, CD16/56+) 
 
o Assessment of acute GVHD (see the Clinical Assessment Manual) if applicable 
 
o Assessment of chronic GVHD (see the Clinical Assessment Manual) if applicable. NIH 2015 
diagnosis and scoring forms will be used.  
 
o Disease reassessment has to be done for end of study only if prior disease assessment is 
more than 4 weeks prior to end of study. Disease reassessment will include: appropriate 
imaging (CT scan and/or PET scan or other imaging) as clinically indicated and bone 
marrow biopsy. PB should be sent for chimerism analyses. Ablative transplants will require 
only % recipient vs. donor. RIC HCT will require sorted chimersims (CD 3: % recipient vs. 
donor and CD33 or lineage specific marker: % recipient vs. donor) 
 
• 
Research:  
 
o Peripheral blood samples on all patients should be sent for Immunoseq for T-cell receptor 
and immunoseqMRD analysis. See the Laboratory Manual for sample acquisition, 
processing and shipping logistics. 
 
o Research: A peripheral blood sample will be collected for CyTOF analyses. See the 
Laboratory Manual for detailed instruction on collection, processing and shipping. 


VICC BMT1651 Protocol v7: 2020DEC09 
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• 
Research: Toxicity assessment for ibrutinib 
 
o Research: Toxicity assessment will be done. In addition, toxicity assessment will be done 30 
days after cessation of ibrutinib.  
 
o Concomitant  medication use will be recorded 
 
HCT outcome (from 1 yr. post HCT until 2 yr. post HCT) 
 
• 
Chronic GVHD assessment: 
 
o Standard of care: assessment per institutional standard.  
 
o If new diagnosis of chronic GVHD or new organ involvement, coordinating center needs 
to be informed within 1 month of occurrence. NIH 2014 diagnosis and scoring forms will 
be used. See the Clinical Assessment Manual for details. 
 
• 
Disease reassessment: 
 
o Standard of care: assessment per institutional standard 
 
o If evidence of progression or relapse, coordinating center needs to be informed within 1 
month of occurrence 
 
o Suspected relapse 
 
 
Research: Although not required by protocol, BM aspirate in patients with active 
marrow disease will be sent to the coordinating center. See the Laboratory Manual 
for detailed instruction on collection, processing and shipping. 
 
 
Research: Although not required by protocol, tumor biopsy performed for suspected 
relapse should be collected and sent to coordinating center.  See the Laboratory 
Manual for detailed instruction on collection, processing and shipping. 
 
• 
Survival 
 
o Standard of care: At months 18 and 24 post HCT, coordinating center will be informed of 
survival status: alive without disease, alive with disease (if new relapse/progression, date of 
event). If patient died between month 12 and 24, coordinating center will be notified within 2 
weeks of event, with date and cause of death (disease or non-relapse) 
 
21. 
SUBJECT WITHDRAWAL 
 
21.1 
Withdrawal from Study Treatment 
 
Study treatment will be withdrawn if: 
 


VICC BMT1651 Protocol v7: 2020DEC09 
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• 
Patient experiences relapse or progression of underlying disease while on ibrutinib, and further 
continuation is not felt to be beneficial.  
 
• 
Unacceptable toxicity: an intercurrent illness or adverse event that prevents further ibrutinib 
administration for more than 28 continuous days 
 
• 
Non-compliance with taking ibrutinib or with following protocol 
 
• 
Investigator decision 
 
• 
Withdrawal of consent for treatment by subject 
 
• 
Subject becomes pregnant 
 
• 
Study termination by sponsor-investigator 
All subjects, regardless of discontinuation of study treatment will undergo end of study visit and be 
followed for progression and survival until 2 y post HCT by imaging (CT scan and/or PET scan or other 
imaging) or other modalities per the discretion of the treating physician. 
 
21.2 
Withdrawal from Study 
 
Withdrawal from study (including all follow-up) will occur under the following circumstances: 
 
• 
Withdrawal of consent for follow-up observation by the subject 
 
• 
Lost to follow-up. Every reasonable effort should be made by the study site personnel to contact 
the patient and the measures should be document. 
 
• 
Study termination by Sponsor -investigator 
 
• 
Death 
 
When a subject withdraws before completing the study, the following information should be 
documented in source documents: 
• 
Reason for withdrawal 
 
• 
Whether the subject withdraws full consent (i.e. withdraws consent to treatment and all further 
contact) or partial consent (i.e. withdraws consent to treatment but agrees to participate in 
follow-up visits). 
 
 
 
 
 
 
 
 
 


VICC BMT1651 Protocol v7: 2020DEC09 
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VICC BMT1651 Protocol v7: 2020DEC09 
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22. 
STUDY TABLE 
 
22.1 
Cohort A 
Assessment 
Within 4 weeks 
prior to starting 
preparative 
regimen for 
HCT 
Start of 
Prep until 
day +60 
post-HCT 
(± 1 week) 
Day +60 to Day 
+90 & prior to 
administration 
of ibrutinib13 
(± 1 week) 
Post-ibrutinib monthly 
assessment unless 
stated otherwise 
(start of ibrutinib until 
1 y post HCT) 
(± 1 week) 
At time of suspected 
relapse/ progression 
(start of ibrutinib 
until 1 y post HCT) 
At time of new dx 
of acute or chronic 
GVHD 
(start of ibrutinib 
until 1 yr post HCT) 
12M post 
HCT 
or EOS15 
(± 2 weeks) 
30 Day 
Follow Up 
(+ 7 days) 
History & Physical Exam 
X 
X 
X 
X 
(monthly until M6, then M9) 
 
 
X 
 
KPS 
(see Clinical 
Assessment Manual) 
X 
X 
(q2 weeks) 
X 
(q2 weeks) 
X  
(monthly until M6, then M9)  
 
 
X 
 
Transplant evaluation 
per institutional criteria 
X1 
 
 
 
 
 
 
 
Hematology labs 
X 
 
X 
X 
(weekly x 4 weeks, then 
monthly until M6, then M9) 
 
 
X 
 
Chemistry labs 
X 
 
X 
X 
(weekly x 4 weeks, then 
monthly until M6, then M9) 
 
 
X 
 
Coagulation studies 
X 
 
X 
 
 
 
 
 
Hepatitis serology 
X 
 
 
 
 
 
 
 
Pregnancy test (for 
WOCBP) 
X 
 
X 
 
 
 
 
 
EKG 
X 
 
X 
 
 
 
 
 
Echocardiogram 
X 
 
 
 
 
 
 
 
PFT 
X 
 
 
 
 
 
 
 
IgG, IgA, IgM 
X 
 
X 
 
 
 
X 
 
Peripheral blood T and B 
cell subsets 
X 
 
X 
X  
(M6, M9 post-HCT) 
 
 
X 
 
Disease assessment 
X1 
X3 
 
X  
(M6, M9 post-HCT) 
X 
 
X9 
 
DNA banking for 
subsequent chimerism 
analyses 
X1 
 
 
 
 
 
 
 
Chimerism analyses 
 
X 
 
X  
(M6, M9 post-HCT) 
X 
 
X9 
 


VICC BMT1651 Protocol v7: 2020DEC09 
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Assessment 
Within 4 weeks 
prior to starting 
preparative 
regimen for 
HCT 
Start of 
Prep until 
day +60 
post-HCT 
(± 1 week) 
Day +60 to Day 
+90 & prior to 
administration 
of ibrutinib13 
(± 1 week) 
Post-ibrutinib monthly 
assessment unless 
stated otherwise 
(start of ibrutinib until 
1 y post HCT) 
(± 1 week) 
At time of suspected 
relapse/ progression 
(start of ibrutinib 
until 1 y post HCT) 
At time of new dx 
of acute or chronic 
GVHD 
(start of ibrutinib 
until 1 yr post HCT) 
12M post 
HCT 
or EOS15 
(± 2 weeks) 
30 Day 
Follow Up 
(+ 7 days) 
Bone marrow biopsy 
X10 
(active marrow 
disease) 
X4 
 
 
X4 
 
 
 
Acute GVHD assessment 
 
X5 
X5 
X12 
 
X 
X 
 
Chronic GVHD 
assessment 
 
X6  
(monthly) 
X6  
(monthly) 
X  
(M6, M9 post-HCT) 
 
X 
X 
 
Study drug (ibrutinib) 
 
 
Start between day 60-90 post HCT until 12 months post HCT 
 
Con meds 
X 
X 
X 
X 
(M6, M9 post-HCT) 
 
 
X 
 
PB samples for CyTOF 
analyses2 
X 
 
X 
X 
(M6, M9 post HCT) 
X 
(if tumor is biopsied, 
tumor sample is 
preferred) 
X 
X9 
 
Diagnostic sample for 
immunoseqMRD anlaysis  
X11 
 
 
 
 
 
 
 
PB sample for 
immunoseqMRD analysis 
assessment7 
X 
 
 
X 
X 
(M6, M9 post HCT) 
X 
(if tumor is biopsied, 
tumor sample is 
preferred) 
X 
 
X9 
 
PB Sample for 
Immunoseq TCR 
analyses7 
 
 
X7 
X7 
(M6, M9 post HCT) 
X7 
X7 
X7,9 
 
Ibrutinib toxicity 
assessment 
X 
X 
X 
X8 
(weekly for first 4 weeks 
then monthly until M11) 
 
 
X14 
X14 
 
Between month 12 and month 24: patients will be followed for chronic GVHD, disease status and survival. See section on HCT outcome 
between 1y and 2y. 
Red font is research  
 
1. Transplant evaluation timing is per institutional criteria and does not have to be within 4 weeks of starting HCT 
2.  Peripheral blood sample for CyTOF analyses. Research sample. See the Laboratory Manual for sample acquisition, processing and shipping 
logistics 
3.  Disease reassessment should be done between day 30 and day 60 post-HCT. Imaging (CT scan and/or PET scan or other imaging) as clinically 
indicated 


VICC BMT1651 Protocol v7: 2020DEC09 
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4.  BM biopsy for disease assessment is considered standard of care. If marrow disease is suspected, a research sample for CYTOF analyses is 
needed. See the Laboratory Manual for sample acquisition, processing and shipping logistics 
5.  Weekly assessment of acute GVHD ± 3 days. Assessment of acute GVHD may start after engraftment.  See the Clinical Assessment Manual. 
6.  Assessment of chronic GVHD should occur monthly (± 1 week) post-transplant. See the Clinical Assessment Manual. 
7.  Peripheral blood samples for IMMUNOSEQ analyses for T-cell receptor assay (TCR) and immunoseqMRD analyses. Research samples. See 
the Laboratory Manual for sample acquisition, processing and shipping logistics 
8.  Ibrutinib toxicity assessment. Weekly toxicity assessment for first 4 weeks after starting ibrutinib. Subsequently toxicity assessment should be 
monthly until month 11 post SCT. Toxicity assessment at month 7, 8, 10, 11 can be done over the phone if patient is unable to travel to the 
transplant center. All other time points for toxicity assessment should be done at the transplant center.  
9.  Disease reassessment needs to be done at end of study, only if previous disease assessment has been done more than 4 weeks prior to end of 
study.  
10. If BM shows active disease, aspirate will be sent to coordinating center for CyTOF analyses. See the Laboratory Manual for sample acquisition, 
processing and shipping logistics.  
11. Diagnostic sample from disease onset (paraffin block of lymph node only) if available must be sent for immunoseqMRD analyses.  See the 
Laboratory Manual for sample acquisition, processing and shipping logistics.  
12. Weekly assessment of acute GVHD: post-ibrutinib, weekly for 4 weeks or until day 100 post HCT whichever is later. See the Clinical 
Assessment Manual. 
13. Please ensure eligibility checklist is complete and has been reviewed by coordinating center prior to the administration of ibrutinib between day 
60 and 90 post HCT. All SOC and research studies must be done within 2 weeks of starting ibrutinib. 
14. Toxicity assessment should be at the transplant center 30 days after cessation of study drug in addition to end of study. 
15. The End of Study visit should be completed even for patients who withdraw from study without initiating Ibrutinib 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


VICC BMT1651 Protocol v7: 2020DEC09 
Page 49 of 107 
 
 
 
22.2 
Cohort B 
Assessment 
Within 4 weeks 
prior to starting 
preparative 
regimen for HCT 
Start of 
Prep until 
day +60 
post-HCT 
(± 1 week) 
Day +60 to Day 
+90 & prior to 
administration 
of ibrutinib12 
(± 1 week) 
Post-ibrutinib monthly 
assessment unless 
stated otherwise 
(start of ibrutinib until 
1 y post HCT) 
(± 1 week) 
At time of suspected 
relapse/ progression 
(start of ibrutinib 
until 1 y post HCT) 
At time of new dx 
of acute or chronic 
GVHD 
(start of ibrutinib 
until 1 yr post HCT) 
12M post 
HCT 
or EOS 
(± 2 weeks)14 
30 Day 
Follow Up 
(+ 7 days) 
History and Physical 
Exam 
X 
X 
X 
X 
(monthly until M6, then M9) 
 
 
X 
 
KPS 
(see the Clinical 
Assessment Manual) 
X 
X 
(q2 weeks) 
X 
(q2 weeks) 
X 
(monthly until M6, then M9 
post-SCT) 
 
 
X 
 
Transplant evaluation 
per institutional criteria 
X1 
 
 
 
 
 
 
 
Hematology labs 
X 
 
X 
X 
(weekly for 4 weeks and 
then monthly until M6, then 
M9) 
 
 
X 
 
Chemistry labs 
X 
 
X 
X 
(weekly for 4 weeks and 
then monthly until M6, then 
M9) 
 
 
X 
 
Coagulation studies 
X 
 
X 
 
 
 
 
 
Hepatitis serology 
X 
 
 
 
 
 
 
 
Pregnancy test (for 
WOCBP) 
X 
 
X 
 
 
 
 
 
EKG 
X 
 
X 
 
 
 
 
 
Echocardiogram 
X 
 
 
 
 
 
 
 
PFT 
X 
 
 
 
 
 
 
 
IgG, IgA, IgM 
X 
 
 
 
 
 
X 
 
Peripheral blood T and B 
cell subsets 
X 
 
 
X  
(M6, M9 post-HCT) 
 
 
X 
 
Disease assessment 
X1 
X3 
 
X  
(M6, M9 post-HCT) 
X 
 
X9 
 
DNA banking for 
subsequent chimerism 
analyses 
X1 
 
 
 
 
 
 
 
Chimersim analyses 
 
X 
 
X 
(M6, M9 post-HCT) 
X 
 
X9 
 
Bone marrow biopsy 
X 
X 
 
 
 
X 
 
 
 


VICC BMT1651 Protocol v7: 2020DEC09 
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Assessment 
Within 4 weeks 
prior to starting 
preparative 
regimen for HCT 
Start of 
Prep until 
day +60 
post-HCT 
(± 1 week) 
Day +60 to Day 
+90 & prior to 
administration 
of ibrutinib12 
(± 1 week) 
Post-ibrutinib monthly 
assessment unless 
stated otherwise 
(start of ibrutinib until 
1 y post HCT) 
(± 1 week) 
At time of suspected 
relapse/ progression 
(start of ibrutinib 
until 1 y post HCT) 
At time of new dx 
of acute or chronic 
GVHD 
(start of ibrutinib 
until 1 yr post HCT) 
12M post 
HCT 
or EOS 
(± 2 weeks)14 
30 Day 
Follow Up 
(+ 7 days) 
Acute GVHD assessment 
 
X5 
X5 
X11 
 
X 
X 
 
Chronic GVHD 
assessment 
 
X6  
(monthly) 
X6  
(monthly) 
X 
(M6, M9 post-SCT) 
 
X 
X 
 
Study drug (ibrutinib) 
 
 
Start between day 60-90 post HCT until 12 months post HCT 
Con meds 
X 
X 
X 
X 
 
 
X 
 
Ibrutinib toxicity 
assessment 
X 
X 
X 
X8 
(weekly for first 4 weeks 
then monthly until M11) 
 
 
X13 
X13 
 
Between month 12 and month 24: patients will be followed for chronic GVHD, disease status and survival. See section on HCT outcome 
between 1y and 2y. 
Red font is research  
 
1.  Transplant evaluation timing is per institutional criteria and does not have to be within 4 weeks of starting HCT 
2.  Peripheral blood sample for CyTOF analyses. Research sample. See the Laboratory Manual for sample acquisition, processing and shipping 
logistics 
3.  Disease reassessment should be done between day 30 and day 60 post-HCT.  Imaging (CT scan and/or PET scan or other imaging) as 
clinically indicated 
4.  BM biopsy for disease assessment is considered standard of care.  
5.  Weekly assessment of acute GVHD ± 3 days. Assessment of acute GVHD may start after engraftment.  See the Clinical Assessment Manual. 
6.  Assessment of chronic GVHD should occur monthly (± 1 week) post-transplant. See the Clinical Assessment Manual. 
7.  Peripheral blood sample for IMMUNOSEQ analyses for T-cell receptor assay (TCR) and for immunoseqMRD analyses. Research sample. See 
the Laboratory Manual for sample acquisition, processing and shipping logistics 
8.  Ibrutinib toxicity assessment. Weekly toxicity assessment for first 4 weeks after starting ibrutinib. Subsequently toxicity assessment should be 
monthly until month 11 post SCT. Toxicity assessment at month 7,8, 10, 11 can be done over the phone if patient is unable to travel to the 
transplant center. All other time points for toxicity assessment should be done at the transplant center. 
9.  Disease reassessment needs to be done at end of study, only if previous disease assessment has been done more than 4 weeks prior to end of 
study.  
10. Diagnostic sample from disease onset (paraffin block of lymph node only) if available must be sent for immunoseqMRD analyses.  See the 
Laboratory Manual for sample acquisition, processing and shipping logistics.  
11. Weekly assessment of acute GVHD: post-ibrutinib, weekly for 4 weeks or until day 100 post HCT whichever is later. See the Clinical 
Assessment Manual. 


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12. Please ensure eligibility checklist is complete and has been reviewed by coordinating center prior to the administration of ibrutinib between day 
60 and 90 post HCT. All SOC and research studies should be done within 2 weeks of starting ibrutinib. 
13. Toxicity assessment should be at the transplant center 30 days after cessation of study drug in addition to end of study 
14. The End of Study visit should be completed even for patients who withdraw from study without initiating Ibrutinib 


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23. 
DRUG SHIPMENT 
Ibrutinib will be considered as an investigational agent for the purpose of this study. The Vanderbilt 
Investigational Pharmacy will be the central pharmacy for receiving ibrutinib from Janssen Scientific 
Affairs and then shipping it to individual site investigational pharmacy. Drug accountability logs will be 
maintained. All sites will perform IP destruction on site. Each site will send drug destruction and 
hazardous waste policy to the coordinating center (at Coordinating.Center@Vanderbilt.edu) for review. 
Study drug destruction at the participating sites will be performed after the approval from the 
coordinating center. Documentation of the review and approval will be maintained in the study binder 
and at each participating site. Any drug that has been prepared but not dispensed, returned by the 
subject, expired, damaged, or otherwise deemed to be unusable will be destroyed on site according to 
the sites SOP for destruction. Each site will dispose of drug on site according to their SOP for 
destruction.  Please refer to the IP Management Plan for additional details.  
 
24. 
STATISTICAL ANALYSES PLAN 
 
24.1 
Analysis Plan 
 
The statistical analysis plan will address the primary aim: To study the use of ibrutinib starting between 
day 60 and day 90 after allogeneic HCT until 12 months post HCT to improve the PFS at 12 months 
post HCT by 25% compared to historical controls. This will be restricted to cohort A which includes the 
diagnoses of CLL and MCL, only. 
 
• 
PFS is defined as time to progression, or relapse of the underlying disease for which transplant 
was undertaken, or death from any non-relapse causes, starting from the date of stem cell 
transplant (SCT). 
 
• 
We will estimate the 12-month PFS rate with a 95% confidence interval using the method of 
Kaplan-Meier and using the Greenwood variance estimator, and we will compare this estimate 
with the rate in the historical controls. 
 
• 
Historical data 
 
o In a study by Sobecks et al53, the outcomes of patients with CLL after ablative (n=163) 
and reduced intensity conditioning (RIC) 134 were reported. Outcomes were stratified 
based on when the HCT occurred (< 2000, or ≥ 2000). We expect the majority of 
patients with CLL on the proposed study to be undergoing RIC allo HCT, thus relevant 
data (≥ 2000 and RIC allo HCT) are taken into account for sample size analyses. One 
year PFS was 62% (95% CI 51-72). 
 
o In a study by Urbano-Ispizua et al54, the outcomes of patients with MCL undergoing 
ablative (n=149) and RIC (n=351) allo-HCT was reported.  The 1y PFS for patients with 
MCL (personal communication, CIBMTR) was 52% (95% CI 47-56) 
 
• 
The proportion of patients with CLL and MCL enrolling in this study will not be known at the start 
of the study or be controlled for during the accrual period. Thus, we studied the impact on power 
of varying proportions of these two diagnoses on outcome for a given effect size.  
 
• 
We will compare our overall PFS rate with the weighted average of the historical rates in CLL 
and MCL, using the proportion of our sample with each of these two diagnoses as the weights. 


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24.2 
Sample Size 
 
The following table reflects the power and effect size, if we enroll 65 patients with varying proportion of 
the diagnoses. These calculations are based on the maximum likelihood estimator (MLE) for the 
mean survival time assuming exponentially-distributed PFS53 using the cube-root 
transformation of the MLE as suggested by Sprott54. The one-year survival probability can be 
calculated once the distribution is specified. The following test statistic has a standard normal 
distribution: 
                                       
 
 
 
 
This is a single arm phase two study. Patients will be accrued uniformly over two years, and then 
followed for two years. The power calculations are based on derivations from Lawless53 with a cube-
root trans-formation of the maximum likelihood estimate (MLE), as suggested by Sprott54 . This is 
implemented in the online calculator (tool of One Arm Survival) found at https://stattools.crab.org  which 
is provided by the SWOG Statistical Center. Thus, 65 patients will give us at least 84% power to detect 
an effect size of 25% improvement in progression-free survival at 1 year compared to the estimated 
historical control rate, for varying proportions of patients with CLL and MCL. The following table reflects 
the power and effect size, if we enroll 65 patients with varying proportion of the diagnoses. 
 
Table: Power achieved for a sample of 65 patients for different effect sizes using a 2-sided parametric 
test with level 0.05, assuming on 2 years of uniform accrual and 2 years of follow-up time. 
 
 
 


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In addition, cohort B will include 10 patients (FL and HD). There is no formal sample calculation for 
cohort B.  
 
24.3 
Safety Analyses 
 
HCT is a complex procedure with varying causes of death post HCT. Patients may die of relapse or 
progression of disease, development or worsening of acute GVHD after exposure to study drug, 
development or worsening of chronic GVHD after exposure to study drug, infections in absence of 
GVHD or other causes (other non-relapse mortality) (includes drug adverse effects).  
 
Both cohort A and B will be at risk for these events and thus will be included in the safety analyses. 
 
In order to safeguard patients, we have set the following limits:  
 
• 
Development of grade 3-4 acute GVHD by day 180 post HCT for patients who have no acute 
GVHD prior to starting experimental therapy should not be higher than 30%.   
 
• 
Development of grade 3-4 acute GVHD for patients with grade1-2 acute GVHD prior to starting 
experimental therapy should not be higher than 40%.   
 
• 
Development of grade 3-4 acute GVHD for patients with any grade acute GVHD prior to starting 
experimental therapy should not be higher than 50%. 
 
• 
Cumulative incidence of infectious disease mortality (not related to GVHD) should not   be 
higher than 30% at 1 y post HCT 
 
• 
Cumulative incidence of non-relapse mortality (all cause) at 1 y post HCT should not be higher 
than 40% 
 
Stopping Rules 
 
Cohort B is an exploratory cohort of 10 patients with diagnoses of follicular lymphoma or Hodgkin 
disease. Combining cohort, A and B with 75 patients in total, the stopping rules are created based on 
Bayesian approach to monitor treatment related AEs defined below during the conduct of a clinical trial.  
We will stop the trial early if the probability that treatment related events of the current regimen exceeds 
conventional treatment related AE is greater than 80%.   
 
The following tables describe the safety rules. There will be 2 conference calls per month during the 
conduct of the study to ensure the implementation of the safety rules. 
 
 
 
 
 
 
 
 


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Development of grade 3-4 acute GVHD by day 180 post HCT for patients who have no acute GVHD 
prior to starting experimental therapy should not be higher than 30%.  
Number of patients in complete  
cohorts of 5 (inclusive) 
Stop the trial if this number  
of toxicities (inclusive) 
5 
3 
10 
5 
15 
7 
20 
8 
25 
10 
30 
12 
 
Development of grade 3-4 acute GVHD for patients with grade1-2 acute GVHD prior to starting 
experimental therapy should not be higher than 40%.   
Number of patients in complete  
cohorts of 5 (inclusive) 
Stop the trial if this number  
of toxicities (inclusive) 
5 
4 
10 
6 
15 
8 
20 
10 
25 
13 
30 
15 
35 
17 
40 
19 
 
Development of grade 3-4 acute GVHD for patients with any grade acute GVHD prior to starting 
experimental therapy should not be higher than 50%. 
Number of patients in complete  
cohorts of 5 (inclusive) 
Stop the trial if this number  
of toxicities (inclusive) 
5 
4 
10 
6 
15 
8 
20 
10 
25 
13 
30 
15 
35 
17 
40 
19 
 
Cumulative incidence of infectious disease mortality (not related to GVHD) should not be higher than 
30% at 1 y post HCT. 
Number of patients in complete  
cohorts of 5 (inclusive) 
Stop the trial if this number  
of toxicities (inclusive) 
5 
4 
10 
6 
15 
8 
20 
10 
25 
13 
30 
15 
35 
17 
40 
19 


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Cumulative incidence of non-relapse mortality (all cause) at 1 y post HCT should not be higher than 
40%. 
Number of patients in complete  
cohorts of 5 (inclusive) 
Stop the trial if this number  
of toxicities (inclusive) 
5 
4 
10 
6 
15 
8 
20 
10 
25 
13 
30 
15 
35 
17 
40 
19 
 
24.4 
Association Analyses with Correlative Studies 
 
Appropriate methodologies for association analyses of immunoseqMRD,, IMMUNOSEQ, and CYTOF 
with relevant clinical variables will be undertaken.  
 
25. 
SAFETY DATA COLLECTION AND REPORTING 
 
25.1 
Management of Safety Data 
 
This Study has been designated as an interventional study.  As such, all adverse events, special 
situations, including pregnancies and product quality complaints will be reported as described in this 
protocol from the time a subject has signed and dated an Informed Consent Form (ICF) until 30 days 
after the last documented use of a product under study within the study. All subsequent AEs and SAEs 
will be collected after this period if the Principal Investigator considers the AE/SAE to be causally-
related to the use of the study drug.  
For the purposes of this study, the J&Jmedicinal product is: Ibrutinib (Imbruvica). 
 
The safety variables to be analyzed include adverse events, clinical laboratory test results (hematology 
and chemistry), and other safety measurements. They will be summarized by descriptive statistics. In 
general, continuous variables will be summarized using descriptive statistics (n, mean, median, 
standard deviation, standard error and range). Categorical variables will be summarized using 
frequencies and percentages. No formal statistical testing is planned. Exposure to ibrutinib first dose 
and reasons for discontinuation from study treatment will be tabulated. 
 
25.2 
Definitions 
 
25.2.1 Adverse Event (AE) 
 
An AE is any untoward medical occurrence in a clinical study subject administered a medicinal 
(investigational or non-investigational) product. An adverse event does not necessarily have a causal 
relationship with the treatment. An adverse event can therefore be any unfavorable and unintended 
sign (including an abnormal finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational or non- investigational) product, whether or not related to that medicinal 
(investigational or non-investigational) product. (Definition per International Conference on 
Harmonisation [ICH])  


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This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities. 
 
Adverse events may include, but are not limited to: 
 
• 
Subjective or objective symptoms provided by the patient and/or observed by the Investigator or 
study staff including laboratory abnormalities of clinical significance. 
 
• 
Any AEs experienced by the patient through the completion of final study procedures. 
 
• 
AEs not previously observed in the patient that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with cGVHD that were not present 
before the AE reporting period 
 
• 
Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as biopsies). 
 
The following are NOT considered AEs: 
 
• 
Pre-existing condition: A pre-existing condition (documented on the medical history CRF) is 
not considered an AE unless the severity, frequency, or character of the event worsens during 
the study period. 
 
• 
Pre-planned or elective hospitalization: A hospitalization planned before signing the informed 
consent form is not considered an SAE, but rather a therapeutic intervention. However, if during 
the pre-planned hospitalization an event occurs, which prolongs the hospitalization or meets any 
other SAE criteria, the event will be considered an SAE. Surgeries or interventions that were 
under consideration, but not performed before enrollment in the study, will not be considered 
serious if they are performed after enrollment in the study for a condition that has not changed 
from its baseline level. Elective hospitalizations for social reasons, solely for the administration 
of chemotherapy, or due to long travel distances are also not SAEs. 
 
• 
Diagnostic Testing and Procedures: Testing and procedures should not to be reported as 
AEs or SAEs, but rather the cause for the test or procedure should be reported. 
 
For the purposes of this clinical study, AEs include events which are either new or represent detectable 
exacerbations of pre-existing conditions as measured prior to HCT and prior to administration of 
ibrutinib. 
 
Adverse Events of Special Interest 
Adverse events of special interest are events that Janssen Scientific Affairs, LLC. is actively monitoring 
as a result of a previously identified signal (even if non-serious). These adverse events are: 
 
 
 


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Major Hemorrhage 
Major hemorrhage is defined as: 
• 
Any treatment-emergent hemorrhagic AE of Grade 3 or higher* 
• 
Any treatment-emergent SAE of bleeding of any grade 
• 
Any treatment-emergent CNS hemorrhage/hematoma of any grade 
• 
*all hemorrhagic AEs requiring a transfusion of red blood cells should be reported as a Grade 3 or higher AEs 
per NCI-CTCAE 
 
 
Any Adverse Event of Special Interest that is to be reported to Janssen Scientific Affairs, LLC should be 
recorded on a Serious Adverse Event Report Form and be reported to Janssen Scientific Affairs, LLC 
within 24 hours of knowledge of the event.  
 
25.2.2 Serious Adverse Event (SAE) 
 
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose: 
 
• 
Results in death (i.e., the AE actually causes or leads to death). 
 
• 
Is life-threatening. Life-threatening is defined as an AE in which the patient was at risk of death 
at the time of the event. It does not refer to an event which hypothetically might have caused 
death if it were more severe. If either the Investigator or the Sponsor believes that an AE meets 
the definition of life-threatening, it will be considered life-threatening. 
 
• 
Requires in-patient hospitalization >24 hours or prolongation of existing hospitalization. 
 
• 
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). 
 
• 
Is a congenital anomaly/birth defect. 
 
• 
Is a suspected transmission of any infectious agent via a medicinal product 
 
• 
Is an important medical event that may not result in death, be immediately life-threatening or 
require hospitalization, but may be considered an SAE when, based upon appropriate medical 
judgment, the event may jeopardize the patient or patient may require intervention to prevent 
one of the other outcomes listed in this definition. Examples of such events are intensive 
treatment in an emergency department or at home for allergic bronchospasm, blood dyscrasias, 
or convulsion that does not result in hospitalization; or development of drug dependency or drug 
abuse. 
 
 Medical and scientific judgment should be exercised in deciding whether expedited reporting is also 
appropriate in other situations, such as important medical events that may not be immediately life 
threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. These should usually be 
considered serious. 


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Severity Criteria (Grade 1-5) 
 
Definitions found in the Common Terminology Criteria for Adverse Events version 4.03 
(CTCAE v4.03) will be used for grading the severity (intensity) of AEs. The CTCAE v4.0 displays 
Grades 1 through 5 with unique clinical descriptions of severity for each referenced AE. Should a 
patient experience any AE not listed in the CTCAE v4.03, the following grading system should be used 
to assess severity: 
 
• 
Grade 1 (Mild AE) – experiences which are usually transient, requiring no special treatment, and 
not interfering with the patient’s daily activities 
 
• 
Grade 2 (Moderate AE) – experiences which introduce some level of inconvenience or concern 
to the patient, and which may interfere with daily activities, but are usually ameliorated by simple 
therapeutic measures 
 
• 
Grade 3 (Severe AE) – experiences which are unacceptable or intolerable, significantly interrupt 
the patient’s usual daily activity, and require systemic drug therapy or other treatment 
 
• 
Grade 4 (Life-threatening or disabling AE) – experiences which cause the patient to be in 
imminent danger of death 
 
• 
Grade 5 (Death related to AE) – experiences which result in patient death 
 
Adverse Event Reporting Timeframe  
 
Adverse events will be captured from the time of consent until 30 days post cessation of study drug. 
 
Causality (Attribution) 
 
The Investigator is to assess the causal relation (i.e., whether there is a reasonable possibility that the 
study drug caused the event) using the following definitions: 
• 
Definite – The AE is clearly related to the study treatment 
• 
Probable – The AE is likely related to the study treatment 
• 
Possible – The AE may be related to the study treatment 
• 
Unlikely - The AE is doubtfully related to the study treatment 
• 
Unrelated - The AE is clearly NOT related to the study treatment 
 
NOTE: DEATH FOR ANY REASON SHOULD BE REPORTED AS A SERIOUS ADVERSE EVENT. 
 
Hospitalization 
 
For reports of hospitalization, it is the sign, symptom or diagnosis which led to the hospitalization that is the 
serious event for which details must be provided. 
 
Any event requiring hospitalization or prolongation of hospitalization that occurs during the study must be 
reported as a serious adverse event, except hospitalizations for the following: 
 


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• 
Hospitalizations not intended to treat an acute illness or adverse event (e.g., social reasons 
such as pending placement in long-term care facility) 
 
• 
Surgery or procedure planned before entry into the study. [Note: Hospitalizations that were 
planned before the start of data collection and where the underlying condition for which the 
hospitalization was planned has not worsened will not be considered serious adverse 
events. Any adverse event that results in a prolongation of the originally planned 
hospitalization is to be reported as a new serious adverse event.] 
Life-Threatening Conditions 
 
Disease progression should not be recorded as an adverse event or serious adverse event term; 
instead, signs and symptoms of clinical sequelae resulting from disease progression/lack of efficacy will 
be reported if they fulfill the serious adverse event definition. 
 
25.3 
Individual Case Safety Report (ICSR) 
 
A valid ICSR must contain the four minimum criteria required to meet regulatory reporting requirements: 
 
• 
an identifiable subject (but not disclosing personal information such as the subject’s name, initials or 
address) 
• 
an identifiable reporter (investigational site) 
• 
a J&Jmedicinal product 
• 
an adverse event, outcome, or certain special situations 
 
The minimum information required is: 
• 
suspected Janssen medicinal product (doses, indication) 
• 
date of therapy (start and end date, if available) 
• 
batch or lot number, if available 
• 
subject details (subject ID and country) 
• 
gender 
• 
age at AE onset 
• 
reporter ID 
• 
adverse event detail (AE verbatim in English), onset date, relatedness, causality, action taken, 
outcome, (if available) 
• 
J&J protocol ID 
 
 
25.4 
Product Quality Complaint (PQC) 
 
A product quality compliant is defined as any suspicion of a product defect related to a potential quality issue 
during manufacturing, packaging, release testing, stability monitoring, dose preparation, storage or 
distribution of the product, or delivery system.  Not all PQCs involve a subject.  Lot and batch numbers are of 
high significance and need to be collected whenever available. 
 
Examples of PQC include but not limited to: 
 
• 
Functional Problem: e.g., altered delivery rate in a controlled release product 


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• 
Physical Defect:  e.g. abnormal odor, broken or crushed tablets/capsules 
• 
Potential Dosing Device Malfunction: e.g. autoinjector button not working, needle detaching from 
syringe 
• 
Suspected Contamination 
• 
Suspected Counterfeit 
 
25.5 
Unlisted (unexpected) Adverse Event/Reference Safety Information 
 
An “unexpected” AE is an AE that is not listed in the Investigator's Brochure/package insert or is not 
listed at the specificity or severity that has been observed. For example, hepatic necrosis would be 
“unexpected” (by virtue of greater severity) if the Investigator's Brochure referred only to elevated 
hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be 
“unexpected” (by virtue of greater specificity) if the Investigator's Brochure/package insert listed only 
cerebral vascular accidents. "Unexpected" also refers to AEs that are mentioned in the Investigator's 
Brochure as occurring with a class of drugs or as anticipated from the pharmacological properties of the 
drug, but are not specifically mentioned as occurring with the study drug under investigation. 
https://www.imbruvicahcp.com/  
https://www.imbruvicahcp.com/docs/librariesprovider2/pdf-downloads/prescribing_information.pdf 
 
 
25.6 
Special Reporting Situation 
 
Safety events of interest for a J&J medicinal product that expedited reporting and/or safety evaluation 
include, but are not limited to: 
• 
Drug exposure during pregnancy (maternal and paternal) 
• 
Overdose of a J&J medicinal product 
• 
Exposure to a J&J  medicinal product from breastfeeding 
• 
Suspected abuse/misuse of a J&J medicinal product  
• 
Inadvertent or accidental exposure to a J&J medicinal product 
• 
Any failure of expected pharmacological action (i.e. lack of effect) of a J&J medicinal product 
• 
Medication error involving a J&J medicinal product (with or without subject/patient exposure 
to the study drug, e.g., name confusion) 
• 
Suspected transmission of any infectious agent via administration of a medicinal product 
• 
Unexpected therapeutic or clinical benefit from use of a J&J medicinal product  
Occurrence of any special reporting situations should be recorded in the eCRF. If any special reporting 
situation meets the criteria of an adverse event, it should be recorded on the adverse events eCRF. If 
the adverse event is considered serious, it should be recorded on the adverse events eCRF as serious 
and should be reported on the Serious Adverse Event Report Form. The SAE Report Form should be 
sent via email or fax to the Coordinating Center. See the Safety Data Collection and Reporting section 
for Coordinating Center contact information. Collection of these events will occur from the time the 
subject signs consent to 30 days after the last dose of study drug.   
25.7 
Pregnancy 
 
Before study enrollment, subjects must agree to take appropriate measures to avoid pregnancy. 


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However, should a pregnancy occur in a female study subject, consent to provide follow-up information 
regarding the outcome of the pregnancy and the health of the infant until 30 days old will be requested. 
 
A female subject must immediately inform the Investigator if she becomes pregnant from the time of 
consent to 30 days after the last dose of study drug. A male subject must immediately inform the 
Investigator if his partner becomes pregnant from the time of consent to 3 months after the last dose of 
study drug. Any female subjects receiving study drug(s) who become pregnant must immediately 
discontinue study drug. The Investigator should counsel the subject, discussing any risks of continuing 
the pregnancy and any possible effects on the fetus.  
 
Although pregnancy itself is not regarded as an adverse event, the outcome will need to be 
documented. Any pregnancy occurring in a subject or subject’s partner from the time of consent to 30 
days after the last dose of study drug must be reported. Any occurrence of pregnancy must be 
recorded on the Pregnancy Report Form Part I and sent via email or fax to the Coordinating Center 
within 1 business day of learning of the event. See the Safety Data Collection and Reporting section for 
Coordinating Center contact information. 
 
All pregnancies will be followed for outcome, which is defined as elective termination of the pregnancy, 
miscarriage, or delivery of the fetus. For pregnancies with an outcome of live birth, the newborn infant 
will be followed until 30 days old by completing the Pregnancy Report Form Part II. Any congenital 
anomaly/birth defect noted in the infant must be reported as a serious adverse event. 
 
All  reports of pregnancy from sub-sites must be reported to the Vanderbilt Coordinating Center 
(Coordinating.Center@vumc.org ) by the site within 24 hours of their knowledge of the event using the 
Janssen Serious Adverse Event Form. Abnormal pregnancy outcomes (e.g. spontaneous abortion, fetal 
death, stillbirth, congenital anomaly, ectopic pregnancy) are considered serious adverse events and 
must be reported using the Serious Adverse Event Form.  
 
Any subject who becomes pregnant during the study must be promptly withdrawn from the study and 
discontinue further study treatment. 
 
Because the effect of the J&J medicinal product on sperm is unknown, pregnancies in partners of male 
subjects exposed to a J&J medicinal product will be reported to the Vanderbilt Coordinating Center 
(Coordinating.Center@vumc.org) by the site within 24 hours of their knowledge of the event using the 
Janssen Serious Adverse Event Form.  Depending on local legislation this may require prior consent of 
the partner. 
 
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the infant 
will be required. 
 
25.8 
Contacting Sponsor-Investigator Regarding Safety 
 
The Sponsor-investigator can be contacted via email (Coordinating.Center@vumc.org)  
 
25.9 
Maintenance of Safety Information 
All safety data should be maintained in a clinical database in a retrievable format. The PRINCIPAL 
INVESTIGATOR shall provide all adverse events, both serious and non-serious, in report format. 


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However, in certain circumstances more frequent provision of safety data may be necessary, e.g. to 
fulfill a regulatory request, and as such the data shall be made available within a reasonable timeframe 
at Janssen Scientific Affairs, LLC request. 
 
25.10 Procedures for Reporting Safety Data and Product Quality Complaints (PQCs) for J&J Medicinal 
Products to the COMPANY 
 
All adverse events and special situations, whether serious or non-serious, related or not related, following 
exposure to a J&J medicinal product are to be documented by the investigator and recorded in the CRF and 
in the subject’s source records. Investigators must record in the CRF their opinion concerning the relationship 
of the adverse event to a J&J medicinal product.  
 
All (serious and non-serious) adverse events reported for a J&J medicinal product should be followed-up in 
accordance with clinical practice. 
 
25.11 SAEs, Adverse Events of Special Interest and Special Reporting Situations 
 
All serious adverse events will be reported from time of consent through 30 days after the last dose of 
study drug.  All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject's participation in the study, must be followed until any of 
the following occurs: 
 
• 
The event resolves 
• 
The event stabilizes 
• 
The event returns to baseline, if a baseline value/status is available 
• 
The event can be attributed to agents other than the study drug or to factors unrelated to study 
conduct 
• 
It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration of due 
diligence with follow-up efforts) 
 
All serious adverse events, regardless of causality to study drug, will be reported to the Principal 
Investigator and/or the Study Coordinator at each institution, and also to the Coordinating Center. 
All serious adverse events must be reported to the Coordinating Center within 24 hours of the 
investigator becoming aware of the event. Events should be reported using the Janssen SAE form, 
located in the packet of supplemental forms. This form must be fully completed and emailed (preferred), 
faxed, or scanned to: 
 
ATTN:  VICC CTSR Personnel 
EMAIL:  Coordinating.center@vumc.org  
FAX:  (615) 875-0040 
 
If SAE documents are faxed, the Coordinating Center must be notified via email as well. Follow-up 
information must also be reported within 24 hours of receipt of the information by the investigator. 
The Coordinating Center will disseminate information regarding serious adverse events to the 
participating sites as described in FDA guidance only in the case that the event(s) is/are unexpected, and 
is/are believed to be related (i.e., possibly, probably or definitely) to the study device/medication. The 


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Coordinating Center will be responsible for reporting of events to the FDA and supporters, as 
appropriate (outlined below). 
 
Institutional Review Board 
All adverse events and serious adverse events will be reported to the IRB per current institutional 
standards. If an adverse event requires modification of the informed consent, these modifications will be 
provided to the IRB with the report of the adverse event. If an adverse event requires modification of the 
study protocol, these modifications will be provided to the IRB as soon as is possible. 
Food and Drug Administration (FDA) 
In this trial, unexpected serious adverse events believed to be definitely, probably, or possibly related to 
study treatment (as determined by the sponsor-investigator) will be reported to the FDA via MedWatch 
3500A (available at 
https://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM048334.pdf. 
Submissions by the sponsor can be submitted via fax or email and must be addressed to Regulatory 
Project Manager  in the FDA review division that has responsibility for review of the IND. The 
Coordinating Center will be responsible for correspondence regarding adverse events with the FDA for 
all participating sites. 
 
 
Reporting to Janssen Scientific Affairs, LLC 
The Vanderbilt Coordinating Center will report all SAEs, Adverse Events of Special Interest and special 
situations regardless of causality occurring after exposure to Ibrutinib to Janssen Scientific Affairs, LLC 
via secure e-mail per the provided instruction manual within 24 hours of becoming aware of the 
event(s). 
Serious Adverse Event Report  
 
All available clinical information relevant to the evaluation of a related SAE, Adverse Event of Special Interest 
or special situation is required. Collection of these events will occur from the time the subject signs consent to 
30 days after the last dose of study drug. 
 
The PRINCIPAL INVESTIGATOR or designee is responsible for ensuring that these cases are complete and if 
not are promptly followed-up.  The Vanderbilt Coordinating Center will follow up with the relevant site until the 
safety report is complete.  A safety report is not considered complete until all clinical details needed to interpret 
the case are received. Reporting of follow-up information should follow the same timeline as initial reports. 
 
Copies of any and all relevant correspondences with regulatory authorities and ethics committees regarding 
any and all serious adverse events, irrespective of association with the J&J Product under study, are to be 
provided to Janssen Scientific Affairs, LLC using a transmission method listed in the Transmission Methods 
section within 24 hours of such report or correspondence being sent to applicable health authorities. 
 
Non-Serious AEs 
 
All non-serious adverse events should be reported to Janssen Scientific Affairs, LLC according to the 
timeframe outlined in section 25.1 Management of Safety Data. 
PQC Reporting 


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A PQC may have an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting 
and analysis of PQC information from studies are crucial for the protection of patients, investigators, and 
Janssen Scientific Affairs, LLC, and are mandated by regulatory agencies worldwide. Janssen Scientific 
Affairs, LLC has established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information. Lot and/or Batch #s shall be collected or any reports failure of 
expected pharmacological action (i.e., lack of effect). The product should be quarantined immediately and if 
possible, take a picture. 
All initial PQCs involving a J&J medicinal product under study must be reported to Janssen Scientific 
Affairs, LLC by the PRINCIPAL INVESTIGATOR or designee within 24 hours after being made aware 
of the event. The J&J contact will provide additional information/form to be completed. 
 
If the defect for a J&J medicinal product under study is combined with either a serious adverse event or 
non-serious adverse event, the PRINCIPAL INVESTIGATOR must report the PQC to Janssen 
Scientific Affairs, LLC according to the serious adverse event reporting timelines.  A sample of the 
suspected product should be maintained for further investigation if requested by Janssen Scientific 
Affairs, LLC. 
 
Reporting Procedures for Reporting Safety Data and Product Quality Complaints (PQCs) for Non-J&J  
Medicinal Products  
 
For SAEs, special reporting situations and PQCs following exposure to a non J&J medicinal product under 
study, the PRINCIPAL INVESTIGATOR should notify the appropriate regulatory/competent authority or the 
manufacturer of that medicinal product (in the absence of appropriate local legislation) as soon as possible. 
 
Transmission Methods 
 
The following methods are acceptable for transmission of safety information to Janssen Scientific 
Affairs, LLC: 
 
• 
Electronically via J&JSECURE Email service (preferred) 
• 
For business continuity purposes, if SECURE Email is non-functional: 
• 
Facsimile (fax), receipt of which is evidenced in a successful fax transmission report 
• 
Telephone (if fax is non-functional). 
 
Please use the contact information and process information provided by Janssen Scientific Affairs, LLC. 
 
 
26. 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS 
 
26.1 
Regulatory and Ethical Compliance 
 
This clinical study was designed and will be implemented in accordance with the protocol, the ICH 
Harmonized Tripartite Guidelines for Good Clinical Practices, with applicable local regulations 
(including US Code of Federal Regulations [CFR] Title 21 and European Directive 2001/20/EC), and 
with the ethical principles laid down in the Declaration of Helsinki.  
 


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The Investigator will submit this protocol, the ICF, IB, and any other relevant supporting information 
(e.g., all advertising materials or materials given to the subject during the study) to the appropriate 
IRB/IEC for review and approval before study initiation. Amendments to the protocol and informed 
consent form must also be approved by the IRB/IEC before the implementation of changes in this 
study. 
 
The Investigator is responsible for providing the IRB/IEC with any required information before or during 
the study, such as SAE expedited reports or study progress reports. 
 
The IRB/IEC must comply with current United States (US) regulations (§21 CFR 56) as well as country-
specific national regulations and/or local laws. 
 
Before a site may enter patients, protocol-specific regulatory and other documents must be submitted 
to the Vanderbilt Coordinating Center as noted in study materials. Detailed information regarding 
document submission and control is provided to each site in separate study materials. 
Any changes to site regulatory documents must be submitted by the investigator or designee to the 
Coordinating Center in a timely manner. Initial study drug shipment will not occur until the regulatory 
packet is complete. No patients will begin protocol therapy without formal registration. 
 
Prior to initiating the trial, the investigator will secure and provide to the Coordinating Center essential 
documents, including but not limited to: 
• 
A signed FDA Form 1572 
• 
A current curriculum vitae for the Principal Investigator and each sub-investigator listed on the 
FDA Form 1572 
• 
A copy of the current medical license for all investigators listed on the FDA Form 1572 as 
applicable (i.e. non licensed personnel listed on the 1572 will not furnish this document). 
• 
A letter from the IRB stipulating approval of the protocol, the informed consent document and 
any other material provided to potential trial participants with information about the trial (e.g. 
advertisements) 
• 
 A copy of the IRB-approved informed consent document 
• 
The current IRB membership list for the reviewing IRB 
• 
A completed financial disclosure form for the investigator and all sub- investigators 
• 
Current laboratory certification for the reference laboratory and curriculum vitae of the laboratory 
director 
• 
A list of current laboratory normal values for the reference laboratory. 
 
 
26.2 
Informed Consent 
 
The ICF and consent process must comply with US regulations (§ 21 CFR Part 50) as well as country 
specific national regulations and/or local laws. The ICF will document the study-specific information the 
Investigator or his/her designee provides to the subject and the subject’s agreement to participate. 
 
The Investigator or designee must explain in terms understandable to the subject the purpose and 
nature of the study, study procedures, anticipated benefits, potential risks, possible AEs, and any 
discomfort participation in the study may entail. This process must be documented in the subject’s 
source record. Each subject must provide a signed and dated ICF before any study-related 
(nonstandard of care) activities are performed. The original and any amended signed and dated 


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consent forms must remain in each subject’s study file at the study site and be available for verification 
by study monitors at any time. A copy of each signed consent form must be given to the subject at the 
time that it is signed by the subject. 
 
Additionally, information on any change in risk and/or significant change in study procedures must be 
provided as appropriate to subjects already actively participating in the study, and they must read, 
understand, and sign the revised ICF confirming willingness to remain in the trial. 
 
26.3 
Quality Control and Quality Assurance 
 
The Sponsor, Vanderbilt, shall implement and maintain quality control and quality assurance 
procedures to ensure that the study is conducted and data are generated, documented and reported in 
compliance with the protocol, GCP, and applicable regulatory requirements. This study shall be 
conducted in accordance with the provisions of the Declaration of Helsinki (October 2008) and all 
revisions thereof, and in accordance with FDA regulations (21 CFR Parts 11, 50, 54, 56, and 312, 
Subpart D – Responsibilities of Sponsors and Investigators) and with the ICH guidelines on GCP (ICH 
E6). 
 
26.4 
Protocol Deviations 
 
The Coordinating Center is responsible for implementing and maintaining quality assurance and quality 
control to ensure that studies are conducted according to the protocol, GCP, and all applicable 
regulatory requirements. A protocol deviation is any noncompliance with the protocol. Noncompliance 
can be on the part of the study participant, the Investigator, or the study site staff. All protocol 
deviations are required to be reported to the Coordinating Center and submitted to the IRB per 
institutional guidelines. Deviations to the protocol are not permitted except when necessary to eliminate 
an immediate hazard to study subjects. 
 
26.5 
Protected Subject Health Information Authorization 
 
Information on maintaining subject confidentiality in accordance to individual local and national subject 
privacy regulations must be provided to each subject as part of the informed consent process (refer to 
the Informed Consent section), either as part of the ICF or as a separate signed document (for 
example, in the US, a site-specific HIPAA consent may be used). The Investigator or designee must 
explain to each subject that for the evaluation of study results, the subject’s protected health 
information obtained during the study may be shared with Vanderbilt and its designees, regulatory 
agencies, and IRBs/IECs, Janssen Scientific Affairs and its co-development partners. As the study 
Sponsor, Vanderbilt will not use the subject’s protected health information or disclose it to a third party 
without applicable subject authorization. It is the Investigator’s or designee’s responsibility to obtain 
written permission to use protected health information from each subject. If a subject withdraws 
permission to use protected health information, it is the Investigator’s responsibility to obtain the 
withdrawal request in writing from the subject and to ensure that no further data will be collected from 
the subject. Any data collected on the subject before withdrawal will be used in the analysis of study 
results.  
 
During the review of source documents by the monitors or auditors, the confidentiality of the subject will 
be respected with strict adherence to professional standards and regulations. 
 


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26.6 
Study files and Record Retention 
 
The Investigator/study staff must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. Essential documentation 
includes, but is not limited to, the IB, signed protocols and amendments, IRB/IEC approval letters 
(dated), signed Form FDA 1572 and Financial Disclosures, signed ICFs (including subject 
confidentiality information), drug dispensing and accountability records, shipping records of 
investigational product and study-related materials, signed (electronically), dated and completed CRFs, 
documentation of CRF corrections, SAE forms transmitted to Vanderbilt, notification of SAEs and 
related reports, source documentation, normal laboratory values, curricula vitae for investigators, and 
all relevant correspondence and other documents pertaining to the conduct of the study. 
 
The Investigator must notify Vanderbilt and obtain written approval from Vanderbilt before destroying 
any clinical study documents or images (e.g., scan, radiograph, ECG tracing) at any time. Should an 
Investigator wish to assign the study records to another party or move them to another location, 
advance written notice will be given to Vanderbilt. Vanderbilt will inform the Investigator of the date that 
study records may be destroyed or returned to Vanderbilt. 
 
Vanderbilt must be notified in advance of, and Vanderbilt must provide express written approval of, any 
change in the maintenance of the foregoing documents if the Investigator wishes to move study records 
to another location or assign responsibility for record retention to another party. If the Investigator 
cannot guarantee the archiving requirements set forth herein at his or her study site for all such 
documents, special arrangements must be made between the 
 
Investigator and Vanderbilt to store such documents in sealed containers away from the study site so 
that they can be returned sealed to the Investigator for audit purposes. 
 
U.S. FDA regulations (21 CFR §312.62[c]) require that records and documents pertaining to the 
conduct of this study and the distribution of investigational drug, including CRFs, consent forms, 
laboratory test results, and medication inventory records, must be retained by each Principal 
Investigator for two years after marketing application approval. If no application is filed, these records 
must be kept two years after the study is discontinued and the U.S. FDA and the applicable national 
and local health authorities are notified. 
 
Following closure of the study, each participating institution will maintain a copy of all site study records 
in a safe and secure location. The Sponsor Investigator will inform the Investigator at each site at such 
time that the records may be destroyed. 
 
26.7 
Case Report Forms and Record Maintenance 
 
CRFs will be used to collect the clinical study data and must be completed for each enrolled subject 
with all required study data accurately recorded such that the information matches the data contained in 
medical records (e.g., physicians’ notes, nurses’ notes, clinic charts and other study-specific source 
documents). Authorized study site personnel (i.e., listed on the Delegation of Authority log) will 
complete CRFs designed for this study according to the completion guidelines that will be provided. 
The Investigator will ensure that the CRFs are accurate, complete, legible, and completed within the 
required amount of time. At all times, the Investigator has final responsibility for the accuracy and 


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authenticity of all clinical data. 
 
The CRFs exist within an electronic data capture (EDC) system called REDCap with controlled access 
managed by Vanderbilt or its authorized representative for this study.  
 
The Vanderbilt University Office of Research will be used as a central location for data processing and 
management. Vanderbilt University, with collaboration from a consortium of institutional partners, has 
developed a software toolset and workflow methodology for electronic collection and management of 
research and clinical trial data. REDCap (Research Electronic Data Capture) is a secure, web-based 
application that is flexible enough to be used for a variety of types of research. REDCap provides an 
intuitive user interface that streamlines project development and improves data entry through real-time 
validation rules (with automated data type and range checks). REDCap also provides easy data 
manipulation (with audit trails for reporting, monitoring and querying patient records) and an automated 
export mechanism to common statistical packages (SPSS, SAS, Stata, R/S-Plus). In addition to 
traditional data capture functionality, REDCap’s survey capabilities are a powerful tool for building and 
managing online surveys. The research team can create and design surveys in a web browser and 
engage potential respondents using a variety of notification methods. All data collection projects rely on 
a thorough, study-specific data dictionary, defined by all members of the research team in an iterative, 
self-documenting process. This iterative development and testing process results in a well-planned and 
individualized data collection strategy. 
 
REDCap servers are housed in a local data center at Vanderbilt, and all web-based information 
transmission is encrypted. REDCap was developed specifically around HIPAA-Security guidelines and 
is recommended to Vanderbilt researchers by both our Privacy Office and Institutional Review Board. 
REDCap has been disseminated for local use at more than 940 other academic/non-profit consortium 
partners in 75 countries. Vanderbilt leads the REDCap Consortium, which currently supports more than 
99,000 projects and 128,000 users. More information about the consortium and system security can be 
found at http://www.projectredcap.org/. 
 
Study staff will be appropriately trained in the use of CRFs and application of electronic signatures 
before the start of the study and before being given access to the EDC system. Original data and any 
changes of data will be recorded using the EDC system, with all changes tracked by the system and 
recorded in an electronic audit trail. The Investigator attests that the information contained in the CRFs 
is true by providing electronic signature within the EDC system.  
 
 
 
 
26.8 
Study Monitoring and Audit Requirements 
 
The Sponsor-investigator will monitor this trial continuously until study completion.  
 
The Vanderbilt-Ingram Cancer Center (VICC) oversees patient safety and data monitoring for its 
investigator-initiated and NIH-NCI funded clinical trials through its Data and Safety Monitoring 
Committee (DSMC). The purpose of the DSMC is to ensure the efficient implementation and 
management of VICC Data and Safety Monitoring Plan (DSMP). The Committee maintains authority to 
intervene in the conduct of studies as necessary to ensure clinical research performed at VICC 
achieves the highest quality standards. 


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The VICC DSMC meets on a quarterly basis and ad hoc to discuss data and safety monitoring of 
clinical trials and to oversee the VICC DSMP. Internal audits for compliance with adverse event 
reporting, regulatory and study requirements, and data accuracy and completion are conducted 
according to the VICC DSMP according to study phase and risk. The committee reviews all serious 
adverse events (SAE) on Vanderbilt sponsored investigator-initiated studies on a quarterly basis and 
provides DSMC SAE review reports to the Vanderbilt IRB. 
 
A Research Compliance auditor under the direction of the DSMC will audit this clinical trial every 6 
months for compliance with adverse event reporting, regulatory and studies requirements, and data 
accuracy and completion. Audit reports detailing the findings are provided to the DSMC. Site visits to 
ensure compliance will be performed on an ad hoc basis, notably under circumstances of high accrual. 
 
The trial additionally will be monitored by the VICC Multi-Institutional Coordinating Center. The actual 
frequency of monitoring will depend on the enrollment rate and performance of the site. Monitoring will 
be conducted through remote monitoring, teleconferences with the Investigator and site staff, and 
appropriate communications by mail, fax, email, or telephone. The purpose of monitoring is to ensure 
that the study is conducted in compliance with the protocol, standard operating procedures (SOPs), and 
other written instructions, and to ensure the quality and integrity of the data.  
 
This study is also subject to other reviews or audits at any time during or after completion of this study. 
All study-related documentation must be made available to the designated auditor. In addition, a 
representative of the FDA or other Regulatory Agencies may choose to inspect a study site at any time 
before, during, or after completion of the clinical study. Janssen Scientific Affairs may choose to inspect 
a study site at any time before, during, or after completion of the clinical study. 
 
To assure the accuracy of data collected in the CRFs, it is mandatory that the monitor/auditor have 
access to all original source documents, including all electronic medical records (EMR) at reasonable 
times and upon reasonable notice. During the review of source documents, every effort will be made to 
maintain the anonymity and confidentiality of all subjects during this clinical study. However, because of 
the experimental nature of this treatment, the Investigator agrees to allow the IRB/IEC and Vanderbilt 
and its authorized employees of the appropriate regulatory authority to inspect the facilities used in this 
study and, for purposes of verification, allow direct access to the hospital or clinic records of all subjects 
enrolled into this study. A statement to this effect will be included in the informed consent and 
permission form authorizing the use of protected health information. 
 
 
 
26.9 
Investigator Responsibilities 
 
A complete list of Investigator responsibilities is outlined in the clinical trial research agreement and the 
Statement of Investigator Form FDA 1572, both of which are signed by the Investigator before 
commencement of the study. In summary, the Investigator will conduct the study according to the 
current protocol; will read and understand the USPI; will obtain IRB/IEC approval to conduct the study; 
will obtain informed consent from each study participant; will maintain and supply to the Sponsor or 
designee, auditors, and regulatory agencies adequate and accurate records of study activity and drug 
accountability for study related monitoring, audits, IRB/IEC reviews and regulatory inspections; will 
report SAEs to the Sponsor or designee and IRB/IEC according to the specifics outlined in this protocol; 


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will personally conduct or supervise the study; and will ensure that colleagues participating in the study 
are informed about their obligations in meeting the above commitments. 
 
26.10 Sponsor-Investigator Responsibilities 
 
A complete list of Sponsor responsibilities is outlined in the clinical trial research agreement and in the 
laws and regulation of the country in which the research is conducted. In summary, the Sponsor will 
select qualified Investigators, provide them with the information they need to properly conduct the 
study, ensure adequate monitoring of the study, conduct the study in accordance with the general 
investigational plan and protocols, and promptly inform Investigators and health and regulatory 
agencies/authorities as appropriate of significant new adverse effects or risks with respect to the drug. 
 
26.11 Financial Disclosure 
 
For this study, each Investigator (as designated on the Form FDA1572) will provide a personally signed 
Financial Disclosure Form in accordance with § 21 CFR 54. Each Investigator will notify the Sponsor 
Investigator of any relevant changes in financial disclosure information during the conduct of the study 
and for one year after the study has been completed. 
 
26.12 Protocol Amendments 
 
The Sponsor Investigator is responsible for the development and coordination of all protocol 
amendments. The Sponsor Investigator will obtain Vanderbilt IRB approval for the protocol amendment 
and then disseminate the amendment to participating institutions for submission to their IRBs/IECs. Any 
change to the informed consent document must be reviewed and approved by the Sponsor before 
being submitted to the IRB/IEC at participating institutions. 
 
Written documentation of IRB/IEC approval must be received by the Sponsor Investigator before the 
amendment may take effect at each site.  
 
No other significant or consistent change in the study procedures, except to eliminate an immediate 
hazard, shall be effected without the mutual agreement of the Investigator and the Sponsor. 
 
26.13 Publication of Study Results 
 
The sponsor investigator may use the results for papers, abstracts, posters, or other material presented 
at scientific meetings or published in professional journals or as part of an academic thesis by an 
Investigator. In all cases, to avoid disclosures that could jeopardize proprietary rights and to ensure 
accuracy of the data, Janssen Scientific Affairs, LLC reserves the right to preview all manuscripts and 
abstracts related to this study, allowing the Janssen Scientific Affairs, LLC sufficient time to make 
appropriate comments before submission for publication.  
 
In most cases, the Investigators at the sites with the highest accruals of eligible subjects shall be listed 
as lead authors on manuscripts and reports of study results. The study director and/or lead statistician 
may also be included in the list of authors. This custom can be adjusted upon mutual agreement of the 
authors, the Sponsor Investigator and Janssen Scientific Affairs and in accordance with current 
standards for authorship as recorded in professional conference and journal submission instructions. 
 


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26.14 Study Discontinuation 
 
The Sponsor-investigator reserves the right to terminate the study at any time. Should this be 
necessary, both the Sponsor-Investigator will arrange discontinuation procedures. In terminating the 
study, the Sponsor-investigator will assure that adequate consideration is given to the protection of the 
subjects’ interests. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX 1: FIGURES 5, 6, 7, 8 
APPENDIX 1 
Figure 5:  Shows the workflow to develop 2 dimensional plots to reflect the 34 dimensional output using 
ViSNE. 
 


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APPENDIX 1 
 
Figure 6: BCR signaling network: Signaling output (orange circles) that can be measured with CyTOF 
 


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APPENDIX 1  
 
Figure 7:  Heat map of the human tonsillar B cell as computed by VISNE 
 
 


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APPENDIX 1 
Figure 8:  The signaling network of the human B cell as interrogated by CyTOF 
 
 
 


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APPENDIX 2:  
 
Disease status assessment: Pre HCT: CLL. CIBMTR form 2013, Revision 2.0, 10 pages.  
 


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APPENDIX 3:  
 
Disease status assessment: Pre HCT: All lymphoma excluding CLL. CIBMTR form 2018, Revision 3, 
17 pages.  


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